American Journal of Medical Genetics 134A:334 –337 (2005)

Research Letter
Karyotype/Phenotype Correlations in Duplication 4q:
Evidence for a Critical Region Within 4q27-28
for Preaxial Defects

To the Editor:
Varying degrees of partial duplication of 4q (dup 4q) have
been reported in over 70 patients since 1972 [reviewed by
Lundin et al., 2002; Rinaldi et al., 2003]. The majority of the
cases include partial trisomy with breakpoints at q25 to ter,
mostly due to unbalanced inherited translocations. The dif-
ferent breakpoints, the associated monosomies, and the
varying ages of reported patients make it difficult to delineate
a recognizable syndrome. However, there are six patients
reported with preaxial defects, ranging from thumb hypoplasia
to duplication, mostly having renal malformations as well. In
the past, Zollino et al. [1995] suggested the presence of genes
involved in the development of the acrorenal field at 4q22-23.
Since then additional informative patients with partial 4q
trisomy have been reported [Mikelsaar et al., 1995; Guillen
Navarro et al., 1996; Goodman et al., 1997; Celle et al., 2000].
The karyotype-phenotype correlations derived from these
recently described patients have moved the proposed critical
region for preaxial defects (or acrorenal field defect) more
telomeric to 4q25-28. We describe two patients with dup 4q28.1 Fig. 1. Patient 1 at age 8 years.
to ter and dup 4q31.3 to ter, respectively, the first one of which
is especially helpful in elucidating the critical region for thumb age, she had a single cluster of very brief seizures, associated
defects in dup 4q. with fever; and, following serious feeding difficulties, she
had required a G tube and Nissan fundoplication. She had a
PATIENT 1 single kidney on the right and a hearing loss on the right. The
PDA had closed. We saw her again at the age of 11 months.
The proposita was the first child of healthy, nonconsangui- Although making steady progress, she was significantly
neous parents. Family history was noncontributory. Preg- delayed in all areas of development. Constipation was a con-
nancy was complicated by bleeding at around 3-month cern. On examination, length was 67.9 cm (5th centile), weight
gestation; but there was no exposure or history of chronic 6.5 kg (<3rd centile), and OFC 42 cm (2nd centile). She had an
illnesses, alcohol, tobacco, or street drugs. She was born at alternating exotropia with bushy eyebrows; long eyelashes;
42 weeks with a nuchal cord, but had no significant problems some narrowness of her bifrontal diameter; small mouth and
after birth. Weight was 3,600 g and length 47 cm. She had a small jaw. The fingers were thin with absence of the right
cardiac murmur, and a PDA was diagnosed on echocardio- thumb, and hypoplasia of the left thumb. Figures 1 and 2
graphy. We first saw her at the age of 50 days. She appeared
to be alert and would fix and follow. Weight was 4,100 g
(25th centile), and length 55 cm (25–50th centile). Micro-
cephaly was evident with the anterior fontanel soft and flat;
eyelashes were quite long; nasal bridge and nasal root were
somewhat prominent; ears appeared to be prominent with a
prominent antihelix and a simple outer helix; palate was
intact, but there was a bifid uvula. A very small umbilical
hernia was noted. The thumb was absent on the right; the left
thenar eminence was somewhat hypoplastic. At 6 months of

Grant sponsor: International Program for Consultation and

Research in Clinical Genetics of the University of Utah; Grant
sponsor: Primary Children’s Research Foundation.
*Correspondence to: Dr. A. Battaglia, Stella Maris Scientific
Research Institute, via dei Giacinti, 2, 56018 Calambrone, Pisa,
Italy. E-mail: [email protected]
Received 18 October 2004; Accepted 23 December 2004
DOI 10.1002/ajmg.a.30644 Fig. 2. The hands of Patient 1.

ß 2005 Wiley-Liss, Inc.

 Research Letter 335

Fig. 3. A composite karyotype of Patient 1 and her mother showing the balanced translocation between chromosomes 4 and 11 in the mother (left) and the
derivative chromosome 11 resulting from the maternal chromosome 4;11 translocation in the patient (right).

show her findings at 8 years of age. She now has a moderate

developmental disability.
Peripheral blood samples were obtained from the patient
and her parents. Cytogenetic analysis on the mother’s blood
showed an apparently balanced translocation between chro-
mosomes 4 and 11 in all 20 cells analyzed. The karyotype was
designated as 46,XX, t(4;11)(q28.3;q24.3). The father’s karyo-
type was normal. All 20 metaphase cells analyzed from
peripheral blood of the patient showed a derivative chromo-
some 11 apparently resulting from the maternal chromosome
4;11 translocation. Her karyotype was designated as 46,XX,
der(11)t(4;11)(q28.3;q24.3)ish der(11)t(4;11)(wep4þ)mat.
The patient, therefore, has a partial 4q trisomy and a very
small deletion of 11q. Figure 3 depicts a partial karyotype of
Patient 1 and her mother.

PATIENT 2
The propositus was the first child of healthy, nonconsangui-
neous parents. Family history showed a previous girl who was
stillborn and known to have an unbalanced translocation. The
patient was born after a normal pregnancy with a birth weight
at 50th centile, length at 10th centile, and OFC at 60th centile.
Truncus arteriosus was repaired neonatally. He was found to
have Hirschsprung disease of the long segment type, which
was repaired at age 1 month; pyloric stenosis was repaired at
age 2 months. He also had vescicoureteric reflux, but the
kidneys were structurally normal. We saw him at follow-up at
the age of 25 months with growth delay, all three parameters
falling below the 2nd centile. He had marked developmental
delay with skills at 6–7 months level in all areas. On examina-
tion (Fig. 4), he had prominent forehead, mildly prominent
nasal bridge, cupped ears, short neck, brachydactyly with
structurally normal thumbs, small feet, and generalized
hypotonia. At an age of 4 years, the patient became acutely ill
and died of overwhelming sepsis. Fig. 4. Patient 2 at age 25 months.
336 Battaglia et al.

Peripheral blood samples were obtained from the patient to be a less frequent but a characteristic finding [Surana
and his parents and prepared as in Patient 1. Cytogenetic and Conen, 1972; Dutrillaux et al., 1975; Vogel et al., 1975;
analysis on the father’s blood showed a male chromosome Biedermann and Bower, 1976; Lundin et al., 2002; Rinaldi
complement with an apparently balanced translocation be- et al., 2003]. To date, 14 cases with de novo partial 4q dupli-
tween chromosomes 4 and 10 in all 20 cells analyzed. cation have been reported [Jeziorowska et al., 1993; Zollino
The karyotype was designated as 46,XY, t(4;10)(q31.3;q26.1). et al., 1995; Guillen Navarro et al., 1996; Rinaldi et al., 2003].
The mother’s karyotype was normal. All 20 metaphase cells Genitourinary abnormalities were described only in five, in
analyzed from peripheral blood of the patient showed a which the minimal duplicated region was 4q25q31.3. How-
male chromosome complement with a derivative chromosome ever, this was not observed in other patients with a similar
10, apparently resulting from the paternal chromosome 4;10 duplication, demonstrating the variability of these findings
translocation. His karyotype was designated as 46,XY, der(10) in dup4q. Congenital heart defects were reported in three
t(4;10)(q31.3;q26.1)pat. patients, and apparently seemed to be associated with the
The patient, therefore, had a partial 4q trisomy and a small 4q26q27 duplication, as this region is the minimal common
deletion of 10q due to an unbalanced, paternally inherited duplicated region in all cases. However, this possibility should
translocation (Fig. 5). The patient’s sister had the der(10) like now be reviewed based on our second patient who had truncus
our patient. Characterization of the breakpoints in the patients arteriosus and a duplication of 4q31.3.
by molecular cytogenetics is in progress. Hypoplastic thumb has been observed in five patients, and
Partial 4q trisomy usually results from an unbalanced the minimal common duplicated region is 4q25q28. This seems
segregation of a familial translocation [Yunis et al., 1977; to be supported by our first patient, who has absence of the
Schinzel, 2001]. The wide phenotypic variability observed in right thumb and hypoplasia of the left thumb, with a dupli-
such patients can be related to the different breakpoints and cation of 4q28.3; whereas our second patient with normal
consequent different sizes of the duplicated 4q segment, to the thumbs has a duplication of 4q31.1. The case reported by
associated monosomies, and to the varying ages of reported Lundin et al. [2002] narrows the critical region to 4q27-28.
propositi. Nevertheless, a number of shared findings seem to Thus, there seems to be enough evidence for a critical region
emerge from several reviews [Biedermann and Bower, 1976; within 4q27q28 for preaxial defects. This region is more distal
Yunis et al., 1977; Bonfante et al., 1979], such as microcephaly, than originally suggested by Zollino et al. [1995]. Since most of
abnormal ears, congenital heart defects, varying renal mal- the patients with preaxial defects have structural renal
formations, and growth and mental retardation. Preaxial defects, including Patient 1, genes important in the develop-
defects, ranging from thumb hypoplasia to duplication, seem ment of the acrorenal field are likely present in 4q25q28.

Fig. 5. A composite karyotype of Patient 2 and his father showing the balanced translocation between chromosome 4 and 10 in the father (left) and the
derivative chromosome 10 resulting from the paternal chromosome 4;10 translocation in the patient (right).
 Research Letter 337

ACKNOWLEDGMENTS Schinzel A. 2001. Catalogue of unbalanced chromosome aberrations in man.

Berlin, New York: Walter de Gruyter. pp 207–218.
This work was supported in part by the International Surana RB, Conen PE. 1972. Partial trisomy 4 resulting from a 4/18
Program for Consultation and Research in Clinical Genetics reciprocal translocation. Ann Génét 15:191–194.
of the University of Utah and the Primary Children’s Research Vogel W, Siebers JW, Gunkel J. 1975. Uneinheitlicher Phanotipbei
Foundation. This work was presented, in part, to the Annual partialtrisomie 4q. Humangenetik 28:103–112.
Meeting of the ASHG in Baltimore, MD (October 15–19, 2002). Yunis E, Iraldo A, Zuniga R, Egel H, Ramirez E. 1977. Partial trisomy 4q.
We thank the families of our patients for help and support. Ann Génét 20:243–248.
Zollino M, Zampino G, Torrioli G, Pomponi MG, Neri G. 1995. Further
REFERENCES contribution to the description of phenotypes associated with partial 4q
duplication. Am J Med Genet 57:69–73.
Biedermann B, Bower P. 1976. Partial trisomy 4q due to familial 2/4
translocation. Hum Genet 33:147–153.
Bonfante A, Stella M, Rossi G. 1979. Partial trisomy 4q: Two cases resulting
from a familial translocation t(4;18)(q27;p11). Hum Genet 52:85–90.
A. Battaglia*
Stella Maris Scientific Research Institute
Celle L, Lee L, Rintoul N, Savani RC, Long W, Mannuti MT, Kranz ID. 2000.
Duplication of chromosome region 4q28.3-qter in monozygotic twins
Calambrone, Pisa, Italy
with discordant phenotypes. Am J Med Genet 94:125–140.
Dutrillaux B, Laurent C, Forabosco A, Noel B, Suerine E, Biemont MC,
Cotton JB. 1975. La trisomie 4q partielle. A propos de trois observations.
Z. Chen
Ann Génét 18:21–27. A.R. Brothman
Goodman BK, Capone GT, Hennessey J, Thomas GH. 1997. Familial tandem
S. Morelli
duplication of band q31.1 to q32.3 on chromosome 4 with mild phenotypic J.C. Palumbos
effect. Am J Med Genet 73:119–124. J.C. Carey
Guillen Navarro E, Martinez Romero MC, Lopez Esposito I, Mendez Velasco Division of Medical Genetics
C, Llamas Gabarron J, Hernandez Ramon FJ, Domingo Jimenez R. Department of Pediatrics
1996. De novo interstitial tandem duplication of chromosome 4(q21-q28). University of Utah Health Sciences Center
Am J Med Genet 62:297–299. Salt Lake City, Utah
Jeziorowska A, Ciesla W, Houck GE, Yao XL, Harris MS, Truszczak B,
Skorski M, Jakubowski L, Jenkins EC, Kaluzewski B. 1993. Cytogenetic
and molecular identification of a de novo direct duplication of the long
arm of chromosome 4(q21.3 ! q31.3). Am J Med Genet 46:83–87.
L. Hudgins
Department of Pediatrics
Lundin C, Zech L, Sjors K, Wadelius C, Anneren G. 2002. Trisomy 4q
syndrome: Presentation of a new case and review of the literature. Ann
Stanford University
Génét 45(2):53–57. Stanford, California
Mikelsaar RV, Lurie IW, Ilus TE. 1995. Pure partial trisomy 4q25-qter
owing to a de novo 4q22 translocation. J Med Genet 33:344–345.
Rinaldi R, De Bernardo C, Assumma M, Grammatico B, Buffone E, Poscente
C. Disteche
M, Grammatico P. 2003. Cytogenetic and molecular characterization of a Department of Pathology
de novo 4q24qter duplication: contribution to the associated phenotype. University of Washington
Am J Med Genet 118A:122–126. Seattle, Washington