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GENETICS OF STRUCTURAL SKIN DISORDERS

Heritable Collagen Disorders: The Paradigm of the

Ehlers–Danlos Syndrome
Peter H. Byers1,2 and Mitzi L. Murray1,2
1
Department of Pathology, University of Washington, Seattle, Washington, USA and 2Department of Medicine, Division of Medical Genetics, University of
Washington, Seattle, Washington, USA
Correspondence: Peter H. Byers, E-mail: [email protected]
doi:10.1038/skinbio.2012.3

INTRODUCTION synthesis of the clinical literature on basis of any of the forms of EDS were
The heritable disorders called Ehlers–- the multisystemic and variable nature sparse, with the exception that light
Danlos syndrome (EDS) are as dispa- of EDS in his 1956 hallmark work on and electron microscopy studies iden-
rate as they are fascinating. Their heritable connective tissue disorders. tified abnormalities in the structure
discovery and description has been an Over a decade later, Barabas (1967) of collagens in the dermal matrix
intimate part of the growth of our proposed at least three distinct sub- (Wechsler and Fisher, 1964; Julkunen
understanding of matrix biology. Joint types: classical, varicose, and arterial et al., 1970). The dam broke in the
hypermobility, skin extensibility, ab- on the basis of his experience with 27 early 1970s as a result of tissue analysis
normal scarring, and tissue friability affected individuals. He suggested that to assess interactions/cross-links bet-
are the hallmark diagnostic features; the clinical subtypes reflected discrete ween collagen molecules, animal
however, McKusick (1956) recognized etiologies, not simply variable expres- studies, and use of cultured cells from
that EDS is under-recognized because sions of one disorder. A short time later, selected individuals to examine col-
when the physical signs are not Peter Beighton published a series of lagen production. Detailed knowledge
‘‘classic’’ the diagnosis may be elusive. papers from a landmark clinical inves- of the structure of cross-links and the
The medical and scientific history of tigation of 100 individuals with EDS. awareness of their importance in tissue
EDS can be seen in three phases: He recognized and expanded Barabas’ integrity provided the background in
clinical characterization, biochemical work to a classification of five types which the study of sisters with hyper-
and molecular genetic analysis, and (Beighton et al., 1969). The first group mobility, soft extensible skin, scoliosis
the use of high throughput genomic included individuals similar to those recalcitrant to surgical intervention,
analysis to extend the phenotypes. initially described with skin hyper- and ocular globe fragility (Krane et al.,
extensibility and fragility, with abnor- 1972; Steinmann et al., 1975) led to the
mal scarring and bruising, and striking identification of lysyl hydroxylase defi-
CREATING THE CLINICAL SPECTRUM joint hypermobility (the gravis form). ciency. In these sisters, hydroxylated
OF EDS
The second was similar but the skin complex cross-links were diminished
Hippocrates described the features of findings were less dramatic (mitis). A and the virtual absence of hydroxyla-
this disorder in 400 BC; however, the hypermobility form in which the joint tion of lysyl residues in triple helical
first medical description of some of the findings were striking almost to the collagen molecules resulted from defi-
characteristics is credited to van Meek’- exclusion of skin changes was the third ciency of lysyl hydroxylase. Once the
ren (1682). Tschernogubow’s presenta- type. The Sack-Barabas group (the gene (PLOD1) was isolated, sequence
tion in 1892 seems to have been largely fourth type) had very severe vascular analysis demonstrated inactivating
overlooked in Western Europe, prob- fragility and was at risk of arterial mutations, the most common of which
ably because it was written in Russian. rupture and bowel rupture. The fifth was a 7-exon duplication mediated
Weber (1936) is credited with chris- group was thought to be X-linked and by Alu–Alu recombination (Heikkinen
tening the disorder as EDS in 1936 was characterized by joint hyper- et al., 1997). This was one of the very
after Ehlers (1901) and Danlos (1908), mobility and intramuscular hemor- early demonstrations of the role of
two dermatologists who separately rhage (Table 1). repetitive elements in the genome as
described affected patients in 1901 mediators of deletions or duplications.
and 1908, respectively. The same This disorder, a recessively inherited
year, Georg Sack, a German physician, THE FIRST PHASE OF BIOCHEMICAL condition, was called EDS type VI and
described a condition that Barabas CHARACTERIZATION OF EDS was the first established true disorder
later identified as the arterial type. During the early phase of clinical of collagen biosynthesis and structure
McKusick (1956) provided the first characterization, clues to the molecular in humans.

E6 NOVEMBER 2012 MILESTONES | CUTANEOUS BIOLOGY

Table 1. Classification of EDS
Numerical
type Descriptive type Genes OMIM Inheritance Clinical features and notes

I (Gravis) Classical1 COL5A1 130000 AD Marked joint hypermobility, skin hyperextensibility, bruising,
and abnormal scarring
II (Mitis) COL5A2 130010
2
III Hypermobility TNXB 130020 AD Marked joint hypermobility, minor skin findings
Largely unknown
IV Vascular COL3A1 130050 AD Thin translucent skin, marked bruising, small joint
hypermobility, high risk for rupture of arteries, bowel, and
gravid uterus
VIA Kyphoscoliosis PLOD1 225400 AR Joint hypermobility and kyphoscoliosis recalcitrant to surgical
intervention, risk for arterial rupture
VIB Musculocontractural CHST14 601776 AR Congenital contractures of digits, dysmorphic features,
kyphoscoliosis and hypermobility, hyperextensible thin skin,
ocular involvement
VIIA Arthrochalasia COL1A1 130060 AD Marked joint hypermobility, bilateral congenital hip dislocation
multiplex congenita
VIIB COL1A2
VIIC Dermatosparaxis ADAMTS2 225410 AR Soft, very fragile skin with late onset skin redundancy, blue
sclerae, joint hypermobility
VIII Periodontitis Probably hetero- 130080 AD Periodontal loss, joint hypermobility, soft skin with
geneous; one characteristic plaque on anterior tibial region
locus at 12p13
Other
Progeroid B4GALT7 130070 AR
Cardiac valvular COL1A2 225320 AR (null) Cardiac valvular insufficiency, joint hypermobility, skin
hyperextensibility
FKBP14 related FKBP14 614557 AR Marked kyphoscoliosis, hearing loss, myopathy, short stature,
joint hypermobility
Spondylocheiro SLC39A13 612350 AR Spondyloepiphyseal dysplasia with mild short stature,
dysplastic hyperelastic thin skin with easy bruising, protuberant eyes,
bluish sclerae, fine wrinkling on palms
Tenascin-X deficient TNXB 606408 AR Joint hypermobility, hyperextensible and sleeve-like character
to skin, marked bruising, normal scarring
Periventricular FLNA 300537 XL Periventricular heterotopia, joint hypermobility
heterotopia
Poorly characterized, disputed, retired, or reclassified3
V X linked Unknown 305200 XL Joint hypermobility with muscle hemorrhage
VIB Brittle Cornea ZNF469 22920 AR Blue sclerae, corneal rupture, keratoconus, hyperextensible
syndrome skin, joint hypermobility
PRDM5 614170
IX Occipital Horn ATP7A 304150 XL Hyperextensible skin and bruising, hernias and bladder
syndrome diverticuli, joint hypermobility
X Fibronectin deficient Unknown 225310 ? One reported family with platelet dysfunction and mild features
of EDS
XI Familial Joint Laxity Unknown 147900 AD Retired
Abbreviations: AD, autosomal dominant; AR, autosomal recessive; EDS, Ehlers–Danlos syndrome; XL, X linked.
1
Specific mutations in COL1A1 (substitutions of cysteine for arginine residues within the triple helical domain of proa1(I) chains) have been recognized to cause
a form of EDS reminiscent of classical type with joint hypermobility, skin hyperextensibility, bruising and abnormal scarring, and predisposition to aortic
aneurysm.
2
One family with a specific mutation in COL3A1 is said to have only joint hypermobility with none of the other consequences seen in EDS type IV.
3
We have included these previously identified ‘‘types’’ of EDS for historical perspective. They are not included in most classifications.

MILESTONES | CUTANEOUS BIOLOGY NOVEMBER 2012 E7

 Cattle with a curious and severe from biallelic mutations in ADAMTS2, the molecular basis of the disorder
form of skin fragility provided the next which encodes the procollagen 1 (Toriello et al., 1996). At the same time,
step in the identification of human N-proteinase (Colige et al., 1999). linkage studies and sequencing of both
collagen disorders, as well as insight Variation in the clinical picture reflec- COL5A1 and COL5A2 led to the
into the question of how an essentially ted the presence of missense mutations identification of mutations in individuals
insoluble molecule—collagen—could rather than the early identified non- with EDS type I/II (Burrows et al., 1996;
be synthesized and secreted from cells. sense mutations (Colige et al., 2004). Nicholls et al., 1996; Wenstrup et al.,
The bovine disorder, dermatosparaxis, The early biochemical discovery 1996). Most affected individuals studied
appeared to be inherited in an auto- phase culminated with the demonstra- had mutations that led to instability of
somal recessive manner, and biochem- tion that alteration in the amount of mRNA derived from one COL5A1 allele
ical studies demonstrated that type III procollagen produced was the (Schwarze et al., 2000; Wenstrup et al.,
affected animals failed to process an underlying cause of EDS type IV, the 2000; Malfait et al., 2005). A critical
amino-terminal precursor peptide Sack Barabas type (Pope et al., 1975). role of type V collagen in fibril nuclea-
from all three chains of type I collagen At first thought to be recessive because tion was established in homozygous
(Lenaers et al., 1971). As a conse- of its rarity, an isolated individual in a COL5A1–knockout mice that failed to
quence, collagen fibrillogenesis was family, and apparent decrease in pro- survive embryogenesis because no large
impaired and skin integrity compro- duction of type III procollagen by cells collagen fibrils were assembled (Wenstrup
mised (Piérard and Lapière, 1976). The from the parents (Pope et al., 1977), et al., 2004).
animal study prompted investigation of subsequent analyses of the COL3A1 Although often cited to suggest that
tissues from a young woman born with gene has shown that this is a dominant only about half of affected individuals
bilateral hip dysplasia/dislocation and disorder (Tsipouras et al., 1986). A with EDS type I or EDS type II (the
very marked joint laxity. Her skin single example of bi-allelic mutations previous gravis and mitis type and
contained a2(I) chains of type I col- has been identified out of more than future ‘‘classical type’’) have mutations
lagen with an extension at the amino- 600 families studied (Plancke et al., in type V collagen genes (Malfait et al.,
terminal end (Lichtenstein et al., 1973; 2009). Some mutations result in failure 2005), a recent study using more con-
Steinmann et al., 1980). Although to secrete type III procollagen from sistent clinical diagnosis places this
initially interpreted to result from en- fibroblasts and accumulation of the number closer to 90% (Symoens et al.,
zymatic deficiency, studies later protein in the rough ER and marked 2012). Although genetic studies failed
showed that the woman had a hetero- alteration in dermal structure that led to to demonstrate that mutations in type I
zygous splice donor mutation in intron the idea that type III collagen formed a collagen genes could cause EDS type I/
6 of one COL1A2 allele that led to exon scaffold on which type I fibrillogenesis II (Sokolov et al., 1991; Wordsworth
skipping and loss of the sequence that occurred (Holbrook and Byers, 1981). et al., 1991), biochemical analysis of
contained both the propeptide clea- A large clinical study proved it difficult type I collagens synthesized in culture
vage site and the amino-terminal non- to identify clear genotype phenotype succeeded. Several individuals with
helical cross-link site (Steinmann et al., correlations (Pepin et al., 2000). Recent substitutions of arginine by cysteine
1980). Consistent with this finding, studies, however, make it clear that within the triple helical domain of
autosomal dominant inheritance was heterozygosity for a null mutation in proa1(I) chains of type I collagen,
soon recognized and mutations in the COL3A1 endows an individual with an encoded by COL1A1, had a clinical
COL1A1 gene that led to loss of the extended natural history compared picture of EDS type I/II and also
sequences of the homologous exon 6 with the effects of missense and exon developed aortic aneurysms or dissec-
were found in other affected indivi- skipping mutations (Leistritz et al., tion (Nuytinck et al., 2000; Malfait
duals (Byers et al., 1997). Although the 2011). et al., 2007). In addition, homozygosity
outcomes of mutations in the preceding EDS type I/II proved to be more or compound heterozygosity for
acceptor site and succeeding donor site difficult than expected to solve at the COL1A2-null mutations were found in
differ in detail, both lead to the same molecular level. Ultrastructural studies several people who had a clinical
phenotype. Fewer individuals have of the skin showed that there were presentation with polyvalvular cardiac
COL1A1 mutations because COL1A1 dramatic alterations in the large dermal involvement, moderate joint hypermo-
donor site mutations lead to use of a collagen fibrils, with variation in fibril bility, skin hyperextensibility, and lim-
cryptic donor site or intron inclusion, diameter and aggregate formation ited bruising (Schwarze et al., 2004;
each of which leads to a frame shift, (Vogel et al., 1979). Despite this, Malfait et al., 2006). Nonetheless,
premature termination codon, mRNA linkage studies in families excluded type mutations in type I collagen genes
instability, and an osteogenesis imper- I collagen genes as candidates (Sokolov account for only a small fraction of
fecta phenotype. More than 20 years et al., 1991; Wordsworth et al., 1991). It patients with EDS type I/II.
after the basis of dermatosparaxis was the finding of an X:9 chromosomal By the mid 1990s there had been a
was explained, a human form of the translocation in a woman with EDS profusion of single case reports that
disorder (then called EDS VIIC) was type I and skin pigment alteration tried to define additional types of EDS,
identified (Nusgens et al., 1992; with identification of a breakpoint in most of which relied largely on clinical
Smith et al., 1992) and shown to result one COL5A1 allele that shed light upon differentiation in single systems and

E8 NOVEMBER 2012 MILESTONES | CUTANEOUS BIOLOGY

were not substantiated by compre- meric to TNXB, which encodes mutations result in a musculocontrac-
hensive genetic or biochemical studies. tenascin X. A copy of the 30 exons of tural form of EDS. Very recently a new
Few survived the later purge done to TNXB (called TNXA) are located on the form of EDS characterized by kyphos-
help stabilize a classification. Notable centromeric side of CYP21A and a coliosis, myopathy, and hearing impair-
among the survivors, but not inclu- deletion mediated by the almost exact ment was identified that results from
ded in the later classification, is what sequence identity between the two biallelic mutations in FKBP14 (Bau-
became known as a progeroid type of tenascin X genes led to 21-hydroxylase mann et al., 2012), a member of the
EDS in which features of early aging deficiency and loss of function of both prolyl cis-trans isomerase family. Muta-
accompanied significant hypermobility copies of TNXB. A member of the tions in a family member, FKBP10,
and appeared to result from defective matrix tenascin protein family, tenascin result in a form of osteogenesis imper-
glycosaminoglycan addition to several X interacts with collagens and other fecta (Alanay et al., 2010), perhaps
proteoglycans (Hernández et al., 1986) matrix macromolecules. Tenascin because of effects on folding of either
(Quentin et al., 1990), ultimately shown X–deficient EDS is distinguished from the proa chains of type I procollagen
to result from mutations in B4GALT7 classical EDS by autosomal recessive or of lysyl hydroxylases. This type of
(Okajima et al., 1999) (Faiyaz-Ul-Haque inheritance, absence of abnormal scar- mechanism might help explain the
et al., 2004). The target matrix proteins ring in the presence of profound joint clinical overlaps among one form of
are probably not limited to decorin and hypermobility, very hyperextensible osteogenesis imperfecta, EDS type VI,
biglycan, but the lack of posttransla- skin, and striking bruising (Schalkwijk Bruck syndrome, and this new form of
tional modification presumably affects et al., 2001). The presence of signifi- EDS. The genetic etiology of another
their function (Götte and Kresse, 2005). cant hypermobility in heterozygous rare form of EDS associated with peri-
The hope to restore order, similar to carriers of null mutations suggested ventricular heterotopia was established
that brought by Beighton’s studies TNXB as a candidate gene in EDS by recognition of the similarity of the
of the 1960s, led to a gathering of type III, the hypermobile type. Indeed, neurology features with that of periven-
interested clinicians and geneticists at obligate heterozygotes demonstrated tricular heterotopia due to FLNA muta-
Villefranche in 1997 and the creation that about 80% of carrier women but tions (Sheen et al., 2005). To date, this is
of a new set of clinical and biochem- only 20% of carrier men had significant the only confirmed X-linked form of
ical criteria for the diagnosis of EDS joint hypermobility (Zweers et al., EDS. Most reported individuals are
(Beighton et al., 1998). This new 2003) but wider screening failed to female, consistent with an embryonic
classification abolished the previous document mutations at sufficient lethal effect in males.
Roman numerical system and substi- frequency to account for EDS type III.
tuted a ‘‘descriptive’’ nomenclature, The genomic complexity of this region
while at the same time banishing some has proven a significant barrier to FINAL CONSIDERATIONS
previous types to an ‘‘other’’ category. molecular diagnostics for this gene. The genomic era promises to shed
Created before genetic testing for many additional light on unsolved forms of
disorders became widespread, this EDS. For example, a form of EDS
classification is showing its age and is GENETIC AND GENOMIC ANALYSIS characterized by joint hypermobility,
in sore need of revision. However, any IDENTIFIES MORE TYPES OF EDS easy bruising, and early periodontal
AND THEIR GENETIC BASES
static classification system may be loss without significant inflammation
challenged by the expanding molecular Astute observation of distinctive clini- was defined as EDS type VIII. This was
characterization of disorders with some cal features in consanguineous families shown not to result from mutations in
features of EDS. The tensions among a coupled with genomic searches led COL3A1 even though some features
purely clinical classification, a purely to recognition of several forms of EDS were shared. Linkage to a locus on the
genetic classification, and a mixed that fall outside the Villefranche classi- short arm of chromosome 12 (12p13)
classification may be difficult to resolve fication system. These include the was identified in a large Swedish family
and could satisfy neither clinicians nor spondylocheiro dysplastic form that but excluded in others, consistent with
molecular geneticists in the long run. results from mutations in SLC39A13 locus heterogeneity (Rahman et al.,
The ‘‘post-Villefranche’’ era has (Fukada et al., 2008; Giunta et al., 2003). To date, the molecular etiology
experienced a proliferation of EDS 2008). The gene encodes an endoplas- of this form remains to be established.
types distinguished by clinical and mic reticulum–located zinc transporter Similarly, the genetic etiology in the
genetic grounds but not yet incorpo- but additional studies suggested that majority of persons affected with
rated into a coherent classification. The transforming growth factor-b signaling hypermobile EDS (type III) remains to
elegant studies by Burch et al. (1997) of may also be defective, although the be determined. There are a variety of
a child with 21-hydroxylase deficiency relationship to phenotype is not clear. challenges to dissecting the genetic
and a form of EDS led to identification Mutations in CHST14 (Malfait et al., causes of hypermobile EDS, including
of a new gene, the loss of function of 2010; Miyake et al., 2010), which but not limited to the clinical varia-
which explained the connective tissue encodes dermatan-4-sulfotransferase 1, bility, seeming sex-related penetrance,
manifestations. The active 21-hydroxy- confirms the importance of this mod- and likely genetic heterogeneity. Iden-
lase gene (CYP21A) is located centro- ification as a part of matrix stability. The tifying and understanding the clinical

MILESTONES | CUTANEOUS BIOLOGY NOVEMBER 2012 E9

 diversity, genetic etiology, and patho- procollagen I N-proteinase gene. Am J Hum Malfait F, Coucke P, Symoens S et al. (2005) The
physiologic mechanisms of various Genet 65:308–17. molecular basis of classic Ehlers-Danlos syn-
Danlos M (1908) Un cas de cutis laxa avec drome: a comprehensive study of biochemical
forms of EDS will undoubtedly con- and molecular findings in 48 unrelated patients.
tumeurs par contusion chronique des coudes et
tinue to expand the work of the last Hum Mutat 25:28–37.
des genoux (xanthome juvénile pseudo-diabé-
50 years toward understanding the tique de MM Hallopeau et Macé de Lépinay). Malfait F, Symoens S, Coucke P et al. (2006)
biology of the extracellular matrix and Bull Soc Franc Dermatol Syph 19:70–2. Total absence of the alpha2(I) chain of collagen
the role of the constituent macromole- Ehlers E (1901) Cutis laxa, neigung zu haemor- type I causes a rare form of Ehlers-Danlos
syndrome with hypermobility and propensity to
cules in human disease. rhagien in der haut, lockerung meherer artikula-
cardiac valvular problems. J Med Genet 43:e36.
tionen. Dermatol Z 8:173–4.
Faiyaz-Ul-Haque M, Zaidi SH, Al-Ali M et al. Malfait F, Symoens S, De Backer J et al. (2007)
CONFLICT OF INTEREST Three arginine to cysteine substitutions in the
The authors state no conflict of interest. (2004) A novel missense mutation in the
galactosyltransferase-I (B4GALT7) gene in a pro-alpha (I)-collagen chain cause Ehlers-Danlos
family exhibiting facioskeletal anomalies and syndrome with a propensity to arterial rupture in
Ehlers-Danlos syndrome resembling the progeroid early adulthood. Hum Mutat 28:387–95.
TO CITE THIS ARTICLE
Byers PH and Murray ML (2012) Heritable type. Am J Med Genet A 128A:39–45. Malfait F, Syx D, Vlummens P et al. (2010)
collagen disorders: the paradigm of the Ehlers–- Fukada T, Civic N, Furuichi T et al. (2008) The Musculocontractural Ehlers-Danlos Syndrome
Danlos syndrome. J Invest Dermatol 132: E6–E11 zinc transporter SLC39A13/ZIP13 is required for (former EDS type VIB) and adducted thumb
connective tissue development; its involvement clubfoot syndrome (ATCS) represent a single
in BMP/TGF-beta signaling pathways. PLoS One clinical entity caused by mutations in the
dermatan-4-sulfotransferase 1 encoding CHST14
3:e3642.
REFERENCES gene. Hum Mutat 31:1233–9.
Giunta C, Elc¸ioglu NH, Albrecht B et al. (2008)
Alanay Y, Avaygan H, Camacho N et al. McKusick VA (1956) Heritable disorders of
Spondylocheiro dysplastic form of the Ehlers-
(2010) Mutations in the gene encoding the RER connective tissue. IV. The Ehlers-Danlos syn-
Danlos syndrome—an autosomal-recessive entity
protein FKBP65 cause autosomal-recessive drome. J Chronic Dis 3:2–24.
caused by mutations in the zinc transporter gene
osteogenesis imperfecta. Am J Hum Genet SLC39A13. Am J Hum Genet 82:1290–305. Miyake N, Kosho T, Mizumoto S et al. (2010)
86:551–9. Loss-of-function mutations of CHST14 in a new
Götte M, Kresse H (2005) Defective glycosami-
Barabas AP (1967) Heterogeneity of the Ehlers- type of Ehlers-Danlos syndrome. Hum Mutat
noglycan substitution of decorin in a patient with
Danlos syndrome: description of three clinical 31:966–74.
progeroid syndrome is a direct consequence of
types and a hypothesis to explain the basic two point mutations in the galactosyltransferase I Nicholls AC, Oliver JE, McCarron S et al. (1996)
defect(s). Br Med J 2:612–3. (beta4GalT-7) gene. Biochem Genet 43:65–77. An exon skipping mutation of a type V collagen
Baumann M, Giunta C, Krabichler B et al. (2012) gene (COL5A1) in Ehlers-Danlos syndrome.
Heikkinen J, Toppinen T, Yeowell H et al. (1997)
Mutations in FKBP14 cause a variant of Ehlers- J Med Genet 33:940–6.
Duplication of seven exons in the lysyl hydro-
Danlos syndrome with progressive kyphoscoliosis, xylase gene is associated with longer forms of a Nusgens BV, Verellen-Dumoulin C, Hermanns-Lê T
myopathy, and hearing loss. Am J Hum Genet repetitive sequence within the gene and is a et al. (1992) Evidence for a relationship between
90:201–16. common cause for the type VI variant of Ehlers- Ehlers-Danlos type VII C in humans and bovine
Beighton P, De Paepe A, Steinmann B et al. Danlos syndrome. Am J Hum Genet 60:48–56. dermatosparaxis. Nat Genet 1:214–7.
(1998) Ehlers-Danlos syndromes: revised nosol- Hernández A, Aguirre-Negrete MG, González- Nuytinck L, Freund M, Lagae L et al. (2000)
ogy, Villefranche, 1997. Ehlers-Danlos National Flores S et al. (1986) Ehlers-Danlos features Classical Ehlers-Danlos syndrome caused by a
Foundation (USA) and Ehlers-Danlos Support with progeroid facies and mild mental retarda- mutation in type I collagen. Am J Hum Genet
Group (UK). Am J Med Genet 77:31–7. tion. Further delineation of the syndrome. Clin 66:1398–402.
Beighton P, Price A, Lord J et al. (1969) Variants Genet 30:456–61. Okajima T, Fukumoto S, Furukawa K et al. (1999)
of the Ehlers-Danlos syndrome. Clinical, bio- Holbrook KA, Byers PH (1981) Ultrastructural Molecular basis for the progeroid variant of
chemical, haematological, and chromosomal fea- characteristics of the skin in a form of the Ehlers- Ehlers-Danlos syndrome. Identification and char-
tures of 100 patients. Ann Rheum Dis Danlos syndrome type IV storage in the rough acterization of two mutations in galactosyltrans-
28:228–45. endoplasmic reticulum. Lab Invest 44:342–50. ferase I gene. J Biol Chem 274:28841–4.
Burch GH, Gong Y, Liu W et al. (1997) Tenascin-X Julkunen H, Rokkanen P, Inoue H (1970) Pepin M, Schwarze U, Superti-Furga A et al.
deficiency is associated with Ehlers-Danlos syn- Scanning electron microscopic study of the (2000) Clinical and genetic features of Ehlers-
drome. Nat Genet 17:104–8. collagen bundles of the skin in the Ehlers-Danlos Danlos syndrome type IV, the vascular type. N Eng
syndrome. Ann Med Exp Biol Fenn 48:201–4. J Med 342:673–80.
Burrows NP, Nicholls AC, Yates JR et al. (1996)
The gene encoding collagen alpha1(V)(COL5A1) Krane SM, Pinnell SR, Erbe RW (1972) Piérard GE, Lapière M (1976) Skin in dermatos-
is linked to mixed Ehlers-Danlos syndrome Lysyl-protocollagen hydroxylase deficiency in paraxis. Dermal microarchitecture and biomecha-
type I/II. J Invest Dermatol 106:1273–6. fibroblasts from siblings with hydroxylysine- nical properties. J Invest Dermatol 66:2–7.
Byers PH, Duvic M, Atkinson M et al. (1997) deficient collagen. Proc Natl Acad Sci USA Plancke A, Holder-Espinasse M, Rigau V et al.
Ehlers-Danlos syndrome type VIIA and VIIB result 69:2899–903. (2009) Homozygosity for a null allele of COL3A1
from splice-junction mutations or genomic dele- Leistritz DF, Pepin MG, Schwarze U et al. (2011) results in recessive Ehlers-Danlos syndrome.
tions that involve exon 6 in the COL1A1 and COL3A1 haploinsufficiency results in a variety of Eur J Hum Genet 17:1411–6.
COL1A2 genes of type I collagen. Am J Med Ehlers-Danlos syndrome type IV with delayed Pope FM, Martin GR, Lichtenstein JR et al.
Genet 72:94–105. onset of complications and longer life expec- (1975) Patients with Ehlers-Danlos syndrome
Colige A, Nuytinck L, Hausser I et al. (2004) tancy. Genet Med 13:717–22. type IV lack type III collagen. Proc Natl Acad Sci
Novel types of mutation responsible for the Lenaers A, Ansay M, Nusgens BV et al. (1971) USA 72:1314–6.
dermatosparactic type of Ehlers-Danlos syn- Collagen made of extended -chains, procollagen, Pope FM, Martin GR, McKusick VA (1977)
drome (Type VIIC) and common polymorphisms in genetically-defective dermatosparaxic calves. Inheritance of Ehlers-Danlos type IV syndrome.
in the ADAMTS2 gene. J Invest Dermatol Eur J Biochem 23:533–43. J Med Genet 14:200–4.
123:656–63. Lichtenstein JR, Martin GR, Kohn LD et al. Quentin E, Gladen A, Rodén L et al. (1990) A
Colige A, Sieron AL, Li SW et al. (1999) Human (1973) Defect in conversion of procollagen to genetic defect in the biosynthesis of dermatan
Ehlers-Danlos syndrome type VII C and bovine collagen in a form of Ehlers-Danlos syndrome. sulfate proteoglycan: galactosyltransferase I
dermatosparaxis are caused by mutations in the Science 182:298–300. deficiency in fibroblasts from a patient with a

E10 NOVEMBER 2012 MILESTONES | CUTANEOUS BIOLOGY

progeroid syndrome. Proc Natl Acad Sci USA Sokolov BP, Prytkov AN, Tromp G et al. (1991) Vogel A, Holbrook KA, Steinmann B et al. (1979)
87:1342–6. Exclusion of COL1A1, COL1A2, and COL3A1 genes Abnormal collagen fibril structure in the
Rahman N, Dunstan M, Teare MD et al. (2003) as candidate genes for Ehlers-Danlos syndrome gravis form (type I) of Ehlers-Danlos syndrome.
type I in one large family. Hum Genet 88:125–9. Lab Invest 40:201–6.
Ehlers-Danlos syndrome with severe early-onset
periodontal disease (EDS-VIII) is a distinct, Steinmann B, Gitzelmann R, Vogel A et al. (1975) Weber FP (1936) Ehlers-Danlos Syndrome. Proc
heterogeneous disorder with one predisposition Ehlers-Danlos syndrome in two siblings with R Soc Med 30:30–1.
gene at chromosome 12p13. Am J Hum Genet deficient lysyl hydroxylase activity in cultured
Wechsler HL, Fisher (1964) Ehlers-Danlos syn-
73:198–204. skin fibroblasts but only mild hydroxylysine
drome. Pathologic, histochemical and electron
deficit in skin. Helv Paediatr Acta 30:255–74.
Schalkwijk J, Zweers MC, Steijlen PM et al. microscopic observations. Arch Pathol 77:613–9.
(2001) A recessive form of the Ehlers-Danlos Steinmann B, Tuderman L, Peltonen L et al.
(1980) Evidence for a structural mutation Wenstrup RJ, Florer JB, Brunskill EW et al. (2004)
syndrome caused by tenascin-X deficiency. Type V collagen controls the initiation of collagen
of procollagen type I in a patient with the
N Engl J Med 345:1167–75. fibril assembly. J Biol Chem 279:53331–7.
Ehlers-Danlos syndrome type VII. J Biol Chem
Schwarze U, Atkinson M, Hoffman GG et al. 255:8887–93. Wenstrup RJ, Florer JB, Willing MC et al. (2000)
(2000) Null alleles of the COL5A1 gene of type V COL5A1 haploinsufficiency is a common mole-
Symoens S, Syx D, Malfait F et al. (2012)
collagen are a cause of the classical forms of Comprehensive molecular analysis demonstrates cular mechanism underlying the classical form
Ehlers-Danlos syndrome (types I and II). Am J type V collagen mutations in over 90% of patients of EDS. Am J Hum Genet 66:1766–76.
Hum Genet 66:1757–65. with classic EDS and allows to refine diagnostic Wenstrup RJ, Langland GT, Willing MC et al.
Schwarze U, Hata R, McKusick VA et al. (2004) criteria. Hum Mutat (e-pub ahead of print 13 June (1996) A splice-junction mutation in the region
Rare autosomal recessive cardiac valvular form of 2012). of COL5A1 that codes for the carboxyl propeptide
Ehlers-Danlos syndrome results from mutations Toriello HV, Glover TW, Takahara K et al. (1996) of pro alpha 1(V) chains results in the gravis form
in the COL1A2 gene that activate the nonsense- A translocation interrupts the COL5A1 gene in a of the Ehlers-Danlos syndrome (type I). Hum Mol
mediated RNA decay pathway. Am J Hum Genet patient with Ehlers-Danlos syndrome and hypo- Genet 5:1733–6.
74:917–30. melanosis of Ito. Nat Genet 13:361–5. Wordsworth BP, Ogilvie DJ, Sykes BC (1991)
Sheen VL, Jansen A, Chen MH et al. (2005) Filamin Tschernogobow A (1892) Ein fall von cutis laxa. Segregation analysis of the structural genes of the
A mutations cause periventricular heterotopia with Jahresber Ges Med 27:562. major fibrillar collagens provides further evidence
Ehlers-Danlos syndrome. Neurology 64:254–62. Tsipouras P, Byers PH, Schwartz RC et al. (1986) of molecular heterogeneity in type II Ehlers-
Smith LT, Wertelecki W, Milstone LM et al. (1992) Ehlers-Danlos syndrome type IV: cosegregation of Danlos syndrome. Br J Rheumatol 30:173–7.
Human dermatosparaxis: a form of Ehlers-Danlos the phenotype to a COL3A1 allele of type III Zweers MC, Bristow J, Steijlen PM et al. (2003)
syndrome that results from failure to remove the procollagen. Hum Genet 74:41–6. Haploinsufficiency of TNXB is associated with
amino-terminal propeptide of type I procollagen. van Meek’ren Ja (1682) De Dilatabilitate Extra- hypermobility type of Ehlers-Danlos syndrome.
Am J Hum Genet 51:235–44. ordinaria Cutis (observationes medico-chirugicae). Am J Hum Genet 73:214–7.

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