Inherited Duplication Xq27-qter at Xp22.3 inSeverely Affected Males: Molecular CytogeneticEvaluation and Clinical Description in ThreeUnrelated Families

Barbara K. Goodman,1,4* Lisa G. Shaffer,2 Julie Rutberg,3,8 Mary Leppert,4 Karen Harum,4Sarantis Gagos,2 James H. Ray,5 Martin G. Bialer,6 Xianting Zhou,5 Beth A. Pletcher,6Stuart K. Shapira,2,7 and Michael T. Geraghty3,8

1Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, Baltimore, Maryland2Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas3Center for Medical Genetics, Johns Hopkins University School of Medicine, Baltimore, Maryland4The Kennedy Krieger Institute, Baltimore, Maryland5Department of Laboratory, North Shore University Hospital, Manhasset, New York6Department of Pediatrics, North Shore University Hospital, Manhasset, New York7Department of Pediatrics, Baylor College of Medicine, Houston, Texas8Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland

We describe the clinical phenotype in fourmales from three families with duplication(X)(qter→q27::p22.3→qter). This is an un-usual duplication of the distal long arm seg-ment, Xq27-qter, onto the distal short arm ofthe X chromosome at Xp22.3, as shown byfluorescent in situ hybridization analysiswith multiple X-specific probes. The pa-tients are young male offspring of three un-related, phenotypically normal carrierwomen. The affected males have similarclinical manifestations including severegrowth retardation and developmental de-lay, severe axial hypotonia, and minoranomalies. Such clinical similarity in threeunrelated families demonstrates that thischromosome abnormality results in a newand distinct clinical phenotype. Replicationstudies, performed on two of the mothers,provided evidence that inactivation of theabnormal X chromosome permitted thestructural abnormality to persist in thesefamilies for a generation or more in femaleswithout phenotypic expression. Am. J. Med.Genet. 80:377–384, 1998. © 1998 Wiley-Liss, Inc.

KEY WORDS: duplication Xq; inherited du-plication; X chromosome ab-normality; hypotonia; devel-opmental delay; growth de-lay

INTRODUCTION

Structural abnormalities resulting in simultaneousduplication and deletion of a chromosome segment of-ten occur in the unbalanced offspring of balancedtranslocation carriers. Resulting phenotypes may becomplicated by accompanying monosomy or trisomy ofa portion of a second chromosome. In contrast, dupli-cation or deletion within a single chromosome permitsclear observation of the phenotypic consequence of gainor loss of specific genetic material [Francke et al.,1985]. In this situation, when a number of unrelatedpatients sharing the same abnormality have consistentclinical findings, a duplication or deletion phenotypemay be defined.

The literature indicates that duplications of the longarm of the X chromosome are infrequent, and of the 20cases reported in males, all have had severe phenotypicoutcome [Schmidt et al., 1991; Shapira et al., 1997a].As is often the case in X-linked disorders, these dupli-cations can be transmitted by unaffected female carri-ers [Schwartz et al., 1986; Schmidt et al., 1991;Willard, 1995]. When a single gene on the X chromo-some is altered by mutation, random X chromosomeinactivation may be sufficient to prevent expression ina female [Migeon, 1971]. However, large chromosomedeletions or duplications are more likely to result in aselective advantage to cells with the normal X active.

Contract grant sponsor: Kennedy/Hopkins NICHD Mental Re-tardation Research Center; Contract grant number: HD24061;Contract grant sponsor: Baylor College of Medicine NICHD Men-tal Retardation Research Center; Contract grant numbers: P30HD24064 and R01 HD28333.

*Correspondence to: Barbara K. Goodman, Ph.D., Dept. ofGYN/OB, Park B240, The Johns Hopkins University School ofMedicine, 600 N. Wolfe St., Baltimore, MD 21287.

Received 20 April 1998; Accepted 17 August 1998

American Journal of Medical Genetics 80:377–384 (1998)

© 1998 Wiley-Liss, Inc.

Thus an apparently nonrandom or ‘‘skewed’’ pattern ofX-inactivation may be observed in a female carrier whoappears phenotypically normal [Therman and Patau,1974; Willard, 1995; Belmont, 1996].

We describe four cases, ascertained at three differentinstitutions, which represent an uncommon abnormal-ity consisting of duplication of a segment of the longarm of the X chromosome (Xq27 to Xqter) at the distalshort arm of the same X chromosome (Xp22.3). Thefour affected children are male, two of whom are fra-ternal twin brothers. All inherited the abnormal X fromphenotypically normal, unrelated carrier mothers. Inone case, grandparental X chromosomes were found tobe normal, indicating a de novo rearrangement in themother. In two of the three families, replication studies

showed the abnormal X chromosome to be inactive inthe carrier mother.

CLINICAL REPORTCase 1

M.C. was referred at age 12 months for a secondopinion on the diagnosis of his developmental delay(Fig. 1A). He was born at 36 weeks of gestation to a32-year-old primigravid woman after an uncomplicatedpregnancy. Delivery was by Caesarian section follow-ing decreased fetal movement and ultrasonographythat showed oligohydramnios and a small placenta. Hislength was 39 cm, weight 1,534 g, and OFC 28 cm, allbelow the 3rd centile. His neonatal course included

Fig. 1. Clinical photographs. A: Case 1 at age 12 months. B: Case 2 at age 5 months. C: Case 3 at age 7 years. D: Case 4 at age 7 years.

378 Goodman et al.

feeding difficulties (orogastric tube feeding was re-quired for 3 weeks) and bilateral herniorrhaphy andorchiopexy. A bicuspid aortic valve was detected at thistime. Initial cytogenetic evaluation and fluorescent insitu hybridization (FISH) analysis of the Prader-Willisyndrome locus (SNRPN) at 15q12 were reported to benormal. DNA testing for the fragile X syndrome, inaddition to plasma amino acids, urine organic acids,and carnitine studies all showed no abnormalities.

Re-evaluation of the patient at age 12 monthsshowed growth retardation, height <5th centile, weight5th to 10th centiles, OFC 41.4 cm (<2nd centile), severeaxial hypotonia, plagiocephaly with a prominent rightocciput, bilateral inferior epicanthal folds, alar hypo-plasia, cupped ears, a bifid uvula with swallowingproblems, prominent alveolar ridges, hypoplasticnipples, hypogonadism of the testes after orchiopexy, aright single transverse palmar crease, 4th and 5th fin-ger clinodactyly, and mild 2nd to 3rd toe syndactyly.Speech was absent, and developmental testing demon-strated a DQ of 44 to 50. A male maternal first cousinhad the VACTERL association. A repeat chromosomeanalysis was performed at this time.

Cytogenetics

Synchronized peripheral blood lymphocytes wereprepared and evaluated using standard methods [Yu-

nis, 1976]. At 550 to 650 bands of resolution, a deriva-tive X chromosome was observed, in which additionalmaterial was present on the distal short arm at Xp22.3(Fig. 2A). Cytogenetic analysis of the patient’s mothershowed the same abnormal X chromosome. FISH withan X-specific chromosome paint probe (Oncor, Inc.) hy-bridized to the entire short arm of the abnormal X,confirming that the additional material was X chromo-some–derived (Fig. 3A). Analysis of the patient’smother, using a probe hybridizing to the distal longarms of both the X and the Y chromosomes (TelomereXq/Yq, Oncor, Inc.) and a probe from the adrenoleuko-dystrophy locus (ALD) at Xq28 (kindly provided by Dr.Kirby D. Smith; data not shown) confirmed the originof the additional material to be the distal long arm ofthe X chromosome. A probe for steroid sulfatase (STS)at Xp22.3 (Oncor, Inc., Fig. 3B) showed no deletion inthe abnormal X chromosome in either the patient or hismother, indicating that the rearrangement occurreddistal to this locus. These data, together with the G-band pattern observed, permitted interpretation of theabnormality as dup(X)(qter→q27.2::p22.33→qter) (Fig.2B).

Replication studies were performed on lymphocytesfrom the patient’s mother by incorporation of bromode-oxyuridine (BrdU) during the last six hours of culture.The abnormal X chromosome was shown to be late rep-

Fig. 2. Partial metaphase karyotypes of each patient and his phenotypically normal mother. A: Case 1’s X and Y chromosomes on the left, and hismother’s X chromosomes on the right. Arrows indicate the duplicated region on the derivative X chromosomes. B: Partial karyotype from case 1’s mother,with ideograms, showing a normal X chromosome on the left (arrows indicate the breakpoints involved in these cases) and the duplicated X chromosomeon the right (images and ideograms generated by Applied Imaging Cytovision workstation). C: Case 2’s X chromosome on the left and his mother’s Xchromosomes on the right. Arrows denote the derivative X chromosomes. D: Examples, from left to right, of S.B.’s, R.B.’s, their mother’s and grand-mother’s X chromosomes in Cases 3 and 4. Arrows denote the derivative X chromosomes.

Duplication Xq27-qter 379

licating (inactive) in every cell examined. Cytogeneticevaluation of the patient’s maternal grandfather, ma-ternal uncle, a maternal aunt, and a maternal cousinwith VACTERL association showed no X chromosomeabnormalities. The patient’s maternal grandmotherwas deceased.

Molecular Studies

Because the maternal grandmother was deceased,DNA analysis was performed to determine the inheri-tance pattern of the abnormal X chromosome. DNAfrom the patient, his mother, maternal grandfather,uncle, aunt, and cousin was examined using the follow-ing 12 polymorphic markers distributed along the Xchromosome (listed in order from Xp22 to Xq27):DXS6807, DXS987, DXS989, DXS6810, DXS1003,DXS7132, DXS6800, DXS6789, DXS6799, DXS6797,DXS1047, and GATA31E08. Results showed that theabnormality shared by the patient and his motherarose on the X chromosome inherited from the patient’sdeceased maternal grandmother.

Case 2

G.T. is a 5-month-old Caucasian boy with minoranomalies and developmental delay (Fig. 1B). He wasborn at 37 weeks of gestation to a 32-year-oldG2P1sAB1 mother. Prenatal care was routine and noexposures to teratogens or medical problems were re-ported. Delivery was via Caesarian section due to abreech presentation. Birth weight was 1,676 g (<3rdcentile). Initial feeding difficulties required orogastrictube feedings, but the patient rapidly progressed tooral feedings without vomiting or tiring. Neonatalevaluations included brain and abdominal ultrasonog-raphy; the brain appeared normal, but possible left kid-ney abnormalities prompted an intravenous pyelogramand voiding cystourethrogram, both of which were nor-mal. Medical problems included a urinary tract infec-tion at 2 months and pneumonia at 4 months. An upperGI study noted gastroesophageal reflux, which wastreated with ranitidine hydrochloride and Cisapride. Abrain CT scan and EEG were normal. At 2 months thepatient could track visually. At 5 months he could lifthis head while lying prone, but could not roll over or situnsupported. His length, weight, and OFC were <5thcentile (average for a 2 month old). Minor anomaliesincluded bitemporal prominence, epicanthal folds, andapparent hypertelorism. Muscle tone was mildly de-creased. Skin was normal, without ichthyosis.

There was no family history of consanguinity, devel-opmental delay, or miscarriages. The patient’s motherand maternal aunt had surgery for strabismus in child-hood. His maternal grandmother had received radia-tion therapy to her ovaries prior to conception of hismother. Due to the patient’s developmental delay andminor anomalies, blood was sent for chromosomeanalysis and a specific request for FISH to excludePrader-Willi syndrome.

Chromosome analysis showed a derivative X chro-mosome (Fig. 2C); FISH for Prader-Willi syndromeshowed no deletion using a probe to the SNRPN locusin 15q12. A chromosome analysis was then performed

on the mother and she was found to show the samederivative X chromosome and one normal X chromo-some. Karyotype analyses of her parents (G.T.’s ma-ternal grandparents) were normal. A total of 20cells was examined from the grandfather, and 30cells from the grandmother (which would exclude mo-saicism greater than 10%). Of course, gonadal mosa-icism remains a possibility that can never be ex-cluded. FISH using probe 112G10 to Xq28 [Parrish etal., 1994] and a centromere control probe (Oncor)showed signals at both ends of the derivative chromo-some for the Xq28 probe in the mother (Fig. 4A). Asin Case 1, these data confirmed a duplication of thisregion: dup(X)(qter→q27::p22.3→qter).

Replication analysis was combined with FISH stud-ies on the patient’s mother using BrdU incorporation.Peripheral blood was cultured in media supplementedwith 0.05 ml of 50 mM BrdU (Sigma). Cells were syn-chronized by washing and resuspending in media con-taining a final concentration of methotrexate (Sigma)of 1 × 10−7 M one day prior to harvest. Cells were re-leased from S phase 4.5 hours prior to harvest using 1× 10−5 M thymidine. BrdU is expected to incorporateinto the early replicating DNA and should be absentfrom late replicating DNA. FISH was performed as pre-viously described [Parrish et al., 1994], and signalswere detected simultaneously with the BrdU detection.BrdU was detected indirectly using 10 ml of anti-BrdU(Boehringer Mannheim) diluted in 50 ml of TNB (100mM Tris pH 8, 150 mM NaF1, 0.5% Tween 20, 0.5%blocking reagent (Boehringer Mannheim)) and incu-bated for 30 min at 37°C. The slides were washed andincubated with 2 ml of anti-mouse-Ig-FITC (BoehringerMannheim) diluted in 58 ml of TNB for 30 min at roomtemperature, then counterstained with DAPI. Thistechnique showed that the normal X chromosome(brightly fluorescing) was early replicating and the de-rivative X chromosome (nonfluorescing) was late repli-cating in all cells examined (Fig. 4B).

Cases 3 and 4

S.B. and R.B. were the products of a 34-week twingestation born by Caesarean section for intrauterinegrowth retardation (IUGR) to a 29-year-old mother(Fig. 1C and D, respectively). The family history wassignificant for a maternal brother who died at aboutage 4 years and had neonatal jaundice, growth delay,developmental delay, cerebral palsy, and frequentpneumonia. S.B.’s birth weight was 1,185 g, length 40cm, and OFC 28.5 cm (all <3rd centile). Respiratorydistress syndrome, hyperbilirubinemia, sepsis, andpossible seizures complicated the postnatal course. Atage 2 months, the patient had lateral nystagmus, mildmicrognathia, thickened maxillary alveolus resultingin a high narrow-appearing palate, and increased tonewith the lower limbs more involved than the upper. Hewas discharged from the hospital at age 4 months. At12 months, his weight was 5.9 kg and length 63.5 cm(both <<3rd centile). He had persistent constipation,hypotonia, poor growth, and developmental delay. Hewas rolling but not sitting and was babbling. Physicalexamination showed dolichocephaly, a broad flat nasal

380 Goodman et al.

bridge, severe hypotonia, mild 5th-finger clinodactyly,and significant alveolar thickening with a high narrowpalate.

At 4 years 10 months, the patient did not speak orwalk. Constipation was still present. Medical problemsincluded three prior episodes of pneumonia and reac-tive airway disease. He could roll, commando crawl,and sit unsupported for up to 1 min. His length was 86cm, weight 10.2 kg, and OFC 46 cm, all <<3rd centile.Physical examination showed bilateral epicanthalfolds, relative ocular hypertelorism, ears with over-folded helices, a broad nasal bridge, flat long philtrum,

downturned mouth, thickened alveolar ridge with ahigh narrow palate, retrognathia, thick gums, retrac-tile testes, mild 4th and 5th finger clinodactyly, de-creased range of motion in the distal interphalangeal(DIP) joints and ankles, and mild laxity in the elbows.Foot lengths measured 10.8 and 10.6 cm (<<3rd centile)and the right 2nd toe overlapped the 3rd. Hypotoniawas present throughout. The patient’s clinical findingsat age 7 were essentially unchanged, with continuedinability to speak or walk, and growth parameters at<<3rd centile.

R.B.’s birth weight was 1,095 g, length 37.5 cm, andOFC 28 cm (all <3rd centile). His postnatal course wassimilar to his brother’s but included seizures and con-stipation. A clinical examination at age 2 monthsshowed the same findings as in his brother S.B., butwithout nystagmus and including a superiorly flat-tened left ear helix and hepatosplenomegaly. He wasdischarged at 4 months. At 12 months his weight was5.6 kg and length was 62 cm (both <<3rd centile). Poor

Fig. 3. Representative FISH analyses on the mother of Case 1. A: TotalX chromosome paint probe hybridized to the full length of both X chromo-somes. An arrow indicates the duplicated X chromosome. B: Probe for STSat Xp22.3 with an X centromere control probe shows signals on both thenormal and the abnormal X chromosomes (arrows).

Fig. 4. A: Probe 112G10 (red signal) and an X centromere control probe(green signal) applied to chromosomes from the mother of Case 2. Note thatthe derivative X chromosome (arrow) shows signals for probe 112G10 onboth ends of the chromosome. B: Representative FISH results for replica-tion studies using BrdU incorporation for the mother of Case 2. The de-rivative X chromosome (arrow) was late replicating (nonfluorescing) andthe normal X chromosome was early replicating (brightly fluorescing).

Duplication Xq27-qter 381

growth and developmental delay were noted, as theywere for his brother. Physical examination was againsimilar to his brother’s, but included the flattened leftsuperior ear helix, a right epicanthal fold, and bilateralplantar displacement of the 3rd toe.

At 4 years 10 months, like his brother, the patientdid not speak or walk. He had no respiratory problemsbut had right focal seizures. A CT scan of the brainshowed hypoplasia of the brainstem and corpus callo-sum. He had tight Achilles tendons. Constipation wasless in R.B. than in his brother, and his attention spanwas longer. He could say one word and use severalconsonants. His length was 85.7 cm, weight 11.4 kg,and OFC 45.7 cm (all <<3rd centile). Physical findingswere the same as in S.B., with the addition of strabis-mus, a left overfolded superior helix, small ears, mildlaxity in the elbows and retractile testes. Foot lengthsmeasured 10.8 cm and 10.9 cm (<<3rd centile). Clinicalfindings at age 7, like his brother’s, were essentiallyunchanged. His growth parameters remained << 3rdcentile, he still did not speak or walk, and testes werenot palpable.

Chromosome analysis of both boys at age 12 monthsshowed a derivative X chromosome consisting of addi-tional material on the short arm. The abnormal chro-mosome was also present in the mother and maternalgrandmother (Fig. 2D). FISH analysis was performedlater. An X chromosome painting probe hybridized tothe entire derived X chromosome, as was shown forCase 1. Probe DXS1140 (Oncor, Inc.), which mapsto Xp22.3, hybridized to the short arm of the deriva-tive X chromosome, indicating the breakpoint in Xp tobe in distal Xp22.3 (not shown). Probe TelXq/Yq (On-cor, Inc.), localized to Xq28-qter and Yq12-qter, notonly hybridized to Xqter and Yqter, but also to Xpter(Fig. 5). These data permitted cytogenetic interpreta-tion of the duplicated region as Xq27-qter, and, asin Cases 1 and 2, the abnormality was described asdup(X)(qter→q27::p22.3→qter).

DISCUSSION

As demonstrated by these four patients, duplicationof the region Xq27-qter appears to be associated with adistinct clinical phenotype (Table I), characterized bygrowth delay of prenatal onset, severe axial hypotonia,and severe global developmental delay with minimal orno speech. The patients also had microcephaly with orwithout abnormal head shape, and minor facial anoma-lies, including epicanthal folds, minor ear anomalies,and palatal abnormalities. It is interesting to note that,due to the hypotonia and growth delay, two of thesecases were referred for possible Prader-Willi syndrome.One patient (Case 1) had a prior chromosome analysisthat was reported to be normal. The phenotypic mani-festations of the duplication in these male patientsprobably resulted from the presence of dosage-sensitivegenes in the duplicated region. The fact that none ofthe female carriers had clinical symptoms is explainedby skewed X inactivation, shown to be present in thetwo mothers who were tested. In this small sample,there was no increase in the incidence of infertility,miscarriages, or neonatal loss. Although the rearrange-ment requires a break in distal Xp22, we did not inves-tigate the extent of the deletion of this region. None ofthe affected males suffered from ichthyosis, so thebreak in Xp22 must have been distal to the STS locus,as shown for Case 1. Detailed clinical follow-up of thesepatients and others as they are ascertained will con-tinue to define common manifestations.

The uncommon nature of this abnormality, the chro-mosomal similarity of the defect and its independentoccurrence in several unrelated families suggest a con-sistent meiotic mechanism. A similar cytogenetic ab-normality, dup(X)(qter→q26.3::p22.3→qter), was re-ported in 1987 [Mohandas et al., 1987]. In that report,a predisposing inversion of the X chromosome(p22.3q26.3) was present in the patient’s mother. A re-combinant (duplicated/deleted) X was detected in heraffected son. The structurally abnormal X was detectedand shown to be inactivated in all amniotic fluid cellsstudied from her subsequent (phenotypically normal)carrier female fetus. The affected male was reported tobe developmentally delayed, but no further clinical de-scription was available. In the cases described here, wewere unable to examine grandmaternal chromosomesin Case 1, but grandparental chromosomes were nor-mal in Case 2 and the duplication was found to bepresent in the maternal grandmother of Cases 3 and 4,who also had a son who may have been affected. The denovo rearrangement in the mother of Case 2 indicatesthat a predisposing inversion need not be present con-stitutionally for this abnormality to occur. Recently,clusters of repeated sequences have been implicated asrecombination hotspots in the formation of severalrelatively common duplication or deletion syndromes.These include Charcot-Marie-Tooth type 1A and HNPP[Chance, 1994], Smith-Magenis syndrome [Chen et al.,1997], the Prader-Willi/Angelman syndromes [Chris-tian et al., 1997], the DiGeorge/velocardiofacial syn-dromes [Morrow et al., 1997] and Williams syndrome[Osborne et al., 1997; Perez-Jurado et al., 1998]. On theX chromosome, a series of low copy-number repeat se-

Fig. 5. Probe for the subtelomeric regions of X and Y hybridized to bothends of the abnormal X and only the long arm of the Y chromosome in Case3. Arrow indicates signal on the short arm of the derivative X chromosome.

382 Goodman et al.

quences at Xp22.3 have been implicated in deletions ofthe steroid sulfatase locus (STS), resulting in X-linkedichthyosis [Ballabio et al., 1990; Yen et al., 1990; Li etal., 1992]. Recently this region was shown to contain acluster of four highly homologous arylsulfatase genes,including STS [Puca et al., 1997]. It is possible thatsequences with some homology to these repeats or geneclusters may reside in the distal long arm of the Xchromosome in the region of Xq27 and provide a sub-strate for recombination events. Ample evidence existsfor the involvement of other structural genomic fea-tures in rearrangements of the X chromosome [Lakichet al., 1993; Small et al., 1997].

Unbalanced, cryptic, subtelomeric chromosome rear-rangements have been shown to be responsible for asignificant proportion of cases of mental retardation[Wilkie et al., 1993; Flint et al., 1995]. Many of theseabnormalities may be detectable only by the use of re-cently developed probes for chromosome-specific sub-telomeric regions [National Institutes of Health andInstitute of Molecular Medicine Collaboration, 1996;Ning et al., 1996]. A disproportionate concentration ofgenes is known to reside at chromosome ends [Sacconeet al., 1992], and this gene-rich character has beenshown specifically for the region, Xq28, duplicated inthe four patients presented here [Porta et al., 1993;Chen et al., 1996]. As these patients demonstrate, du-plication of such regions can result in a specific andsevere constellation of clinical manifestations. Closescrutiny of subtelomeric regions using molecularprobes will be increasingly important in cases of oth-erwise unexplained mental retardation, particularly inpatients who have multiple minor anomalies or othersystem involvement. It is likely that small abnormali-ties of the ends of particular chromosome arms willdefine a number of specific, recognizable clinical phe-notypes, such as the one described here and the phe-notypes recently associated with deletions of the distalshort arm of chromosome 1 [Shapira et al., 1997b] and

the distal long arm of chromosome 22 [Biesecker et al.,1995; Doheny et al., 1997].

ACKNOWLEDGMENTS

We would like to acknowledge the Cytogenetic Labo-ratory at the Kennedy Krieger Institute and LauraKasch-Semenza of The Johns Hopkins School of Medi-cine for excellent technical assistance in Case 1. Wethank Dr. Brenden Lee and the Kleberg CytogeneticsLaboratory (Baylor College of Medicine) for their con-tributions to Case 2. For Cases 3 and 4, we acknowl-edge the fine technical assistance of Roberta Perrone.We would also like to thank the families of these pa-tients for their generous cooperation. This work wassupported in part by the Kennedy/Hopkins NICHDMental Retardation Research Center Core GrantHD24061, the Baylor College of Medicine NICHD Men-tal Retardation Research Center Grant P30 HD24064and R01 Grant HD28333 (L.G.S.).

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TABLE I. Clinical Manifestations of the Duplication (Xq27→qter) Phenotype*

Case 1 M.C. Case 2 G.T. Case 3 S.B. Case 4 R.B.

Duplicated region Xq27.2→qter Xq27→qter Xq27→qter Xq27→qterShort arm breakpoint Xp22.33 Xp22.3 Xp22.3 Xp22.3Age/Sex 12 mo/M 5 mo/M 7 yr/M 7 yr/MBirth weight 1534 g 1676 g 1185 g 1095 gGrowth delay (prenatal

onset) + + + +Developmental delay (MR) + + + +Speech delay + NA + +Hypotonia + + + +Microcephaly/abnormal

head shape + + + +Epicanthal folds + + + +Hypertelorism − + + +Ear anomalies (minor) + − + +Palatal abnormalities + − + +Bilateral 5th finger

clinodactyly + − + +Cryptorchidism/retractile

testes + − + +Inheritance of abnormal

chromosome Maternal duplication Maternal duplicationa Maternal duplication Maternal duplication

*NA 4 not applicableade novo duplication in mother

Duplication Xq27-qter 383

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