Endocrine Reviews, 2023, 44, 779–818

https://doi.org/10.1210/endrev/bnad009
Advance access publication 24 March 2023
Review

Molecular and Clinical Spectrum of Primary

Hyperparathyroidism
Smita Jha1 and William F. Simonds1
1
Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD
20892-1752, USA
Correspondence: Smita Jha, MD, Metabolic Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health,

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Building 10, Room 9C432A; 10 Center Drive, Bethesda, MD 20892-1752; Email: [email protected].

Abstract
Recent data suggest an increase in the overall incidence of parathyroid disorders, with primary hyperparathyroidism (PHPT) being the most
prevalent parathyroid disorder. PHPT is associated with morbidities (fractures, kidney stones, chronic kidney disease) and increased risk of
death. The symptoms of PHPT can be nonspecific, potentially delaying the diagnosis. Approximately 15% of patients with PHPT have an
underlying heritable form of PHPT that may be associated with extraparathyroidal manifestations, requiring active surveillance for these
manifestations as seen in multiple endocrine neoplasia type 1 and 2A. Genetic testing for heritable forms should be offered to patients with
multiglandular disease, recurrent PHPT, young onset PHPT (age ≤40 years), and those with a family history of parathyroid tumors. However,
the underlying genetic cause for the majority of patients with heritable forms of PHPT remains unknown. Distinction between sporadic and
heritable forms of PHPT is useful in surgical planning for parathyroidectomy and has implications for the family. The genes currently known to
be associated with heritable forms of PHPT account for approximately half of sporadic parathyroid tumors. But the genetic cause in
approximately half of the sporadic parathyroid tumors remains unknown. Furthermore, there is no systemic therapy for parathyroid
carcinoma, a rare but potentially fatal cause of PHPT. Improved understanding of the molecular characteristics of parathyroid tumors will
allow us to identify biomarkers for diagnosis and novel targets for therapy.

Graphical Abstract

Received: 17 October 2022. Editorial Decision: 17 March 2023. Corrected and Typeset: 19 April 2023
Published by Oxford University Press on behalf of the Endocrine Society 2023.
This work is written by (a) US Government employee(s) and is in the public domain in the US.
780 Endocrine Reviews, 2023, Vol. 44, No. 5

Key Words: parathyroid tumors, PTH, calcium, genetics of hyperparathyroidism, parathyroid cancer, parathyroid adenomas
Abbreviations: APT, atypical parathyroid tumor; CASR, calcium sensing receptor; CCND1, cyclin D1; CDK, cyclin-dependent kinase; CDKI, cyclin-dependent
kinase inhibitor; CKD, chronic kidney disease; EZH, enhancer of zeste homolog; FHH, familial hypocalciuric hypercalcemia; GCM2, glial cell missing
transcription factor 2; CT, computed tomography; FGF23, fibroblast growth factor 23; GEP-NET, gastroenteropancreatic neuroendocrine tumor; GPCR,
G-protein–coupled receptor; HPT-JT, hyperparathyroidism jaw-tumor; HVDRR, hereditary vitamin D–resistant rickets; LOH, loss of heterozygosity; MEN,
multiple endocrine neoplasia; MLL, mixed lineage leukemia; MTC, medullary thyroid carcinoma; NET, neuroendocrine tumor; NF-PNET, nonfunctioning
pancreatic neuroendocrine tumor; OF, ossifying fibroma; PA, parathyroid adenoma; PAF1, Polymerase Associated Factor 1; PC, parathyroid carcinoma;
PHPT, primary hyperparathyroidism; PNET, pancreatic neuroendocrine tumor; PTH, parathyroid hormone; PTHR, parathyroid hormone receptor; PTHrP,
parathyroid hormone–related peptide; RET, REarranged during Transfection; VDDR, vitamin D–dependent rickets; VDR, vitamin D receptor; ZES, Zollinger–
Ellison syndrome.

parathyroid glands are seen in 2.5% to 15% patients while

ESSENTIAL POINTS <3% patients may have only 3 glands (7, 8).
• Although rare, the heritable syndromes of primary

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hyperparathyroidism have been critical for the dis­ Evolution
covery of consequential genes that regulate parathy­ Parathyroid glands are found in all land vertebrates but have
roid growth and function and whose mutation, in not been identified in aquatic vertebrates (9). This may be in­
either a sporadic or a familial context, causes para­ dicative of the need for greater control of calcium homeostasis
thyroid neoplasia in terrestrial animals as marine aquatic animals have a con­
• Analysis of kindreds with familial isolated hyper­ stant supply of calcium from seawater. Humans and chickens
parathyroidism, after exclusion of MEN1, CASR, have 4 parathyroid glands while mice have 2.
CDC73/HRPT2, and GCM2 mutation, suggests
that the majority harbor yet to be discovered genetic Gross Anatomy and Histology
risk factors for their primary hyperparathyroidism.
• In MEN1, the most common form of syndromic pri­ Overall, normal parathyroid glands measure 2 to 7 mm in
mary hyperparathyroidism, the parathyroid disease length, 2 to 4 mm in width, 0.5 to 2 mm in height and weigh
is almost always benign despite its high penetrance 35 to 55 mg. On histology, the gland is enveloped by a thin fi­
and frequency of recurrence, and the greatest nega­ brous capsule that extends into the parenchyma delineating it
tive impact on life expectancy results from the pres­ into multiple lobules (Fig. 1B). It consists of parenchymal cells
ence and spread of functional or nonfunctional (chief, oxyphil, clear, and transitional oxyphil cells arranged
gastroenteropancreatic neuroendocrine tumors in nests and cords with a rich capillary network), fat cells,
• Clinically impactful parathyroid tumors can be small and fibrovascular stroma (10, 11). In addition to these compo­
and difficult to localize, even with the best existing im­ nents, tumor-infiltrating lymphocytes are seen in parathyroid
aging techniques, justifying future investment in the tumors although their functional relevance remains unclear
discovery, development, and optimization of superior (12). Stromal fat content of a parathyroid gland in an adult
parathyroid-specific imaging modalities for initial and is approximately 50% of the mass of the gland although it
reoperative cases of primary hyperparathyroidism can vary with nutritional status and weight of the individual
(13). It is believed that all other parenchymal cell types, in­
cluding oxyphil cells, are derived from chief cells (14). Both
chief and oxyphil cells contain an eosinophilic cytoplasm,
but the oxyphil cells are larger and stain lighter. Oxyphil
History cells contain many large mitochondria which is thought to ac­
The parathyroid glands were serendipitously noted by Richard count for localization of a hyperfunctioning gland using
Owen, an English anatomist while dissecting an Indian rhi­ 99m
Tc-sestamibi (15). Both chief and oxyphil cells express
noceros in 1850. Ivar Sandstrom, a Swedish anatomist and hist­ comparable amount of calcium sensing receptor (CASR) but
ologist, is credited for its discovery in humans in 1877. Some 50 there may be a difference in their calcium responsiveness
years later parathyroid hormone (PTH) was extracted from the (12). The functional relevance of oxyphil cells remains
gland (1), and another 50 years later when the complete pri­ unclear, although they have been shown to secrete PTH in sec­
mary amino acid sequence of PTH became known (2, 3). ondary hyperparathyroidism and express the parathyroid-
relevant genes to produce PTH-related peptide (PTHrP) and
calcitriol (16). Of note, oxyphil cells are not present in the
Embryology parathyroid glands of rats or other lower animals.
Embryologically, the parathyroid glands are derived from the Clear cells are a form of chief cells with abundant cytoplas­
endoderm of the third and fourth branchial pouches. The su­ mic glycogen seen primarily in embryos and fetuses that de­
perior glands develop from the fourth branchial pouch and are cline in number with age (17). Cells with cytologic features
commonly located near the posterolateral aspects of the thy­ intermediate between chief and oxyphil cells are termed tran­
roid. Notably, the inferior glands (typically located near the sitional oxyphil cells. Both oxyphil and transitional oxyphil
inferior poles of the thyroid) develop from the third branchial cells are few at birth but increase with age (18, 19).
pouch along with the thymus. The inferior glands are in this Immunostaining with GATA-3 and glial cell missing tran­
typical location in ∼80% (4-6). The variable location of the in­ scription factor 2 (GCM2), transcription factors of parathy­
ferior glands is likely explained by their longer descent roid development, PTH, and CASR can be used to confirm
(Fig. 1A). Most individuals have 4 glands, although deviations parathyroid tissue on histology (20-22). Parathyroid glands
may be seen, most commonly 3 or 5 glands. Supernumerary have a rich blood supply from inferior thyroid arteries or
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A B

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Figure 1. (A) Parathyroid glands are derived from the endoderm of the third and fourth pharyngeal pouches. The third pharyngeal pouch gives rise to the
inferior parathyroid glands and thymus while the fourth pharyngeal pouch gives rise to the superior parathyroid gland. Note the longer path of descent of
inferior parathyroid glands and increased likelihood of its ectopic location. The inferior parathyroid glands may descend lower into the thymus or chest or
leave residual tissue along the path of descent. (B) Microscopically, the parathyroid gland is enveloped by a thin fibrous capsule that extends into the
parenchyma dividing the gland into multiple lobules. The gland consists of the following parenchymal cells: chief, oxyphil, clear, and transitional. Both
chief and oxyphil cells are eosinophilic, express calcium-sensing receptor, and secrete parathyroid hormone. Clear cells decrease with age while oxyphil
and transitional oxyphil cells increase with age. The stromal fat content of the gland (∼50%) varies with nutritional status and weight of the patient.

from anastomosis between superior and inferior vessels. abaloparatide, a synthetic PTHrP analog, is FDA approved
Parathyroid veins drain into the thyroid vein plexus whereas as an antiosteoporosis therapy to reduce the risk of both verte­
the lymph vessels drain into the deep cervical and paratracheal bral and nonvertebral fractures in postmenopausal women.
lymph nodes. The nerves to the parathyroid glands are vaso­ Recombinant human PTH(1-34) is also FDA approved for
motor but not secretomotor. The nerve supply is sympathetic, postmenopausal osteoporosis, osteoporosis secondary to hypo­
derived from the thyroid branches of the cervical ganglia. gonadism or glucocorticoid-induced osteoporosis. PTH(1-84)
produced by recombinant DNA technology is available com­
mercially for use in patients with hypoparathyroidism.
PTH and PTH-Related Peptide
The chief cells of the parathyroid glands secrete pre-pro-PTH,
a 115 amino acid precursor peptide which undergoes process­ Measurement of PTH Hormone
ing in the endoplasmic reticulum and Golgi apparatus to ma­ Various molecular forms of the hormone exist in circulation ei­
ture into PTH—an 84 amino acid peptide (Fig. 2A). PTHrP ther due to direct secretion by the parathyroid gland or as by­
was first described in 1987 as the cause of humoral hypercal­ products of peripheral metabolism of PTH(1-84). The
cemia of malignancy (23). However, it has since been noted to various circulating forms of PTH, particularly the small and
have several other physiological functions such as regulation large carboxy-terminal PTH fragments which accumulate in
of chondrocyte maturation (24), promotion of bone forma­ patients with renal failure, present a challenge for measuring
tion and resorption (25), promotion of branching morphogen­ PTH(1-84). Roger Guillemin, Andrew Schally, and Rosalyn
esis in mammary glands (26), regulation of keratinocyte Yalow developed the first immunoassay for measuring PTH
differentiation (27), facilitation of tooth eruption (28), regula­ in 1977. To have an assay that only recognizes intact
tion of vascular smooth muscle, regulation of beta cell prolif­ PTH(1-84), the amino terminal antibody used should recognize
eration, and insulin production in the pancreas (29) and the very first amino acids (Fig. 2B). The current second- or
promotion of calcium transport in the placenta (30). Thus, un­ third-generation PTH assays have equivalent clinical utility in
like PTH, which is produced only in the parathyroid gland, diagnosing primary hyperparathyroidism (PHPT) (32). The
PTHrP is produced locally by many tissues and has autocrine use of mass spectrometry is currently being explored for accur­
(effects on same cell), paracrine (effects on adjacent cells), and ate measurement of the intact PTH(1-84) hormone.
intracrine functions (travels directly following translation into Nontruncated amino-terminal PTH is a post-transcriptionally
the nucleus or nucleolus) both during development and in the modified form of PTH(1-84) that can be picked up on an ele­
adult. Despite low sequence homology in the receptor-binding vated whole PTH (third-generation)/total (second-generation)
domain, PTHrP and PTH bind to the common PTH receptor PTH assay ratio (n > 0.8). It has been proposed that a ­
(PTHR1) with comparable affinity (31) (Fig. 2A). Clinically, progressive rise in the third/second–generation PTH
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B

Figure 2. (A) PTH is an 84 amino acid peptide with its biologic activity attributed to the first 7 amino acids in its amino terminal. The first 34 amino acids of
the peptide are as potent as the intact native hormone, with signaling and receptor binding domains residing within N-terminal and C-terminal portions
of PTH(1-34), respectively. PTH(7-34) peptide analogs function as potent antagonists as these fragments are devoid of signaling activity but can bind to
the PTH receptor. The PTH(15-34) fragment is the shortest length peptide of native sequence that exhibits detectable binding to the PTH receptor while
PTH(1-14) is the shortest length N-terminal peptide that exhibits cyclic adenosine monophosphate signaling activity (although its potency is 5 times
weaker, likely from the absence of receptor binding domain). PTH-related peptide is a 141 amino acid peptide with variants that are 139 or 173 amino acids
long. Structurally, the region of homology with PTH runs around the N-terminal sequence with the first 13 residues being identical (36). (B) The evolution
of PTH assays can be divided into 3 stages: competitive immunoassays (first generation), “sandwich” immunometric assays (second and third gener­
ation). In the first-generation assays, a single polyclonal antibody competed for labeled PTH and the serum forms. In comparison, second-generation
assays are based on recognition of 2 distinct antibodies (typically monoclonal): 1 carboxyl terminal and the other amino terminal specific (targeting an­
tigenic site located around amino acids 20-25). However, all these assays also measure forms other than intact PTH(1-84); for instance, PTH(7-84),
predominantly an issue in patients with chronic kidney disease.

assay ratio or measurement of nontruncated amino- also been solved (38). The gene is located on chromosome 3p
terminal PTH may have clinical utility in monitoring para­ and consists of 14 coding exons. Evolutionarily, PTHR1 is
thyroid cancer recurrence (33). highly conserved (39) with orthologs detected in fish (40), birds
(41), and sea squirt Ciona intestinalis (42). Mutations in
PTHR1 cause Jansen’s metaphyseal chondrodysplasia and
PTH, Calcium, and Vitamin D Signaling Bloomstrand’s chondrodysplasia. The PTH-2 receptor
(PTHR2) is found in vertebrates but is absent in birds (43). It
PTH signaling
can bind to PTH but not to PTHrP. It is heavily expressed in
All nucleated cells in human body contain the PTH gene but it is the central nervous system, cardiovascular, and gastrointestinal
expressed only in chief cells of the parathyroid glands. Variants systems as well as in lung and testes, although the role of
in PTH gene cause heritable forms of hypoparathyroidism (34). PTHR2 in these systems and tissues is unknown.
PTHrP is encoded by a single copy PTHLH gene. PTH and
PTHrP gene share similar exon/intron boundaries and are be­
lieved to have arisen through gene duplication on chromosome CASR signaling
11 and 12 respectively (35). PTH/PTHrP receptor (PTHR1) is a CASR is an evolutionarily conserved family C GPCR (along
family B G-protein–coupled receptor (GPCR), such as recep­ with GABA type B and metabotropic glutamate receptors) ex­
tors for calcitonin, secretin, glucagon, glucagon-like peptide-1, pressed predominantly in the parathyroid glands (maximal)
corticotrophin-releasing factor, and others, with its characteris­ and kidneys (Fig. 4). In the parathyroid glands, it interacts
tic 7 transmembrane domain protein structure (Fig. 3). There is with Klotho, a transmembrane protein to regulate PTH secre­
low amino acid sequence homology between the different fam­ tion (44). In the kidney tubules, CASR regulates calcium re­
ily B GPCRs at about 35%; however, these conserved residues absorption independent of PTH. CASR expressed on
likely define the overall protein fold used by these receptors chondrocyte is important for growth plate chondrogenesis,
(36). The cDNA encoding the receptor was cloned in 1991 longitudinal bone growth, and skeletal mineralization, prob­
leading to a host of molecular developments in the field (37). ably by counteracting PTHrP–PTH1R signaling. Osteoblast
Since then, its 3D cryo-electron microscopic structure has expression of CASR also has a role in skeletal development,
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Figure 3. Upon ligand (PTH and PTH-related peptide) activation, the PTH receptor undergoes a series of conformational changes resulting in coupling to
the stimulatory G-protein located on the inner, cytoplasmic surface of the cell membrane. Gαs activates adenylate cyclase, which results in synthesis of
cyclic adenosine monophosphate (cAMP). cAMP binds to the regulatory 1A subunits (R) of protein kinase A (PKA), the primary effector of cAMP. On
activation, the catalytic subunits (C) dissociate from the R subunits and phosphorylate several transcription factors, including cAMP-responsive elem­
ent-binding (CREB) protein which interacts with cAMP-responsive element (CRE) in the nucleus and regulates transcription of target genes. Created with
Biorender.com.

mineralization, and remodeling (44). CASR is also expressed elevated 1,25(OH)2D3. The parathyroid glands also express
in other tissues such as the brain, lungs, vasculature, breast CYP27B1; however, the functional relevance of this expres­
(promotes lactation), gastrointestinal tract, pancreatic islets, sion remains unknown. Rare cases of vitamin D–dependent
and skin where it is involved in diverse physiological roles (44). rickets type 1B (VDDR1B), caused by inactivating mutations
Inactivating mutations of CASR cause familial hypocalciuric in CYP27A1, expressing 25-hydroxylase have been described
hypercalcemia type 1 (FHH-1) while activating CASR muta­ (46, 47). Inactivating mutations in CYP24A1, encoding
tions cause autosomal dominant hypocalcemia type 1. 24,25-α-hydroxylase, cause idiopathic infantile hypercalce­
mia characterized by hypercalcemia, hypercalciuria, and re­
Vitamin D receptor signaling current nephrolithiasis. VDR signaling during negative
calcium balance decreases matrix mineralization to preserve
Vitamin D receptor (VDR) is a ubiquitously expressed, evolu­ serum calcium. However, the role of VDR during normal cal­
tionarily conserved steroid receptor and transcription factor, cium balance remains unclear. Growing evidence suggests a
which is regulated by 1, 25(OH)2 vitamin D binding role of fibroblast growth factor 23 (FGF23) in calcium homeo­
(Fig. 5). Inactivating mutations in VDR cause hereditary vita­ stasis by increasing calcium reabsorption in distal tubules
min D resistant rickets (HVDRR). Alopecia seen in HVDRR (48). During pregnancy and lactation, the level of both calci­
and VDR knockout models is not seen in vitamin D deficiency, tonin and prolactin are increased, and these hormones can
indicating that VDR may have ligands other than 1,25(OH)2 stimulate CYP27B1, expressed in fetal trophoblasts and ma­
vitamin D at least in hair follicles (45). Intravenous or oral cal­ ternal decidua of the placenta, to increase intestinal calcium
cium reverses the mineral and skeletal phenotype of HVDRR, absorption for the growing fetus.
indicating the critical role of 1,25(OH)2 vitamin D and VDR
on intestinal calcium absorption. Physiologically important
VDRs are also present in osteoblasts which mediate Calcium Homeostasis
1,25(OH)2 vitamin D effects on bone homeostasis. Osteoblast The total body content of calcium is ∼1000 to 1200 g.
VDR signaling modulates transcription of RANKL, which in­ Ninety-nine percent of this body calcium resides in the skel­
creases osteoclast formation and action. eton while the remaining 1% is freely exchangeable (∼0.9%
Vitamin D3 (cholecalciferol) is the natural form of vitamin intracellular and ∼0.1% in extracellular fluid). Total serum
D produced in skin from 7-dehydrocholesterol, but it is not calcium is composed of 3 distinct compartments: ionized
biologically active. Adequate vitamin D levels can be difficult (48%)—physiologically active form; protein bound (46%)—
to maintain through diet alone, as it is found in only few foods largely bound to albumin; and calcium complexed with inor­
(fortified dairy and fish oils). Inactivating mutations in ganic compounds such as citrate or phosphate (7%). Calcium
CYP27B1 (CYP2R1), encoding 25(OH)D 1-α-hydroxylase absorption in the intestine occurs by an active, carrier-
cause vitamin D–dependent rickets type 1 (VDDR1), also dependent process (vitamin D dependent) and a passive, para­
known as pseudovitamin D deficiency rickets. CYP27B1 is cellular process (Fig. 6A). Since the passive absorption is
only expressed in kidney and placenta (during pregnancy) in independent of vitamin D, high calcium intake can reduce
states of health and, additionally, in macrophages in sarcoid­ the effect of vitamin D insufficiency and consequent poor cal­
osis or Crohn disease. Unlike CYP27B1 expressed in kidneys, cium absorption efficiency. Calcium homeostasis is maintained
CYP27B1 expressed in macrophages is not suppressed by through a complex network of cellular interactions involving
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Figure 4. CASR binds to many physiological ligands including cations such as magnesium, l-amino acids, polyamines, and γ-glutamyl peptides like gl­
utathione. CASR has a large extracellular domain that consists of a bilobed Venus flytrap module and a cysteine-rich domain. The Venus flytrap has 3
distinct extracellular calcium (Ca2+
e ) binding sites. CASR exists as a dimer through interactions at the amino terminal of the Venus flytrap lobe. The tr­
ansmembrane domain of the protein is typical of other GPCRs and consists of 7 hydrophobic helical domains connected by 3 extracellular and intracellular
loops each. Signal transduction on activation of CASR propagates through Gq/11 family proteins that activate phospholipase C-beta, resulting in the release
of 2 second messengers, diacylglycerol (DAG) and inositol 14,5-triphosphate (IP3). DAG activates protein kinase C, which activates extracellular signal–
regulated kinases 1 and 2 (mitogen activated protein kinases [MAPKs] signaling). IP3 binds to its receptors on the endoplasmic reticulum and raises
intracellular calcium by releasing calcium from the reticulum. CASR activates the Gi/o proteins, which results in suppression of adenylate cyclase–
mediated cAMP production eventually resulting in decreased PTH secretion and increased urinary calcium excretion. CASR can also activate MAPK
signaling via a G-protein–independent mechanism involving β-arrestins. CASR demonstrates biased signaling in showing preferential activation of distinct
intracellular signaling responses in different tissues. The mechanism for this functional selectivity is unclear. Ligand-induced insertional signaling drives
cell surface expression of CASR by anterograde trafficking. The σ subunit of adaptor protein 2 (AP2σ) mediates the endocytosis and trafficking of CASR in
combination with clathrin and β-arrestin. Mutations in CASR, Gq/11 family (GNA11) and AP2σ (AP2S1) can cause familial hypercalcemic hypocalciuria and
autosomal dominant hypocalcemia. Created with Biorender.com.

Figure 5. Upon binding to 1,25(OH)2 vitamin D, VDR heterodimerizes with other nuclear hormone receptors, particularly the family of retinoid x receptors
(RXRs), and this complex then binds to vitamin D response elements (VDREs) within the promoters of a large number of genes it regulates, modulating
their transcription and subsequent effects in a ligand-dependent manner. Coactivators and corepressors are additional proteins that complex with VDR to
regulate transcription. Created with Biorender.com.
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Figure 6 (A) Course of calcium absorption and contribution of active and passive calcium absorption over the course of jejunum, ileum, and colon. Most of
the total calcium absorption (65%) takes place in ileum because transit time through the ileum is almost ten times longer than through duodenum.
Created with Biorender.com. (B) The adult kidney has a glomerular filtration rate (GFR) of ∼100 mL/min and produces >8000 mg of calcium in the
GFR/24 hours; ∼98% of the filtered calcium is reabsorbed, with only about 200 mg/24 hours of calcium appearing in the urine. Sixty to 70% of the
filtered calcium is reabsorbed at the proximal convoluted tubule mainly by passive diffusion. However, 10% to 15% of total proximal tubule calcium
reabsorption occurs via active transport and is mainly regulated by parathyroid hormone and calcitonin. No calcium reabsorption occurs within the thin
segment of the loop of Henle. Twenty percent of the filtered calcium is reabsorbed in the cortical thick ascending limb, 10% in the distal convoluted
tubule, and another 3% to 10% in the connecting tubule. PHP, pseudohypoparathyroidism. Created with Biorender.com.

the kidney (Figs. 6B and 7), skeleton, gastrointestinal tract, excess disorders, (2) PTH deficiency disorders, and (3) PTH
parathyroid gland, and mammary glands (during pregnancy signaling defects. This review will focus on the molecular
and lactation) (Fig. 7). and clinical spectrum of PHPT—disorders of PTH excess.

Epidemiology of Parathyroid Disorders PHPT (Disorders of PTH Excess)

Parathyroid disorders are a heterogenous group that encom­ PHPT has an estimated prevalence of 23 cases per 10 000
passes disorders of PTH excess, deficit, or signaling defect. women and 8.5 per 10 000 men, with an incidence of 66 cases
The majority of parathyroid disorders are sporadic. Recent per 100 000 person years in women and 25 per 100 000
data suggest an increase in the overall incidence of parathy­ person-years in men (52). The reason for higher prevalence
roid disorders, with PHPT being the most prevalent (49-51). of PHPT in women remains uncertain but may be explained
Parathyroid disorders can be broadly divided into (1) PTH by estrogen signaling through ERβ1 and ERβ2, which have
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Figure 7. Vitamin D3 is transported via vitamin D binding protein (DBP) to the liver for synthesis of 25-hydroxyvitamin D3 [25(OH)D3], the major circulating
form of vitamin D. Subsequently, 25(OH)D3 is then transported via DBP to the kidney where it is taken up by the tubular epithelial cells. Low calcium
sensed through the calcium sensing receptor (CASR) in parathyroid cells stimulates release of parathyroid hormone (PTH). PTH hormone acts via PTHR1
expressed predominantly in osteoblasts and osteocytes (induces release of calcium from bone) and renal proximal (decreases rate of phosphorus re­
absorption, stimulates the rate of transcription of CYP27B1, encoding 25(OH)D 1-α-hydroxylase) and distal (increases rate of calcium reabsorption) tubule
cells. 25(OH)D 1-α-hydroxylase converts 25(OH)D3 to 1,25(OH)2D3, the functionally active form of vitamin D. The primary function of 1,25(OH)2D3 and
VDR is intestinal calcium absorption, which although most rapid in the duodenum occurs primarily in the distal segments of the intestine (only ∼10% in
duodenum). 1,25(OH)2D3 in turn suppresses PTH synthesis directly at the level of transcription of PTH gene (through vitamin D response element (VDRE)
within PTH) and indirectly by increasing serum calcium and upregulating the expression and transcription of CASR (by binding to VDRE within the CASR
promoter). 1,25(OH)2D3 regulates its own synthesis by inhibiting CYP27B1. 25(OH)D3 (and 1,25(OH)2D3 acting as the preferred substrate) can also be
converted to 24,25(OH)2D3, products targeted for excretion by the enzyme 24,25-α-hydroxylase (encoded by CYP24A1, present in all cells containing
VDR). This process helps in regulation of levels of circulating and, possibly, intracellular 1,25(OH)2D3. The regulation of CYP24A1 is opposite to CYP27B1
—stimulated by 1,25(OH)2D3 and inhibited by low calcium and PTH. 1,25(OH)2D3 and elevations in serum phosphate stimulate production of fibroblast
growth factor-23 (FGF23), a “phosphate-wasting” glycoprotein produced by osteoblasts and osteocytes. FGF23 and its coreceptor, α-klotho, suppress
1-α-hydroxylase and induce 24,25-α-hydroxylase. In addition to the parathyroid gland, CASR is expressed at a low level in the proximal convoluted tubule
(regulates expression of 25(OH)D 1-α-hydroxylase and inhibits PTH-mediated phosphate excretion); distal convoluted tubule (increases calcium re­
absorption via transient receptor potential cation channel subfamily V member 5 (TRPV5) channel when tubular fluid calcium concentration is high); and is
highly expressed in the thick ascending limb, where it has a PTH-independent key role in maintaining calcium homeostasis (senses increases in calcium
and promotes calcium excretion via Claudin 14 tight junction protein), and in renal collecting ducts (prevents development of hypercalciuria-mediated
nephrocalcinosis by increasing urinary acidification and water excretion).

been demonstrated to be widely expressed in parathyroid tu­ hyperplasia” is reserved for secondary hyperplasia in the con­
mors or through epigenetic mechanisms (53, 54). PHPT is as­ text of CKD. Most parathyroid tumors are solid; however,
sociated with morbidities (fractures, kidney stones, chronic ∼4% can be cystic (typically >50% of tumor volume) or partly
kidney disease [CKD]) and increased risk of death (55-57). cystic based on imaging or pathology (60). Tumors arising
Understanding the pathophysiology of parathyroid tumors is from chief or oxyphilic cells have partly overlapping but dis­
critical for improving the management of patients affected tinct molecular profiles (61). Lipoadenomas of the parathyroid
with this disorder. gland are rare sporadic tumors manifesting as enlarged glands
The disease is characterized by inappropriate excess of PTH with >50% fat on histology in the setting of PHPT (62). Most
in circulation relative to the serum calcium level due to a pri­ of the tumors of the parathyroid gland (approximately 75%)
mary parathyroid pathology. It is typically caused by tumors were initially believed to be monoclonal in origin (12, 63).
of the parathyroid glands which may be (1) single gland aden­ However, current evidence supports heterogeneity in their clo­
omas, (2) due to multiple diseased glands (multi-gland disease), nal origin with affected glands being typically composed of
or (3) parathyroid carcinomas (PCs). Multigland disease is typ­ multiple “clonal” neoplastic proliferations (12, 59).
ically seen in heritable forms of PHPT (10-15%) and include Tumors of parathyroid gland result from 2 events: (1) prolif­
both hyperplasia affecting multiple glands and double aden­ eration of the cells of the parathyroid gland, or (2) altered cal­
omas (58). There are no specific diagnostic criteria to differen­ cium sensing mechanism leading to inappropriate excess of
tiate parathyroid hyperplasia from adenoma. The diagnosis of PTH first followed by secondary proliferation of parathyroid
adenoma vs hyperplasia is a clinical one based on history of in­ cells (64). The genes identified to cause sporadic parathyroid tu­
volvement of single or multiple glands. The 2022 WHO classi­ mors support the former as the more common mechanism.
fication of parathyroid tumors supports the use of the term Although several studies suggest an impairment of the PTH se­
“primary hyperparathyroidism related multiglandular para­ cretory capacity in patients with PHPT, mutations in CASR
thyroid disease” as a germline susceptibility-driven multi­ have not been identified in patients with sporadic parathyroid
glandular parathyroid neoplasia (59). The term “parathyroid adenomas (PAs).
Endocrine Reviews, 2023, Vol. 44, No. 5 787

Figure 8. Spectrum of disorders leading to primary hyperparathyroidism (PHPT). The heritable forms of the disease are followed by the gene causing the
disease enclosed in brackets. Similar to sporadic PHPT, heritable forms of PHPT can also be classified based on histological findings as parathyroid a­

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denoma, carcinoma, or parathyromatosis.

PHPT is frequently diagnosed incidentally in an asymptom­ occur in sporadic PAs, the latter being more common, occur­
atic patient (80%) due to ease of diagnostic testing in the ring in nearly 50% of cases (74).
Western world. However, in resource-limited countries pa­ MEN1 is ubiquitously expressed and encodes for menin, a
tients are often symptomatic (neuromuscular weakness, fa­ tumor suppressor protein. It is a multifunctional protein
tigue, impaired memory, obtundation) due to presentation with a role in transcription and epigenetic regulation; cell ad­
with more advanced disease leading to complications of kid­ hesion, division, motility and signaling; cytoskeletal structure,
ney stones or fractures (65). PHPT can occur either sporadic­ DNA repair and genomic stability (75). Menin is required for
ally or due to underlying heritable predisposition discussed epithelial to mesenchymal transition and loss of menin may be
below. the mechanism by which a progenitor cell differentiates to­
wards a more neuroendocrine cell-like state (76). The 3D crys­
tal structure of menin has been successfully solved and
Sporadic PHPT resembles a “curved left hand” with a pocket formed by the
Sporadic PHPT is characterized by inappropriate excess of “thumb” and the “palm” (77, 78). The 3D structure of menin
PTH in circulation relative to the serum calcium level in the ab­ shows a central cavity that forms a binding pocket for protein
sence of a family history of parathyroid tumors. Sporadic PHPT interaction but no obvious DNA binding domain, indicating
can result from an adenoma or carcinoma of the parathyroid that menin is dependent on its interactions with components
and is caused by the accumulation of somatic mutation(s) in of the transcription regulatory machinery and does not direct­
parathyroid cells over time. Additionally, parathyromatosis, ly bind to DNA to control transcription (78). Studies investi­
autoimmune hypercalcemia, or lithium-associated PHPT may gating the function of menin have been challenging due to the
result in disease phenotype (Fig. 8). lack of (1) similarity between menin and other known pro­
teins, (2) recognizable functional motifs/domains in menin,
(3) normal or menin-null endocrine cell lines, and (4) success­
Sporadic PA ful ex vivo models of MEN1 tumors and corresponding nor­
While only multiple endocrine neoplasia type 1 (MEN1) and mal tissues (organoids or patient-derived xenograft) (75).
cyclin D1 (CCND1) are established drivers of parathyroid The interaction of menin with over 50 different proteins of
tumorigenesis based on in vivo clinical and preclinical studies, known function provides some insight about its role. It inter­
several candidate driver genes have emerged in the recent acts with the mixed lineage leukemia (MLL) fusion protein as
years with the advent of Next Generation Sequencing. These a transcription cofactor. This fusion protein drives about
findings are summarized below. 10% of acute leukemias, called the MLL-rearranged (MLLr)
leukemias. The interaction of menin with MLL fusion protein
is critical for the maintenance of MLL fusion–driven gene ex­
Multiple endocrine neoplasia type 1 pression program (79). Small molecules that inhibit the inter­
Somatic biallelic inactivation of MEN1 accounts for 30% to action of MLL with menin are currently in clinical trials for
40% of sporadic PAs (66-68). Parathyroid-specific Men1 the treatment of MLLr leukemias (NCT04067336,
knockout mice (Men1f/f; PTH-Cre) develop parathyroid NCT04065399) (75). MLL1 fusion genes are gain-of-function
hyperplasia and hypercalcemia establishing MEN1 as the mutations in contrast to MEN1-associated tumor cells where
driver of tumorigenesis in sporadic adenomas (69). Germline menin acts as a tumor suppressor, limiting the utility of me­
inactivating mutations in MEN1 cause multiple endocrine neo­ nin–MLL interaction inhibitors in MEN1.
plasia type 1 (MEN1) discussed below under “Heritable
Hyperparathyroid Disorders” subsection “Multiple endocrine
neoplasia type 1”. The gene was initially identified in the con­ Cyclin D1 (CCND1)
text of familial MEN1 through linkage analysis (70, 71) with Pericentromeric inversions of chromosome 11 involving the
a precise locus on 11q13 as the underlying cause of MEN1 PTH promoter and a gene at the 11q13 locus was initially de­
and later confirmed by positional cloning (72, 73). Both somat­ scribed in sporadic PAs and named parathyroid adenoma 1
ic intragenic mutations (indels, frameshift, nonsense, and mis­ (PRAD1) gene (80). The gene was later renamed as cyclin
sense mutations) and larger deletion or mitotic recombination D1 (CCND1) after the encoded protein was identified as a
events detected as loss of heterozygosity (LOH) at MEN1 locus novel member of the cyclin family (81) that drives the
788 Endocrine Reviews, 2023, Vol. 44, No. 5

transitions through the cell cycle. The name reflects their fluc­ renewal. WNT proteins can signal via a canonical β-catenin
tuating levels through the cell cycle. The chromosomal re­ dependent pathway or a noncanonical β-catenin–independent
arrangement identified in adenomas places the PTH promoter pathway. Mutation in the genes involved in the WNT signal­
upstream of CCND1 which drives the overexpression of ing pathway have been identified in several cancers. CTNNB1
CCND1 in parathyroid glands. Cyclins provide the binding encodes β-catenin, the primary signal propagator of the ca­
interface for their cognate cyclin-dependent kinases (CDKs). nonical pathway. Somatic mutations in CTNNB1, previously
D cyclins coordinate cell cycle transitions with extracellular thought to be common, are now established to be rare in PAs
stimulation like specific physical and chemical cues (82). with an incidence of <1% (74, 109-112). Furthermore, the
Cyclin D1 binds to CDK4 and CDK6 at the G1–S phase tran­ CTNNB1 mutations reported in sporadic parathyroid tumors
sition of the cell cycle. Although cyclin D1 protein overexpres­ are yet to be demonstrated to drive parathyroid tumorigenesis
sion has been described in 18% to 40% PAs (83-86), in in vivo models. Aberrant nuclear localization and overex­
rearrangements involving CCND1 occur in only about 8% of pression of β-catenin appears to be rare in PAs (84, 109,
PAs indicating presence of unidentified mechanism(s) of cyclin 110, 113, 114).
D1 overexpression (87, 88). Among the other genes of the WNT pathway implicated in

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Transgenic mouse model of the PTH-CCND1 rearrange­ parathyroid tumorigenesis, LRP5 was noted to be expressed
ment with parathyroid-specific overexpression of cyclin D1 as an alternatively spliced transcript in 86% of sporadic PAs
result in parathyroid cell proliferation and subsequent bio­ (115). There has been a rare report of biallelic loss of LRP5
chemical PHPT, indicating proliferation of parathyroid tissue from a germline heterozygous mutation and an acquired
as the primary process for CCND1-driven parathyroid LOH in the tumor in a patient with apparently sporadic PA
tumorigenesis (89, 90). (68). However, the LRP5 mutation co-occurred with a frame-
shift deletion in MEN1 limiting the ability to evaluate its func­
Cyclin-dependent kinase inhibitor tional significance. Transcriptional repression of negative reg­
ulators of WNT signaling like APC, RASSF1A or members of
Cyclin-dependent kinases (CDKs) require the binding of their
the secreted frizzled-related proteins, resulting in the accumu­
cognate cyclins for phosphorylation of target proteins. CDK in­
lation of β-catenin in the nucleus has been described in sporad­
hibitors (CDKIs) bind to CDK/cyclin complexes and stop or de­
ic PAs (107, 108, 116, 117). Germline inactivating mutations
lay the progression of cell cycle (91, 92). Two CDKI families
in the tumor suppressor gene APC cause familial adenoma­
have been identified: Cip/Kip family (CDKN1) and INK4a/
tous polyposis syndrome defined by numerous adenomatous
ARF (CDKN2). CDKN1 proteins inhibit CDKs while
polyps which can progress to colorectal carcinoma. An in­
CDKN2 proteins can activate or inhibit both cyclin and
creased prevalence of colon cancer in patients with PHPT
CDKs. CDKN1B encoding P27KIP1 (p27) appears most rele­
has been suggested (118, 119). While absence of APC expres­
vant of the CDKN1 family in parathyroid tumorigenesis.
sion and promoter hypermethylation have been demonstrated
Germline mutations of CDKN1B cause multiple endocrine
in a significant proportion of parathyroid tumors, including
neoplasia type 4 (MEN4), discussed below in “Heritable
∼75% of PCs (116, 120-124), a mutation or gene amplifica­
Hyperparathyroid Disorders” subsection “Multiple
tion in APC has not been identified. Thus, the role of
Endocrine Neoplasia Type 4”. Somatic CDKN1B mutations
β-catenin and WNT pathway in parathyroid tumorigenesis re­
have been reported in adult T-cell leukemia/lymphoma (93),
mains to be established.
breast cancer (94), myeloproliferative disorder (95), hairy-cell
leukemia (96), and small intestinal neuroendocrine tumor
(NET) (97, 98). Somatic CDKN1B mutations are rare however Enhancer of zeste homolog 1 and 2
in sporadic PA or neoplasia (99, 100). Both somatic and germ­
The chromatin modifier, enhancer of zeste homolog 2 (EZH2)
line mutation in CDKN2C, encoding P18INK4C (p18) have
is the enzymatic subunit of the complex that methylates lysine
been described (101, 102).
27 of histone H3 (H3K27) to promote epigenetic silencing.
When associated with germline MEN1 mutation, CDKNIB
EZH2 overexpression was first identified in prostate cancer
can act as a disease modifier suggesting a common tumorigen­
and subsequently in several other cancers including breast,
esis pathway between the 2 (103, 104). Alternatively, it is
esophageal, gastric, anaplastic thyroid, nasopharyngeal, and
plausible that mutations in CDKIs alone are insufficient for
endometrial cancer (125). Somatic mutations in EZH2 have
parathyroid tumorigenesis as somatic mutations in MEN1
been reported in hematologic malignancies and associated
have been described in a large proportion of tumors with
with poor clinical outcomes (126). Apparent mutational acti­
CDKN1B mutation or underexpression (100, 105).
vation of EZH2 is rare in sporadic PAs (67, 68, 127, 128). It
Nevertheless, low mRNA expression of CDKN1A, encoding
seems likely that perturbations in EZH2 are a downstream ef­
P21CIP1 (p21) in 53% and of CDKN2C, encoding
fect of mutations in another driver gene of parathyroid
P18INK6 (p18) in 42% of parathyroid tumors suggests a
tumorigenesis as it has been implicated in pathways involving
functional association of CDKIs with parathyroid tumorigen­
other parathyroid tumor genes like MEN1 (129, 130).
esis (106). Furthermore, methylation defects and low mRNA
Activating mutations in EZH2 could theoretically phenocopy
or protein expression of CDKN2A, encoding P16INK4A and
inactivating mutations in MEN1. In addition, EZH2 may be
CDKN2B encoding P15INK4B have been described in para­
involved in WNT signaling (131, 132).
thyroid tumors (107, 108). Thus, CDKIs are rare predispos­
Somatic mutations in enhancer of zeste homolog 1 (EZH1)
ition alleles for sporadic PAs.
are rare in sporadic PAs (67). EZH1 mediates the methylation
of H3K27 like EZH2. Mutations in EZH1 have been impli­
β-Catenin (CTNNB1) and WNT pathway cated in several hematological malignancies and thyroid tu­
The WNT family is a group of proteins implicated in cell pro­ mors (133, 134). Thus, both EZH1 and EZH2 mutations
liferation, differentiation, survival, angiogenesis, and cell are rare in sporadic PAs.
Endocrine Reviews, 2023, Vol. 44, No. 5 789

Zinc finger X-linked during Transfection gene (RET) are rarely associated with
Zinc finger X-linked (ZFX) located on the X chromosome PAs (169, 170). Germline mutations in RET cause MEN2 dis­
encodes a nearly identical protein to the 1 encoded by ZFY, lo­ cussed below in “Heritable Hyperparathyroid Disorders” sub­
cated on the Y chromosome. It is a transcription factor that section “Multiple Endocrine Neoplasia Type 2”. Somatic
regulates embryonic stem cell renewal (135, 136). It has mutations in CDC73 are rare in sporadic PAs but frequent in
been implicated in the initiation or progression of several dif­ a PC as discussed below. Germline inactivating CDC73 muta­
ferent types of human cancers including prostate, breast, colo­ tions cause hyperparathyroidism jaw-tumor (HPT-JT) syn­
rectal, renal, gastric, nonsmall cell lung, laryngeal squamous drome discussed in “Heritable Hyperparathyroid Disorders”
cell, gallbladder cancer, and gliomas (137). ZFX mutations subsection “Novel MEN syndrome—MEN5” (171, 172).
have been described in 5% of sporadic PAs with the identified While mutations in PIK3CA have been reported in parathyroid
variants located in the DNA-binding domain which are likely malignancy (see Sporadic Primary Hyperparathyroidism sub­
to have resulted in alterations in ZFX’s DNA-binding affinity section “Sporadic Parathyroid Carcinoma”), these are rare in
or specificity (67, 138, 139). In the context of PAs, the PAs (127, 173).
reported variants in ZFX in the DNA-binding domain appear The telomerase reverse transcriptase (TERT) gene is re­

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to function as a direct-acting oncogene (140). Overexpression sponsible for maintaining the telomere length. Mutations in
of ZFX has been associated with unfavorable prognosis in TERT have been implicated in several endocrine tumors.
other tumor types (141). However, functional studies to es­ Nuclear staining for TERT was noted to be positive in PC
tablish ZFX as a driver of parathyroid tumorigenesis are yet but absent in PA (174, 175). However, mutations in TERT
to be performed. An evaluation for mutations in ZFY in were noted to be rare in a study investigating 88 PAs, 22
117 sporadic PAs did not reveal any (142). PCs and 10 atypical tumors (176). Similarly, Protection of te­
lomeres 1 (POT1) gene binds and protects telomeres.
Glial cell missing transcription factor 2 Germline variants in POT1 have been associated with several
familial cancers including glioma, melanoma, and colorectal
Somatic glial cell missing transcription factor 2 (GCM2) mu­
cancer while germline and somatic variants in POT1 have
tations are rare in PAs (143, 144). Germline activating muta­
been associated with chronic lymphocytic leukemia. Somatic
tions in GCM2 cause familial isolated hyperparathyroidism
POT1 variant was observed in 1 study in a single sporadic
(FIHP) discussed in “Heritable Hyperparathyroid
PA with a high mutation rate and with LOH involving mul­
Disorders” subsection “GCM2-mediated PHPT” below.
tiple chromosomes indicating genomic instability (66).
GCM2 is a homolog of the Drosophila glial cells missing
Hypermethylated in cancer 1 (HIC1) is a tumor suppressor
(Gcm) gene that was identified for its role in gliagenesis
gene that is frequently deleted or epigenetically silenced in
(145, 146). Subsequently, 2 analogous genes were discovered
most cancers and associated with poor clinical outcomes
in mouse, rat and human—Gcm1 and Gcm2, with the
(177). Homozygous deletion of Hic1 is embryonically lethal
DNA-binding domain being the only common well-conserved
(178) while heterozygous mutants develop several spontan­
region (147-151). Gcm2 is expressed in kidney, fetal brain,
eous tumors in an age-dependent manner (179). HIC1 was
gliomas, medulloblastomas and 4 of 8 nonneuroepithelial tu­
found to be underexpressed in parathyroid tumors regardless
mor cell lines, namely pancreatic adenocarcinomas, leuke­
of functional status of the tumor (180). In addition, overex­
mias, renal carcinomas, and teratocarcinomas (151). It is the
pression of HIC1 lead to a decreased survival of parathyroid
master regulator of parathyroid gland development as evi­
tumor cells, supporting its growth-regulatory role in the para­
denced by congenital hypoparathyroidism in Gcm2-deficient
thyroid glands (180).
mice (152). Intrathymic PAs express GCM2 although normal
Recurrent somatic mutations in Additional sex combs like 3
thymus does not, further supporting the parathyroid-specific
(ASXL3) were identified in 2 patients with sporadic PA (127).
nature of the gene. The expression of GCM2 in human hyper­
ASXL3 gene has an important role in deubiquitination and is
plastic and neoplastic parathyroid glands has been shown
expressed in several organ systems. Germline mutations in
to be higher in comparison to normal parathyroid tissue
ASXL3 are associated with a neurodevelopment disorder,
(153, 154).
Bainbridge—Ropers syndrome. Somatic ASXL3 variants
have been identified in myeloid leukemias and in solid tumors
Calcium sensing receptor
like breast, prostate, and pancreatic cancer (181). Mutation in
Mice with parathyroid-specific CASR ablation develop severe Ras-related protein, RAP1B, a GTP-binding protein associ­
hyperparathyroidism and hypercalcemia. Reduced expression ated with the Ras family has been reported to be involved in
of CASR has been found in majority of sporadic PHPT tumors several different malignancies with its abnormal expression
(155-160). However, mutations in CASR or VDR have not associated with poor prognosis (182). Somatic variant in
been identified (161, 162). Epigenetic deregulation of CASR RAP1B was reported in PA from 1 patient with co-occurring
via hypermethylation and histone modification has been pro­ somatic MEN1 mutation making it difficult to interpret the
posed (163). In addition, regulator of G protein signaling 5 functional relevance of this gene in parathyroid tumorigenesis
(RGS5), orphan adhesion GPCR, GPR64/ADGRG2, filamin (68). Somatic variants in SCL25A3 were observed in 3 PAs in
A, and Yes-associated protein 1 (YAP1) have been proposed a study (67). SCL25A3 is a phosphate carrier protein located
as physiologic regulator(s) of calcium signaling through in the mitochondrial inner membrane with a key role in oxida­
CASR in tumor tissue (164-167). tive phosphorylation. Germline mutations in this gene cause
mitochondrial phosphate carrier deficiency which is fatal in
Other candidate genes the first year of life. A role for early stem core genes SOX2,
Two reported cases of AIP mutations in sporadic PAs were POU5F1/OCT4, and NANOG has been suggested in para­
both germline in nature despite the lack of a family history of thyroid tumorigenesis (183). In addition to GCM2, aberrant
PHPT (168). Similarly, somatic mutations in REarranged expression of embryonic transcription factors like HOX
790 Endocrine Reviews, 2023, Vol. 44, No. 5

(184), T-box transcription factor 1 (TBX1), and the with the latter (51% vs 8%) (210). Several putative markers
microRNA cluster C19MC has been described in parathyroid for diagnosis of PC have been suggested (Table 1). Most
tumors (185, 186). Epigenetic changes of DNA methylation, PCs arise de novo and do not represent progression from
regulation of gene expression by noncoding RNAs and post- APTs or PAs as evidenced by their distinct molecular distribu­
translational histone methylation have been described in para­ tion profile (248-250).
thyroid tumors and are particularly attractive because of the About 6% to 30% patients with PC can present with lymph
prospect of reversibility (54, 187-191). To summarize, the node metastases (194, 197). The utility of TNM cancer sta­
molecular signature in a large majority of sporadic PAs re­ ging in PC and its correlation to clinical outcomes remains
mains unknown. Somatic mutations in MEN1 are the most controversial (193, 251). However, recent studies demon­
frequent genetic change seen in sporadic PAs. strate that the presence of distant metastasis predicts overall
survival (193, 252). The most common sites of distant metas­
tasis are lung, bone, and liver occurring in approximately
Sporadic PC 25% patients (193, 194, 202). While mostly functional, PCs
The first case of PC was reported by Fritz de Quervain in 1909 may rarely present as nonfunctional (253). Nonfunctional

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—a 68-year-old man who presented with a large neck mass PCs tend to be larger at presentation and patients may present
and died from lung metastases (192). The incidence of PC with locally compressive symptoms such as palpable neck
has increased by 60% from 1988 to 2003 with a 10-year all- mass or hoarseness from recurrent laryngeal nerve invasion
cause mortality rate of 33.2% and the 10-year cancer-related (254, 255).
mortality rate of 12.4% (193). Thus, overall, PC is an indolent The efficacy of adjuvant systemic therapy has not been eval­
disease (194, 195). Nevertheless, it has a high recurrence rate uated in clinical trials. Case reports of remission with im­
at 50% to 100% with majority of the recurrences occurring in munotherapy have been described (256, 257). Sorafenib was
the locoregional field which increases the risks of reoperations associated with decrease in the size of lung metastases in 1 pa­
(196-199). Survival rates for patients who undergo complete tient with metastatic PC (258). The role of radiotherapy in PC
en bloc resection with negative margins is up to 90% at 5 years remains controversial (210). The morbidity and mortality
and 67% at 10 years (200). from PC are primarily the sequelae of hypercalcemia and its
An unequivocal diagnosis of parathyroid malignancy can complications. Cinacalcet, bisphosphonate, denosumab and
only be established in the presence of invasion into adjacent intravenous fluids are all treatment options to be considered
structures, capsular, lymphovascular, or perineural invasion for management of hypercalcemia in patients who are not sur­
and/or documented distant metastases (201, 202). There is gical candidates. We discuss the genes that have implicated in
an increasing emphasis on standardizing the pathological re­ the pathogenesis of PC below.
porting of PC and atypical parathyroid tumors (APTs)
(203). APTs are parathyroid tumors that lack unequivocal
histological signs of malignancy but share some histological CDC73
features of PC, such as solid growth pattern, fibrous bands, While somatic mutations in CDC73 are rare in PAs, these are
cellular atypia, etc. The distinction between PC and APTs seen in 40% to 75% of patients with sporadic parathyroid
can be difficult and it is not unusual for an initial diagnosis cancer (171, 199, 259-261). Germline mutations in CDC73
of APT to be modified to PC on follow-up and occurrence cause HPT-JT discussed in “Heritable Hyperparathyroid
of unequivocal features of malignancy particularly distant me­ Disorders” subsection “Hyperparathyroidism Jaw Tumor
tastases (204). It is unclear if APTs represent an early stage of Syndrome” . Parathyroid-targeted deletion of Cdc73 by cross­
PC. However, most patients with APT have a good prognosis ing floxed-Cdc73 mice with PTH-Cre mice, resulted in para­
without any recurrence (205, 206). thyroid gland features consistent with APTs and PCs in both
One of the biggest challenges in the management of PC is homozygous and heterozygous mice (262). All patients with
the lack of a biomarker to establish the diagnosis preopera­ seemingly sporadic PC should be screened for germline var­
tively. PC should be suspected in the presence of abnormal iants in CDC73, even in the absence of a family history, given
high serum calcium concentration (>12 mg/dL) and iPTH lev­ incomplete penetrance seen with CDC73 mutations (259).
els >3 times upper limit of normal, parathyroid lesions >3 cm, CDC73 encodes a ubiquitously expressed, evolutionarily con­
or in patients with PHPT who present with a palpable neck served 531 amino acid protein called parafibromin, a predom­
mass associated with hoarseness or dysphagia (207-209). inantly nuclear protein (263, 264). Cytoplasmic parafibromin
Preoperative suspicion for PC is important in planning the ex­ may be distinct from nuclear parafibromin. In vitro studies
tent and radical nature of initial surgery. Cytology is not use­ suggest that parafibromin needs to interact with targets in
ful in differentiating between adenoma vs malignancy in the nucleolus to execute its tumor suppressor functions as in­
parathyroid tumors. In addition, fine needle aspiration predis­ dicated by simultaneous loss of nucleolar localization and ac­
poses patients to the risk of tumor seeding and is, hence, quisition of a growth stimulatory phenotype in mutant cells
avoided. En bloc resection to achieve negative margins is the (265). Parafibromin is a component of the Polymerase
preferred surgical procedure. Intraoperatively, PC may be sus­ Associated Factor 1 (PAF1) transcriptional–regulatory pro­
pected by features of local invasion, adhesion to surrounding tein complex in human, fly, and yeast. The PAF1 complex
structures or an enlarged firm to hard gland with greyish white binds to the C-terminal domain of RNA polymerase II and
cut surface. Differentiation of benign vs malignant parathy­ is involved in transcriptional initiation, elongation, and post-
roid tumors cannot be reliably established on frozen section translational events (266, 267). The clinically relevant muta­
immediate-read pathology although frozen section pathology tions reported in CDC73 occur throughout the coding region
can help identify metastases to regional lymph nodes. A revi­ and splice sites of the gene (268). Exons 1, 2, and 7 account for
sion surgery with en bloc resection may be needed if gland ex­ the maximum frequency of mutations but this is not explained
cision was initially performed given higher rate of recurrence by their larger size as these exons remain overrepresented even
Endocrine Reviews, 2023, Vol. 44, No. 5 791

Table 1. Markers of potential diagnostic utility in patients with parathyroid carcinoma

Biomarker Description Current data

Gene
CDC73 Chromosomal location 1q31.2; encodes Somatic inactivating mutations can be seen in
parafibromin; germline mutation associated parathyroid carcinoma and adenoma (particularly,
with HPT-JT atypical parathyroid tumors).
Copy number loss at 1p and 13 Chromosomal locations harbor putative tumor Seen in CDC73-mutated PCs but not
suppressor genes? CDC73-mutated Pas (211)
CD24, HMOX1, VCAM1, and Overexpression of transcript and/or protein in PC Potential marker for PC (212)
KCNA3 relative to PA
RNA
miR-296 Small, noncoding RNAa (micro-RNA) Downregulated in PCs compared to normal
parathyroid tissue (213)

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miR-126 Small, noncoding RNAa (micro-RNA) Most accurate differentiator between PC and PAs
(71% sensitivity, 82% specificity) (214)
C19MC (miR-371-3) micro-RNA cluster Aberrations characteristic of PC (186)
Combined analysis of miR-139 and Can distinguish PC from PAs (215)
miR-30b
hsa_circ_0075005 and MYC mRNA Circular RNA (noncoding RNAs) Differentially expressed in PCs (216)
LINC00959, Inc-FLT3-2:2, Long noncoding RNA differentially expressed in PCs (217)
lnc-FEZF2-9:2, and
lnc-RP11-1035H13.3.1-2:1
lncRNAPVT1 and GLIS2-AS1 Long noncoding RNA Increased in PCs (218)
exosome has-miR-27a-5p exosomal miRNA upregulated in serum exosomes of patients with PC
(219)
Protein
Parafibromin Tumor suppressor encoded by CDC73—contains Potentially useful in diagnosis of APTs (220, 221)
nuclear and nucleolar localization signals; Loss of staining shows ∼70% sensitivity for diagnosis
predominantly nuclear protein of PC (222, 223-231)
High specificity for PC (∼95%) (224, 226, 227, 232)
Loss of staining may predict lower overall survival in
PC (233)
Galactin-3 Member of lectin family; overexpression related Strong staining in ∼95% PCs but low sensitivity
to ability of tumor to evade apoptosis (223, 229, 230, 234)
Can serve as an adjunct to histology for PC diagnosis
particularly in combination with parafibromin
(231)
Protein gene product 9.5 (PGP9.5) Encodes ubiquitin carboxy-terminal hydrolase L1 Strong staining for PC (sensitivity: 78%; specificity:
(UCHL1); initially thought to have an 100%) (224, 230, 231)
expression specific to NETs but has since been Stains 22-35% APTs and <22% PAs thus unlikely to
shown to be expressed in large number of be useful as diagnostic marker of PC
non-NETs. Predictor for recurrent hypercalcemia in PC and
APTs (220)
Ki-67 Monoclonal antibody Ki-67 identifies a nuclear Higher proliferation index suspicious for malignancy
protein antigen (encoded by gene MKI67) that (223, 228, 229, 234)
is associated with cellular proliferation; marker Poor sensitivity for PC diagnosis (230)
in cells that increases as they prepare to divide Potentially useful in combination with other
into new cells immunohistochemical markers (235)
Cyclin D1 Cyclin encoded by the gene CCND1; required for No difference in expression in PCs, APTs, and PAs
progression through the G1 phase of the cell (221, 230, 235-237)
cycle
Adenomatous polyposis coli (APC) Encoded by APC gene; tumor suppressor that is Not informative (231, 238)
negative regulator of WNT signaling; germline
mutations associated with familial
adenomatous polyposis (FAP)
Calcium-sensing receptor (CASR) Calcium-sensing GPCR expressed in parathyroid Downregulation of CASR strongly associated with ↑
cells and kidney tubules; negative regulator of malignant potential in PC (239)
PTH secretion
Retinoblastoma (RB) Tumor suppressor encoded by RB1 associated 88% of PC had absence of nuclear staining which
with childhood intraocular cancer was not seen in any of the 19 adenomas (240)
However, subsequent studies showed lower
sensitivity with loss of expression in 30% PCs only
(223)
(continued)
792 Endocrine Reviews, 2023, Vol. 44, No. 5

Table 1. Continued

Biomarker Description Current data

B-cell lymphoma-2 (BCL-2) Encoded by the gene BCL2; regulates Positive expression can potentially distinguish PAs
programmed cell death (apoptosis); positive from APTs and PCs (234, 235)
expression in PAs Staining can be positive in ∼40% PCs (234)
Potentially useful in combination with other
immunohistochemical markers (235)
APOLLON Encoded by gene BIRC6; inhibits apoptosis by Increased expression in PC (241)
facilitating the degradation of apoptotic
proteins by ubiquitination
E-cadherin Component of adherens junction integral in cell Expression detected in normal parathyroid and PAs
adhesion (242)
Loss promotes tumor metastasis Findings in APTs not consistent (243)
Loss of membranous staining in PC (242)

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CDKN1B P27Kip1, a.k.a. cyclin-dependent kinase inhibitor Not useful as a diagnostic marker between different
1B, encoded by the CDKN1B gene; cell cycle tumor types (223)
inhibitor and tumor suppressor: loss of staining Poor sensitivity and specificity (234)
anticipated in PC; germline mutations Potentially useful in combination with other
associated with MEN4 immunohistochemical markers (235)
Mouse Double Minute 2 (MDM2) Encoded by MDM2 gene; negative regulator of Not useful as a diagnostic marker between different
p53 tumor suppressor; overexpression tumor types (223)
associated with several cancers Potentially useful in combination with other
immunohistochemical markers (235)
Programmed death-ligand 1 (PD-L1) Encoded by CD274; transmembrane protein that Expression not increased in normal parathyroid
suppresses the adaptive arm of immune (244)
response, involved in interaction of tumor cells Deficient PD-L1 expression in PAs, PCs, and APTs
with host immune response suggesting limited effectiveness of immunotherapy
although studies not consistent (245, 246)
No difference in expression between APTs and PCs
(247)
Hector Battifora mesothelial cell-1 marker of mesothelial cells, positive in various Not informative as a diagnostic marker for PC (229)
(HBME-1) thyroid carcinomas

Abbreviations: APT, atypical parathyroid tumor; GPCR, G-protein–coupled receptor; HPT-JT, hyperparathyroidism jaw tumor; PA, parathyroid adenoma;
PC, parathyroid carcinoma; PTH, parathyroid hormone; NET, neuroendocrine tumor.

when mutation rate is calculated accounting for exon size “Multiple Endocrine Neoplasia Type 2”); however, the germ­
(268). There is no reported difference between the types of line or somatic status of RET mutations is not always clarified
germline and somatic CDC73 mutations with majority being (282). Overall, mutations in RET appear to be rare in PC.
frameshift (54% in germline and 42% in somatic) (268). The
crystal structure of the N-terminal 111 amino acids of human PI3K/mTOR
parafibromin has been solved (269-271). The precise mechan­
The PI3K/AKT/mTOR pathway has emerged as a major onco­
ism by which inactivation of CDC73 results in parathyroid
genic pathway and may serve as a diagnostic marker for PC as
neoplasia remains elusive. It is possible that parafibromin
it appears to be rarely involved in PAs. The identification of
may act as both a tumor suppressor and an oncogene, depend­
mutations in PIK3CA, PTEN, AKT1, mTOR, and TSC1
ing on the tissue micro-environment (272). Some studies sug­
(20-30%) in the presence of the wild-type CDC73 allele sug­
gest a role of parafibromin in WNT signaling (273, 274).
gests their potential role in driving parathyroid neoplasia
Upon tyrosine dephosphorylation, parafibromin acquires the
(124, 283, 284). However, functional characterization of
ability to stably bind β-catenin, thereby activating promito­
these mutations has not been performed. An activating
genic WNT signaling (275).
PIK3CA mutation found in primary PC sample was surpris­
ingly noted to be lost in the evolution of the tumor from pri­
Multiple endocrine neoplasia type 1 mary to recurrence (285). Variants in TSC1 and NF1 with
While PC associated with germline mutations in MEN1 is rare allele frequency >0.5 indicating LOH were observed among
and may occur in up to 2% of patients, somatic mutations in 29 samples of PC (286). More recently, gene alterations in
MEN1 have been reported to occur in ∼15% PCs (276-281). PI3K/AKT/mTOR pathway (somatic or germline) were found
However, overall, mutations (germline or somatic) in MEN1 in ∼80% of tumors on whole genome sequencing of 23 PC
appear to be rare in PC. samples (261).

Rearranged during Transfection WNT pathway

There are rare case reports of PC in MEN2A (discussed in Increased nuclear accumulation of active, nonphosphorylated
“Heritable Hyperparathyroid Disorders” subsection β-catenin in PC tumor samples relative to adjacent normal
Endocrine Reviews, 2023, Vol. 44, No. 5 793

control samples implicate the canonical WNT/β-catenin path­ catalytic polypeptide-like, particularly in samples with
way as an important oncogenic pathway in PC (123). higher mutational burden (124, 291).
Activation of the WNT pathway due to epigenetic regulation • Allelic loss of RB1 has been observed in 30% to 100% of
such as hypermethylation of APC has been proposed as the PCs and reported to be associated with recurrence (236).
underlying mechanism of increased β-catenin accumulation. In contrast, allelic loss of RB1 is only seen in <5% of
Inactivating somatic mutation(s) in APC and RNF43 were ob­ PAs (240-297). Decreased RB1 expression has been de­
served in 1 of 24 PC sample each, although it is unclear if this scribed in >85% PCs. However, no mutations in RB1
was a biallelic event (124). Furthermore, functional character­ have been identified (298).
ization of these variants was not performed. • FAT3 encodes a large protein with multiple cadherin and
EGF-like motifs which is predicted to enable calcium ion
binding activity and have a role in cell adhesion (299,
Cyclin D1/CCND1 300). It has been implicated in PCs (124) and multiple oth­
Higher CCND1 mRNA levels and protein expression are fre­ er cancers including lung (301).
quent (∼70%) in PC in contrast to PAs (∼20%) (287). Of the • Extracellular matrix–related genes have been implicated

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5 PC samples with CCND1 gene amplifications, only 1 also in the early phase of parathyroid carcinogenesis while up­
harbored a somatic CDC73 mutation (124). However, the regulation of MMP9, ANGPTL4, BMP7, FGFR1, and
mechanism linking CCND1, and malignancy remains un­ SOX2, and downregulation of ERBB3, TBX1, FBP1,
known, and it is possible that gene amplifications in and RAB25 contribute to metastatic phenotype of PC
CCDND1 synergize with mutations with other candidate driv­ (219, 248, 302).
ers of carcinogenesis.
Other candidate genes: Thus, the genomic landscape of PC remains largely un­
known and is further limited by the rarity of the disease and
availability of tissue samples being limited to archived
• Somatic activating GCM2 mutations have been described formalin-fixed paraffin embedded samples.
in patients with sporadic PC (154, 288).
• Tumor protein 53 (TP53) encodes p53, a transcription
factor and tumor suppressor. Somatic mutations in Parathyromatosis
TP53 have been reported in a subset of PC and PAs al­ Parathyromatosis is a rare cause of recurrent PHPT due to
though their contribution to tumorigenesis remains un­ presence of nodules of benign hyperfunctioning parathyroid
known (284, 286, 289, 290). Low expression of p53 is tissue scattered outside the gland usually in the neck and medi­
seen in both PC and PAs. astinum, that was first described in 1975. It affects women
• Recurrent germline and somatic mutations in prune more than men. It can be of 2 forms (303):
homolog 2 (Drosophila) (PRUNE2) have been described
in 1 study of exome sequencing on 8 paired PCs (291). 1. Primary or type 1 parathyromatosis results from prolifer­
The reported PRUNE2 mutations were a single germline ation of parathyroid rests during its descent in embryo­
and 2 somatic missense mutations in a CDC73 wild type logic development.
sample. PRUNE2 is a tumor suppressor reported to be 2. Secondary or type 2 parathyromatosis is the more com­
mutated in prostate cancer. mon form and results from seeding during parathyroidec­
• Glycogen synthase kinase 3 beta (GSK3B) protein expres­ tomy or percutaneous ablation from rupture of capsule,
sion was found to be lost in ∼35% PCs (121). However, typically in patients with CKD (304-306). The metabolic
loss of GSK3B in parathyroid tumors was not associated derangements in CKD likely provide a persistent stimula­
with an increased β-catenin or CCND1 expression indi­ tion for PTH secretion.
cating an unrelated mechanism. Furthermore, mutations
in GSK3B have not been described in PC. GSK3B regu­ Parathyromatosis may be considered a low-grade locally in­
lates glycogen synthesis, energy homeostasis and apoptot­ vasive malignancy. Preoperative diagnosis of parathyromato­
ic pathways and is implicated in the pathogenesis of sis is rare and the diagnosis is typically made based on clinical
Alzheimer and Parkinson disease. presentation, imaging findings and histology. These nodules
• While decreased expression of ten-eleven translocation-1 can be localized on 99mTc-sestamibi, 4-dimensional computed
(TET1) and ten-eleven translocation-2 (TET2) in PC tomography (CT) or 18F-fluorocholine positron emission tom­
was seen in 1 study, mutations in TET proteins have not ography/CT, although available data on sensitivity in disease
been described (292). The TET family of proteins regulate is limited (307, 308). Parathyromatosis tissue shows positivity
DNA methylation and play an important role in various for chromogranin and synaptophysin and is positive for PTH
cancers. and cytokeratin (CAM 5.2). While the distinction of parathyr­
• EZH2 and ZFX, which are rarely mutated in PAs, appear omatosis from APTs and PCs can be challenging, this distinc­
to be even more rarely mutated in PCs (293, 294). Gene tion is unlikely to change management as surgery is first line
amplification of EZH2 has been reported in ∼60% PCs for all 3 (309). Management of parathyromatosis is challen­
(295). Furthermore, overexpression of EZH2 mRNA ging with a high failure rate with both surgical and medical
has been observed in samples without gene amplification management. The possibility of unidentified miliary parathy­
suggesting indirect mechanism possibly through its inter­ roid tissue dissemination should be considered in the medical
action with WNT-β-catenin pathway or histone modifica­ decision-making for these patients. Cinacalcet and bisphosph­
tion via HIC1 (180). onates, alone or in combination are the main treatment op­
• PC samples demonstrated a strong presence of the muta­ tions for medical therapy. Recent reports of denosumab use
tion signature of apolipoprotein B mRNA editing enzyme, for long-term therapy have also emerged (310-314).
794 Endocrine Reviews, 2023, Vol. 44, No. 5

Table 2. Heritable forms of hyperparathyroidism

Disorder Genetic cause Gene location Functional Associated clinical features

effect

Multiple endocrine MEN1 11q13 Inactivating Pituitary tumors, GEP-NETs

neoplasia type 1
Multiple endocrine RET 10q11.21 Activating Medullary thyroid cancer, pheochromocytoma
neoplasia type 2
Multiple endocrine CDKN1B 12p13.1 Inactivating “MEN1-like”; pituitary tumors, GEP-NETs, milder
neoplasia type 4 disease phenotype
Multiple endocrine MYC-associated factor X 14q23.3 Inactivating Pheochromocytoma, pituitary tumors, (evolving
neoplasia type 5 (MAX) phenotype)
Hyperparathyroid jaw CDC73 1q31.2 Inactivating Jaw, uterine, kidney tumors; 20-25% risk of parathyroid
tumor syndrome carcinoma; incomplete penetrance

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Familial hypocalciuric CASR 3q13.3-q21.1 Inactivating Mild elevation in serum calcium and PTH, minimal
hypercalcemia type 1 target organ effect, Asymptomatic, parathyroidectomy
Familial hypocalciuric GNA11 19p13.3 Inactivating does not resolve hypercalcemia, present since birth
hypercalcemia type 2
Familial hypocalciuric AP2S1 19q13.32 Inactivating Most severe form of FHH; may be associated with target
hypercalcemia type 3 organ effects (for example, kidney stones or fractures)
Neonatal severe CASR (homozygous/ 3q13.3-q21.1 Inactivating Seen in first week of life; life-threatening
hyperparathyroidism compound
heterozygous)
Familial isolated GCM2 6p24.2 Activating Poor penetrance; parathyroid carcinoma reported;
hyperparathyroidism enriched in Ashkenazi Jewish populations

Abbreviations: FHH, familial hypocalciuric hypercalcemia; GEP-NET, gastroenteropancreatic neuroendocrine tumor; PTH, parathyroid hormone.

Other Acquired Disorders With Primary Heritable Hyperparathyroid Disorders

Hyperparathyroidism Approximately 10% to 15% of PHPT consists of heritable
Autoimmune Hypocalciuric Hypercalcemia forms with MEN1 being the most common heritable form, af­
These patients have clinical features of FHH (biochemical fecting 2% to 4% of patients with PHPT (320).
phenotype of PHPT and hypocalciuria—see “Heritable Hyperparathyroidism is often the first manifestation of the syn­
Hyperparathyroid Disorders” subsection “FHH and dromic forms of heritable PHPT (MEN1, MEN4, and
Neonatal Severe Hyperparathyroidism”) but negative genetic HPT-JT). Early diagnosis of these disorders is useful in plan­
testing and presence of autoantibodies against CASR with ning the extent of surgery and establishing an optimal surveil­
lymphocytic infiltration of the parathyroid gland (315-317). lance for recurrence of PHPT and the associated
Typically, this is seen in a patient with other autoimmune con­ extraparathyroidal manifestations of these disorders
ditions. Mechanistically, these antibodies can induce biased (Table 2). The distinction between sporadic vs heritable form
signaling of CASR. These patients may respond to gluco­ of PHPT can often be difficult due to (1) the incomplete pene­
corticoid or calcimimetic therapy (318). trance of some heritable syndromic forms, (2) presence of de
novo mutations in patients with no family history, and (3) oc­
cult PHPT in family members limiting the utility of family his­
Lithium-associated hypercalcemia tory in such cases. Thus, consideration of heritable causes of
Lithium-associated hypercalcemia has a prevalence of 26% PHPT should be done in patients of any age, particularly those
among all patients on lithium for bipolar disease (319) and with additional risk factors.
presents as PHPT phenotype with PTH-mediated hypercalce­
mia. The speculated mechanisms for this association include
Syndromic Forms of Primary Hyperparathyroidism
(1) the inhibition of inositol monophosphatase by lithium in
chief cells results in alterations in intracellular calcium levels Syndromic forms of PHPT are conditions that are character­
and subsequent PTH secretion, (2) interaction of lithium ized by a set of associated signs, symptoms, and/or extrapar­
with CASR resulting in an increased calcium-PTH secretory athyroidal manifestations like the multiple endocrine
“set point” (extracellular calcium concentration at which neoplasias and HPT-JT discussed below. Multiple
PTH secretion is half maximally suppressed) and increased endocrine neoplasias are characterized by tumors in at least
PTH secretion through the development of hyperplasia or ad­ 2 endocrine tissue.
enoma, (3) inhibition of glycogen synthase kinase 3 by lithium
may contribute to irregular WNT/β-catenin signaling, which Multiple endocrine neoplasia type 1
is implicated in parathyroid tumorigenesis, and (4) unmasking History. MEN1 was first recognized as a distinct clinical and
of an adenoma. Multigland disease with persistent/recurrent familial syndrome by Wermer accounting for why the original
disease seems more common in lithium-associated hypercalce­ name of MEN1 was Wermer syndrome (321). It has an esti­
mia indicating that bilateral neck exploration should be con­ mated prevalence of 3-20/100 000 and 1 % to 18% among
sidered in these patients (319). patients with primary hyperparathyroidism (75, 322), 16%
Endocrine Reviews, 2023, Vol. 44, No. 5 795

A B C

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D E

Figure 9. Clinical manifestations in syndromic forms of primary hyperparathyroidism with its reported frequency. (A) Multiple endocrine neoplasia type 1
(MEN1). (B) Multiple endocrine neoplasia type 2 (MEN2). (C) Multiple endocrine neoplasia type 4 (MEN4). (D) Multiple endocrine neoplasia type 5 (MEN5);
*comprehensive phenotype evolving. (E) Hyperparathyroidism-jaw tumor syndrome (HPT-JT). Frequency reported in parenthesis.

to 38% in patients with gastrinomas (323) and less than 3% in 4 years (335). Preoperative localization is of limited value in
patients with pituitary tumors (324-326). It is an autosomal index operations as bilateral neck exploration is recom­
dominant disease; however, its prevalence seems to be higher mended irrespective of the findings on preoperative localiza­
in females. tion studies. There is no consensus regarding the timing of
surgery for index or reoperation in MEN1-related PHPT
Clinical manifestations. Patients with MEN1 (Fig. 9A) are at and a shared decision-making approach considering the surgi­
an increased risk of premature death (327) justifying the cal experience, access to testing for long-term monitoring of
need for genetic screening (328) and periodic prospective serum calcium, and acceptance of risk for possible postsurgi­
clinical screening of carriers of MEN1 mutation (329-331). cal hypoparathyroidism is recommended. Our practice is to
While the management of MEN1-related neuroendocrine evaluate patients for symptoms and complications and delay
tumors (NETs) is no different to the management of the re­ the initial parathyroid surgery in the absence of either, in
spective NETs in sporadic cases, the treatment outcomes are view of likely need for future reoperations.
not as successful (325). This is likely explained by (1) tumor Preoperative diagnosis of MEN1 helps guide the extent of
multiplicity reducing the probability of surgical cure, (2) initial parathyroidectomy and is associated with lower recur­
higher frequency of occult metastatic disease in MEN1, rence rates (336). Open bilateral neck exploration is recom­
and (3) tendency for MEN1-related NETs to be larger, mended given the preponderance of multigland disease in
more aggressive, and therefore more resistant to treatment MEN1. Subtotal parathyroidectomy with removal of ∼3.5
(325). glands with bilateral transcervical thymectomy is the surgery
of choice for index operations in MEN1-related PHPT to bal­
Primary hyperparathyroidism ance the risks of recurrent or persistent disease vs those from
PHPT is the most penetrant manifestation of MEN1 occurring permanent hypoparathyroidism (325, 337-344). The choice
in ∼100% patients by age 50 (332, 333). Comparison with of remnant creation (weighing 60 mg, approximately twice
sporadic PHPT, the PHPT seen in MEN1 has an earlier age the size of a normal gland) is guided by relative macroscopic
of onset (20-25 year vs 55 year), more often involves several normality, the accessibility of the preserved gland for subse­
glands, has an equal gender predilection, greater reduction quent reoperations (inferior glands lie more anteriorly, away
in bone mineral density (334), and a higher risk of recurrence from the recurrent laryngeal nerve and are preferred), and vas­
(325). The youngest reported case of PHPT in MEN1 is at age cular viability which should be confirmed before resection of
796 Endocrine Reviews, 2023, Vol. 44, No. 5

other glands (75). Autotransplantation of fresh or cryopre­ Newfoundland with a high occurrence of prolactinomas and
served parathyroid tissue has been used when no functioning a low occurrence of gastrinomas with nonsense mutations
parathyroid tissue is assumed to remain in the body, predom­ (Tyr312Stop and Arg460Stop) in MEN1, and (2) Tasmania
inantly for reoperations; however, its success is largely de­ variant (367), with a splice site mutation (c.446-3c→g). In
pendent on storage duration in the case of cryopreserved this variant however, the prolactinomas were not evenly dis­
tissue and its consequent vitality. Cinacalcet, may be useful tributed, present in >50% of MEN1 affected members in
for the medical management of PHPT in patients who are branches of overall genealogy but uncommon in the remain­
not surgical candidates (345). Prophylactic transcervical ing pedigree (368).
thymectomy is performed to mitigate risk of mediastinal re­
currence from ectopic or supernumerary glands seen in 12% Gastroenteropancreatic neuroendocrine tumors
MEN1 cases (346). About 30% to 80% of patients with MEN1 develop gastroen­
The multiglandular parathyroid involvement in MEN1 can teropancreatic neuroendocrine tumors (GEP-NETs) which
be asymmetrical and asynchronous. The involved glands are may be functional, resulting in distinct clinical syndromes,
grossly enlarged (>6-8 mm) and increased in weight or nonfunctional (325, 369). Comparison with sporadic

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(>40-60 mg). Multiglandular parathyroid chief cell hyperpla­ GEP-NETs, MEN1-related GEP-NETs have an earlier age of
sia of nodular type composed of multiple monoclonal prolifer­ onset and are frequently multiple (332, 335, 370), making it
ations, constituting multiple microadenomas is the major challenging to correlate circulating hormonal status with tu­
manifestation of MEN1-related PHPT (347-349). mor source. GEP-NETs including nonfunctional GEP-NETs
MEN1-related parathyroid proliferations lack the character­ increase the risk of death in MEN1 (371). Unlike patients
istic atrophic rim of nonlesional parathyroid tissue. When pre­ with sporadic GEP-NETs where patients are often diagnosed
sent, these rim-like areas are cellular rather than atrophic. after the disease has metastasized, in MEN1 there exists a win­
Cystic parathyroid changes may be seen occasionally in dow of opportunity to prevent metastatic disease. One of the
MEN1 (350). APTs or PC is rarely seen in PC (351). goals of research in MEN1 is to develop biomarkers that can
Typically, PHPT is the earliest and most penetrant manifest­ predict aggressive vs indolent GEP-NETs early in the disease
ation of MEN1. Fortunately, given the availability of widely course and prevent metastases.
available biomarkers like serum calcium and PTH, patients Functional GEP-NETs
with MEN1 can be easily monitored for the onset or recur­ Zollinger–Ellison syndrome/gastrinomas
rence of PHPT. Zollinger–Ellison syndrome (ZES) is characterized by gas­
tric acid hypersecretion and resulting severe peptic ulcer dis­
Pituitary adenomas ease and diarrhea caused by secretion of the hormone
The incidence of pituitary tumors in patients with MEN1 var­ gastrin by GEP-NETs (gastrinomas). It is important to note
ies from 15% to 50% with a mean age of onset 38.0 ± 15.3 that the designation of a tumor as gastrinoma relies on the
year (325, 335, 352-354). Pituitary disease is the initial pre­ presence of symptoms of hypergastrinemia and not on
senting manifestation of MEN1 in ∼20% cases (352) and histological or immunohistochemical characteristics.
may occur as early as age 5 (355-357). Plurihormonal aden­ Gastrinomas are the most common functional GEP-NETs in
omas and multiple pituitary adenomas are seen at a higher fre­ MEN1, present in some 30% to 50% of patients (325).
quency in MEN1 patients (353). In addition, a higher Approximately 20% to 30% of all gastrinomas occur in pa­
proportion of MEN1-related pituitary tumors are macroade­ tients with MEN1 (325). Gastrinomas predominantly occur
nomas and show invasive features with reduced response to in the submucosa of the first part of the duodenum, with
therapy in comparison to tumors in non-MEN1 patients only about 20% to 25% of gastrinomas occurring in the pan­
(326, 352, 353, 358). However, prevalence of pituitary car­ creas (372). Nevertheless, pancreatic gastrinomas metastasize
cinoma is not increased in MEN1 (359) and asymptomatic to the liver more frequently than duodenal gastrinomas (372,
nonfunctional adenomas may be followed safely with serial 373). Rarely, gastrinomas may arise in other abdominal (eg,
MRI (354). A recent study showed a lower prevalence of mac­ stomach, liver, lymph nodes, bile duct, ovary) or extra-
roadenomas in MEN1-related pituitary adenomas (about abdominal (lung) sites. MEN1-related gastrinomas have an
30%) than older reports (85%), perhaps reflecting detection aggressive disease course with distant metastases and early
bias from improved and increased imaging and assays (352, death however, some inconsistencies in the reported studies
354). There are no histological characteristics distinguishing regarding prognosis prevail (373-376). Treatment of associ­
MEN1-related pituitary adenomas from the corresponding ated PHPT with restoration of normocalcemia has been re­
non-MEN1 pituitary tumors (353). ported to ameliorate symptoms of hypergastrinemia in
Functional pituitary adenomas are more common in MEN1 approximately 20% of MEN1 patients with ZES (377).
with a frequency of 60% for prolactinomas, 25% for growth Current evidence only supports surgery for pancreatic gastri­
hormone–secreting tumors, 5% for Cushing disease (360) and nomas greater than 2 cm (373, 374). The risk of hepatic me­
remaining being nonfunctioning or glycoprotein subunit se­ tastases, a prognostic marker of MEN1-related gastrinomas
creting, although these numbers may represent detection increases with tumor size (374). The presence of lymph node
bias (325). The increased female to male ratio in the frequency metastases does not appear to adversely affect survival in
of pituitary adenomas in MEN1 patients (352, 354) is similar MEN1-related gastrinomas (373).
to the observation in non-MEN1 patients (361). The manage­ Insulinomas
ment of MEN1-related pituitary adenomas is identical to its Insulinomas constitute 10% to 30% of all pancreatic neu­
management in non-MEN1 patients (362-364). There are 2 roendocrine tumors (PNETs) in MEN1 and approximately
MEN1 variants in which prolactinomas seem to be predomin­ 4% of patients with insulinomas will have MEN1 (325).
ant: (1) Burin or prolactinoma variant (365, 366), indicating MEN1-related insulinomas differ from sporadic insulinomas
the region of origin from the Burin peninsula of in presenting at an earlier age and in having a higher rate of
Endocrine Reviews, 2023, Vol. 44, No. 5 797

recurrence (21% in MEN1 vs 7% for non-MEN1) (378). Of a 10-year survival of 35% to 45% (402-405). Almost half
note, a recurrence before 4 years suggests fracture of the insu­ of MEN1 patients with thymic carcinoids already have distant
linoma at original enucleation (379). Insulinoma may be the metastases at the time of diagnosis which may explain their
presenting manifestation of MEN1 in about 10% of MEN1 poor prognosis (403). Transcervical thymectomy does not af­
patients (325). Insulinomas can be associated with other ford prevention from thymic carcinoids raising the question of
PNETs in 10% MEN1 patients and the tumors may arise at prophylactic thymectomy in high-risk patients (406, 407).
different times (380) necessitating specialized insulinoma lo­ The rarity of the manifestation and lack of definitive evidence
calization procedures like selective pancreatic arterial calcium have precluded the determination of the best approach to pa­
stimulation testing. tient care in these high-risk patients. Male gender, a smoking
Other functional GEP-NETs seen more rarely in MEN1 in­ history, and a familial history of thymic carcinoids appear to
clude glucagonoma, VIPoma, GHRHoma, and be risk factors for thymic carcinoids in MEN1 (402, 405, 408,
somatostatinoma. 409).
Nonfunctioning GEP-NETs Bronchopulmonary carcinoids
Nonfunctioning PNETs (NF-PNETs) are the most frequent Multifocal tumorlets and neuroendocrine cell hyperplasia

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PNET in MEN1 (369, 381) and are a clinically heterogenous may represent the precursor lesions of bronchopulmonary
group (382). NF-PNETs have been reported to occur in chil­ carcinoids (410). Their natural course seems benign although,
dren (370, 383). Thus, imaging assessment for GEP-NET is poorly differentiated aggressive bronchopulmonary carci­
recommended starting at age 10 (325). Malignant NF-PNET noids can increase mortality (404, 405, 410-413). There is
are the commonest cause of death in MEN1, likely due to de­ no consensus regarding management (observation vs resec­
layed diagnosis given lack of clinical syndrome (327, 371, tion) of bronchopulmonary carcinoids in MEN1. MEN1 mu­
381, 384). Nevertheless, the clinical relevance of detecting tations have been described in sporadic carcinoid tumors of
small GEP-NETs in an asymptomatic individual remains un­ the lung (414) and are associated with poor prognosis (415).
certain. The optimal frequency of surveillance and timing of Gastric carcinoids
surgery remains controversial and may be personalized based Gastric carcinoids (type II) are associated with MEN1 and
on tumor size, location, grade, symptoms, overall clinical sta­ ZES and may be detected incidentally on endoscopy in 70%
tus, and operative risk (385). Surgical resection is currently MEN1 patients. These are usually multiple, smaller than
recommended for tumors >2 cm in size or those with signifi­ 1.5 cm and have an indolent clinical course. Endoscopic resec­
cant progression (doubling of tumor size within 3-6 month tion followed by endoscopic surveillance is adequate therapy
or increase > 1 cm) (325, 386-390). for most patients.

Carcinoid tumors Adrenal tumors

The term “carcinoid” means “carcinoma-like” underscoring a About 20% to 73% of patients with MEN1 have adrenal tu­
benign behavior despite microscopic resemblance to a carcin­ mors detected on imaging, the majority of which are asymp­
oma (391). Carcinoids occur in about 3% MEN1 patients tomatic. The spectrum of adrenal lesions includes cortical
arising predominantly from the foregut (thymus, bronchopul­ adenomas, hyperplasia, multiple adenomas, nodular hyper­
monary system and stomach) (325). Carcinoid syndrome plasia, cysts, or carcinomas (325). About 10% to 15% of
characterizes the constellation of symptoms including diar­ these lesions are functional with aldosteronomas and cortisol-
rhea, episodic flushing, bronchoconstriction, and right sided secreting adrenocortical tumors being the most frequent (360,
valvular heart disease mediated by the release of humoral fac­ 416, 417). Pheochromocytoma and adrenocortical carcinoma
tors like serotonin into systemic circulation. Most MEN1 pa­ (1%) are rare in MEN1 (416, 417). Similarly, somatic MEN1
tients with carcinoid tumors remain asymptomatic and lack a mutations are rare in sporadic adrenocortical carcinomas
consistent biochemical abnormality (325). Rarely, ectopic (418). Adrenal tumors with radiological characteristics con­
hormonal secretion, such as adrenocorticotropin may occur cerning for malignancy, with significant increase in size, or
from thymic or bronchopulmonary carcinoid in MEN1 those larger than 4 cm should be considered for surgery
(392-394). (417, 419).
Thymic carcinoids
The thymus contains elements derived from all 3 germinal Skin findings
layers. Thymomas and thymic carcinoids should be consid­ Multiple angiofibromas (22-88%), collagenomas (0-72%),
ered in the differential diagnosis of an anterior mediastinal and lipomas (33%) are cutaneous manifestations of MEN1
mass in MEN1 (395, 396). While both are epithelial in origin, (420-424). The presence of skin lesions does not correlate
thymomas have a dual population of epithelial cells and lym­ with age, disease duration or other MEN1 features (423).
phocytes, not seen in carcinoids. Additionally, the staining for As a diagnostic criterion, the combination of multiple angiofi­
neuroendocrine markers in thymomas, if present, is more fo­ bromas (more than 3) and any collagenomas had the highest
cal (397). Somatic LOH at the MEN1 locus was recently dem­ sensitivity for identifying MEN1 (423, 425). Management is
onstrated as the mechanism for tumor development in both conservative; however, these may need to be removed for cos­
thymic carcinoids and thymomas (398). An association of metic reasons. Risk of recurrence does not appear to be in­
thymomas with myasthenia gravis and paraneoplastic syn­ creased with surgical removal (325).
dromes, while not uncommon in the non-MEN1 setting, has
not been described in MEN1. About 25% of thymic carci­ Other associations
noids arise in patients with MEN1 (399). Central nervous system tumors including ependymoma,
Thymic carcinoids may be the initial manifestation of schwannomas, and meningiomas are a part of the MEN1 syn­
MEN1 (400, 401) and have been reported as early as age 16 drome (325). LOH at the MEN1 locus was demonstrated in
(402). These tumors have an aggressive disease course with the resected meningioma from a MEN1 patient (426). These
798 Endocrine Reviews, 2023, Vol. 44, No. 5

typically are asymptomatic and show no growth (426). at the Men1 locus in Men1+/− mice. Furthermore, knock­
Thyroid tumors comprising adenomas, colloid goiters, and out of the cell cycle genes (Rb1, Tp53, Cdk2, Cdk4,
carcinomas occur in 25% MEN1 patients (325). However, Cdkn2c, and Cdkn1b) in the Men1−/+ mice suggests that
it is assumed that this may represent an incidental finding re­ Cdkn2c inactivation and Cdk4 activation may be critical
sulting from the high background prevalence of such thyroid for islet tumor formation after menin loss (445-449).
disorders combined with the increased imaging studies per­ • Conditional mouse models of MEN1:
formed in MEN1 patients (427). Somatic MEN1 mutations • Mice with conditional loss of menin in the liver (Men1f/f;
have been reported in 4% of patients with Hurthle cell thyroid ALB-Cre) do not develop tumors in the liver (450).
carcinoma, a rare thyroid malignancy which often presents at • Mice with conditional loss of menin in the whole pan­
an advanced stage (428). Leiomyomas of the esophagus, ute­ creas (Men1f/f; PDX1-Cre) develop tumors of β-cells
rus and ureter but not lung have been demonstrated to be part but not from the exocrine pancreas (451). Of note,
of MEN1 syndrome, arising as independent clones (429, 430). mice with conditional loss of menin in the β-cells of
Menin loss has been implicated in breast cancer via stimula­ the pancreatic islets (Men1f/f; GLU-Cre) primarily de­
tion of estrogen receptor (431). While an association may ex­ velop insulinomas but not glucagonomas (452). It has

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ist, current level of evidence does not support heightened been speculated that this may be due to (1) transdiffer­
surveillance (432, 433). Similarly, somatic MEN1 mutations entiation of α-cells into β-cells after menin loss (453) or
were identified in 4% of BRAF mutant colorectal neoplasia (2) paracrine signals form menin-null α-cells inducing
samples supporting a role for menin as a tumor suppressor β-cell proliferation. As expected, β-cell-specific Men1
in colorectal tissue (434). Nevertheless, existing data does knockout mice (Men1f/f; RIP-Cre) develop insulinomas
not suggest an increased predisposition to colon cancer in (454). However, in addition to insulinomas these mice
MEN1 patients. A higher than expected frequency (0.5%) also develop prolactinomas due to leaky expression of
of pathogenic or likely pathogenic germline variant in the RIP-Cre transgene in pituitary lactotroph cells
MEN1 was observed in patients with osteosarcoma of (455).
European ancestry (435). While osteosarcomas have not
been reported in MEN1 patients, these findings suggest a Although the conditional Men1 knockout mice do not de­
role of menin as a tumor suppressor in bone. pend on a spontaneous second hit for LOH of Men1, tumor
development is nevertheless delayed until about 8-10 months
after embryonic menin loss, the reason for which remains un­
Genetic and molecular characteristics. Sequencing and deletion/ clear (456). The reason for the tissue-restricted pattern of
duplication analysis can identify a heterozygous MEN1 germ­ MEN1 syndromic tumors despite the ubiquitous expression
line mutation in 70% to 90% of families with MEN1 (325). of MEN1 remains uncertain. In the pancreatic islets, it is
The mutations in MEN1 cover the entire coding region with thought to be related to the regulation of tissue-specific target
no hot spots or phenotype–genotype correlations (436, genes by menin such as Hlxb9 and other β-cell differentiation
437). Large deletions (2.5%) or nonsense (14%), frameshift factors (457-460).
(42%), and splice-site (10.5%) mutations predict premature
truncation of menin while missense mutations (25.5%) and
in-frame insertion or deletion of 1 or more amino acids Multiple endocrine neoplasia type 2
(5.5%) do not predict obvious menin inactivation (75). MEN2 is an autosomal dominant disorder with an estimated
Genetic testing for MEN1 should be offered to (1) index cases prevalence of 1:30 000. It is caused by a germline
with 2 or more MEN1-associated endocrine tumors, (2) gain-of-function in the RET proto-oncogene encoding the
asymptomatic first-degree relatives of a MEN1-mutation car­ RET tyrosine kinase receptor, a cell surface molecule involved
rier, (3) symptomatic first-degree relatives of a in signal transduction for cell growth and differentiation. RET
MEN1-mutation carrier presenting with at least 1 is expressed in cells derived from the neural crest, branchial
MEN1-associated tumor, and (4) patients with multigland arches, and urogenital system (461). Activation of RET results
parathyroid disease, gastrinoma, or multiple pancreatic islet in activation of several downstream pathways, including the
tumors at any age (59, 75). Germline MEN1 mutations are RAS/MAPK and PIK3/AKT pathways. The primary clinical
not found in 10% to 30% patients with MEN1 and this group manifestations of the disease are multiple endocrine tumors
of germline MEN1-mutation–negative MEN1 seems to have a that typically include medullary thyroid carcinoma (MTC),
distinct clinical course compared with patients with germline pheochromocytoma (often bilateral), and PHPT (typically
MEN1-mutation–positive MEN1 (438, 439). mild, single gland adenoma with hyperplasia). A genotype–
The various mice models of MEN1 are summarized below: phenotype correlation has been recognized in that RET codon
mutations predispose to characteristic phenotypic expressions
• Germline homozygous knockout of Men1 (Men1−/−) is of MEN2 (see below).
embryonically lethal at E11.5-E14.5 (440, 441).
• Germline heterozygous knockout of Men1 (Men1−/+) de­
velop tumors from the 3 primary tissues affected in MEN2 (previously called MEN2A). While MTC and pheochro­
MEN1 at age >12-15 months: anterior pituitary (mainly mocytoma commonly precede the diagnosis of PHPT in
prolactinomas), pancreatic islets (mainly insulinomas), MEN2 (Fig. 9B), rare reports of PHPT as the initial manifest­
and parathyroid glands (mainly hyperplasia) (440, 442, ation have been described (462). All parathyroid glands
443). A second hit to the wild type allele of Men1 resulting should be examined during surgery and current preference is
in LOH and subsequent biallelic inactivation is essential for resection of only visibly enlarged glands with intraopera­
for tumor formation in Men1+/− mice (444). A pretumor tive PTH monitoring to document surgical cure (461, 463).
stage of hyperplasia and dysplasia is seen prior to LOH Given the low penetrance of PHPT (30%), prophylactic
Endocrine Reviews, 2023, Vol. 44, No. 5 799

parathyroidectomy at the time of thyroidectomy is not advised (p27) or Men1 in addition to Cdkn2c (p18), indicating redun­
(461). dant or overlapping function (449, 472). CDKN1B is not a
Four disease variants have been identified: classic tumor suppressor gene, and the second allele is rarely
mutated or lost by LOH in human cancers (475, 476). The re­
1. Classic MEN2 with manifestations of MTC (90%), duced expression of P27KIP1 protein without a somatic muta­
pheochromocytoma (10-50%), and PHPT (30%): RET tion in the second CDKN1B allele suggests that
codon 634 mutation is associated with a moderate pene­ haploinsufficiency of CDKN1B is adequate to confer
trance of PHPT and mutations in codons 609, 611, 618, tumorigenicity.
and 620 are associated with a penetrance between 2% MENX was renamed as MEN4 in 2008 (477). The esti­
and 12% (464). mated prevalence of MEN4 among patients with
2. MEN2 with cutaneous lichen amyloidosis: These derma­ MEN1-like manifestations is 1.5% to 3.7% (478-480). The
tological lesions are most frequent in the scapular region. earliest reported onset of manifestations is at age 15 years
3. MEN2 with Hirschsprung disease: Paradoxically, RET (481). While there exists a significant overlap in the clinical
mutations associated with Hirschsprung disease are features of MEN1 and MEN4 (Fig. 9C), some differences ex­

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loss-of-function mutations in contrast to the ist: (1) PHPT seems to occur at a later age in MEN4 than in
gain-of-function RET mutation causing MEN2. This MEN1 (mean age 56 years vs 25 years respectively), (2)
dual occurrence is explained by constitutive activation PHPT in MEN4 is milder with low likelihood of recurrence,
of RET being sufficient to trigger neoplastic transform­ (3) pituitary tumors in MEN4 are not as aggressive as seen
ation of C-cells and adrenal chromaffin cells but not in in MEN1, and (4) the penetrance of GEP-NET is lower in
the precursor neurons due to a lack of expression of the comparison to MEN1 (482). However, these differences
RET protein at the cell surface (465). should be considered with caution given the small number
4. Familial medullary thyroid cancer: These patients de­ of reported cases of MEN4. Recent works suggests that pa­
velop neither pheochromocytoma nor PHPT. tients with indels (CDKN1B) have higher risk for PHPT vs
point mutations and variants in codons 94-96 were associated
with higher risk of PHPT and pituitary adenoma (483).
MEN3 (previously called MEN2B). This constitutes about 6% of
previously classified MEN2 patients (466). Unlike MEN2,
PHPT is not seen in MEN3. MTC is the most frequent compo­ Novel MEN syndrome—MEN5
nent of the syndrome and is typically more aggressive and has Rare reports of families with inactivating mutations in
an earlier onset than MEN2 (461). In addition, these patients MYC-associated factor X (MAX), with paragangliomas,
can have the specific clinical feature of mucosal neuromas of pheochromocytomas (bilateral and/or metastatic), and pituit­
the lips, tongue and conjunctiva, musculoskeletal abnormal­ ary adenoma, have been described (484). Additional endo­
ities (467), narrow long face, thickened lips and ganglioneur­ crine tumors reported in patients with germline MAX
omas of the gastrointestinal tract resulting in abnormal variant include ganglioneuroma, ganglioneuroblastoma,
gastrointestinal motility leading to diarrhea, constipation, or adrenomedullary hyperplasia, PNETs, and PAs (Fig. 9D).
colonic dilatation (megacolon) at a young age. These nonen­ MAX is a transcription factor regulating cell proliferation, dif­
docrine manifestations can result in an early diagnosis even ferentiation, angiogenesis, and apoptosis. It is a classic tumor
before the endocrine manifestations (468). Although, 80% suppressor gene, with somatic loss of the second allele.
patients with MEN3 develop MTC in the first year of life, Comprehensive phenotyping of this novel syndrome is
the median age of thyroidectomy in MEN3 is 14 years evolving.
(469). The delay in diagnosis may be explained by the prepon­
derance of de novo mutation in MEN3, which typically in­ Hyperparathyroidism Jaw Tumor Syndrome
volves a methionine-to-threonine substitution at RET codon
History. HPT-JT (OMIM #145001) was first characterized in
918 (M918T). Somatic RET mutations have been identified
a kindred with familial hyperparathyroidism originally de­
in sporadic MTC (60%), papillary thyroid cancer (10-20%)
scribed 3 decades earlier by Jackson (485). Several decades
and nonsmall cell lung cancer (1-2%). A patient with a mixed
after initial ascertainment, 2 affected members of the third
MEN1/MEN2 phenotype without any mutations in MEN1 or
generation of the kindred were shown to have ossifying jaw fi­
RET has been described (470).
bromas similar to 4 of the 5 affected members of the first gen­
eration leading to identification of HPT-JT as a clinically and
Multiple Endocrine Neoplasia type 4 genetically distinct syndrome (486). Linkage analysis mapped
MEN4 was described initially in rats (MENX) in 2000 and a single locus associated with the syndrome to chromosomal
subsequently in humans. The syndrome is caused by germline region 1q25-q32 (487-489). Using a positional candidate ap­
mutations in Cdkn1b in rats and CDKN1B in humans, encod­ proach through multi-site collaboration, heterozygous germ­
ing P27KIP1 (p27), a gene regulating cell cycle progression line inactivating mutations in HRPT2 were identified in 13
(471-473). Rats exhibiting MENX phenotype show develop­ of 14 families in 2002 (490). After the cloning of the gene, it
ment of a wide spectrum of NETs, including pituitary, adre­ was found that the homologs were present in several species
nals, thyroid, parathyroid and gastroduodenal tract. including Drosophila (54% identical and 67% similar) and
However, the rat models exhibit parathyroid hyperplasia yeast (25% identical and 45% similar) (490). The homolog
and not tumor development. The human and mouse in the yeast called cdc73 (cell division cycle protein 73) had al­
CDKN1B share >90% sequence homology in cDNA (474). ready been well-studied and hence, HRPT2 was renamed as
Homozygous knockout mice model of Cdkn2c (p18) show CDC73. The disease has an autosomal dominant pattern of
low-penetrance parathyroid neoplasia, which is enhanced in inheritance, but mutations may occur de novo (491).
double mutant mice lacking either Cdkn1a (p21) or Cdkn1b Concomitant demonstration of a somatic mutation in tumor
800 Endocrine Reviews, 2023, Vol. 44, No. 5

tissue from a patient with germline CDC73 mutation is con­ parathyroid malignancy although CDC73-mutation status is
sistent with biallelic inactivation and a putative tumor sup­ not reported in most published cases with nonfunctional para­
pressor function in accordance with Knudson’s “two hit” thyroid malignancy (253, 255, 505). Patients with high-
model of hereditary cancer (492). impact germline CDC73 mutations that predict significant
In its fullest clinical expression, HPT-JT may manifest with conformational disruption or loss of expression of parafibro­
PHPT, jaw tumors involving the maxilla or mandible, kidney min (such as truncation and frameshift mutations and gene de­
cysts or tumors, and uterine tumors (Fig. 9E). HPT-JT is char­ letions) have a higher (6.6-fold) risk of PC in comparison to
acterized by variable and incomplete penetrance, such that patients with low-impact mutations despite a similar risk of
some 20% of obligate or proven CDC73 mutation carriers developing PHPT between the 2 patient groups (506). This
may exhibit no obvious expressions. may be due to disruption of C-terminal domain of parafibro­
min by the high-impact mutations. The C-terminal domain is
believed to constitute a protein interaction surface that cou­
Clinical manifestations. ples PAF1 complex to RNA polymerase II elongation machin­
Primary hyperparathyroidism ery (270).

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The most common, earliest, and sometimes sole feature of
HPT-JT is PHPT. The earliest reported onset of hyperpara­
thyroidism in a patient with HPT-JT is 7 years (493). Jaw tumors
Median age of diagnosis of hyperparathyroidism is approxi­ Jaw tumors are rare and seen in approximately 10% to 30%
mately 28.5 years (range 16-58) (494-497). Penetrance of of patients in HPT-JT (495, 496). Pathologically, these tumors
PHPT in 43 Dutch nonindex CDC73 mutation carriers was are consistent with “ossifying fibromas” (OF) under the class
shown to increase with age (65% and 83% at ages 50 and fibro-osseous lesions (507). In HPT-JT, OFs may precede the
70, respectively) (497). The oldest reported asymptomatic onset of PHPT (494). Multiple jaw lesions are rare in sporadic
gene carrier is at age 72 years (494) and oldest reported onset OFs but may be seen in about 30% patients with HPT-JT
of PHPT is at age 60. Approximately 20% of patients with the (508). The precise cell of origin from which OF arise remains
clinical diagnosis of HPT-JT do not have a detectable patho­ unclear. It is speculated that OFs are derived from the mesen­
genic variant in CDC73 (498). These patients may have chymal blast cells of periodontal membrane with the tumor
CDC73 mutations in the promoter, untranslated regions, or consisting of highly cellular fibrous tissue containing varying
introns or they may have whole exon or gene deletions that amounts of calcified tissue resembling bone, cementum or
can be missed on sequencing analysis (499). Single gland para­ both (509). OFs are distinct from the “brown tumors” de­
thyroid involvement is more common than multi-gland dis­ scribed in osteitis fibrosa cystica or severe PHPT as the former
ease (86.1 vs 13.9%) in HPT-JT relative to other forms of (1) can appear or enlarge even after parathyroidectomy (510),
familial hyperparathyroidism such as MEN1 (500). Thus, a (2) are limited to the maxilla (491) or mandible while brown
targeted unilateral exploration with selective parathyroidec­ tumors can appear anywhere in the skeleton, (3) lack the
tomy is typically performed in patients with preoperative abundant multi-nucleated giant cells seen in “brown tumors”
single-gland localization (501). Bilateral neck exploration is (510), and (4) typically have a sclerotic rim on imaging unlike
reserved for patients with negative or discordant preoperative brown tumors that are purely lytic and lack the sclerotic rim
localization. Overall, recurrence rate for hyperparathyroidism (511). Jaw tumors are the presenting manifestation in about
in patients with HPT-JT is approximately 25% after a median 30% patients with HPT-JT (512). These tumors can be man­
disease-free interval of 8.5 years (500). Recurrence is more fre­ aged conservatively unless excision is warranted due to dis­
quently seen in patients with discordant preoperative localiza­ placement of teeth or of the inferior alveolar canal.
tion (60% vs 9%; P = .06) and subsequent long-term cure is Complete excision of these tumors (vs enucleation or curet­
typically achieved after reoperation (500). tage) is recommended considering the possibility of recurrence
On pathology, parafibromin-negative tumors can demon­ (511). Somatic CDC73 mutations are rare in sporadic OFs of
strate distinctive morphology including extensive sheet-like the jaw (513-515).
rather than acinar growth, eosinophilic cytoplasm, nuclear en­
largement with distinctive coarse chromatin, perinuclear cyto­
plasmic clearing, prominent arborizing vasculature and Uterine tumors
frequently, a thick capsule (502). Loss of immunohistochem­ Several studies have shown a high frequency of uterine tumors
ical expression of parafibromin can be a marker of biallelic in women with HPT-JT (495, 496, 498). The reported uterine
CDC73 inactivation in parathyroid tumors. Parafibromin lo­ pathology includes benign and malignant tumors like adeno­
calizes in the nucleolar compartment (503). Evaluation of not sarcoma, adenofibroma, leiomyomas, adenomyosis, and
only nuclear but also nucleolar staining for parafibromin in­ endometrial hyperplasia (498). These uterine tumors have a
creases the sensitivity for detection of malignancy (504). common embryological origin from the mesodermal
Clinically, loss of parafibromin staining can be particularly Mullerian duct system. Affected women typically present
useful in predicting the behavior of atypical PAs (220, 222). with menorrhagia in their second to fourth decade and may
However, the technique is not widely available, and process need hysterectomy leading to decreased fecundity (494,
can be technically demanding. In addition, the existence of dif­ 498). We reported the successful use of aromatase inhibitor
ferent scoring systems and lack of a standard antiparafibro­ in a young nulligravid woman with HPT-JT and multiple
min antibody or antiserum for immunostaining limit a atypical endometrial polyp-like lesions filling the entire uter­
uniform interpretation. ine cavity subsequently leading to a successful pregnancy
Patients with HPT-JT have a higher prevalence of atypical (516). Ovarian granulosa cell tumor in a young woman with
adenomas and carcinomas of the parathyroid (20%) (494, genotype-positive HPT-JT has been described although
496). Rarely, patients may develop a nonfunctioning LOH in tumor tissue was not demonstrated (517).
Endocrine Reviews, 2023, Vol. 44, No. 5 801

Kidney tumors FHH. However, a calcium to creatinine clearance ratio

Kidney tumors including cysts, hamartomas, Wilms’ tumors, <0.01 can be seen in up to 10% of patients with sporadic
mixed epithelial and stromal tumors, and adenocarcinomas PHPT, underscoring the important role of genetic testing
have been reported in 25% to 30% of patients with HPT-JT (44, 530). In addition, some patients diagnosed as FHH based
(488, 494, 496, 518). The earliest reported case of kidney tu­ on the calcium to creatinine clearance ratio do not have an
mor is at age 8 (519). While allelic imbalances in CDC73 have identifiable mutation in any of the genes known to cause the
been reported in sporadic renal tumors, somatic mutations in disease. Establishing a correct diagnosis of FHH has implica­
the gene are rare (520). tions for management of PHPT in addition to the implications
for family. Another tool called “pro-FHH” which factors
Other manifestations plasma calcium, PTH, serum osteocalcin and calcium to cre­
Thoracic aortic aneurysm was described a young male (age 32) atinine clearance ratio has been recently proposed to improve
with genotype-positive HPT-JT and his father (CDC73 testing the reliability of diagnosis in comparison to the use of calcium
not available in father, mother negative) raising the possibility to creatinine clearance ratio alone (531).
of it being a feature of this disorder (521). Other manifestations The disease typically has a benign course although rare pa­

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potentially related to HPT-JT are thyroid, renal and colon car­ tients may manifest chondrocalcinosis or recurrent pancrea­
cinoma (495). Parafibromin has been shown to be downregu­ titis. In general, patients with FHH should not undergo
lated in other tumors like chromophobe renal cell carcinoma parathyroidectomy as it would not correct the hypercalcemia
(522), gastric carcinomas (523), and breast cancer (524), al­ (unless the parathyroidectomy were total). However, rare re­
though no mutations in CDC73 have been identified in these ports of concurrent PA in FHH patients with improvement in
tumors. The reason for the tissue-restrictive manifestations hypercalcemia after parathyroidectomy have been described
of CDC73 despite its ubiquitous expression remains unclear. (532). The use of a calcimimetic may be considered in case
of symptoms from hypercalcemia or target organ damage
Cdc73 null mice are em­
Genetic and molecular characteristics. (533). Imaging in FHH can be inaccurate resulting in an inad­
bryonic lethal by 6.5 days postcoitum, the timing of implant­ vertent surgery (534). On pathology, parathyroid glands in
ation indicating that parafibromin has a key role in embryonic FHH demonstrate hyperplasia with multigland involvement.
development (525). Increased proliferation rate was noted in Cardiometabolic phenotyping of patients with FHH has not
the parathyroid glands of the conventional (Cdc73+/−) mouse revealed any alterations of clinical significance in this cohort
models starting from 9 months of age (262). Although the het­ as might be expected based on the ubiquitous expression
erozygotes do not develop jaw or renal tumors, female heter­ and role of CASR (535, 536).
ozygotes develop uterine neoplasms at approximately 18
months of age (262). Familial hypocalciuric hypercalcemia type 1.This is the most com­
We believe that all patients with seemingly sporadic para­ mon and first genetically defined form of FHH (∼65%) caused by
thyroid cancer should undergo germline testing for CDC73 germline heterozygous inactivating mutations of CASR de­
because of the potential implications for family members scribed in “PTH, calcium, and vitamin D signaling” (537).
(526). In the absence of published guidelines from a consensus Majority (>85%) of these mutations are missense while remain­
of experts, annual laboratory testing for hypercalcemia with ing cases can be attributed to nonsense, deletion, insertion and
imaging of the jaw and abdomen–pelvis every 4 to 5 years splice site mutations leading to truncated CASR protein.
seems to be a reasonable surveillance plan for patients who Almost half of the inactivating mutations causing FHH1 impair
are germline CDC73 mutation positive. the biosynthesis and post-translational processing of CASR (in­
creased proteasomal degradation, decreased anterograde traf­
Nonsyndromic Forms ficking), while some other mutations located in extracellular
This subgroup of heritable forms of PHPT is not associated and transmembrane domain induce biased signaling (preferential
with extraparathyroid signs and symptoms. signaling through pERK1/pERK2 or equal signaling via intracel­
lular Ca2+ and pERK1/pERK2 instead of preferential coupling
with intracellular Ca2+ signaling seen in wild-type CASR) (44).
FHH and neonatal severe hyperparathyroidism
FHH was first described in 1972 (527). It is a genetically heter­
ogenous group of autosomal dominant disorders (FHH1, Familial hypocalciuric hypercalcemia type 2. This rare form of
FHH2, and FHH3) with a reported prevalence of 1.3 per FHH is caused by germline heterozygous inactivating muta­
100 000 which is likely an underestimation due to the occult tions of GNA11 encoding the Gα11 protein. The identified
nature of the disease (528). It makes up about 2% of patients mutations in GNA11 impair CASR-mediated signaling and
with PHPT (529). All 3 forms of FHH are caused by mutations have revealed the key residues critical for Gα11 function.
in genes involved in calcium signaling. Patients with FHH
manifest mild to moderate hypercalcemia, mild hypermagne­ This is the most se­
Familial hypocalciuric hypercalcemia type 3.
semia and “inappropriately” normal or elevated PTH. The vere form of FHH with significant hypercalcemia, hypermag­
underlying pathophysiology is nonneoplastic and results nesemia, and hypocalciuria compared with other forms. It is
from an increased calcium-PTH secretory “set point” (extra­ caused by germline heterozygous inactivating mutations in
cellular calcium concentration at which PTH secretion is AP2S1, which encodes AP2σ, a subunit of a multimeric com­
half maximally suppressed) due to impaired calcium sensing plex involved in clathrin-related endocytosis of GPCRs.
by, or signal transduction downstream of, the CASR. Nearly all mutations in AP2σ causing FHH3 identified to
Clinically, FHH is characterized by the biochemical pheno­ date affect the Arg15 residue of the protein. These mutations
type of PHPT and hypocalciuria with a calcium to creatinine disrupt an interaction between AP2σ and the CASR intracellu­
clearance ratio <0.01, seen in 80% to 95% of patients with lar domain, reducing the endocytosis of CASR (538, 539).
802 Endocrine Reviews, 2023, Vol. 44, No. 5

Neonatal severe hyperparathyroidism. Children of parents with processes as well as the significance of PTH in the regulation
FHH1 can have homozygous or compound heterozygous of calcium and bone homeostasis. The diverse clinical findings
CASR mutations manifesting as NSHPT (540). It is a life- associated with parathyroid disorders also reflect the multiple
threatening disorder with severe hypercalcemia, respiratory roles and expressions of a subset of genes vital for parathyroid
distress, rib cage deformities, hypotonia and bone demineral­ gland and bone development, function, and growth. Clinical
ization which can be seen as early as in the first week of life. An and genetic investigation of the molecular pathogenesis of
urgent parathyroidectomy may be needed (541, 542). rare heritable syndromes of PHPT, even though such forms
Children may respond to cinacalcet initially, but parathyroi­ of PHPT represent only a small fraction of total cases, has
dectomy is typically needed eventually (543). Occasionally, been critical for our discovery of key genes that regulate para­
NSHPT may be caused by sporadic heterozygous CASR muta­ thyroid growth and function and whose mutation can lead to
tions that have a dominant negative effect on CASR function parathyroid neoplasia, whether in a sporadic or familial con­
despite the presence of a wild-type allele (533). text. Such investigation first illuminated the importance of
genes such as MEN1, CDKN1B, CDC73, CASR, AP2S1,
GCM2-mediated PHPT GNA11, and GCM2 in parathyroid neoplasia.

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In vivo studies in Gcm2 knockout mice suggest that Gcm2
plays an important role in parathyroid cell proliferation and Genetics of Heritable Hyperparathyroidism of
maintenance (544). In humans, germline homozygous dele­ Unknown Etiology
tion in GCM2 has also been shown to cause familial isolated Given such historical success, an outstanding challenge for the
hypoparathyroidism (154, 545, 546). Germline activating future is to advance high-yield clinical investigation that delin­
mutations of the small C-terminal conserved inhibitory do­ eates additional genes, variants in which predispose to para­
main that increased the transcriptional activity of GCM2 in thyroid tumor development. It seems quite likely that other
in vitro studies have been reported in 18% of patients with genes remain to be discovered whose gain- or loss-of-function
FIHP (144). These activating variants appear enriched among can also initiate or promote the development of parathyroid
PHPT patients of Ashkenazi Jewish descent (547). GCM2 tumors. This hypothesis is perhaps best illustrated by the ob­
Y282D polymorphism has been observed to be more preva­ servation that parathyroid disease in the majority of FIHP kin­
lent in Italian PHPT patients relative to controls with variant dreds results from the germline mutation of genes not
GCM2 showing an increased transcriptional activity com­ presently recognized to play a role in parathyroid tumor for­
pared with wild type (548). However, the penetrance of acti­ mation (see Section “Nonsyndromic Forms” subsection
vating variants in the C-terminal conserved inhibitory domain “Familial isolated hyperparathyroidism” above). From FIHP
is low in patients with sporadic or heritable PHPT, suggesting kindreds which are MEN1, CASR, and CDC73/HRPT2 mu­
that majority of individuals with such variants will not de­ tation negative, it has been estimated that only 10% to 20%
velop a sporadic PA (549-551). The low penetrance raises carry germline mutations in the proto-oncogene GCM2
questions about the utility of including GCM2 in screening (144, 559), leaving some 80% to 90% of prescreened FIHP
for heritable causes of PHPT. GCM2-mediated FIHP has kindreds with yet to be discovered genetic risk factors for their
been shown to be associated with a higher preoperative PHPT. Somatic mutation in PTH gene was detected in a PA;
PTH levels, frequency of multigland disease, frequency of per­ however, deeper molecular understanding of the parathyroid
sistent hyperparathyroidism and risk of PC (154, 552, 553). gland remains to be established. Lack of parathyroid cell lines
severely limits our ability to understand the molecular mech­
Familial isolated hyperparathyroidism anism of parathyroid in state of health and disease as parathy­
FIHP is characterized by familial hyperparathyroidism with­ roid cells in primary culture are hard to maintain and the
out any apparent extraparathyroidal manifestation. This is a expression of CASR can be severely reduced in primary para­
genetically heterogenous group consisting of patients with thyroid culture after 24 hours.
(1) incomplete expression of MEN1, CDC73 (554-556), or
CASR, (2) germline activating GCM2-mutations, and (3) un­ Localization of Small Parathyroid Tumors
known heritable cause of PHPT (557). Patients with FIHP Metabolically significant parathyroid tumors can be very
should undergo screening for established heritable causes of small, so more sensitive, and specific parathyroid tumor loca­
PHPT (171, 259). Our preference is to classify the patients tion methodologies remain a major future challenge. This is
who fall in the first 2 categories in their respective group of pa­ particularly true in reoperative cases of PHPT, since the surgi­
tients with the same molecular signature. Furthermore, the cal risk is much greater, and the benefit of focused, targeted
majority of FIHP patients fall in the third group with an un­ surgery is even more evident. Beyond 99mTc-sestamibi, 4-
known molecular etiology and small kindreds (558). The dimensional CT and 18F-fluorocholine positron emission
search for other genetic causes to explain FIHP in majority tomography/CT have shown promise, but even deeper invest­
of kindreds has so far been unrevealing (559) (Fig. 10). ment in discovering and optimizing superior parathyroid spe­
Thus, more work to elucidate the genetic cause of FIHP in ma­ cific imaging modalities is warranted. Localization and
jority of patients with the disease remains. management of patients with normocalcemic PHPT is particu­
larly challenging as these tumors can be smaller than typical
adenomas. It is unknown if the molecular spectrum of tumors
Perspective: Important Questions for the
causing normocalcemic PHPT or ectopic parathyroid tumors
Future differs from sporadic adenomas.
The broad spectrum of clinical manifestations associated with Near-infrared autofluorescence used label-free or in
various disorders of parathyroid function as described above combination with indocyanine green is an emerging tool for
reflects the important role calcium plays in diverse cellular real-time intraoperative detection of parathyroid glands or
Endocrine Reviews, 2023, Vol. 44, No. 5 803

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Figure 10. Genes implicated in parathyroid tumorigenesis. The thick outlined boxes represent the genes known to cause parathyroid tumors when
mutated in the germline and somatic. PA, parathyroid adenoma; PC, parathyroid carcinoma. Created with Biorender.com.

to confirm parathyroid origin of tissue in combination with (or insensitive to irradiation, although little research has explored
in lieu of) frozen section (560). Potential usefulness of near- potential radiosensitizing agents. In general, conventional
infrared autofluorescence in reducing post-thyroidectomy cytotoxic chemotherapy has been ineffective in PC with sur­
hypoparathyroidism or in patients with unrevealing preopera­ vival benefit shown. There is a need for large scale prospective
tive localization warrants further investigations. clinical trials that employ tyrosine kinase inhibitors for the
treatment of PC, since therapy with multitarget tyrosine kin­
Management of Primary Hyperparathyroidism in ase inhibitors that potentially inhibit both angiogenesis and
Pregnancy tumor cell proliferation have shown some efficacy in limited
Management of PHPT in pregnancy remains an area with studies. The potential use of biologic drugs, such as vaccines
sparse data and little evidence. Current practice is to manage or antibodies, for the treatment of inoperable PC is a relatively
pregnant women conservatively with consideration of para­ unexplored area, worthy of deeper investigation. There are
thyroidectomy in second trimester for severe or symptomatic case reports, for example, of prolonged clinical response in a
hyperparathyroidism. Preoperative imaging in pregnant patient with inoperable PC immunized with fragments of
women should be limited to ultrasonogram. Cinacalcet, deno­ PTH (256, 565). Thus, future research to enhance our under­
sumab, or bisphosphonates are contraindicated in pregnancy, standing of parathyroid gland and PTH is warranted.
limiting available medical therapy primarily to intravenous
fluids. Furthermore, symptoms of hypercalcemia can be diffi­ Management of PHPT in heritable forms of PHPT
cult to distinguish from clinical features of pregnancy. There is little evidence to guide the management of recurrent
Retrospective data indicates that patients treated with para­ or index PHPT presentation in heritable forms like MEN1
thyroidectomy have lower rates of preeclampsia and preterm or HPT-JT wherein patients may manifest with PHPT as early
delivery compared to pregnant women treated medically as age 5 (335). Our current practice is to extrapolate the target
(561). Maternal hypercalcemia can suppress fetal parathyroid organ–based indications (kidney stones, hypercalciuria, or
glands and result in neonatal hypocalcemia. osteoporosis) recommended for asymptomatic patients with
sporadic PHPT (566). Recent studies challenge the notion of
Clinical Relevance of FGF23 in Primary bilateral exploration in patients with MEN1 or HPT-JT (567).
Hyperparathyroidism
Studies in mouse models and humans indicate an elevated Polygenic risk score to predict risk of PHPT
FGF23 level in PHPT (562). Elevated FGF23 in these patients Recent work investigating genetic associations with PHPT us­
is associated with greater weight of the PA and greater PTH ing both GWAS and candidate gene approaches in a Scottish
levels as well as metabolic markers associated with long-term population suggests involvement of genetic variants in the
cardiovascular risk (563). It has been suggested that this is an vicinity of SOX9, SLITRK5, LPAR3, and BCDIN3D-
adaptive response to counteract the PTH-induced increase in AS1(568). Findings also suggest that carriers of greater
1,25(OH)2D levels (564). Whether the elevated FGF23 has a number of PHPT-risk alleles are associated with statistically
role either alone or in conjunction with PTH in some of the significant increased risk of PHPT in men and women.
little-known associations of PHPT like cardiometabolic com­ While this is a novel finding in the field of population genetics
plications remains unknown. for PHPT, the value of polygenic risk score in patient manage­
ment remains uncertain. Furthermore, these findings have lim­
Management of Parathyroid Cancer ited generalizability across non-European population as is
Another outstanding future challenge is to develop effective typical with GWAS studies. Nevertheless, population genetics
therapies for inoperable PC. PC is generally considered can enhance our understanding of parathyroid biology.
804 Endocrine Reviews, 2023, Vol. 44, No. 5

Indication(s) for genetic testing for heritable forms of PHPT DK043012-21 and ZIA DK043006-46) supported this
Despite a prevalence of 10% to 15% for heritable forms of research.
PHPT, germline screening for heritable forms is infrequently
performed or emphasized in guidelines (566). We suggest Disclosure
that the following should be an indication for genetic testing
The authors have no conflicts of interest to disclose.
(single gene or panel-based testing):

• Positive family history of PHPT or its manifestations (oc­ References

cult disease) is the strongest predictor of a positive genetic 1. Collip J, Clark E. Further studies on the physiological action of a
test (569). parathyroid hormone. J Biol Chem. 1925;64(2):485-507.
• Synchronous or asynchronous multigland disease. 2. Brewer HB J, Ronan R. Bovine parathyroid hormone: amino acid
• Recurrent or persistent (despite resection of histologically sequence. Proc Natl Acad Sci U S A. 1970;67(4):1862-1869.
abnormal gland). 3. Niall HD, Keutmann H, Sauer R, et al. The amino acid sequence
of bovine parathyroid hormone I. Hoppe Seylers Z Physiol Chem.
• Age ≤ 45 years has ∼10% yield of heritable forms

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

1970;351(12):1586-1588.
(570-572). The threshold for genetic testing is controver­ 4. Summers GW. Parathyroid update: a review of 220 cases. Ear
sial and varying thresholds ranging from 30 to 45 years Nose Throat J. 1996;75(7):434-439.
have been used in different guidelines (573, 574). 5. Thompson NW, Eckhauser FE, Harness JK. The anatomy of pri­
• Parathyroid cancer: germline variants in CDC73 confer a mary hyperparathyroidism. Surgery. 1982;92(5):814-821.
20% increased risk of parathyroid cancer or atypical tumors. 6. Levin KE, Clark OH. The reasons for failure in parathyroid oper­
• Suspected FHH: patients should be counselled to avoid ations. Arch Surg. 1989;124(8):911-914.
parathyroidectomy. 7. Akerstrom G, Malmaeus J, Bergstrom R. Surgical anatomy of hu­
• Diagnosis of gastrinoma: American College of Medical man parathyroid glands. Surgery. 1984;95(1):14-21.
Genetics recommends that all patients with gastrinomas 8. Carter WB, Carter DL, Cohn HE. Cause and current management of
reoperative hyperparathyroidism. Am Surg. 1993;59(2):120-124.
or multifocal PNETs should be offered genetic testing
9. Mannstadt M, Kronenberg HM. Parathyroid hormone gene:
for MEN1. structure, evolution, and regulation. In: Bilezikian JP (ed.), The
• Presence of 2 classical MEN1-associated tumors: patients Parathyroids, Basic and Clinical Concepts. 3rd ed. Academic
should be tested for variants in MEN1. Press, 2015:37-44.
• Presence of at least 1 classical MEN1-associated endo­ 10. Akerstrom G, Grimelius L, Johansson H, Pertoft H, Lundqvist H.
crine tumor in the context of positive family history of Estimation of the parathyroid parenchymal cell mass by density
MEN1(or its manifestations in case of occult disease): gradients. Am J Pathol. 1980;99(3):685-694.
presence of MEN1 variants should be assessed. 11. Dekker A, Dunsford HA, Geyer SJ. The normal parathyroid gland
at autopsy: the significance of stromal fat in adult patients. J
Genetic testing (germline) is useful in: Pathol. 1979;128(3):127-132.
12. Shi Y, Hogue J, Dixit D, Koh J, Olson JA Jr. Functional and gen­
etic studies of isolated cells from parathyroid tumors reveal the
• cascade screening for family members
complex pathogenesis of parathyroid neoplasia. Proc Natl Acad
• patient management as in FHH (avoid parathyroidec­ Sci U S A. 2014;111(8):3092-3097.
tomy), MEN1 (subtotal parathyroidectomy with bilateral 13. Dufour DR, Wilkerson SY. The normal parathyroid revisited: per­
transcervical thymectomy) or MEN2 (prophylactic centage of stromal fat. Hum Pathol. 1982;13(8):717-721.
thyroidectomy) 14. Emura S, Shoumura S, Utsumi M, et al. Origin of the water-clear
• instituting surveillance for associated manifestations as in cell in the parathyroid gland of the golden hamster. Acta Anat
multiple endocrine neoplasias (Basel). 1991;140(4):357-361.
• access to preimplantation and prenatal genetic testing if de­ 15. Cordes M, Dworak O, Papadopoulos T, Coerper S, Kuwert T. MIBI
sired by prospective parents at risk of transmitting the disease scintigraphy of parathyroid adenomas: correlation with biochemical
and histological markers. Endocr Res. 2018;43(3):141-148.
• relieving family members at risk of inheriting from the
16. Ritter CS, Haughey BH, Miller B, Brown AJ. Differential gene ex­
burden of chronic surveillance and anxiety in case of a
pression by oxyphil and chief cells of human parathyroid glands. J
negative test. Clin Endocrinol Metab. 2012;97(8):E1499-E1505.
17. Butterworth PC, Nicholson ML. Surgical anatomy of the parathy­
Thus, while we have come a long way in management of pa­ roid glands in secondary hyperparathyroidism. J R Coll Surg
tients with PHPT, areas of unmet needs persist. Future re­ Edinb. 1998;43(4):271-273.
search to gather more evidence to optimize patient 18. Akerstrom G, Malmaeus J, Grimelius L, Ljunghall S, Bergstrom R.
management is warranted. Histological changes in parathyroid glands in subclinical and clin­
ical renal disease. An autopsy investigation. Scand J Urol Nephrol.
1984;18(1):75-84.
Acknowledgments 19. Malmaeus J, Grimelius L, Johansson H, Akerstrom G, Ljunghall
S. Parathyroid pathology in hyperparathyroidism secondary to
The authors wish to thank past and present members of the chronic renal failure. Scand J Urol Nephrol. 1984;18(2):157-166.
Metabolic Diseases Branch, NIDDK for many informative 20. Shi Y, Brandler TC, Yee-Chang M, et al. Application of GATA 3
and inspirational discussions and suggestions. and TTF-1 in differentiating parathyroid and thyroid nodules on
cytology specimens. Diagn Cytopathol. 2020;48(2):128-137.
21. Nonaka D. Study of parathyroid transcription factor Gcm2 ex­
Funding pression in parathyroid lesions. Am J Surg Pathol. 2011;35(1):
145-151.
The Intramural Research Program of the National Institute 22. Yu Q, Hardin H, Chu YH, Rehrauer W, Lloyd RV. Parathyroid
of Diabetes and Digestive and Kidney Diseases (ZIA neoplasms: immunohistochemical characterization and long
Endocrine Reviews, 2023, Vol. 44, No. 5 805

noncoding RNA (lncRNA) expression. Endocr Pathol. 43. Bhattacharya P, Yan YL, Postlethwait J, Rubin DA. Evolution of
2019;30(2):96-105. the vertebrate pth2 (tip39) gene family and the regulation of PTH
23. Suva LJ, Winslow GA, Wettenhall RE, et al. A parathyroid type 2 receptor (pth2r) and its endogenous ligand pth2 by hedge­
hormone-related protein implicated in malignant hypercalcemia: hog signaling in zebrafish development. J Endocrinol.
cloning and expression. Science. 1987;237(4817):893-896. 2011;211(2):187-200.
24. Karaplis AC, Luz A, Glowacki J, et al. Lethal skeletal dysplasia 44. Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV. The
from targeted disruption of the parathyroid hormone-related pep­ calcium-sensing receptor in physiology and in calcitropic and non­
tide gene. Genes & development. 1994;8(3):277-289. calcitropic diseases. Nat Rev Endocrinol. 2018;15(1):33-51.
25. Philbrick WM, Wysolmerski JJ, Galbraith S, et al. Defining the 45. Bouillon R, Marcocci C, Carmeliet G, et al. Skeletal and extraske­
roles of parathyroid hormone-related protein in normal physi­ letal actions of vitamin d: current evidence and outstanding ques­
ology. Physiol Rev. 1996;76(1):127-173. tions. Endocr Rev. 2019;40(4):1109-1151.
26. Wysolmerski JJ, McCaughern-Carucci JF, Daifotis AG, Broadus 46. Al Mutair AN, Nasrat GH, Russell DW. Mutation of the CYP2R1
AE, Philbrick WM. Overexpression of parathyroid vitamin D 25-hydroxylase in a Saudi Arabian family with severe
hormone-related protein or parathyroid hormone in transgenic vitamin D deficiency. J Clin Endocrinol Metab. 2012;97(10):
mice impairs branching morphogenesis during mammary gland de­ E2022-2025.
velopment. Development. 1995;121(11):3539-3547.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

47. Thacher TD, Fischer PR, Singh RJ, Roizen J, Levine MA. CYP2R1
27. Wysolmerski JJ, Broadus AE, Zhou J, Fuchs E, Milstone LM, mutations impair generation of 25-hydroxyvitamin D and cause
Philbrick WM. Overexpression of parathyroid hormone-related an atypical form of vitamin D deficiency. J Clin Endocrinol
protein in the skin of transgenic mice interferes with hair follicle Metab. 2015;100(7):E1005-1013.
development. Proc Natl Acad Sci U S A. 1994;91(3):1133-1137. 48. Rodriguez-Ortiz ME, Rodriguez M. FGF23 as a calciotropic hor­
28. Philbrick WM, Dreyer BE, Nakchbandi IA, Karaplis AC. mone. F1000Res. 2015;4(December 18):F1000 Faculty
Parathyroid hormone-related protein is required for tooth erup­ Rev-1472.
tion. Proc Natl Acad Sci U S A. 1998;95(20):11846-11851. 49. Darba J, Marsa A. Epidemiology and management of parathyroid
29. Vasavada RC, Cavaliere C, D’Ercole AJ, et al. Overexpression of gland disorders in Spain over 15 years: a retrospective multicentre
parathyroid hormone-related protein in the pancreatic islets of analysis. PLoS One. 2020;15(3):e0230130.
transgenic mice causes islet hyperplasia, hyperinsulinemia, and 50. Griebeler ML, Kearns AE, Ryu E, Hathcock MA, Melton LJ 3rd,
hypoglycemia. J Biol Chem. 1996;271(2):1200-1208. Wermers RA. Secular trends in the incidence of primary
30. Care AD, Abbas SK, Pickard DW, et al. Stimulation of ovine
hyperparathyroidism over five decades (1965-2010). Bone.
placental transport of calcium and magnesium by mid-molecule
2015;73(April):1-7.
fragments of human parathyroid hormone-related protein. Exp
51. Golden SH, Robinson KA, Saldanha I, Anton B, Ladenson PW.
Physiol. 1990;75(4):605-608.
Clinical review: Prevalence and incidence of endocrine and meta­
31. Kemp BE, Moseley JM, Rodda CP, et al. Parathyroid
bolic disorders in the United States: a comprehensive review. J Clin
hormone-related protein of malignancy: active synthetic frag­
Endocrinol Metab. 2009;94(6):1853-1878.
ments. Science. 1987;238(4833):1568-1570.
52. Yeh MW, Ituarte PH, Zhou HC, et al. Incidence and prevalence of
32. Bilezikian JP, Brandi ML, Eastell R, et al. Guidelines for the man­
primary hyperparathyroidism in a racially mixed population. J
agement of asymptomatic primary hyperparathyroidism: sum­
Clin Endocrinol Metab. 2013;98(3):1122-1129.
mary statement from the Fourth International Workshop. J Clin
53. Haglund F, Ma R, Huss M, et al. Evidence of a functional estrogen
Endocrinol Metab. 2014;99(10):3561-3569.
receptor in parathyroid adenomas. J Clin Endocrinol Metab.
33. Caron P, Simonds WF, Maiza JC, et al. Nontruncated amino-
2012;97(12):4631-4639.
terminal parathyroid hormone overproduction in two patients
54. Yavropoulou MP, Poulios C, Michalopoulos N, et al. A role for
with parathyroid carcinoma: a possible link to HRPT2 gene in­
circular non-coding RNAs in the pathogenesis of sporadic para­
activation. Clin Endocrinol (Oxf). 2011;74(6):694-698.
34. Lee JH, Davaatseren M, Lee S. Rare PTH gene mutations causing thyroid adenomas and the impact of gender-specific epigenetic
parathyroid disorders: a review. Endocrinol Metab (Seoul). regulation. Cells. 2018;8(1):15.
2020;35(1):64-70. 55. Axelsson KF, Wallander M, Johansson H, et al. Analysis of co­
35. Suva LJ, Freeman AN, Martin TJ. Parathyroid hormone-related morbidities, clinical outcomes, and parathyroidectomy in adults
protein. In: Bilezikian JP, ed. The Parathyroids, Basic and with primary hyperparathyroidism. JAMA Netw Open.
Clinical Concepts. 3rd ed. Academic Press, 2015:45-64. 2022;5(6):e2215396.
36. Gardella TJ. Interactions of PTH with receptors and signaling 56. Pretorius M, Lundstam K, Heck A, et al. Mortality and morbidity
In: Bilezikian JP, ed. The Parathyroids, Basic and Clinical in mild primary hyperparathyroidism: results from a 10-year pro­
Concepts. 3rd ed. Academic Press, 2015:65-80. spective randomized controlled trial of parathyroidectomy versus
37. Juppner H, Abou-Samra AB, Freeman M, et al. A G protein-linked observation. Ann Intern Med. 2022;175(6):812-819.
receptor for parathyroid hormone and parathyroid 57. Clifton-Bligh PB, Nery ML, Supramaniam R, et al. Mortality asso­
hormone-related peptide. Science. 1991;254(5034):1024-1026. ciated with primary hyperparathyroidism. Bone. 2015;74(May):
38. Zhao LH, Ma S, Sutkeviciute I, et al. Structure and dynamics of 121-124.
the active human parathyroid hormone receptor-1. Science. 58. Vandenbulcke O, Delaere P, Vander Poorten V, Debruyne F.
2019;364(6436):148-153. Incidence of multiglandular disease in sporadic primary hyper­
39. Cardoso JC, Pinto VC, Vieira FA, Clark MS, Power DM. parathyroidism. B-ENT. 2014;10(1):1-6.
Evolution of secretin family GPCR members in the metazoa. 59. Erickson LA, Mete O, Juhlin CC, Perren A, Gill AJ. Overview of
BMC Evol Biol. 2006;6(December 13):108. 2022 WHO classification of parathyroid tumors. Endocr Pathol.
40. Suzuki N, Danks JA, Maruyama Y, et al. Parathyroid hormone 1 2022;33(1):64-89.
(1-34) acts on the scales and involves calcium metabolism in gold­ 60. Hu Y, Cui M, Xia Y, et al. The clinical features of cystic parathy­
fish. Bone. 2011;48(5):1186-1193. roid adenoma in Chinese population: a single-center experience.
41. Pinheiro PL, Cardoso JC, Power DM, Canario AV. Functional Int J Endocrinol. 2018;2018(July 15):3745239.
characterization and evolution of PTH/PTHrP receptors: insights 61. Lu M, Kjellin H, Fotouhi O, et al. Molecular profiles of oxyphilic
from the chicken. BMC Evol Biol. 2012;12(July 6):110. and chief cell parathyroid adenoma. Mol Cell Endocrinol.
42. Kamesh N, Aradhyam GK, Manoj N. The repertoire of G protein- 2018;470(July 15):84-95.
coupled receptors in the sea squirt Ciona intestinalis. BMC Evol 62. Juhlin CC, Falhammar H, Zedenius J, Nilsson IL, Höög A.
Biol. 2008;8(May 1):129. Lipoadenoma of the parathyroid gland: characterization of an
806 Endocrine Reviews, 2023, Vol. 44, No. 5

institutional series spanning 28 years. Endocr Pathol. 2020;31(2): and hyperplasias: a paraffin immunohistochemical study. Mod
156-165. Pathol. 1999;12(4):412-416.
63. Arnold A, Staunton CE, Kim HG, Gaz RD, Kronenberg HM. 84. Ikeda S, Ishizaki Y, Shimizu Y, et al. Immunohistochemistry of
Monoclonality and abnormal parathyroid hormone genes in para­ cyclin D1 and beta-catenin, and mutational analysis of exon 3
thyroid adenomas. N Engl J Med. 1988;318(11):658-662. of beta-catenin gene in parathyroid adenomas. Int J Oncol.
64. Cetani F, Picone A, Cerrai P, et al. Parathyroid expression of 2002;20(3):463-466.
calcium-sensing receptor protein and in vivo parathyroid 85. Hsi ED, Zukerberg LR, Yang WI, Arnold A. Cyclin D1/PRAD1
hormone-Ca2+ set-point in patients with primary hyperparathyr­ expression in parathyroid adenomas: an immunohistochemical
oidism. J Clin Endocrinol Metab. 2000;85(12):4789-4794. study. J Clin Endocrinol Metab. 1996;81(5):1736-1739.
65. Insogna KL. Primary hyperparathyroidism. N Engl J Med. 86. Hemmer S, Wasenius VM, Haglund C, et al. Deletion of 11q23
2018;379(11):1050-1059. and cyclin D1 overexpression are frequent aberrations in parathy­
66. Newey PJ, Nesbit MA, Rimmer AJ, et al. Whole-exome sequen­ roid adenomas. Am J Pathol. 2001;158(4):1355-1362.
cing studies of nonhereditary (sporadic) parathyroid adenomas. 87. Tominaga Y, Tsuzuki T, Uchida K, et al. Expression of PRAD1/
J Clin Endocrinol Metab. 2012;97(10):E1995-E2005. cyclin D1, retinoblastoma gene products, and Ki67 in parathyroid
67. Hu Y, Zhang X, Wang O, et al. Integrated whole-exome and tran­ hyperplasia caused by chronic renal failure versus primary aden­
scriptome sequencing of sporadic parathyroid adenoma. Front oma. Kidney Int. 1999;55(4):1375-1383.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

Endocrinol (Lausanne). 2021;12(May 14):631680. 88. Yi Y, Nowak NJ, Pacchia AL, Morrison C. Chromosome 11 gen­
68. Cromer MK, Starker LF, Choi M, et al. Identification of somatic omic changes in parathyroid adenoma and hyperplasia: array
mutations in parathyroid tumors using whole-exome sequencing. CGH, FISH, and tissue microarrays. Genes Chromosomes
J Clin Endocrinol Metab. 2012;97(9):E1774-1781. Cancer. 2008;47(8):639-648.
69. Libutti SK, Crabtree JS, Lorang D, et al. Parathyroid gland- 89. Mallya SM, Gallagher JJ, Wild YK, et al. Abnormal parathyroid
specific deletion of the mouse Men1 gene results in parathyroid cell proliferation precedes biochemical abnormalities in a mouse
neoplasia and hypercalcemic hyperparathyroidism. Cancer Res. model of primary hyperparathyroidism. Mol Endocrinol.
2003;63(22):8022-8028. 2005;19(10):2603-2609.
70. Larsson C, Skogseid B, Oberg K, Nakamura Y, Nordenskjold M. 90. Imanishi Y, Hosokawa Y, Yoshimoto K, et al. Primary hyperpara­
Multiple endocrine neoplasia type 1 gene maps to chromosome 11 thyroidism caused by parathyroid-targeted overexpression of cyc­
and is lost in insulinoma. Nature. 1988;332(6159):85-87. lin D1 in transgenic mice. J Clin Invest. 2001;107(9):1093-1102.
71. Bystrom C, Larsson C, Blomberg C, et al. Localization of the 91. Polyak K, Lee MH, Erdjument-Bromage H, et al. Cloning of
MEN1 gene to a small region within chromosome 11q13 by dele­ p27Kip1, a cyclin-dependent kinase inhibitor and a potential me­
tion mapping in tumors. Proc Natl Acad Sci U S A. 1990;87(5): diator of extracellular antimitogenic signals. Cell. 1994;78(1):
1968-1972. 59-66.
72. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional 92. Hengst L, Reed SI. Translational control of p27Kip1 accumula­
cloning of the gene for multiple endocrine neoplasia-type 1. tion during the cell cycle. Science. 1996;271(5257):1861-1864.
Science. 1997;276(5311):404-407. 93. Morosetti R, Kawamata N, Gombart AF, et al. Alterations of the
73. Lemmens I, Van de Ven WJ, Kas K, et al. Identification of the mul­ p27KIP1 gene in non-Hodgkin’s lymphomas and adult T-cell leu­
tiple endocrine neoplasia type 1 (MEN1) gene. The European kemia/lymphoma. Blood. 1995;86(5):1924-1930.
Consortium on MEN1. Hum Mol Genet. 1997;6(7):1177-1183. 94. Spirin KS, Simpson JF, Takeuchi S, Kawamata N, Miller CW,
74. Alvelos MI, Vinagre J, Fonseca E, et al. MEN1 intragenic deletions Koeffler HP. p27/Kip1 mutation found in breast cancer. Cancer
may represent the most prevalent somatic event in sporadic pri­ Res. 1996;56(10):2400-2404.
mary hyperparathyroidism. Eur J Endocrinol. 2013;168(2): 95. Pappa V, Papageorgiou S, Papageorgiou E, et al. A novel p27 gene
119-128. mutation in a case of unclassified myeloproliferative disorder.
75. Brandi ML, Agarwal SK, Perrier ND, Lines KE, Valk GD, Leuk Res. 2005;29(2):229-231.
Thakker RV. Multiple endocrine neoplasia type 1: latest insights. 96. Dietrich S, Hullein J, Lee SC, et al. Recurrent CDKN1B (p27) mu­
Endocr Rev. 2020;42(2):133-170. tations in hairy cell leukemia. Blood. 2015;126(8):1005-1008.
76. Qiu H, Jin BM, Wang ZF, et al. MEN1 deficiency leads to neuro­ 97. Francis JM, Kiezun A, Ramos AH, et al. Somatic mutation of
endocrine differentiation of lung cancer and disrupts the DNA CDKN1B in small intestine neuroendocrine tumors. Nat Genet.
damage response. Nat Commun. 2020;11(1):1009. 2013;45(12):1483-1486.
77. Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T. 98. Crona J, Gustavsson T, Norlen O, et al. Somatic mutations and
Crystal structure of menin reveals binding site for mixed lineage genetic heterogeneity at the CDKN1B locus in small intestinal
leukemia (MLL) protein. J Biol Chem. 2011;286(36): neuroendocrine tumors. Ann Surg Oncol. 2015;22(Suppl 3):
31742-31748. S1428-1435.
78. Huang J, Gurung B, Wan B, et al. The same pocket in menin binds 99. Tahara H, Smith AP, Gaz RD, Zariwala M, Xiong Y, Arnold A.
both MLL and JUND but has opposite effects on transcription. Parathyroid tumor suppressor on 1p: analysis of the p18 cyclin-
Nature. 2012;482(7386):542-546. dependent kinase inhibitor gene as a candidate. J Bone Miner
79. Yokoyama A, Somervaille TC, Smith KS, Rozenblatt-Rosen O, Res. 1997;12(9):1330-1334.
Meyerson M, Cleary ML. The menin tumor suppressor protein 100. Costa-Guda J, Marinoni I, Molatore S, Pellegata NS, Arnold A.
is an essential oncogenic cofactor for MLL-associated leukemo­ Somatic mutation and germline sequence abnormalities in
genesis. Cell. 2005;123(2):207-218. CDKN1B, encoding p27Kip1, in sporadic parathyroid adenomas.
80. Arnold A, Kim HG, Gaz RD, et al. Molecular cloning and J Clin Endocrinol Metab. 2011;96(4):E701-E706.
chromosomal mapping of DNA rearranged with the parathyroid 101. Costa-Guda J, Soong CP, Parekh VI, Agarwal SK, Arnold A.
hormone gene in a parathyroid adenoma. J Clin Invest. Germline and somatic mutations in cyclin-dependent kinase in­
1989;83(6):2034-2040. hibitor genes CDKN1A, CDKN2B, and CDKN2C in sporadic
81. Motokura T, Bloom T, Kim HG, et al. A novel cyclin encoded by a parathyroid adenomas. Horm Cancer. 2013;4(5):301-307.
bcl1-linked candidate oncogene. Nature. 1991;350(6318): 102. Gluick T, Yuan Z, Libutti SK, Marx SJ. Mutations in CDKN2C
512-515. (p18) and CDKN2D (p19) may cause sporadic parathyroid aden­
82. Coleman ML, Marshall CJ. A family outing: small GTPases cyc­ oma. Endocr Relat Cancer. 2013;20(6):L27-L29.
lin’ through G1. Nat Cell Biol. 2001;3(11):E250-251. 103. Hughes CM, Rozenblatt-Rosen O, Milne TA, et al. Menin associ­
83. Vasef MA, Brynes RK, Sturm M, Bromley C, Robinson RA. ates with a trithorax family histone methyltransferase complex
Expression of cyclin D1 in parathyroid carcinomas, adenomas, and with the hoxc8 locus. Mol Cell. 2004;13(4):587-597.
Endocrine Reviews, 2023, Vol. 44, No. 5 807

104. Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic 123. Svedlund J, Auren M, Sundstrom M, et al. Aberrant WNT/beta-
islet growth by promoting histone methylation and expression catenin signaling in parathyroid carcinoma. Mol Cancer. 2010;9­
of genes encoding p27Kip1 and p18INK4c. Proc Natl Acad Sci (15):294.
U S A. 2005;102(41):14659-14664. 124. Pandya C, Uzilov AV, Bellizzi J, et al. Genomic profiling reveals
105. Borsari S, Pardi E, Pellegata NS, et al. Loss of p27 expression is as­ mutational landscape in parathyroid carcinomas. JCI Insight.
sociated with MEN1 gene mutations in sporadic parathyroid ad­ 2017;2(6):e92061.
enomas. Endocrine. 2017;55(2):386-397. 125. Duan R, Du W, Guo W. EZH2: a novel target for cancer treat­
106. Buchwald PC, Akerstrom G, Westin G. Reduced p18INK4c, ment. J Hematol Oncol. 2020;13(1):104.
p21CIP1/WAF1 and p27KIP1 mRNA levels in tumours of pri­ 126. Zhang Q, Han Q, Zi J, et al. Mutations in EZH2 are associated
mary and secondary hyperparathyroidism. Clin Endocrinol with poor prognosis for patients with myeloid neoplasms. Genes
(Oxf). 2004;60(3):389-393. Dis. 2019;6(3):276-281.
107. Arya AK, Bhadada SK, Singh P, et al. Promoter hypermethylation 127. Wei Z, Sun B, Wang ZP, et al. Whole-exome sequencing identifies
inactivates CDKN2A, CDKN2B and RASSF1A genes in sporadic novel recurrent somatic mutations in sporadic parathyroid aden­
parathyroid adenomas. Sci Rep. 2017;7(1):3123. omas. Endocrinology. 2018;159(8):3061-3068.
108. Starker LF, Svedlund J, Udelsman R, et al. The DNA methylome of 128. Romano R, Soong CP, Rose M, Costa-Guda J, Bellizzi J, Arnold

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

benign and malignant parathyroid tumors. Genes Chromosomes A. EZH2 copy number and mutational analyses in sporadic para­
Cancer. 2011;50(9):735-745. thyroid adenomas. Endocrine. 2017;55(3):985-988.
109. Starker LF, Fonseca AL, Akerström G, Björklund P, Westin G, 129. Yap DB, Chu J, Berg T, et al. Somatic mutations at EZH2 Y641
Carling T. Evidence of a stabilizing mutation of β-catenin encoded act dominantly through a mechanism of selectively altered PRC2
by CTNNB1 exon 3 in a large series of sporadic parathyroid aden­ catalytic activity, to increase H3K27 trimethylation. Blood.
omas. Endocrine. 2012;42(3):612-615. 2011;117(8):2451-2459.
110. Guarnieri V, Baorda F, Battista C, et al. A rare S33C mutation of 130. Wu T, Hua X. Menin represses tumorigenesis via repressing cell
CTNNB1 encoding β-catenin in a parathyroid adenoma found in proliferation. Am J Cancer Res. 2011;1(6):726-739.
an Italian primary hyperparathyroid cohort. Endocrine. 131. Cheng AS, Lau SS, Chen Y, et al. EZH2-mediated concordant re­
2012;41(1):152-155. pression of Wnt antagonists promotes beta-catenin-dependent
111. Bjorklund P, Akerstrom G, Westin G. Accumulation of nonphos­
hepatocarcinogenesis. Cancer Res. 2011;71(11):4028-4039.
phorylated beta-catenin and c-myc in primary and uremic second­ 132. Jung HY, Jun S, Lee M, et al. PAF and EZH2 induce Wnt/beta-
ary hyperparathyroid tumors. J Clin Endocrinol Metab.
catenin signaling hyperactivation. Mol Cell. 2013;52(2):193-205.
2007;92(1):338-344. 133. Jung CK, Kim Y, Jeon S, Jo K, Lee S, Bae JS. Clinical utility of
112. Bjorklund P, Lindberg D, Akerstrom G, Westin G. Stabilizing mu­
EZH1 mutations in the diagnosis of follicular-patterned thyroid
tation of CTNNB1/beta-catenin and protein accumulation ana­
tumors. Hum Pathol. 2018;81(November):9-17.
lyzed in a large series of parathyroid tumors of Swedish patients.
134. Nakagawa M, Kitabayashi I. Oncogenic roles of enhancer of zeste
Mol Cancer. 2008;7(June 9):53.
homolog 1/2 in hematological malignancies. Cancer Sci.
113. Cetani F, Pardi E, Banti C, et al. Beta-catenin activation is not in­
2018;109(8):2342-2348.
volved in sporadic parathyroid carcinomas and adenomas.
135. Galan-Caridad JM, Harel S, Arenzana TL, et al. Zfx controls the
Endocr Relat Cancer. 2010;17(1):1-6.
self-renewal of embryonic and hematopoietic stem cells. Cell.
114. Semba S, Kusumi R, Moriya T, Sasano H. Nuclear accumulation
2007;129(2):345-357.
of B-catenin in human endocrine tumors: association with Ki-67
136. Harel S, Tu EY, Weisberg S, et al. ZFX controls the self-renewal of
(MIB-1) proliferative activity. Endocr Pathol. 2000;11(3):
human embryonic stem cells. PLoS One. 2012;7(8):e42302.
243-250.
137. Ni W, Perez AA, Schreiner S, Nicolet CM, Farnham PJ.
115. Bjorklund P, Akerstrom G, Westin G. An LRP5 receptor with in­
Characterization of the ZFX family of transcription factors that
ternal deletion in hyperparathyroid tumors with implications for
bind downstream of the start site of CpG island promoters.
deregulated WNT/beta-catenin signaling. PLoS Med. 2007;4­
(11):e328. Nucleic Acids Res. 2020;48(11):5986-6000.
116. Juhlin CC, Kiss NB, Villablanca A, et al. Frequent promoter hy­ 138. Soong CP, Arnold A. Recurrent ZFX mutations in human sporad­
permethylation of the APC and RASSF1A tumour suppressors in ic parathyroid adenomas. Oncoscience. 2014;1(5):360-366.
parathyroid tumours. PLoS One. 2010;5(3):e9472. 139. Arnold A, Soong CP. New role for ZFX in oncogenesis. Cell Cycle.
117. Sulaiman L, Juhlin CC, Nilsson IL, Fotouhi O, Larsson C, 2014;13(22):3465-3466.
Hashemi J. Global and gene-specific promoter methylation ana­ 140. Forbes SA, Beare D, Boutselakis H, et al. COSMIC: somatic cancer
lysis in primary hyperparathyroidism. Epigenetics. 2013;8(6): genetics at high-resolution. Nucleic Acids Res. 2017;45(D1):
646-655. D777-D783.
118. Nilsson IL, Zedenius J, Yin L, Ekbom A. The association between 141. Yang F, Ma H, Feng L, et al. Zinc finger protein x-linked (ZFX)
primary hyperparathyroidism and malignancy: nationwide cohort contributes to patient prognosis, cell proliferation and apoptosis
analysis on cancer incidence after parathyroidectomy. Endocr in human laryngeal squamous cell carcinoma. Int J Clin Exp
Relat Cancer. 2007;14(1):135-140. Pathol. 2015;8(11):13886-13899.
119. Afreen S, Weinstein LS, Simonds WF, Jha S. Case of recurrent pri­ 142. Romano R, Ellis S, Yu N, et al. Mutational analysis of ZFY in
mary hyperparathyroidism, congenital granular cell tumor, and sporadic parathyroid adenomas. J Endocr Soc. 2017;1(4):
aggressive colorectal cancer. J Endocr Soc. 2022;6(8):bvac096. 313-316.
120. Andreasson A, Sulaiman L, do Vale S, et al. Molecular character­ 143. Mannstadt M, Holick E, Zhao W, Juppner H. Mutational analysis
ization of parathyroid tumors from two patients with hereditary of GCMB, a parathyroid-specific transcription factor, in parathy­
colorectal cancer syndromes. Fam Cancer. 2012;11(3):355-362. roid adenoma of primary hyperparathyroidism. J Endocrinol.
121. Juhlin CC, Haglund F, Villablanca A, et al. Loss of expression for 2011;210(2):165-171.
the Wnt pathway components adenomatous polyposis coli and 144. Guan B, Welch JM, Sapp JC, et al. GCM2-activating mutations in
glycogen synthase kinase 3-beta in parathyroid carcinomas. Int J familial isolated hyperparathyroidism. Am J Hum Genet.
Oncol. 2009;34(2):481-492. 2016;99(5):1034-1044.
122. Juhlin CC, Nilsson IL, Johansson K, et al. Parafibromin and APC 145. Hosoya T, Takizawa K, Nitta K. Hotta Y. glial cells missing: a bin­
as screening markers for malignant potential in atypical parathy­ ary switch between neuronal and glial determination in
roid adenomas. Endocr Pathol. 2010;21(3):166-177. Drosophila. Cell. 1995;82(6):1025-1036.
808 Endocrine Reviews, 2023, Vol. 44, No. 5

146. Jones BW, Fetter RD, Tear G. Goodman CS. glial cells missing: a and attenuates calcium-sensing receptor-mediated signaling. J
genetic switch that controls glial versus neuronal fate. Cell. Bone Miner Res. 2017;32(3):654-666.
1995;82(6):1013-1023. 166. Mingione A, Verdelli C, Ferrero S, et al. Filamin A is reduced and
147. Kammerer M, Pirola B, Giglio S, Giangrande A. GCMB, a second contributes to the CASR sensitivity in human parathyroid tumors.
human homolog of the fly glide/gcm gene. Cytogenet Cell Genet. J Mol Endocrinol. 2017;58(2):91-103.
1999;84(1-2):43-47. 167. Tavanti GS, Verdelli C, Morotti A, et al. Yes-associated protein 1
148. Akiyama Y, Hosoya T, Poole AM, Hotta Y. The gcm-motif: a nov­ is a novel calcium sensing receptor target in human parathyroid
el DNA-binding motif conserved in Drosophila and mammals. tumors. Int J Mol Sci. 2021;22(4):2016.
Proc Natl Acad Sci U S A. 1996;93(25):14912-14916. 168. Pardi E, Marcocci C, Borsari S, et al. Aryl hydrocarbon receptor
149. Altshuller Y, Copeland NG, Gilbert DJ, Jenkins NA, Frohman interacting protein (AIP) mutations occur rarely in sporadic para­
MA. Gcm1, a mammalian homolog of Drosophila glial cells miss­ thyroid adenomas. J Clin Endocrinol Metab. 2013;98(7):
ing. FEBS Lett. 1996;393(2-3):201-204. 2800-2810.
150. Kim J, Jones BW, Zock C, et al. Isolation and characterization of 169. Pausova Z, Soliman E, Amizuka N, et al. Role of the RET proto-
mammalian homologs of the Drosophila gene glial cells missing. oncogene in sporadic hyperparathyroidism and in hyperparathyr­
Proc Natl Acad Sci U S A. 1998;95(21):12364-12369. oidism of multiple endocrine neoplasia type 2. J Clin Endocrinol
151. Kanemura Y, Hiraga S, Arita N, et al. Isolation and expression

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

Metab. 1996;81(7):2711-2718.
analysis of a novel human homologue of the Drosophila glial cells 170. Willeke F, Hauer MP, Buchcik R, et al. Multiple endocrine neopla­
missing (gcm) gene. FEBS Lett. 1999;442(2-3):151-156. sia type 2-associated RET proto-oncogene mutations do not con­
152. Gunther T, Chen ZF, Kim J, et al. Genetic ablation of parathyroid tribute to the pathogenesis of sporadic parathyroid tumors.
glands reveals another source of parathyroid hormone. Nature. Surgery. 1998;124(3):484-490.
2000;406(6792):199-203. 171. Howell VM, Haven CJ, Kahnoski K, et al. HRPT2 mutations are
153. Kebebew E, Peng M, Wong MG, Ginzinger D, Duh QY, Clark associated with malignancy in sporadic parathyroid tumours. J
OH. GCMB gene, a master regulator of parathyroid gland devel­ Med Genet. 2003;40(9):657-663.
opment, expression, and regulation in hyperparathyroidism. 172. Krebs LJ, Shattuck TM, Arnold A. HRPT2 mutational analysis of
Surgery. 2004;136(6):1261-1266. typical sporadic parathyroid adenomas. J Clin Endocrinol Metab.
154. Canaff L, Guarnieri V, Kim Y, et al. Novel glial cells missing-2 2005;90(9):5015-5017.
(GCM2) variants in parathyroid disorders. Eur J Endocrinol. 173. Riccardi A, Lemos C, Ramos R, et al. PIK3CA mutational analysis
2022;186(3):351-366. of parathyroid adenomas. JBMR Plus. 2020;4(6):e10360.
155. Varshney S, Bhadada SK, Saikia UN, et al. Simultaneous expres­ 174. Onoda N, Ogisawa K, Ishikawa T, et al. Telomerase activation
sion analysis of vitamin D receptor, calcium-sensing receptor, cyc­ and expression of its catalytic subunits in benign and malignant
lin D1, and PTH in symptomatic primary hyperparathyroidism in tumors of the parathyroid. Surg Today. 2004;34(5):389-393.
Asian Indians. Eur J Endocrinol. 2013;169(1):109-116. 175. Osawa N, Onoda N, Kawajiri H, et al. Diagnosis of parathyroid
156. Corbetta S, Mantovani G, Lania A, et al. Calcium-sensing receptor carcinoma using immunohistochemical staining against hTERT.
expression and signalling in human parathyroid adenomas and Int J Mol Med. 2009;24(6):733-741.
primary hyperplasia. Clin Endocrinol (Oxf). 2000;52(3): 176. Haglund F, Juhlin CC, Brown T, et al. TERT promoter mutations
339-348. are rare in parathyroid tumors. Endocr Relat Cancer. 2015;22(3):
157. Gogusev J, Duchambon P, Hory B, et al. Depressed expression of L9-l11.
calcium receptor in parathyroid gland tissue of patients with 177. Tseng RC, Lee CC, Hsu HS, Tzao C, Wang YC. Distinct
hyperparathyroidism. Kidney Int. 1997;51(1):328-336. HIC1-SIRT1-p53 loop deregulation in lung squamous carcinoma
158. Kifor O, Moore FD Jr, Wang P, et al. Reduced immunostaining for and adenocarcinoma patients. Neoplasia. 2009;11(8):763-770.
the extracellular Ca2+-sensing receptor in primary and uremic sec­ 178. Carter MG, Johns MA, Zeng X, et al. Mice deficient in the candi­
ondary hyperparathyroidism. J Clin Endocrinol Metab. date tumor suppressor gene Hic1 exhibit developmental defects of
1996;81(4):1598-1606. structures affected in the Miller-Dieker syndrome. Hum Mol
159. Farnebo F, Enberg U, Grimelius L, et al. Tumor-specific decreased Genet. 2000;9(3):413-419.
expression of calcium sensing receptor messenger ribonucleic acid 179. Chen WY, Zeng X, Carter MG, et al. Heterozygous disruption of
in sporadic primary hyperparathyroidism. J Clin Endocrinol Hic1 predisposes mice to a gender-dependent spectrum of malig­
Metab. 1997;82(10):3481-3486. nant tumors. Nat Genet. 2003;33(2):197-202.
160. Farnebo F, Hoog A, Sandelin K, Larsson C, Farnebo LO. 180. Svedlund J, Koskinen Edblom S, Marquez VE, Åkerström G,
Decreased expression of calcium-sensing receptor messenger ribo­ Björklund P, Westin G. Hypermethylated in cancer 1 (HIC1), a tu­
nucleic acids in parathyroid adenomas. Surgery. 1998;124(6): mor suppressor gene epigenetically deregulated in hyperparathyr­
1094-1098. discussion 1098-1099. oid tumors by histone H3 lysine modification. J Clin Endocrinol
161. Samander EH, Arnold A. Mutational analysis of the vitamin D re­ Metab. 2012;97(7):E1307-1315.
ceptor does not support its candidacy as a tumor suppressor gene 181. Micol JB, Abdel-Wahab O. The role of additional sex combs-like
in parathyroid adenomas. J Clin Endocrinol Metab. 2006;91(12): proteins in cancer. Cold Spring Harb Perspect Med. 2016;6(10):
5019-5021. a026526.
162. Cetani F, Pinchera A, Pardi E, et al. No evidence for mutations in 182. Cui G, Wang C, Lin Z, et al. Prognostic and immunological role of
the calcium-sensing receptor gene in sporadic parathyroid aden­ Ras-related protein Rap1b in pan-cancer. Bioengineered.
omas. J Bone Miner Res. 1999;14(6):878-882. 2021;12(1):4828-4840.
163. Singh P, Bhadada SK, Dahiya D, et al. Reduced calcium sensing re­ 183. Verdelli C, Morotti A, Tavanti GS, et al. The core stem genes
ceptor (CaSR) expression is epigenetically deregulated in parathy­ SOX2, POU5F1/OCT4, and NANOG are expressed in human
roid adenomas. J Clin Endocrinol Metab. 2020;105(9): parathyroid tumors and modulated by MEN1, YAP1, and
3015-3024. β-catenin pathways activation. Biomedicines. 2021;9(6):637.
164. Koh J, Dar M, Untch BR, et al. Regulator of G protein signaling 5 184. Shen HC, Rosen JE, Yang LM, et al. Parathyroid tumor develop­
is highly expressed in parathyroid tumors and inhibits signaling by ment involves deregulation of homeobox genes. Endocr Relat
the calcium-sensing receptor. Mol Endocrinol. 2011;25(5): Cancer. 2008;15(1):267-275.
867-876. 185. Verdelli C, Avagliano L, Guarnieri V, et al. Expression, function,
165. Balenga N, Azimzadeh P, Hogue JA, et al. Orphan adhesion and regulation of the embryonic transcription factor TBX1 in
GPCR GPR64/ADGRG2 is overexpressed in parathyroid tumors parathyroid tumors. Lab Invest. 2017;97(12):1488-1499.
Endocrine Reviews, 2023, Vol. 44, No. 5 809

186. Vaira V, Elli F, Forno I, et al. The microRNA cluster C19MC is population-based study in The Netherlands estimating the pre­
deregulated in parathyroid tumours. J Mol Endocrinol. operative diagnosis. Am J Surg. 2011;202(5):590-597.
2012;49(2):115-124. 210. Fingeret AL. Contemporary evaluation and management of para­
187. Silva-Figueroa AM, Perrier ND. Epigenetic processes in sporadic thyroid carcinoma. JCO Oncol Pract. 2021;17(1):17-21.
parathyroid neoplasms. Mol Cell Endocrinol. 2018;469:54-59. 211. Sulaiman L, Haglund F, Hashemi J, et al. Genome-wide and locus
188. Verdelli C, Forno I, Vaira V, Corbetta S. Epigenetic alterations in specific alterations in CDC73/HRPT2-mutated parathyroid tu­
human parathyroid tumors. Endocrine. 2015;49(2):324-332. mors. PLoS One. 2012;7(9):e46325.
189. Verdelli C, Forno I, Morotti A, et al. The aberrantly expressed 212. Zhao J, Hu Y, Liao Q, et al. Gene identification of potential ma­
miR-372 partly impairs sensitivity to apoptosis in parathyroid tu­ lignant parathyroid tumors phenotype in Chinese population.
mor cells. Endocr Relat Cancer. 2018;25(7):761-771. Endocr J. 2014;61(6):597-605.
190. Vaira V, Verdelli C, Forno I, Corbetta S. MicroRNAs in parathy­ 213. Corbetta S, Vaira V, Guarnieri V, et al. Differential expression of
roid physiopathology. Mol Cell Endocrinol. 2017;456:9-15. microRNAs in human parathyroid carcinomas compared with
191. Guarnieri V, Muscarella LA, Verdelli C, Corbetta S. Alterations of normal parathyroid tissue. Endocr Relat Cancer. 2010;17(1):
DNA methylation in parathyroid tumors. Mol Cell Endocrinol. 135-146.
2018;469:60-69. 214. Rahbari R, Holloway AK, He M, Khanafshar E, Clark OH,
192. Quervain F. Parastruma maligna aberrata. Deutsche Zeitschrift Kebebew E. Identification of differentially expressed microRNA

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

fur Chirurgie. 1909;100(1):334-353. in parathyroid tumors. Ann Surg Oncol. 2011;18(4):1158-1165.
193. Lee PK, Jarosek SL, Virnig BA, Evasovich M, Tuttle TM. Trends 215. Hu Y, Zhang X, Cui M, et al. Verification of candidate microRNA
in the incidence and treatment of parathyroid cancer in the United markers for parathyroid carcinoma. Endocrine. 2018;60(2):
States. Cancer. 2007;109(9):1736-1741. 246-254.
194. Busaidy NL, Jimenez C, Habra MA, et al. Parathyroid carcinoma: 216. Hu Y, Zhang X, Cui M, et al. Circular RNA profile of parathyroid
a 22-year experience. Head Neck. 2004;26(8):716-726. neoplasms: analysis of co-expression networks of circular RNAs
195. Hakaim AG, Esselstyn CB Jr. Parathyroid carcinoma: 50-year ex­ and mRNAs. RNA Biol. 2019;16(9):1228-1236.
perience at the Cleveland Clinic Foundation. Cleve Clin J Med. 217. Jiang T, Wei BJ, Zhang DX, et al. Genome-wide analysis of differ­
1993;60(4):331-335. entially expressed lncRNA in sporadic parathyroid tumors.
196. Iihara M, Okamoto T, Suzuki R, et al. Functional parathyroid car­ Osteoporos Int. 2019;30(7):1511-1519.
cinoma: long-term treatment outcome and risk factor analysis. 218. Zhang X, Hu Y, Wang M, et al. Profiling analysis of long non-
Surgery. 2007;142(6):936-943. coding RNA and mRNA in parathyroid carcinoma. Endocr
197. Harari A, Waring A, Fernandez-Ranvier G, et al. Parathyroid car­ Relat Cancer. 2019;26(2):163-176.
cinoma: a 43-year outcome and survival analysis. J Clin 219. Wang J, Wang Q, Zhao T, et al. Expression profile of serum-
Endocrinol Metab. 2011;96(12):3679-3686. related exosomal miRNAs from parathyroid tumor. Endocrine.
198. Kebebew E, Arici C, Duh QY, Clark OH. Localization and reop­ 2021;72(1):239-248.
eration results for persistent and recurrent parathyroid carcinoma. 220. Kruijff S, Sidhu SB, Sywak MS, Gill AJ, Delbridge LW. Negative
Arch Surg. 2001;136(8):878-885. parafibromin staining predicts malignant behavior in atypical
199. Perrier ND, Arnold A, Costa-Guda J, et al. Hereditary endocrine parathyroid adenomas. Ann Surg Oncol. 2014;21(2):426-433.
tumours: current state-of-the-art and research opportunities: 221. Cetani F, Ambrogini E, Viacava P, et al. Should parafibromin
new and future perspectives for parathyroid carcinoma. Endocr staining replace HRTP2 gene analysis as an additional tool for
Relat Cancer. 2020;27(8):T53-T63. histologic diagnosis of parathyroid carcinoma? Eur J
200. Kleinpeter KP, Lovato JF, Clark PB, et al. Is parathyroid carcin­ Endocrinol. 2007;156(5):547-554.
oma indeed a lethal disease? Ann Surg Oncol. 2005;12(3): 222. Juhlin CC, Nilsson IL, Lagerstedt-Robinson K, et al. Parafibromin
260-266. immunostainings of parathyroid tumors in clinical routine: a near-
201. DeLellis RA, Arnold A, Bilezikian J, et al. Parathyroid carcinoma. decade experience from a tertiary center. Mod Pathol. 2019;32(8):
In: Lloyd RV, Osamura RY, Klöppel G, Rosai J, eds. WHO 1082-1094.
Classification of Tumours of Endocrine Organs. 4th ed. Lyon: 223. Fernandez-Ranvier GG, Khanafshar E, Tacha D, et al. Defining a
IARC Publications, 2017:147-152. molecular phenotype for benign and malignant parathyroid tu­
202. Sandelin K, Auer G, Bondeson L, Grimelius L, Farnebo LO. mors. Cancer. 2009;115(2):334-344.
Prognostic factors in parathyroid cancer: a review of 95 cases. 224. Howell VM, Gill A, Clarkson A, et al. Accuracy of combined pro­
World J Surg. 1992;16(4):724-731. tein gene product 9.5 and parafibromin markers for immunohisto­
203. Williams MD, DeLellis RA, Erickson LA, et al. Pathology chemical diagnosis of parathyroid carcinoma. J Clin Endocrinol
data set for reporting parathyroid carcinoma and atypical para­ Metab. 2009;94(2):434-441.
thyroid neoplasm: recommendations from the International 225. Guarnieri V, Battista C, Muscarella LA, et al. CDC73 mutations
Collaboration on Cancer Reporting. Hum Pathol. 2021; and parafibromin immunohistochemistry in parathyroid tumors:
110(April):73-82. clinical correlations in a single-centre patient cohort. Cell Oncol
204. Levin KE, Galante M, Clark OH. Parathyroid carcinoma versus (Dordr). 2012;35(6):411-422.
parathyroid adenoma in patients with profound hypercalcemia. 226. Wang O, Wang C, Nie M, et al. Novel HRPT2/CDC73 gene mu­
Surgery. 1987;101(6):649-660. tations and loss of expression of parafibromin in Chinese patients
205. Saponaro F, Pardi E, Mazoni L, et al. Do patients with atypical with clinically sporadic parathyroid carcinomas. PLoS One.
parathyroid adenoma need a close follow-up? J Clin Endocrinol 2012;7(9):e45567.
Metab. 2021;106(11):e4565-e4579. 227. Hu Y, Liao Q, Cao S, Gao X, Zhao Y. Diagnostic performance of
206. Christakis I, Bussaidy N, Clarke C, et al. Differentiating atypical parafibromin immunohistochemical staining for sporadic para­
parathyroid neoplasm from parathyroid cancer. Ann Surg thyroid carcinoma: a meta-analysis. Endocrine. 2016;54(3):
Oncol. 2016;23(9):2889-2897. 612-619.
207. Ryhänen EM, Leijon H, Metso S, et al. A nationwide study on 228. Ozolins A, Narbuts Z, Vanags A, et al. Evaluation of malignant
parathyroid carcinoma. Acta Oncol. 2017;56(7):991-1003. parathyroid tumours in two European cohorts of patients with
208. Wynne AG, van Heerden J, Carney JA, Fitzpatrick LA. sporadic primary hyperparathyroidism. Langenbecks Arch Surg.
Parathyroid carcinoma: clinical and pathologic features in 43 pa­ 2016;401(7):943-951.
tients. Medicine (Baltimore). 1992;71(4):197-205. 229. Karaarslan S, Yurum FN, Kumbaraci BS, et al. The role of parafi­
209. Schaapveld M, Jorna FH, Aben KK, Haak HR, Plukker JT, Links bromin, galectin-3, HBME-1, and Ki-67 in the differential diagno­
TP. Incidence and prognosis of parathyroid gland carcinoma: a sis of parathyroid tumors. Oman Med J. 2015;30(6):421-427.
810 Endocrine Reviews, 2023, Vol. 44, No. 5

230. Truran PP, Johnson SJ, Bliss RD, Lennard TW, Aspinall SR. 250. Haven CJ, Howell VM, Eilers PH, et al. Gene expression of para­
Parafibromin, galectin-3, PGP9.5, Ki67, and cyclin D1: using an thyroid tumors: molecular subclassification and identification of
immunohistochemical panel to aid in the diagnosis of parathyroid the potential malignant phenotype. Cancer Res. 2004;64(20):
cancer. World J Surg. 2014;38(11):2845-2854. 7405-7411.
231. Kumari N, Chaudhary N, Pradhan R, Agarwal A, Krishnani N. 251. Hundahl SA, Fleming ID, Fremgen AM, Menck HR. Two hundred
Role of histological criteria and immunohistochemical markers eighty-six cases of parathyroid carcinoma treated in the U.S. be­
in predicting risk of malignancy in parathyroid neoplasms. tween 1985-1995: a National Cancer Data Base Report. The
Endocr Pathol. 2016;27(2):87-96. American College of Surgeons Commission on Cancer and the
232. Kim HK, Oh YL, Kim SH, et al. Parafibromin immunohistochem­ American Cancer Society. Cancer. 1999;86(3):538-544.
ical staining to differentiate parathyroid carcinoma from parathy­ 252. Asare EA, Silva-Figueroa A, Hess KR, et al. Risk of distant metas­
roid adenoma. Head Neck. 2012;34(2):201-206. tasis in parathyroid carcinoma and its effect on survival: a retro­
233. Cetani F, Banti C, Pardi E, et al. CDC73 mutational status and loss spective review from a high-volume center. Ann Surg Oncol.
of parafibromin in the outcome of parathyroid cancer. Endocr 2019;26(11):3593-3599.
Connect. 2013;2(4):186-195. 253. Piciu D, Irimie A, Kontogeorgos G, Piciu A, Buiga R. Highly ag­
234. Bergero N, De Pompa R, Sacerdote C, et al. Galectin-3 expression gressive pathology of non-functional parathyroid carcinoma.
in parathyroid carcinoma: immunohistochemical study of 26 Orphanet J Rare Dis. 2013;8:115.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

cases. Hum Pathol. 2005;36(8):908-914. 254. Posada-González M, Gómez-Ramírez J, Luque-Ramírez M, et al.
235. Stojadinovic A, Hoos A, Nissan A, et al. Parathyroid neoplasms: Nonfunctional metastatic parathyroid carcinoma in the setting of
clinical, histopathological, and tissue microarray-based molecular multiple endocrine neoplasia type 2A syndrome. Surg Res Pract.
analysis. Hum Pathol. 2003;34(1):54-64. 2014;2014:731481.
236. Szijan I, Orlow I, Dalamon V, et al. Alterations in the retinoblast­ 255. Wilkins BJ, Lewis JS Jr. Non-functional parathyroid carcinoma: a
oma pathway of cell cycle control in parathyroid tumors. Oncol review of the literature and report of a case requiring extensive
Rep. 2000;7(2):421-425. surgery. Head Neck Pathol. 2009;3(2):140-149.
237. Sungu N, Dogan HT, Kiliçarslan A, et al. Role of calcium-sensing 256. Sarquis M, Marx SJ, Beckers A, et al. Long-term remission of dis­
receptor, Galectin-3, Cyclin D1, and Ki-67 immunohistochemis­ seminated parathyroid cancer following immunotherapy.
try to favor in the diagnosis of parathyroid carcinoma. Indian J Endocrine. 2020;67(1):204-208.
Pathol Microbiol. 2018;61(1):22-26. 257. Park D, Airi R, Sherman M. Microsatellite instability driven meta­
238. Agarwal A, Pradhan R, Kumari N, et al. Molecular characteristics static parathyroid carcinoma managed with the anti-PD1 im­
of large parathyroid adenomas. World J Surg. 2016;40(3): munotherapy, pembrolizumab. BMJ case Rep. 2020;13(9):
607-614. e235293.
239. Witteveen JE, Hamdy NA, Dekkers OM, et al. Downregulation of 258. Rozhinskaya L, Pigarova E, Sabanova E, et al. Diagnosis and
CASR expression and global loss of parafibromin staining are treatment challenges of parathyroid carcinoma in a 27-year-old
strong negative determinants of prognosis in parathyroid carcin­ woman with multiple lung metastases. Endocrinol Diabetes
oma. Mod Pathol. 2011;24(5):688-697. Metab Case Rep. 2017;2017:16-0113.
240. Cryns VL, Thor A, Xu HJ, et al. Loss of the retinoblastoma tumor- 259. Cetani F, Pardi E, Borsari S, et al. Genetic analyses of the HRPT2
suppressor gene in parathyroid carcinoma. N Engl J Med. gene in primary hyperparathyroidism: germline and somatic mu­
1994;330(11):757-761. tations in familial and sporadic parathyroid tumors. J Clin
241. Árvai K, Nagy K, Barti-Juhász H, et al. Molecular profiling of Endocrinol Metab. 2004;89(11):5583-5591.
parathyroid hyperplasia, adenoma and carcinoma. Pathol Oncol 260. Shattuck TM, Valimaki S, Obara T, et al. Somatic and germ-line
Res. 2012;18(3):607-614. mutations of the HRPT2 gene in sporadic parathyroid carcinoma.
242. Fendrich V, Waldmann J, Feldmann G, et al. Unique expression N Engl J Med. 2003;349(18):1722-1729.
pattern of the EMT markers Snail, Twist and E-cadherin in benign 261. Hu Y, Zhang X, Wang O, et al. The genomic profile of parathy­
and malignant parathyroid neoplasia. Eur J Endocrinol. roid carcinoma based on whole-genome sequencing. Int J
2009;160(4):695-703. Cancer. 2020;147(9):2446-2457.
243. Schneider R, Bartsch-Herzog S, Ramaswamy A, Bartsch DK, 262. Walls GV, Stevenson M, Lines KE, et al. Mice deleted for cell div­
Karakas E. Immunohistochemical expression of E-Cadherin in ision cycle 73 gene develop parathyroid and uterine tumours:
atypical parathyroid adenoma. World J Surg. 2015;39(10): model for the hyperparathyroidism-jaw tumour syndrome.
2477-2483. Oncogene. 2017;36(28):4025-4036.
244. Pollack R, Kagan M, Dresner-Pollak R, Neuman T. Pd-L1 expres­ 263. Hahn MA, Marsh DJ. Identification of a functional bipartite nu­
sion in normal endocrine tissues is not increased despite high inci­ clear localization signal in the tumor suppressor parafibromin.
dence of Pd-1 inhibitor-associated endocrinopathies. Endocr Oncogene. 2005;24(41):6241-6248.
Pract. 2021;27(1):34-37. 264. Bradley KJ, Bowl MR, Williams SE, et al. Parafibromin is a nuclear
245. Pan B, Wang A, Pang J, et al. Programmed death ligand 1 (PD-L1) protein with a functional monopartite nuclear localization signal.
expression in parathyroid tumors. Endocr Connect. 2019;8(7): Oncogene. 2007;26(8):1213-1221.
887-897. 265. Panicker LM, Zhang JH, Dagur PK, Gastinger MJ, Simonds WF.
246. Du X, Wang L, Shen B, He H, Chang H, Wei B. Clinical signifi­ Defective nucleolar localization and dominant interfering proper­
cance of Pd-L1 expression in parathyroid cancer. Acta ties of a parafibromin L95P missense mutant causing the
Endocrinol (Buchar). 2016;12(4):383-386. hyperparathyroidism-jaw tumor syndrome. Endocr Relat
247. Silva-Figueroa A, Villalobos P Jr, Williams MD, et al. Cancer. 2010;17(2):513-524.
Characterizing parathyroid carcinomas and atypical neoplasms 266. Rozenblatt-Rosen O, Hughes CM, Nannepaga SJ, et al. The par­
based on the expression of programmed death-ligand 1 expression afibromin tumor suppressor protein is part of a human Paf1 com­
and the presence of tumor-infiltrating lymphocytes and macro­ plex. Mol Cell Biol. 2005;25(2):612-620.
phages. Surgery. 2018;164(5):960-964. 267. Yart A, Gstaiger M, Wirbelauer C, et al. The HRPT2 tumor sup­
248. Condello V, Cetani F, Denaro M, et al. Gene expression profile in pressor gene product parafibromin associates with human PAF1
metastatic and non-metastatic parathyroid carcinoma. Endocr and RNA polymerase II. Mol Cell Biol. 2005;25(12):5052-5060.
Relat Cancer. 2021;28(2):111-134. 268. Newey PJ, Bowl MR, Cranston T, Thakker RV. Cell division cycle
249. Costa-Guda J, Imanishi Y, Palanisamy N, et al. Allelic imbalance protein 73 homolog (CDC73) mutations in the
in sporadic parathyroid carcinoma and evidence for its de novo hyperparathyroidism-jaw tumor syndrome (HPT-JT) and para­
origins. Endocrine. 2013;44(2):489-495. thyroid tumors. Human mutation. 2010;31(3):295-307.
Endocrine Reviews, 2023, Vol. 44, No. 5 811

269. Sun W, Kuang XL, Liu YP, Tian LF, Yan XX, Xu W. Crystal struc­ parathyroid tumorigenesis-The Y282D variant of the GCM2
ture of the N-terminal domain of human CDC73 and its implica­ gene. Biomed Pharmacother. 2017;92:843-848.
tions for the hyperparathyroidism-jaw tumor (HPT-JT) 289. Hakim JP, Levine MA. Absence of p53 point mutations in para­
syndrome. Sci Rep. 2017;7(1):15638. thyroid adenoma and carcinoma. J Clin Endocrinol Metab.
270. Amrich CG, Davis CP, Rogal WP, et al. Cdc73 subunit of Paf1 1994;78(1):103-106.
complex contains C-terminal Ras-like domain that promotes asso­ 290. Kishikawa S, Shan L, Ogihara K, et al. Overexpression and genetic
ciation of Paf1 complex with chromatin. J Biol Chem. 2012;287­ abnormality of p53 in parathyroid adenomas. Pathol Int.
(14):10863-10875. 1999;49(10):853-857.
271. Chen H, Shi N, Gao Y, Li X, Teng M, Niu L. Crystallographic 291. Yu W, McPherson JR, Stevenson M, et al. Whole-exome sequen­
analysis of the conserved C-terminal domain of transcription fac­ cing studies of parathyroid carcinomas reveal novel PRUNE2 mu­
tor Cdc73 from Saccharomyces cerevisiae reveals a GTPase-like tations, distinctive mutational spectra related to
fold. Acta Crystallogr D Biol Crystallogr. 2012;68(Pt 8):953-959. APOBEC-catalyzed DNA mutagenesis and mutational enrich­
272. Iwata T, Mizusawa N, Taketani Y, Itakura M, Yoshimoto K. ment in kinases associated with cell migration and invasion. J
Parafibromin tumor suppressor enhances cell growth in the cells Clin Endocrinol Metab. 2015;100(2):E360-364.
expressing SV40 large T antigen. Oncogene. 2007;26(42): 292. Barazeghi E, Gill AJ, Sidhu S, et al. A role for TET2 in parathyroid
6176-6183. carcinoma. Endocr Relat Cancer. 2017;24(7):329-338.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

273. Mosimann C, Hausmann G, Basler K. Parafibromin/Hyrax acti­ 293. Sanpaolo E, Miroballo M, Corbetta S, et al. EZH2 and ZFX on­
vates Wnt/Wg target gene transcription by direct association cogenes in malignant behaviour of parathyroid neoplasms.
with beta-catenin/armadillo. Cell. 2006;125(2):327-341. Endocrine. 2016;54(1):55-59.
274. Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N, et al. 294. Giusti L, Cetani F, Da Valle Y, et al. First evidence of TRPV5 and
Dephosphorylated parafibromin is a transcriptional coactivator TRPV6 channels in human parathyroid glands: possible involve­
of the Wnt/Hedgehog/Notch pathways. Nat Commun. 2016;7: ment in neoplastic transformation. J Cell Mol Med. 2014;18­
12887. (10):1944-1952.
275. Takahashi A, Tsutsumi R, Kikuchi I, et al. SHP2 tyrosine phos­ 295. Svedlund J, Barazeghi E, Stalberg P, et al. The histone methyltrans­
phatase converts parafibromin/Cdc73 from a tumor suppressor ferase EZH2, an oncogene common to benign and malignant
to an oncogenic driver. Mol Cell. 2011;43(1):45-56. parathyroid tumors. Endocr Relat Cancer. 2014;21(2):231-239.
276. Song A, Yang Y, Liu S, et al. Prevalence of parathyroid carcinoma 296. Dotzenrath C, Teh BT, Farnebo F, et al. Allelic loss of the retino­
and atypical parathyroid neoplasms in 153 patients with multiple blastoma tumor suppressor gene: a marker for aggressive parathy­
endocrine neoplasia type 1: case series and literature review. Front roid tumors? J Clin Endocrinol Metab. 1996;81(9):3194-3196.
Endocrinol (Lausanne). 2020;11:557050. 297. Pearce SH, Trump D, Wooding C, Sheppard MN, Clayton RN,
277. Shih RY, Fackler S, Maturo S, True MW, Brennan J, Wells D. Thakker RV. Loss of heterozygosity studies at the retinoblastoma
Parathyroid carcinoma in multiple endocrine neoplasia type 1 and breast cancer susceptibility (BRCA2) loci in pituitary, para­
with a classic germline mutation. Endocr Pract. 2009;15(6): thyroid, pancreatic and carcinoid tumours. Clin Endocrinol
567-572. (Oxf). 1996;45(2):195-200.
278. Kang H, Pettinga D, Schubert AD, et al. Genomic profiling of 298. Shattuck TM, Kim TS, Costa J, et al. Mutational analyses of RB
parathyroid carcinoma reveals genomic alterations suggesting and BRCA2 as candidate tumour suppressor genes in parathyroid
benefit from therapy. Oncologist. 2019;24(6):791-797. carcinoma. Clin Endocrinol (Oxf). 2003;59(2):180-189.
279. Haven CJ, van Puijenbroek M, Tan MH, et al. Identification of 299. Mitsui K, Nakajima D, Ohara O, Nakayama M. Mammalian fat3:
MEN1 and HRPT2 somatic mutations in paraffin-embedded a large protein that contains multiple cadherin and EGF-like mo­
(sporadic) parathyroid carcinomas. Clin Endocrinol (Oxf). tifs. Biochem Biophys Res Commun. 2002;290(4):1260-1266.
2007;67(3):370-376. 300. Katoh M. Function and cancer genomics of FAT family genes (re­
280. del Pozo C, Garcia-Pascual L, Balsells M, et al. Parathyroid carcin­ view). Int J Oncol. 2012;41(6):1913-1918.
oma in multiple endocrine neoplasia type 1. Case report and re­ 301. Rohrbeck A, Borlak J. Cancer genomics identifies regulatory gene
view of the literature. Hormones (Athens). 2011;10(4):326-331. networks associated with the transition from dysplasia to ad­
281. Singh Ospina N, Sebo TJ, Thompson GB, Clarke BL, Young WF vanced lung adenocarcinomas induced by c-Raf-1. PLoS One.
Jr. Prevalence of parathyroid carcinoma in 348 patients with mul­ 2009;4(10):e7315.
tiple endocrine neoplasia type 1—case report and review of the lit­ 302. Marini F, Giusti F, Palmini G, Perigli G, Santoro R, Brandi ML.
erature. Clin Endocrinol (Oxf). 2016;84(2):244-249. Genetics and epigenetics of parathyroid carcinoma. Front
282. Cardoso L, Stevenson M, Thakker RV. Molecular genetics of syn­ Endocrinol (Lausanne). 2022;13:834362.
dromic and non-syndromic forms of parathyroid carcinoma. 303. Reddick RL, Costa JC, Marx SJ. Parathyroid hyperplasia and par­
Human mutation. 2017;38(12):1621-1648. athyromatosis. Lancet. 1977;1(8010):549.
283. Cui M, Hu Y, Bi Y, et al. Preliminary exploration of potential mo­ 304. Nakamura M, Tanaka K, Fujii T. Hyperparathyroidism caused by
lecular therapeutic targets in recurrent and metastatic parathyroid distant pulmonary lesions and parathyromatosis after ethanol in­
carcinomas. Int J Cancer. 2019;144(3):525-532. jection/parathyroidectomy for secondary hyperparathyroidism.
284. Kutahyalioglu M, Nguyen HT, Kwatampora L, et al. Genetic pro­ Hemodial Int. 2017;21(3):E45-E49.
filing as a clinical tool in advanced parathyroid carcinoma. J 305. Twigt BA, van Dalen T, Vroonhoven TJ, Consten EC. Recurrent
Cancer Res Clin Oncol. 2019;145(8):1977-1986. hyperparathyroidism caused by benign neoplastic seeding: two
285. Kasaian K, Wiseman SM, Thiessen N, et al. Complete genomic cases of parathyromatosis and a review of the literature. Acta
landscape of a recurring sporadic parathyroid carcinoma. J Chir Belg. 2013;113(3):228-232.
Pathol. 2013;230(3):249-260. 306. Matsuoka S, Tominaga Y, Sato T, et al. Recurrent renal hyper­
286. Clarke CN, Katsonis P, Hsu TK, et al. Comprehensive genomic parathyroidism caused by parathyromatosis. World J Surg.
characterization of parathyroid cancer identifies novel candidate 2007;31(2):299-305.
driver mutations and core pathways. J Endocr Soc. 2019;3(3): 307. Pinnamaneni N, Shankar PR, Muthukrishnan A. (99 m)Tc MIBI
544-559. SPECT findings in parathyromatosis-a rare entity causing recur­
287. Zhao L, Sun LH, Liu DM, et al. Copy number variation in rent hyperparathyroidism. Clin Nucl Med. 2013;38(11):
CCND1 gene is implicated in the pathogenesis of sporadic para­ e443-445.
thyroid carcinoma. World J Surg. 2014;38(7):1730-1737. 308. Latgé A, Averous G, Helali M, Bachellier P, Imperiale A.
288. Marchiori E, Pelizzo MR, Herten M, Townsend DM, Rubello D, Parathyromatosis: a challenging cause of recurrent primary hyper­
Boschin IM. Specifying the molecular pattern of sporadic parathyroidism. QJM. 2022;115(4):235-236.
812 Endocrine Reviews, 2023, Vol. 44, No. 5

309. Schulte JJ, Pease G, Taxy JB, Hall C, Cipriani NA. Distinguishing 329. Geerdink EA, Van der Luijt RB, Lips CJ. Do patients with multiple
parathyromatosis, atypical parathyroid adenomas, and parathy­ endocrine neoplasia syndrome type 1 benefit from periodical
roid carcinomas utilizing histologic and clinical features. Head screening? Eur J Endocrinol. 2003;149(6):577-582.
Neck Pathol. 2021;15(3):727-736. 330. Langer P, Kann PH, Fendrich V, et al. Prospective evaluation of
310. Tzotzas T, Goropoulos A, Karras S, et al. Effective long-term man­ imaging procedures for the detection of pancreaticoduodenal
agement of parathyromatosis-related refractory hypercalcemia endocrine tumors in patients with multiple endocrine neoplasia
with a combination of denosumab and cinacalcet treatment. type 1. World J Surg. 2004;28(12):1317-1322.
Hormones (Athens). 2022;21(1):171-176. 331. Kouvaraki MA, Shapiro SE, Cote GJ, et al. Management of pan­
311. Jain M, Krasne DL, Singer FR, Giuliano AE. Recurrent primary creatic endocrine tumors in multiple endocrine neoplasia type 1.
hyperparathyroidism due to Type 1 parathyromatosis. World J Surg. 2006;30(5):643-653.
Endocrine. 2017;55(2):643-650. 332. Machens A, Schaaf L, Karges W, et al. Age-related penetrance of
312. Palmer JA, Brown WA, Kerr WH, Rosen IB, Watters NA. The sur­ endocrine tumours in multiple endocrine neoplasia type 1
gical aspects of hyperparathyroidism. Arch Surg. 1975;110(8): (MEN1): a multicentre study of 258 gene carriers. Clin
1004-1007. Endocrinol (Oxf). 2007;67(4):613-622.
313. Scorza AB, Moore AG, Terry M, Bricker LA. Secondary parathyr­ 333. Kamilaris CDC, Stratakis CA. Multiple endocrine neoplasia type
omatosis in a patient with normal kidney function: review of diag­ 1 (MEN1): an update and the significance of early genetic and clin­

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

nostic modalities and approaches to management. Endocr Pract. ical diagnosis. Front Endocrinol (Lausanne). 2019;10:339.
2014;20(1):e4-e7. 334. Eller-Vainicher C, Chiodini I, Battista C, et al. Sporadic and
314. Hage MP, Salti I, El-Hajj Fuleihan G. Parathyromatosis: a rare yet MEN1-related primary hyperparathyroidism: differences in clin­
problematic etiology of recurrent and persistent hyperparathyr­ ical expression and severity. J Bone Miner Res. 2009;24(8):
oidism. Metabolism. 2012;61(6):762-775. 1404-1410.
315. Pallais JC, Kifor O, Chen YB, Slovik D, Brown EM. Acquired hy­ 335. Goudet P, Dalac A, Le Bras M, et al. MEN1 disease occurring be­
pocalciuric hypercalcemia due to autoantibodies against the fore 21 years old: a 160-patient cohort study from the Groupe d’e­
calcium-sensing receptor. N Engl J Med. 2004;351(4):362-369. tude des Tumeurs Endocrines. J Clin Endocrinol Metab.
316. Kifor O, Moore FD Jr, Delaney M, et al. A syndrome of hypocal­ 2015;100(4):1568-1577.
ciuric hypercalcemia caused by autoantibodies directed at the 336. Romero Arenas MA, Morris LF, Rich TA, et al. Preoperative mul­
calcium-sensing receptor. J Clin Endocrinol Metab. 2003;88(1): tiple endocrine neoplasia type 1 diagnosis improves the surgical
60-72. outcomes of pediatric patients with primary hyperparathyroid­
317. Song L, Liu L, Miller RT, et al. Glucocorticoid-responsive ism. J Pediatr Surg. 2014;49(4):546-550.
lymphocytic parathyroiditis and hypocalciuric hypercalcemia 337. Pieterman CR, van Hulsteijn LT, den Heijer M, et al. Primary
due to autoantibodies against the calcium-sensing receptor: a hyperparathyroidism in MEN1 patients: a cohort study with long­
case report and literature review. Eur J Endocrinol. term follow-up on preferred surgical procedure and the relation
2017;177(1):K1-K6. with genotype. Ann Surg. 2012;255(6):1171-1178.
318. Makita N, Sato J, Manaka K, et al. Successful prednisolone or cal­ 338. Nilubol N, Weinstein LS, Simonds WF, Jensen RT, Marx SJ,
cimimetic treatment of acquired hypocalciuric hypercalcemia Kebebew E. Limited parathyroidectomy in multiple endocrine
caused by biased allosteric CaSR autoantibodies. JCI Insight. neoplasia type 1-associated primary hyperparathyroidism: a setup
2022. for failure. Ann Surg Oncol. 2016;23(2):416-423.
319. Meehan AD, Udumyan R, Kardell M, Landen M, Jarhult J, Wallin 339. Schreinemakers JM, Pieterman CR, Scholten A, Vriens MR, Valk
G. Lithium-associated hypercalcemia: pathophysiology, preva­ GD, Rinkes IH. The optimal surgical treatment for primary hyper­
lence, management. World J Surg. 2018;42(2):415-424. parathyroidism in MEN1 patients: a systematic review. World J
320. Udelsman R. Six hundred fifty-six consecutive explorations for Surg. 2011;35(9):1993-2005.
primary hyperparathyroidism. Ann Surg. 2002;235(5):665-670. 340. Waldmann J, Lopez CL, Langer P, Rothmund M, Bartsch DK.
discussion 670-662. Surgery for multiple endocrine neoplasia type 1-associated pri­
321. Wermer P. Genetic aspects of adenomatosis of endocrine glands. mary hyperparathyroidism. Br J Surg. 2010;97(10):1528-1534.
Am J Med Sci. 1954;16:363-371. 341. Lambert LA, Shapiro SE, Lee JE, et al. Surgical treatment of hyper­
322. Boey JH, Cooke TJ, Gilbert GM, Sweeney EC, Taylor S. parathyroidism in patients with multiple endocrine neoplasia type
Occurrence of other endocrine tumours in primary hyperpara­ 1. Arch Surg. 2005;140(4):374-382.
thyroidism. Lancet. 1975;2(7939):781-784. 342. Tonelli F, Marcucci T, Fratini G, Tommasi MS, Falchetti A,
323. Bardram L, Stage JG. Frequency of endocrine disorders in patients Brandi ML. Is total parathyroidectomy the treatment of choice
with the Zollinger-Ellison syndrome. Scand J Gastroenterol. for hyperparathyroidism in multiple endocrine neoplasia type 1?
1985;20(2):233-238. Ann Surg. 2007;246(6):1075-1082.
324. Corbetta S, Pizzocaro A, Peracchi M, Beck-Peccoz P, Faglia G, 343. Norton JA, Venzon DJ, Berna MJ, et al. Prospective study of sur­
Spada A. Multiple endocrine neoplasia type 1 in patients with rec­ gery for primary hyperparathyroidism (HPT) in multiple endo­
ognized pituitary tumours of different types. Clin Endocrinol crine neoplasia-type 1 and Zollinger-Ellison syndrome:
(Oxf). 1997;47(5):507-512. long-term outcome of a more virulent form of HPT. Ann Surg.
325. Thakker RV, Newey PJ, Walls GV, et al. Clinical practice guide­ 2008;247(3):501-510.
lines for multiple endocrine neoplasia type 1 (MEN1). J Clin 344. Nastos C, Papaconstantinou D, Kofopoulos-Lymperis E, et al.
Endocrinol Metab. 2012;97(9):2990-3011. Optimal extent of initial parathyroid resection in patients with
326. Salenave S, Ancelle D, Bahougne T, et al. Macroprolactinomas in multiple endocrine neoplasia syndrome type 1: a meta-analysis.
children and adolescents: factors associated with the response to Surgery. 2021;169(2):302-310.
treatment in 77 patients. J Clin Endocrinol Metab. 2015;100(3): 345. Moyes VJ, Monson JP, Chew SL, Akker SA. Clinical use of cina­
1177-1186. calcet in MEN1 hyperparathyroidism. Int J Endocrinol.
327. Dean PG, van Heerden JA, Farley DR, et al. Are patients with mul­ 2010;2010:906163.
tiple endocrine neoplasia type I prone to premature death? World 346. d’Alessandro AF, Montenegro FL, Brandao LG, Lourenco DM Jr,
J Surg. 2000;24(11):1437-1441. Toledo Sde A, Cordeiro AC. Supernumerary parathyroid glands in
328. Pieterman CR, Schreinemakers JM, Koppeschaar HP, et al. hyperparathyroidism associated with multiple endocrine neopla­
Multiple endocrine neoplasia type 1 (MEN1): its manifestations sia type 1. Rev Assoc Med Bras (1992). 2012;58(3):323-327.
and effect of genetic screening on clinical outcome. Clin 347. Dwight T, Nelson AE, Theodosopoulos G, et al. Independent gen­
Endocrinol (Oxf). 2009;70(4):575-581. etic events associated with the development of multiple
Endocrine Reviews, 2023, Vol. 44, No. 5 813

parathyroid tumors in patients with primary hyperparathyroid­ 367. Burgess JR, Nord B, David R, et al. Phenotype and phenocopy: the
ism. Am J Pathol. 2002;161(4):1299-1306. relationship between genotype and clinical phenotype in a single
348. Lubensky IA, Debelenko LV, Zhuang Z, et al. Allelic deletions on large family with multiple endocrine neoplasia type 1 (MEN 1).
chromosome 11q13 in multiple tumors from individual MEN1 Clin Endocrinol (Oxf). 2000;53(2):205-211.
patients. Cancer Res. 1996;56(22):5272-5278. 368. Beckers A, Betea D, Valdes Socin H, Stevenaert A. The treatment
349. Friedman E, Sakaguchi K, Bale AE, et al. Clonality of parathyroid of sporadic versus MEN1-related pituitary adenomas. J Intern
tumors in familial multiple endocrine neoplasia type 1. N Engl J Med. 2003;253(6):599-605.
Med. 1989;321(4):213-218. 369. Thomas-Marques L, Murat A, Delemer B, et al. Prospective endo­
350. Tamiya H, Miyakawa M, Suzuki H, et al. A large functioning scopic ultrasonographic evaluation of the frequency of nonfunc­
parathyroid cyst in a patient with multiple endocrine neoplasia tioning pancreaticoduodenal endocrine tumors in patients with
type 1. Endocr J. 2013;60(6):709-714. multiple endocrine neoplasia type 1. Am J Gastroenterol.
351. Cinque L, Sparaneo A, Salcuni AS, et al. MEN1 gene mutation 2006;101(2):266-273.
with parathyroid carcinoma: first report of a familial case. 370. Newey PJ, Jeyabalan J, Walls GV, et al. Asymptomatic children
Endocr Connect. 2017;6(8):886-891. with multiple endocrine neoplasia type 1 mutations may harbor
352. Verges B, Boureille F, Goudet P, et al. Pituitary disease in MEN nonfunctioning pancreatic neuroendocrine tumors. J Clin
type 1 (MEN1): data from the France-Belgium MEN1 multicenter

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

Endocrinol Metab. 2009;94(10):3640-3646.
study. J Clin Endocrinol Metab. 2002;87(2):457-465. 371. Goudet P, Murat A, Binquet C, et al. Risk factors and causes of
353. Trouillas J, Labat-Moleur F, Sturm N, et al. Pituitary tumors and death in MEN1 disease. A GTE (Groupe d’Etude des Tumeurs
hyperplasia in multiple endocrine neoplasia type 1 syndrome Endocrines) cohort study among 758 patients. World J Surg.
(MEN1): a case-control study in a series of 77 patients versus 2010;34(2):249-255.
2509 non-MEN1 patients. Am J Surg Pathol. 2008;32(4): 372. Anlauf M, Garbrecht N, Henopp T, et al. Sporadic versus heredi­
534-543. tary gastrinomas of the duodenum and pancreas: distinct clinico-
354. Cohen-Cohen S, Brown DA, Himes BT, et al. Pituitary adenomas pathological and epidemiological features. World J Gastroenterol.
in the setting of multiple endocrine neoplasia type 1: a single- 2006;12(34):5440-5446.
institution experience. J Neurosurg. 2020;134(3):1132-1138. 373. Cadiot G, Vuagnat A, Doukhan I, et al. Prognostic factors in pa­
355. Dantas NCB, Soares CEL, Martins MRA, Lourenco DM Jr, tients with Zollinger-Ellison syndrome and multiple endocrine
Quidute ARP. Giant prolactinoma causing hydrocephalus and neoplasia type 1. Groupe d’Etude des Neoplasies Endocriniennes
intracranial hypertension as first manifestations of multiple endo­ Multiples (GENEM and groupe de Recherche et d’Etude du
crine neoplasia type 1. Front Endocrinol (Lausanne). 2019;10: Syndrome de Zollinger-Ellison (GRESZE). Gastroenterology.
582. 1999;116(2):286-293.
356. Stratakis CA, Schussheim DH, Freedman SM, et al. Pituitary mac­ 374. Vinault S, Mariet AS, Le Bras M, et al. Metastatic potential and
roadenoma in a 5-year-old: an early expression of multiple endo­ survival of duodenal and pancreatic tumors in multiple endocrine
crine neoplasia type 1. J Clin Endocrinol Metab. 2000;85(12): neoplasia type 1: a GTE and AFCE cohort study (Groupe d’etude
4776-4780. des tumeurs endocrines and association francophone de chirurgie
357. Rix M, Hertel NT, Nielsen FC, et al. Cushing’s disease in child­ endocrinienne). Ann Surg. 2020;272(6):1094-1101.
hood as the first manifestation of multiple endocrine neoplasia 375. van Beek DJ, Nell S, Pieterman CRC, et al. Prognostic factors and
syndrome type 1. Eur J Endocrinol. 2004;151(6):709-715. survival in MEN1 patients with gastrinomas: results from the
358. Burgess JR, Shepherd JJ, Parameswaran V, Hoffman L, DutchMEN study group (DMSG). J Surg Oncol. 2019;120(6):
Greenaway TM. Spectrum of pituitary disease in multiple endo­ 966-975.
crine neoplasia type 1 (MEN 1): clinical, biochemical, and radio­ 376. Gibril F, Venzon DJ, Ojeaburu JV, Bashir S, Jensen RT.
logical features of pituitary disease in a large MEN 1 kindred. J Prospective study of the natural history of gastrinoma in patients
Clin Endocrinol Metab. 1996;81(7):2642-2646. with MEN1: definition of an aggressive and a nonaggressive form.
359. Scheithauer BW, Kovacs K, Nose V, et al. Multiple endocrine neo­ J Clin Endocrinol Metab. 2001;86(11):5282-5293.
plasia type 1-associated thyrotropin-producing pituitary carcin­ 377. Gibril F, Schumann M, Pace A, Jensen RT. Multiple endocrine
oma: report of a probable de novo example. Hum Pathol. neoplasia type 1 and Zollinger-Ellison syndrome: a prospective
2009;40(2):270-278. study of 107 cases and comparison with 1009 cases from the lit­
360. Simonds WF, Varghese S, Marx SJ, Nieman LK. Cushing’s syn­ erature. Medicine (Baltimore). 2004;83(1):43-83.
drome in multiple endocrine neoplasia type 1. Clin Endocrinol 378. Service FJ, McMahon MM, O’Brien PC, Ballard DJ. Functioning
(Oxf). 2012;76(3):379-386. insulinoma-incidence, recurrence, and long-term survival of pa­
361. Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary aden­ tients: a 60-year study. Mayo Clin Proc. 1991;66(7):711-719.
omas: a community-based, cross-sectional study in Banbury 379. Service FJ. Recurrent hyperinsulinemic hypoglycemia caused by
(Oxfordshire, UK). Clin Endocrinol (Oxf). 2010;72(3):377-382. an insulin-secreting insulinoma. Nat Clin Pract Endocrinol
362. Katznelson L, Laws ER Jr, Melmed S, et al. Acromegaly: an endo­ Metab. 2006;2(8):467-470; quiz following 470.
crine society clinical practice guideline. J Clin Endocrinol Metab. 380. Cryer PE, Axelrod L, Grossman AB, et al. Evaluation and manage­
2014;99(11):3933-3951. ment of adult hypoglycemic disorders: an Endocrine Society
363. Melmed S, Casanueva FF, Hoffman AR, et al. Diagnosis and treat­ Clinical Practice Guideline. J Clin Endocrinol Metab.
ment of hyperprolactinemia: an Endocrine Society clinical practice 2009;94(3):709-728.
guideline. J Clin Endocrinol Metab. 2011;96(2):273-288. 381. Triponez F, Dosseh D, Goudet P, et al. Epidemiology data on 108
364. Nieman LK, Biller BM, Findling JW, et al. Treatment of Cushing’s MEN 1 patients from the GTE with isolated nonfunctioning tu­
syndrome: an Endocrine Society clinical practice guideline. J Clin mors of the pancreas. Ann Surg. 2006;243(2):265-272.
Endocrinol Metab. 2015;100(8):2807-2831. 382. Anlauf M, Schlenger R, Perren A, et al. Microadenomatosis of the
365. Hao W, Skarulis MC, Simonds WF, et al. Multiple endocrine neo­ endocrine pancreas in patients with and without the multiple
plasia type 1 variant with frequent prolactinoma and rare gastri­ endocrine neoplasia type 1 syndrome. Am J Surg Pathol.
noma. J Clin Endocrinol Metab. 2004;89(8):3776-3784. 2006;30(5):560-574.
366. Olufemi SE, Green JS, Manickam P, et al. Common ancestral mu­ 383. Goncalves TD, Toledo RA, Sekiya T, et al. Penetrance of function­
tation in the MEN1 gene is likely responsible for the prolactinoma ing and nonfunctioning pancreatic neuroendocrine tumors in mul­
variant of MEN1 (MEN1Burin) in four kindreds from tiple endocrine neoplasia type 1 in the second decade of life. J Clin
Newfoundland. Human mutation. 1998;11(4):264-269. Endocrinol Metab. 2014;99(1):E89-96.
814 Endocrine Reviews, 2023, Vol. 44, No. 5

384. Dralle H, Krohn SL, Karges W, Boehm BO, Brauckhoff M, Gimm 403. Christakis I, Qiu W, Silva Figueroa AM, et al. Clinical features,
O. Surgery of resectable nonfunctioning neuroendocrine pancre­ treatments, and outcomes of patients with thymic carcinoids and
atic tumors. World J Surg. 2004;28(12):1248-1260. multiple endocrine neoplasia type 1 syndrome at MD Anderson
385. D’Souza S L, Elmunzer BJ, Scheiman JM. Long-term follow-up of Cancer Center. Horm Cancer. 2016;7(4):279-287.
asymptomatic pancreatic neuroendocrine tumors in multiple 404. de Laat JM, Pieterman CR, van den Broek MF, et al. Natural
endocrine neoplasia type I syndrome. J Clin Gastroenterol. course and survival of neuroendocrine tumors of thymus and
2014;48(5):458-461. lung in MEN1 patients. J Clin Endocrinol Metab. 2014;99(9):
386. Nell S, Verkooijen HM, Pieterman CRC, et al. Management of 3325-3333.
MEN1 related nonfunctioning pancreatic NETs: a shifting para­ 405. Singh Ospina N, Thompson GB, Nichols FC, Cassivi SD, Young
digm: results from the Dutch MEN1 study group. Ann Surg. WF Jr. Thymic and bronchial carcinoid tumors in multiple endo­
2018;267(6):1155-1160. crine neoplasia type 1: the mayo clinic experience from 1977 to
387. Partelli S, Tamburrino D, Lopez C, et al. Active surveillance versus 2013. Horm Cancer. 2015;6(5-6):247-253.
surgery of nonfunctioning pancreatic neuroendocrine neoplasms 406. Burgess JR, Giles N, Shepherd JJ. Malignant thymic carcinoid is
≤2 cm in MEN1 patients. Neuroendocrinology. 2016;103(6): not prevented by transcervical thymectomy in multiple endocrine
779-786. neoplasia type 1. Clin Endocrinol (Oxf). 2001;55(5):689-693.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

388. Triponez F, Goudet P, Dosseh D, et al. Is surgery beneficial for 407. Lim LC, Tan MH, Eng C, Teh BT, Rajasoorya RC. Thymic carcin­
MEN1 patients with small (< or = 2 cm), nonfunctioning pancrea­ oid in multiple endocrine neoplasia 1: genotype-phenotype correl­
ticoduodenal endocrine tumor? An analysis of 65 patients from ation and prevention. J Intern Med. 2006;259(4):428-432.
the GTE. World J Surg. 2006;30(5):654-662. 408. Ferolla P, Falchetti A, Filosso P, et al. Thymic neuroendocrine car­
389. Pieterman CRC, de Laat JM, Twisk JWR, et al. Long-term natural cinoma (carcinoid) in multiple endocrine neoplasia type 1 syn­
course of small nonfunctional pancreatic neuroendocrine tumors drome: the Italian series. J Clin Endocrinol Metab. 2005;90(5):
in MEN1-results from the Dutch MEN1 study group. J Clin 2603-2609.
Endocrinol Metab. 2017;102(10):3795-3805. 409. Gibril F, Chen YJ, Schrump DS, et al. Prospective study of thymic
390. Bartsch DK, Fendrich V, Langer P, Celik I, Kann PH, Rothmund carcinoids in patients with multiple endocrine neoplasia type 1. J
M. Outcome of duodenopancreatic resections in patients with Clin Endocrinol Metab. 2003;88(3):1066-1081.
multiple endocrine neoplasia type 1. Ann Surg. 2005;242(6): 410. Bartsch DK, Albers MB, Lopez CL, et al. Bronchopulmonary neu­
757-764. roendocrine neoplasms and their precursor lesions in multiple
391. Pinchot SN, Holen K, Sippel RS, Chen H. Carcinoid tumors.
endocrine neoplasia type 1. Neuroendocrinology. 2016;103­
Oncologist. 2008;13(12):1255-1269.
(3-4):240-247.
392. Yano M, Fukai I, Kobayashi Y, et al. ACTH-secreting thymic car­
411. Lecomte P, Binquet C, Le Bras M, et al. histologically proven
cinoid associated with multiple endocrine neoplasia type 1. Ann
bronchial neuroendocrine tumors in MEN1: a GTE 51-case co­
Thorac Surg. 2006;81(1):366-368.
hort study. World J Surg. 2018;42(1):143-152.
393. Ghazi AA, Dezfooli AA, Mohamadi F, et al. Cushing syndrome
412. Sachithanandan N, Harle RA, Burgess JR. Bronchopulmonary
secondary to a thymic carcinoid tumor due to multiple endocrine
carcinoid in multiple endocrine neoplasia type 1. Cancer.
neoplasia type 1. Endocr Pract. 2011;17(4):e92-96.
2005;103(3):509-515.
394. Li X, Su J, Zhao L, et al. Familial Cushing syndrome due to thymic
413. van den Broek MFM, de Laat JM, van Leeuwaarde RS, et al. The
carcinoids in a multiple endocrine neoplasia type 1 kindred.
management of neuroendocrine tumors of the lung in MEN1: re­
Endocrine. 2014;47(1):183-190.
sults from the Dutch MEN1 study group. J Clin Endocrinol
395. Kojima Y, Ito H, Hasegawa S, Sasaki T, Inui K. Resected invasive
Metab. 2021;106(2):e1014-e1027.
thymoma with multiple endocrine neoplasia type 1. Jpn J Thorac
414. Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of
Cardiovasc Surg. 2006;54(4):171-173.
396. Tomita M, Ichiki N, Ayabe T, Tanaka H, Kataoka H, Nakamura MEN1 gene mutations in sporadic carcinoid tumors of the lung.
K. Thymoma (World Health Organization type B3) with neuroen­ Hum Mol Genet. 1997;6(13):2285-2290.
docrine differentiation in multiple endocrine neoplasia type 1. J 415. Swarts DR, Scarpa A, Corbo V, et al. MEN1 gene mutation and
Surg Case Rep. 2017;2017(4):rjx071. reduced expression are associated with poor prognosis in pulmon­
397. Hishima T, Fukayama M, Hayashi Y, et al. Neuroendocrine dif­ ary carcinoids. J Clin Endocrinol Metab. 2014;99(2):E374-378.
ferentiation in thymic epithelial tumors with special reference to 416. Gatta-Cherifi B, Chabre O, Murat A, et al. Adrenal involvement in
thymic carcinoma and atypical thymoma. Hum Pathol. MEN1. Analysis of 715 cases from the Groupe d’Etude des
1998;29(4):330-338. Tumeurs Endocrines database. Eur J Endocrinol. 2012;166(2):
398. Mandl A, Welch JM, Kapoor G, et al. Two distinct classes of 269-279.
thymic tumors in patients with MEN1 show LOH at the MEN1 417. Langer P, Cupisti K, Bartsch DK, et al. Adrenal involvement in
locus. Endocr Relat Cancer. 2021;28(11):L15-L19. multiple endocrine neoplasia type 1. World J Surg. 2002;26(8):
399. Teh BT, McArdle J, Chan SP, et al. Clinicopathologic studies of 891-896.
thymic carcinoids in multiple endocrine neoplasia type 1. 418. Heppner C, Reincke M, Agarwal SK, et al. MEN1 gene analysis in
Medicine (Baltimore). 1997;76(1):21-29. sporadic adrenocortical neoplasms. J Clin Endocrinol Metab.
400. Zheng M, Chen S, Qi C, et al. Thymic Carcinoid as the First 1999;84(1):216-219.
Manifestation of Multiple Endocrine Neoplasia Type 1 419. Schaefer S, Shipotko M, Meyer S, et al. Natural course of small ad­
Syndrome: a Case Report and Review of the Literature. Ann renal lesions in multiple endocrine neoplasia type 1: an endoscopic
Clin Lab Sci. 2020;50(6):825-833. ultrasound imaging study. Eur J Endocrinol. 2008;158(5):
401. Hasani-Ranjbar S, Rahmanian M, Ebrahim-Habibi A, et al. 699-704.
Ectopic Cushing syndrome associated with thymic carcinoid tu­ 420. Darling TN, Skarulis MC, Steinberg SM, Marx SJ, Spiegel AM,
mor as the first presentation of MEN1 syndrome-report of a fam­ Turner M. Multiple facial angiofibromas and collagenomas in pa­
ily with MEN1 gene mutation. Fam Cancer. 2014;13(2):267-272. tients with multiple endocrine neoplasia type 1. Arch Dermatol.
402. Goudet P, Murat A, Cardot-Bauters C, et al. Thymic neuroendo­ 1997;133(7):853-857.
crine tumors in multiple endocrine neoplasia type 1: a comparative 421. Vortmeyer AO, Böni R, Pack SD, Darling TN, Zhuang Z.
study on 21 cases among a series of 761 MEN1 from the GTE Perivascular cells harboring multiple endocrine neoplasia type 1
(Groupe des Tumeurs Endocrines). World J Surg. 2009;33(6): alterations are neoplastic cells in angiofibromas. Cancer Res.
1197-1207. 1999;59(2):274-278.
Endocrine Reviews, 2023, Vol. 44, No. 5 815

422. Sakurai A, Matsumoto K, Ikeo Y, et al. Frequency of facial angio­ 442. Bertolino P, Tong WM, Galendo D, Wang ZQ, Zhang CX.
fibromas in Japanese patients with multiple endocrine neoplasia Heterozygous Men1 mutant mice develop a range of endocrine tu­
type 1. Endocr J. 2000;47(5):569-573. mors mimicking multiple endocrine neoplasia type 1. Mol
423. Asgharian B, Turner ML, Gibril F, Entsuah LK, Serrano J, Jensen Endocrinol. 2003;17(9):1880-1892.
RT. Cutaneous tumors in patients with multiple endocrine neo­ 443. Harding B, Lemos MC, Reed AA, et al. Multiple endocrine neo­
plasm type 1 (MEN1) and gastrinomas: prospective study of fre­ plasia type 1 knockout mice develop parathyroid, pancreatic, pitu­
quency and development of criteria with high sensitivity and itary and adrenal tumours with hypercalcaemia,
specificity for MEN1. J Clin Endocrinol Metab. 2004;89(11): hypophosphataemia and hypercorticosteronaemia. Endocr Relat
5328-5336. Cancer. 2009;16(4):1313-1327.
424. Vidal A, Iglesias MJ, Fernández B, Fonseca E, Cordido F. 444. Loffler KA, Biondi CA, Gartside M, et al. Broad tumor spectrum
Cutaneous lesions associated to multiple endocrine neoplasia syn­ in a mouse model of multiple endocrine neoplasia type 1. Int J
drome type 1. J Eur Acad Dermatol Venereol. 2008;22(7): Cancer. 2007;120(2):259-267.
835-838. 445. Loffler KA, Biondi CA, Gartside MG, et al. Lack of augmentation
425. Roman JW, Logemann NF, Adams E. Incidental angiofibromas of tumor spectrum or severity in dual heterozygous Men1 and Rb1
prompt a diagnosis of multiple endocrine neoplasia type-1 knockout mice. Oncogene. 2007;26(27):4009-4017.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

(MEN-1). Dermatol Online J. 2014;20(9):13030/qt4kq2z97b. 446. Matoso A, Zhou Z, Hayama R, Flesken-Nikitin A, Nikitin AY.
426. Asgharian B, Chen YJ, Patronas NJ, et al. Meningiomas may be a Cell lineage-specific interactions between Men1 and Rb in neuro­
component tumor of multiple endocrine neoplasia type 1. Clin endocrine neoplasia. Carcinogenesis. 2008;29(3):620-628.
Cancer Res. 2004;10(3):869-880. 447. Loffler KA, Mould AW, Waring PM, Hayward NK, Kay GF.
427. Desai D, McPherson LA, Higgins JP, Weigel RJ. Genetic analysis Menin and p53 have non-synergistic effects on tumorigenesis in
of a papillary thyroid carcinoma in a patient with MEN1. Ann mice. BMC Cancer. 2012;12:252.
Surg Oncol. 2001;8(4):342-346. 448. Gillam MP, Nimbalkar D, Sun L, et al. MEN1 tumorigenesis in
428. Kasaian K, Chindris AM, Wiseman SM, et al. MEN1 mutations in the pituitary and pancreatic islet requires Cdk4 but not Cdk2.
Hurthle cell (oncocytic) thyroid carcinoma. J Clin Endocrinol Oncogene. 2015;34(7):932-938.
Metab. 2015;100(4):E611-615. 449. Bai F, Pei XH, Nishikawa T, Smith MD, Xiong Y. p18Ink4c, but
429. McKeeby JL, Li X, Zhuang Z, et al. Multiple leiomyomas of the not p27Kip1, collaborates with Men1 to suppress neuroendocrine
esophagus, lung, and uterus in multiple endocrine neoplasia type organ tumors. Mol Cell Biol. 2007;27(4):1495-1504.
1. Am J Pathol. 2001;159(3):1121-1127. 450. Scacheri PC, Crabtree JS, Kennedy AL, et al. Homozygous loss of
430. Ikota H, Tanimoto A, Komatsu H, Ozawa Y, Matsushita H. menin is well tolerated in liver, a tissue not affected in MEN1.
Ureteral leiomyoma causing hydronephrosis in Type 1 multiple Mamm Genome. 2004;15(11):872-877.
endocrine neoplasia. Pathol Int. 2004;54(6):457-459. 451. Shen HC, He M, Powell A, et al. Recapitulation of pancreatic neu­
431. Dreijerink KM, Goudet P, Burgess JR, Valk GD. International roendocrine tumors in human multiple endocrine neoplasia type I
Breast Cancer in MENSG. Breast-cancer predisposition in mul­ syndrome via Pdx1-directed inactivation of Men1. Cancer Res.
tiple endocrine neoplasia type 1. N Engl J Med. 2014;371(6): 2009;69(5):1858-1866.
583-584. 452. Shen HC, Ylaya K, Pechhold K, et al. Multiple endocrine neopla­
432. Brennan P. Breast cancer risk in MEN1—a cancer genetics per­ sia type 1 deletion in pancreatic alpha-cells leads to development
spective. Clin Endocrinol (Oxf). 2015;82(3):327-229. of insulinomas in mice. Endocrinology. 2010;151(8):4024-4030.
433. van Leeuwaarde RS, Dreijerink KM, Ausems MG, et al. 453. Lu J, Herrera PL, Carreira C, et al. Alpha cell-specific Men1 abla­
MEN1-dependent breast cancer: indication for early screening? tion triggers the transdifferentiation of glucagon-expressing cells
Results from the Dutch MEN1 study group. J Clin Endocrinol and insulinoma development. Gastroenterology. 2010;138(5):
Metab. 2017;102(6):2083-2090. 1954-1965.
434. Fennell LJ, Kane A, Liu C, et al. APC mutation marks an aggres­ 454. Bertolino P, Tong WM, Herrera PL, Casse H, Zhang CX, Wang
sive subtype of BRAF mutant colorectal cancers. Cancers (Basel). ZQ. Pancreatic beta-cell-specific ablation of the multiple endo­
2020;12(5):1171. crine neoplasia type 1 (MEN1) gene causes full penetrance of insu­
435. Mirabello L, Zhu B, Koster R, et al. Frequency of pathogenic linoma development in mice. Cancer Res. 2003;63(16):
germline variants in cancer-susceptibility genes in patients with 4836-4841.
osteosarcoma. JAMA Oncol. 2020;6(5):724-734. 455. Biondi CA, Gartside MG, Waring P, et al. Conditional inactiva­
436. Tham E, Grandell U, Lindgren E, Toss G, Skogseid B, tion of the MEN1 gene leads to pancreatic and pituitary tumori­
Nordenskjold M. Clinical testing for mutations in the MEN1 genesis but does not affect normal development of these tissues.
gene in Sweden: a report on 200 unrelated cases. J Clin Mol Cell Biol. 2004;24(8):3125-3131.
Endocrinol Metab. 2007;92(9):3389-3395. 456. Crabtree JS, Scacheri PC, Ward JM, et al. Of mice and MEN1:
437. Wautot V, Vercherat C, Lespinasse J, et al. Germline mutation Insulinomas in a conditional mouse knockout. Mol Cell Biol.
profile of MEN1 in multiple endocrine neoplasia type 1: search 2003;23(17):6075-6085.
for correlation between phenotype and the functional domains 457. Zhang HL, Li WY, Zhang CP, et al. Differentially expressed genes
of the MEN1 protein. Human mutation. 2002;20:35-47. in Men1 knockout and wildtype embryoid bodies for pancreatic
438. de Laat JM, van der Luijt RB, Pieterman CR, et al. MEN1 rede­ islet development. Mol Med Rep. 2011;4(2):301-305.
fined, a clinical comparison of mutation-positive and mutation- 458. Hamze Z, Vercherat C, Bernigaud-Lacheretz A, et al. Altered
negative patients. BMC Med. 2016;14(1):182. MENIN expression disrupts the MAFA differentiation pathway
439. Pieterman CRC, Hyde SM, Wu SY, et al. Understanding the clin­ in insulinoma. Endocr Relat Cancer. 2013;20(6):833-848.
ical course of genotype-negative MEN1 patients can inform man­ 459. Lu J, Hamze Z, Bonnavion R, et al. Reexpression of oncoprotein
agement strategies. Surgery. 2021;169(1):175-184. MafB in proliferative beta-cells and Men1 insulinomas in mouse.
440. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of mul­ Oncogene. 2012;31(31):3647-3654.
tiple endocrine neoplasia, type 1, develops multiple endocrine tu­ 460. Shi K, Parekh VI, Roy S, Desai SS, Agarwal SK. The embryonic
mors. Proc Natl Acad Sci U S A. 2001;98(3):1118-1123. transcription factor Hlxb9 is a menin interacting partner that con­
441. Bertolino P, Radovanovic I, Casse H, Aguzzi A, Wang ZQ, Zhang trols pancreatic beta-cell proliferation and the expression of insu­
CX. Genetic ablation of the tumor suppressor menin causes lethal­ lin regulators. Endocr Relat Cancer. 2013;20(1):111-122.
ity at mid-gestation with defects in multiple organs. Mech Dev. 461. Wells SA J, Asa SL, Dralle H, et al. American Thyroid Association
2003;120(5):549-560. Guidelines Task Force on Medullary Thyroid C. Revised
816 Endocrine Reviews, 2023, Vol. 44, No. 5

American Thyroid Association guidelines for the management of 481. Elston MS, Meyer-Rochow GY, Dray M, Swarbrick M, Conaglen
medullary thyroid carcinoma. Thyroid. 2015;25(6):567-610. JV. Early Onset Primary Hyperparathyroidism Associated with a
462. Larsen LV, Mirebeau-Prunier D, Imai T, et al. Primary hyperpara­ Novel Germline Mutation in CDKN1B. Case Rep Endocrinol.
thyroidism as first manifestation in multiple endocrine neoplasia 2015;2015:510985.
type 2A: an international multicenter study. Endocr Connect. 482. Alrezk R, Hannah-Shmouni F, Stratakis CA. MEN4 and
2020;9(6):489-497. CDKN1B mutations: the latest of the MEN syndromes. Endocr
463. Herfarth KK, Bartsch D, Doherty GM, Wells SA Jr, Lairmore TC. Relat Cancer. 2017;24(10):T195-T208.
Surgical management of hyperparathyroidism in patients with 483. Halperin R, Arnon L, Nasirov S, et al. Germline CDKN1B variant
multiple endocrine neoplasia type 2A. Surgery. 1996;120(6): type and site are associated with phenotype in MEN4. Endocr
966-973. Relat Cancer. 2023;30(1):e220174.
464. Frank-Raue K, Rybicki LA, Erlic Z, et al. Risk profiles and pene­ 484. Seabrook AJ, Harris JE, Velosa SB, et al. Multiple endocrine tu­
trance estimations in multiple endocrine neoplasia type 2A caused mors associated with germline MAX mutations: multiple endo­
by germline RET mutations located in exon 10. Human mutation. crine neoplasia type 5? J Clin Endocrinol Metab. 2021;106(4):
2011;32(1):51-58. 1163-1182.
465. Asai N, Jijiwa M, Enomoto A, et al. RET receptor signaling: dys­ 485. Jackson CE. Hereditary hyperparathyroidism associated with re­
current pancreatitis. Ann Intern Med. 1958;49(4):829-836.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

function in thyroid cancer and Hirschsprung’s disease. Pathol Int.
2006;56(4):164-172. 486. Jackson CE, Norum RA, Boyd SB, et al. Hereditary hyperpara­
466. Znaczko A, Donnelly DE, Morrison PJ. Epidemiology, clinical thyroidism and multiple ossifying jaw fibromas: a clinically and
features, and genetics of multiple endocrine neoplasia type 2B in genetically distinct syndrome. Surgery. 1990;108(6):1006-1012.
a complete population. Oncologist. 2014;19(12):1284-1286. 487. Hobbs MR, Rosen IB, Jackson CE. Revised 14.7-cM locus for the
467. van den Broek MFM, van Santen HM, Valk GD, Verrijn Stuart hyperparathyroidism-jaw tumor syndrome gene, HRPT2. Am J
AA. Children with multiple endocrine neoplasia type 2B: Not Hum Genet. 2002;70(5):1376-1377.
tall and marfanoid, but short with normal body proportions. 488. Teh BT, Farnebo F, Kristoffersson U, et al. Autosomal dominant
Clin Endocrinol (Oxf). 2021;95(3):453-459. primary hyperparathyroidism and jaw tumor syndrome associ­
468. van den Broek MFM, Rijks EBG, Nikkels PGJ, et al. Timely diag­ ated with renal hamartomas and cystic kidney disease: linkage
nosis of multiple endocrine neoplasia 2B by identification of intes­ to 1q21-q32 and loss of the wild type allele in renal hamartomas.
tinal ganglioneuromatosis: a case series. Endocrine. 2021;72(3): J Clin Endocrinol Metab. 1996;81(12):4204-4211.
489. Szabo J, Heath B, Hill VM, et al. Hereditary hyperparathyroidism-
905-914.
jaw tumor syndrome: the endocrine tumor gene HRPT2 maps to
469. Castinetti F, Waguespack SG, Machens A, et al. Natural history,
chromosome 1q21-q31. Am J Hum Genet. 1995;56(4):944-950.
treatment, and long-term follow up of patients with multiple
490. Carpten JD, Robbins CM, Villablanca A, et al. HRPT2, encoding
endocrine neoplasia type 2B: an international, multicentre, retro­
parafibromin, is mutated in hyperparathyroidism-jaw tumor syn­
spective study. Lancet Diabetes Endocrinol. 2019;7(3):213-220.
drome. Nat Genet. 2002;32(4):676-680.
470. El-Maouche D, Welch J, Agarwal SK, Weinstein LS, Simonds WF,
491. Yamashita Y, Akiyama T, Mizusawa N, Yoshimoto K, Goto M. A
Marx SJ. A patient with MEN1 typical features and MEN2-like
case of hyperparathyroidism-jaw tumour syndrome found in the
features. Int J Endocr Oncol. 2016;3(2):89-95.
treatment of an ossifying fibroma in the maxillary bone. Int J
471. Fritz A, Walch A, Piotrowska K, et al. Recessive transmission of a
Oral Maxillofac Surg. 2007;36(4):365-369.
multiple endocrine neoplasia syndrome in the rat. Cancer Res.
492. Bradley KJ, Cavaco BM, Bowl MR, et al. Parafibromin mutations
2002;62(11):3048-3051.
in hereditary hyperparathyroidism syndromes and parathyroid tu­
472. Franklin DS, Godfrey VL, O’Brien DA, Deng C, Xiong Y.
mours. Clin Endocrinol (Oxf). 2006;64(3):299-306.
Functional collaboration between different cyclin-dependent kin­
493. Pichardo-Lowden AR, Manni A, Saunders BD, Baker MJ. Familial
ase inhibitors suppresses tumor growth with distinct tissue speci­ hyperparathyroidism due to a germline mutation of the CDC73
ficity. Mol Cell Biol. 2000;20(16):6147-6158. gene: implications for management and age-appropriate testing
473. Pellegata NS, Quintanilla-Martinez L, Siggelkow H, et al. of relatives at risk. Endocr Pract. 2011;17(4):602-609.
Germ-line mutations in p27Kip1 cause a multiple endocrine neo­ 494. Frank-Raue K, Haag C, Schulze E, et al. CDC73-related heredi­
plasia syndrome in rats and humans. Proc Natl Acad Sci U S A. tary hyperparathyroidism: five new mutations and the clinical
2006;103(42):15558-15563. spectrum. Eur J Endocrinol. 2011;165(3):477-483.
474. Philipp-Staheli J, Payne SR, Kemp CJ. p27(Kip1): regulation and 495. Iacobone M, Masi G, Barzon L, et al. Hyperparathyroidism-jaw
function of a haploinsufficient tumor suppressor and its misregu­ tumor syndrome: a report of three large kindred. Langenbecks
lation in cancer. Exp Cell Res. 2001;264(1):148-168. Arch Surg. 2009;394(5):817-825.
475. Fero ML, Rivkin M, Tasch M, et al. A syndrome of multiorgan 496. Bricaire L, Odou MF, Cardot-Bauters C, et al. Frequent large
hyperplasia with features of gigantism, tumorigenesis, and female germline HRPT2 deletions in a French national cohort of patients
sterility in p27(Kip1)-deficient mice. Cell. 1996;85(5):733-744. with primary hyperparathyroidism. J Clin Endocrinol Metab.
476. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The mur­ 2013;98(2):E403-408.
ine gene p27Kip1 is haplo-insufficient for tumour suppression. 497. van der Tuin K, Tops CMJ, Adank MA, et al. CDC73-related dis­
Nature. 1998;396(6707):177-180. orders: clinical manifestations and case detection in primary
477. Alevizaki M, Stratakis CA. Multiple endocrine neoplasias: advan­ hyperparathyroidism. J Clin Endocrinol Metab. 2017;102(12):
ces and challenges for the future. J Intern Med. 2009;266(1):1-4. 4534-4540.
478. Georgitsi M, Raitila A, Karhu A, et al. Germline CDKN1B/ 498. Bradley KJ, Hobbs MR, Buley ID, et al. Uterine tumours are a
p27Kip1 mutation in multiple endocrine neoplasia. J Clin phenotypic manifestation of the hyperparathyroidism-jaw tumor
Endocrinol Metab. 2007;92(8):3321-3325. syndrome. J Inter Med. 2005;257:18-26.
479. Agarwal SK, Mateo CM, Marx SJ. Rare germline mutations in 499. Cascón A, Huarte-Mendicoa CV, Javier Leandro-García L, et al.
cyclin-dependent kinase inhibitor genes in multiple endocrine neo­ Detection of the first gross CDC73 germline deletion in an
plasia type 1 and related states. J Clin Endocrinol Metab. HPT-JT syndrome family. Genes Chromosomes Cancer. 2011;50­
2009;94(5):1826-1834. (11):922-929.
480. Molatore S, Marinoni I, Lee M, et al. A novel germline CDKN1B 500. Iacobone M, Camozzi V, Mian C, et al. Long-term outcomes of
mutation causing multiple endocrine tumors: clinical, genetic and parathyroidectomy in hyperparathyroidism-jaw tumor syndrome:
functional characterization. Human mutation. 2010;31(11): analysis of five families with CDC73 mutations. World J Surg.
E1825-1835. 2020;44(2):508-516.
Endocrine Reviews, 2023, Vol. 44, No. 5 817

501. Iacobone M, Carnaille B, Palazzo FF, Vriens M. Hereditary 522. Tan MH, Wong CF, Tan HL, et al. Genomic expression and
hyperparathyroidism-a consensus report of the European Society single-nucleotide polymorphism profiling discriminates chromo­
of Endocrine Surgeons (ESES). Langenbecks Arch Surg. phobe renal cell carcinoma and oncocytoma. BMC Cancer.
2015;400(8):867-886. 2010;10:196.
502. Gill AJ, Lim G, Cheung VKY, et al. Parafibromin-deficient 523. Zheng HC, Takahashi H, Li XH, et al. Downregulated parafibro­
(HPT-JT Type, CDC73 mutated) parathyroid tumors demon­ min expression is a promising marker for pathogenesis, invasion,
strate distinctive morphologic features. Am J Surg Pathol. metastasis and prognosis of gastric carcinomas. Virchows Arch.
2019;43(1):35-46. 2008;452(2):147-155.
503. Hahn MA, Marsh DJ. Nucleolar localization of parafibromin is 524. Selvarajan S, Sii LH, Lee A, et al. Parafibromin expression in
mediated by three nucleolar localization signals. FEBS Lett. breast cancer: a novel marker for prognostication? J Clin
2007;581(26):5070-5074. Pathol. 2008;61(1):64-67.
504. Juhlin CC, Haglund F, Obara T, Arnold A, Larsson C, Höög A. 525. Wang P, Bowl MR, Bender S, et al. Parafibromin, a component of
Absence of nucleolar parafibromin immunoreactivity in subsets the human PAF complex, regulates growth factors and is required
of parathyroid malignant tumours. Virchows Arch. for embryonic development and survival in adult mice. Mol Cell
2011;459(1):47-53. Biol. 2008;28(9):2930-2940.

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

505. Wang L, Han D, Chen W, et al. Non-functional parathyroid car­ 526. Weinstein LS, Simonds WF. HRPT2, a marker of parathyroid can­
cinoma: a case report and review of the literature. Cancer Biol cer. N Engl J Med. 2003;349(18):1691-1692.
Ther. 2015;16(11):1569-1576. 527. Foley TP J, Harrison HC, Arnaud CD, Harrison HE. Familial be­
506. Li Y, Zhang J, Adikaram PR, et al. Genotype of CDC73 germline nign hypercalcemia. J Pediatr. 1972;81(6):1060-1067.
mutation determines risk of parathyroid cancer. Endocr Relat 528. Hinnie J, Bell E, McKillop E, Gallacher S. The prevalence of famil­
Cancer. 2020;27(9):483-494. ial hypocalciuric hypercalcemia. Calcif Tissue Int. 2001;68(4):
507. Wright JM, Vered M. Update from the 4th edition of the World 216-218.
Health Organization classification of head and neck tumours: 529. Marx SJ. Familial hypocalciuric hypercalcemia as an atypical form
odontogenic and maxillofacial bone tumors. Head Neck Pathol. of primary Hyperparathyroidism. J Bone Miner Res. 2018;33(1):
2017;11(1):68-77. 27-31.
508. Wang TT, Zhang R, Wang L, Chen Y, Dong Q, Li TJ. Two cases 530. Marx SJ. Letter to the editor: Distinguishing typical primary
of multiple ossifying fibromas in the jaws. Diagn Pathol. 2014;9: hyperparathyroidism from familial hypocalciuric hypercalcemia
75. by using an index of urinary calcium. J Clin Endocrinol Metab.
509. Liu Y, Wang H, You M, et al. Ossifying fibromas of the jaw bone:
2015;100(2):L29-30.
20 cases. Dentomaxillofac Radiol. 2010;39(1):57-63. 531. Bertocchio JP, Tafflet M, Koumakis E, et al. Pro-FHH: a risk equa­
510. Nezhad F A, Payab M, Nayebandi S, Hasani-Ranjbar S. Jaw tu­
tion to facilitate the diagnosis of parathyroid-related hypercalce­
mor in recurrent primary hyperparathyroidism: a case report.
mia. J Clin Endocrinol Metab. 2018;103(7):2534-2542.
Int J Surg Case Rep. 2018;52:54-58.
532. Burski K, Torjussen B, Paulsen AQ, Boman H, Bollerslev J.
511. du Preez H, Adams A, Richards P, Whitley S.
Parathyroid adenoma in a subject with familial hypocalciuric hy­
Hyperparathyroidism jaw tumour syndrome: a pictoral review.
percalcemia: coincidence or causality? J Clin Endocrinol Metab.
Insights Imaging. 2016;7(6):793-800.
2002;87(3):1015-1016.
512. Bellido V, Larrañaga I, Guimón M, et al. A novel mutation in a pa­
533. Lee JY, Shoback DM. Familial hypocalciuric hypercalcemia and
tient with hyperparathyroidism-jaw tumour syndrome. Endocr
related disorders. Best Pract Res Clin Endocrinol Metab.
Pathol. 2016;27(2):142-146.
2018;32(5):609-619.
513. Chen Y, Hu DY, Wang TT, et al. CDC73 gene mutations in spor­
534. Mukhtar NN, Abouzied MEM, Alqahtani MH, Hammami MM.
adic ossifying fibroma of the jaws. Diagn Pathol. 2016;11(1):91.
Misleading localization by 18F-fluorocholine PET/CT in familial
514. Costa-Guda J, Pandya C, Strahl M, et al. Parafibromin abnormal­
hypocalciuric hypercalcemia type-3: a case report. BMC Endocr
ities in ossifying fibroma. J Endocr Soc. 2021;5(7):bvab087.
515. Pimenta FJ, Gontijo Silveira LF, Tavares GC, et al. HRPT2 gene Disord. 2021;21(1):20.
alterations in ossifying fibroma of the jaws. Oral Oncol. 535. Wolf P, Krssak M, Winhofer Y, et al. Cardiometabolic phenotyp­
2006;42(7):735-739. ing of patients with familial hypocalcuric hypercalcemia. J Clin
516. Wolff EF, Hill MJ, Simonds WF, Segars JH. Aromatase inhibitor Endocrinol Metab. 2014;99(9):E1721-1726.
treatment of menorrhagia and subsequent pregnancy in a patient 536. Jakobsen NF B, Laugesen E, Rolighed L, et al. The cardiovascular
with familial hyperparathyroidism-jaw tumor syndrome. Fertil system in familial hypocalciuric hypercalcemia: a cross-sectional
Steril. 2012;98(6):1616-1619. study on physiological effects of inactivating variants in the
517. Sirbiladze RL, Uyar D, Geurts JL, Shaker JL. Ovarian granulosa calcium-sensing receptor gene. Eur J Endocrinol. 2016;175(4):
cell tumor in a patient with a pathogenic variant in the cdc73 299-309.
gene (hyperparathyroidism-jaw tumor syndrome). AACE Clin 537. Ho C, Conner DA, Pollak MR, et al. A mouse model of human fa­
Case Rep. 2019;5(3):e222-e225. milial hypocalciuric hypercalcemia and neonatal severe hyper­
518. Vocke CD, Ricketts CJ, Ball MW, et al. CDC73 germline mutation parathyroidism. Nat Genet. 1995;11(4):389-394.
in a family with mixed epithelial and stromal tumors. Urology. 538. Hannan FM, Howles SA, Rogers A, et al. Adaptor protein-2 sigma
2019;124:91-97. subunit mutations causing familial hypocalciuric hypercalcaemia
519. Wijewickrama PSA, Somasundaram NP. Hyperparathyroidism type 3 (FHH3) demonstrate genotype-phenotype correlations, co­
jaw tumor syndrome presenting as recurrent femur fractures in a don bias and dominant-negative effects. Hum Mol Genet.
young woman; a rare presentation of a rare disease. Case Rep 2015;24(18):5079-5092.
Endocrinol. 2020;2020:9298147. 539. Hannan FM, Stevenson M, Bayliss AL, et al. Ap2s1 mutation
520. Zhao J, Yart A, Frigerio S, et al. Sporadic human renal tumors dis­ causes hypercalcaemia in mice and impairs interaction between
play frequent allelic imbalances and novel mutations of the calcium-sensing receptor and adaptor protein-2. Hum Mol
HRPT2 gene. Oncogene. 2007;26(23):3440-3449. Genet. 2021;30(10):880-892.
521. Korpi-Hyövälti E, Cranston T, Ryhänen E, et al. CDC73 intragen­ 540. Pollak MR, Chou YH, Marx SJ, et al. Familial hypocalciuric hy­
ic deletion in familial primary hyperparathyroidism associated percalcemia and neonatal severe hyperparathyroidism. Effects of
with parathyroid carcinoma. J Clin Endocrinol Metab. mutant gene dosage on phenotype. J Clin Invest. 1994;93(3):
2014;99(9):3044-3048. 1108-1112.
818 Endocrine Reviews, 2023, Vol. 44, No. 5

541. Marx SJ, Sinaii N. Neonatal severe hyperparathyroidism: novel in thyroid and parathyroid surgery. Surgery. 2023;173(1):
insights from Calcium, PTH, and the CASR Gene. J Clin 132-137.
Endocrinol Metab. 2020;105(4):1061-1078. 561. Rigg J, Gilbertson E, Barrett HL, Britten FL, Lust K. Primary
542. Al-Shanafey S, Al-Hosaini R, Al-Ashwal A, Al-Rabeeah A. hyperparathyroidism in pregnancy: maternofetal outcomes at a
Surgical management of severe neonatal hyperparathyroidism: 1 quaternary referral obstetric hospital, 2000 through 2015. J
center’s experience. J Pediatr Surg. 2010;45(4):714-717. Clin Endocrinol Metab. 2019;104(3):721-729.
543. Fisher MM, Cabrera SM, Imel EA. Successful treatment of neo­ 562. Nagata Y, Imanishi Y, Tateishi T, et al. Parathyroid hormone reg­
natal severe hyperparathyroidism with cinacalcet in two patients. ulates circulating levels of Sclerostin and FGF23 in a primary
Endocrinol Diabetes Metab Case Rep. 2015;2015:150040. hyperparathyroidism model. J Endocr Soc. 2022;6(4):bvac027.
544. Yamada T, Tatsumi N, Anraku A, et al. Gcm2 regulates the main­ 563. Nilsson IL, Norenstedt S, Granath F, Zedenius J, Pernow Y,
tenance of parathyroid cells in adult mice. PLoS One. 2019;14(1): Larsson TE. FGF23, metabolic risk factors, and blood pressure
e0210662. in patients with primary hyperparathyroidism undergoing para­
545. Ding C, Buckingham B, Levine MA. Familial isolated hypopara­ thyroid adenomectomy. Surgery. 2016;159(1):211-217.
thyroidism caused by a mutation in the gene for the transcription 564. Witteveen JE, van Lierop AH, Papapoulos SE, Hamdy NA.
factor GCMB. J Clin Invest. 2001;108(8):1215-1220. Increased circulating levels of FGF23: an adaptive response in pri­
546. García-Castaño A, Madariaga L, Gómez-Conde S, et al. Five pa­ mary hyperparathyroidism? Eur J Endocrinol. 2012;166(1):

Downloaded from https://academic.oup.com/edrv/article/44/5/779/7085685 by guest on 13 October 2023

tients with disorders of calcium metabolism presented with 55-60.
GCM2 gene variants. Sci Rep. 2021;11(1):2968. 565. Betea D, Bradwell AR, Harvey TC, et al. Hormonal and biochem­
547. Guan B, Welch JM, Vemulapalli M, et al. Ethnicity of patients ical normalization and tumor shrinkage induced by anti-
with germline GCM2-activating variants and primary hyperpara­ parathyroid hormone immunotherapy in a patient with metastatic
thyroidism. J Endocr Soc. 2017;1(5):488-499. parathyroid carcinoma. J Clin Endocrinol Metab. 2004;89(7):
548. D’Agruma L, Coco M, Guarnieri V, et al. Increased prevalence of 3413-3420.
the GCM2 polymorphism, Y282D, in primary hyperparathyroid­ 566. Bilezikian JP, Khan AA, Silverberg SJ, et al. International work­
ism: analysis of three Italian cohorts. J Clin Endocrinol Metab. shop on primary H. Evaluation and management of primary
2014;99(12):E2794-2798.
hyperparathyroidism: summary statement and guidelines from
549. Riccardi A, Aspir T, Shen L, et al. Analysis of activating GCM2
the fifth international workshop. J Bone Miner Res. 2022;37­
sequence variants in sporadic parathyroid adenomas. J Clin
(11):2293-2314.
Endocrinol Metab. 2019;104(6):1948-1952.
567. Manoharan J, Albers MB, Bollmann C, et al. Single gland excision
550. Coppin L, Dufosse M, Romanet P, et al. Should the GCM2 gene be
for MEN1-associated primary hyperparathyroidism. Clin
tested when screening for familial primary hyperparathyroidism?
Endocrinol (Oxf). 2020;92(1):63-70.
Eur J Endocrinol. 2020;182(1):57-65.
568. Soto-Pedre E, Newey PJ, Srinivasan S, Siddiqui MK, Palmer CNA,
551. Vincze S, Peters NV, Kuo CL, et al. GCM2 Variants in familial and
Leese GP. Identification of 4 new loci associated With Primary
multiglandular primary hyperparathyroidism. J Clin Endocrinol
Hyperparathyroidism (PHPT) and a Polygenic risk score for
Metab. 2021;107(5):e2021-e2026.
PHPT. J Clin Endocrinol Metab. 2022;107(12):3302-3308.
552. Lakis M E, Nockel P, Guan B, et al. Familial isolated primary
569. Mariathasan S, Andrews KA, Thompson E, et al. Genetic testing
hyperparathyroidism associated with germline GCM2 mutations
for hereditary hyperparathyroidism and familial hypocalciuric hy­
is more aggressive and has a lesser rate of biochemical cure.
percalcaemia in a large UK cohort. Clin Endocrinol (Oxf).
Surgery. 2018;163(1):31-34.
553. Song A, Yang Y, Wang Y, et al. Germline GCM2 Mutation 2020;93(4):409-418.
Screening in Chinese Primary Hyperparathyroidism Patients. 570. Lakis M E, Nockel P, Gaitanidis A, et al. Probability of positive
Endocr Pract. 2020;26(10):1093-1104. genetic testing results in patients with family history of primary
554. Ghemigian A, Ghemigian M, Popescu I, et al. Familial isolated pri­ hyperparathyroidism. J Am Coll Surg. 2018;226(5):933-938.
mary hyperparathyroidism due to HRPT2 mutation. Hormones 571. Thakker RV. Genetics of parathyroid tumours. J Intern Med.
(Athens). 2013;12(3):454-460. 2016;280(6):574-583.
555. Kong J, Wang O, Nie M, et al. Familial isolated primary hyper­ 572. Starker LF, Akerstrom T, Long WD, et al. Frequent germ-line mu­
parathyroidism/hyperparathyroidism-jaw tumour syndrome tations of the MEN1, CASR, and HRPT2/CDC73 genes in young
caused by germline gross deletion or point mutations of CDC73 patients with clinically non-familial primary hyperparathyroid­
gene in Chinese. Clin Endocrinol (Oxf). 2014;81(2):222-230. ism. Horm Cancer. 2012;3(1-2):44-51.
556. Luján D, Sánchez A, Meoro A, Albarracín A, Candel MF. Familial 573. Milat F, Ramchand SK, Herath M, et al. Primary hyperparathyr­
isolated hyperparathyroidism due to HRPT2 mutation. oidism in adults-(Part I) assessment and medical management:
Endocrinol Diabetes Nutr (Engl Ed). 2018;65(8):470-472. position statement of the Endocrine Society of Australia, the
557. Pontikides N, Karras S, Kaprara A, et al. Genetic basis of familial Australian & New Zealand Endocrine Surgeons, and the
isolated hyperparathyroidism: a case series and a narrative review Australian & New Zealand Bone and Mineral Society. Clin
of the literature. J Bone Miner Metab. 2014;32(4):351-366. Endocrinol (Oxf). 2021.
558. Marx SJ. New Concepts About Familial Isolated 574. Khan AA, Hanley DA, Rizzoli R, et al. Primary hyperparathyroid­
Hyperparathyroidism. J Clin Endocrinol Metab. 2019;104(9): ism: review and recommendations on evaluation, diagnosis, and
4058-4066. management. A Canadian and international consensus.
559. Cetani F, Pardi E, Aretini P, et al. Whole exome sequencing in fa­ Osteoporos Int. 2017;28(1):1-19.
milial isolated primary hyperparathyroidism. J Endocrinol Invest. 575. Wilhelm SM, Wang TS, Ruan DT, et al. The American Association
2020;43(2):231-245. of Endocrine Surgeons guidelines for definitive management of
560. Sehnem L J, Noureldine SI, Avci S, et al. A multicenter evaluation primary hyperparathyroidism. JAMA Surg. 2016;151(10):
of near-infrared autofluorescence imaging of parathyroid glands 959-968.