American Journal of Medical Genetics 109:306310 (2002)

Clinical Report

Phenotypic Spectrum of Interstitial 7p Duplicationin Mosaic and Non-Mosaic Forms

Helen Cox,1* Helen Stewart,2 Lucy Hall,3 and Dian Donnai4

1Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom2Oxford Regional Genetics Service, The Churchill, Oxford, United Kingdom3North West Regional Cytogenetics Service, St. Marys Hospital, Manchester, United Kingdom4Department of Clinical Genetics and Regional Genetics Centre, St. Marys Hospital, Manchester, United Kingdom

The phenotypes of a mother and child witha duplication of 7p157p22 are described.The mother is mosaic for the cytogeneticabnormality, whereas all cells are affectedin her son. Fewer than 5 patients with in-terstitial 7p duplications are described inthe world literature whereas over 30 pheno-typic descriptions of individuals with term-inal 7p duplication can be found. Authorshave suggested that the associated pheno-type amounts to a recognizable syndrome.The current cases give further insights intothe phenotype that results from pure 7pduplication, both in its mosaic and in its fullform. Comparisons are made with previouscases, in the light of the shorter segmentinvolved in the current patients, whose dup-lication does not extend to pter. This casedescription will be useful in counselingpatients with duplications of 7p and lendssupport to the existence of characteristiccraniofacial features and congenital mal-formations in this chromosome rearrange-ment. In addition, as earlier case reports alldescribe the phenotype associatedwith non-mosaic partial 7p trisomy, the current ob-servations amount to clear evidence thatmosaicism attenuates the phenotype of thisrearrangement. 2002 Wiley-Liss, Inc.

KEY WORDS: partial 7p trisomy; recog-nized phenotype; criticalregion; mosaicism

INTRODUCTION

The most common mechanism leading to 7p duplica-tion is unbalanced segregation of a parental recipro-cal translocation at meiosis. Attempts to delineate aphenotype due to 7p duplication are therefore compli-cated by uncertainty regarding the contribution of theco-existingmonosomic segment to the phenotype [Reishet al., 1996]. Four published reports describe the clini-cal features in pure 7p trisomy [Zerres et al., 1989;Kleczkowska et al., 1994; Redha et al., 1996; Wolpertet al., 2001]. We report a mother who has mosaic pure7p duplication and her son with non-mosaic duplica-tion. The most likely mechanism leading to 7p duplica-tion in the current patients is direct duplication due tounequal sister chromatid exchange at mitosis occurringas a postzygotic event in the mother. Any phenotypiceffects of this rearrangement in the mother and childare thus attributable to trisomy for the affected seg-ments of 7p.In 1996, Reish et al. [1996] reviewed all documented

cases of 7p duplication in an attempt to delineatethe critical region for this syndrome. Given that telo-meric sequences are not duplicated in the currentpatients, studying their phenotype allows us to refineprevious analyses of the critical region for a 7p dupli-cation syndrome.

CLINICAL REPORT

Patient 1

Patient 1 was a 40-year-old woman with a history ofglobal intellectual impairment, rebellious behavior,and psychosis of unknown cause in adult life. She hadnever lived independently of her parents nor worked.Craniofacial characteristics included a sloping fore-

head, shallow supraorbital ridges, proptosis, large nosewith an angulated bridge and prominent pointed tip,flat midface, full lower lip, high palate, and small chin(Fig. 1).She was referred for genetic counseling in her first

pregnancy after the detection of cerebral ventriculome-

*Correspondence to: Helen Cox, Wessex Clinical GeneticsService, Princess Anne Hospital, Coxford Road, Southampton,SO16 5YA UK. E-mail: hc2@soton.ac.uk

Received 25 September 2000; Accepted 25 January 2002

DOI 10.1002/ajmg.10368

2002 Wiley-Liss, Inc.

galy, bilateral hydronephrosis, and persistently clench-ed fists on ultrasound scan of the fetus at 21 weeksgestation. Amniocentesis showed an abnormal karyo-type: 46,XY,dup(7)(?p15.3?p22)mat (550 bph resolu-tion). The maternal karyotype was also abnormal with75/90 cells examined having an apparently identicalduplication of chromosome 7p and the remaining 15/90cells having an apparently normal female karyotype.She elected to continue the pregnancy.

Patient 2

The male infant was delivered at 36 weeks gestation,weighing 2.68 kg (1025th centile), with a head cir-cumference of 33.8 cm (7590th centile). He had a deep,furrowed forehead, hypertelorism, with down-slantingpalpebral fissures, micrognathia and tongue-tie (Fig. 2).His hands were clenched, but were structurally normaland his general tone and primitive reflexes were allwithin normal limits. Feeding was established slowlyover a 4-week period. A cardiac murmur was presentdue to an ostium secundum atrial septal defect. Mildcerebral ventriculomegaly was confirmed postnatallyon ultrasound scans (ventricular index above the 95thcentile for both ventricles), but remained non-progres-sive over the first 6 months of life. Bilateral hydrone-phrosis was also confirmed postnatally and antibioticprophylaxis was initiated after a urinary tract infection.

At the age of 4 months he fed slowly using anorthodontic teat and suffered from constipation. Hewas growing well and was alert and responsive.Despite mild hypotonia, his early motor developmentwas normal as were his hearing and vision. His headshape was dolichocephalic, the anterior fontanellewas large (3 3 cm) and his forehead was broad andsmooth. Occipitofrontal circumference was 43.5 cm(90th centile). His palpebral fissures were downslant-ing, there was hypertelorism (inner canthal distance3 cm, outer canthal distance 7.5 cm, both 7590thcentile), the zygomatic arches were flat and his earswere low set and posteriorly angulated with squareouter helices. His palate was high, the nares ante-verted, the philtrum smooth, the upper lip was thinand the lower lip was everted. He had contractures ofhis 5th fingers, bulbous tips of his toes and the peniswas tethered.After birth, G-banded preparations were obtained on

peripheral blood lymphocytes from 72- hr thymidinesynchronized cultures using standard protocols. Cellswere examined at the 550 bph resolution level and allcells were found to have the 7p duplication, confirmingthe results of amniotic fluid cell culture, i.e., 46,XY,dup(7)(?p15.3?p22)mat (Fig. 3). FISH studies usingwhole chromosome paint for chromosome 7 confirmedthe chromosome 7 origin of the additional material on7p (Fig. 4a). Only one signal was obtained using the 7p

Fig. 1. Appearance of mother (Patient 1); sloping forehead, scanty eyebrows, shallow orbits, proptosis, large nose with an angulated bridge andprominent pointed tip, flat midface, long philtrum, full lower lip and small chin.

Phenotypic Spectrum of 7p Duplication 307

Fig. 2. Appearance of infant (Patient 2). A: Age 14 days; (B) age 4 months; dolichocephaly, broad forehead, broad nasal bridge, downslanting palpebralfissures and hypertelorism. Flat zygomatic arches, low set, posteriorly angulated ears, anteverted nares, smooth philtrum, thin upper lip and everted lowerlip. Micrognathia was present.

308 Cox et al.

subtelomere probe, showing that terminal 7p was notinvolved in the rearrangement (Fig. 4b).

DISCUSSION

This case study reinforces reports that a distinctiveand recognizable phenotype is seen in patients withduplications of 7p. Clinical features observed in thecurrent patient are tabulated alongside those previous-ly summarized in the 1996 review of Reish et al. [1996](Table I). There is striking concordance between thefindings in the current patient and all described cases ofdistal 7p trisomy. Learning disability is a consistentfeature in all patients old enough to undergo assess-ment. This is in keeping with the current observationthat, even in its mosaic form, partial 7p trisomy cancause significant intellectual disability. Overall, struc-tural malformations, such as those observed in therenal tract, cardiovascular and central nervous systemof Case II do not affect a high proportion of individualswho are trisomic for distal 7p.

There are very few reports of individuals known tobe mosaic for an unbalanced chromosome rearrange-ment having children with the same rearrangementin non-mosaic form. This can be explained by reducedreproductive fitness and reduced or non-viability ofmany unbalanced chromosome rearrangements inher-ited in non-mosaic form. Predicting likely reproductiveoutcome for patients such as Patient 1 is hampered byinability to predict the percentage of oocytes carryingthe unbalanced chromosome rearrangement.The wide anterior fontanelle and abnormal skull

shape seen in Patient 2 are consistent features in distal7p trisomy. The TWIST gene is located at 7p21.1.Haploinsufficiency for this gene causes craniosynosto-sis of the Saethre-Chotzen type. It is interesting tospeculate on the underlying mechanisms of skull ab-normalities found in the patients reviewed by Reishet al. [1996], all of whom would be expected to havethree copies of the TWIST gene. It has been postulatedthat delayed closure of sutures leading to a wide ante-rior fontanelle is a dose-effect relationship of havingthree copies of TWIST [Reish et al., 1996]. The current

Fig. 3. G-banded chromosome preparation from Patient 2 showing dup(7)(p15.3p22).

Phenotypic Spectrum of 7p Duplication 309

patients cytogenetic abnormality is consistent with theTWIST gene being implicated in skull abnormalitiesin trisomy 7p. A recent case report describes a patienttrisomic for 7p21.2pter [Cai et al., 1999], in whom awide anterior fontanelle and flat occiput were present.If the TWIST gene is implicated, then either the dup-licated segment includes more proximal sequences oradditional genes are involved in the etiology of skullabnormalities. The only common region of duplicationthat is shared with the current patient is 7p21.222and yet the phenotype includes hypertelorism, high,

narrow palate, low-set ears, a small mandible andhypotonia. The authors draw attention to similaritieswith the cases reviewed by Reish et al. [1996], postu-lating that the critical region for a 7p duplication syn-drome must lie between 7p21.2 and pter. Patient 2narrows the critical region down to a much shortersegment, namely 7p21.222.Foot abnormalities (talipes and rocker bottom feet)

were seen with duplications involving segments over-lapping with those of the current patients, althoughPatient 2 had neither of these features. These factsare, however, difficult to interpret, given that talipes islikely to be determined by multiple genes.In summary, although 7p22pter was not duplicated

in the current patient, clinical features were as des-cribed in larger terminal duplications of 7p, and alsoone smaller terminal deletion, including only a shortregion of overlap.

REFERENCES

Cai T, Yu P, Tagle DA, Xia J. 1999. Duplication of 7p21.2!pter due tomaternal 7p:21q translocation: implications for critical segment assign-ment in the 7p duplication syndrome. Am J Med Genet 86:305311.

Kleczkowska A, Decock P, van den Berghe H, Fryns JP. 1994. Borderlineintelligence and discrete craniofacial dysmorphism in an adolescentfemale with partial trisomy 7p due to a de novo tandem duplication 7(p15.1!p21.3). Genet Couns 5:393397.

Redha MA, Krishna Murthy DS, al-Awadi SA, al-Sulaiman IS, SabryMA, el-Bahey SA, Farag TI. 1996. De novo direct duplication 7p(p11.2!pter) in an Arab child with MCA/MR syndrome: trisomy 7p adelineated syndrome? Ann Genet 39:59.

Reish O, Berry SA, Dewald G, King R. 1996. Duplication of 7p: Furtherdelineation of the phenotype and restriction of the critical region to thedistal part of the short arm. Am J Med Genet 61:2125.

Wolpert CM, Donnelly SL, Cuccaro ML, Hedges DJ, Poole CP, Wright HH,Gilbert JR, Pericak-Vance MA. 2001. De novo partial duplication ofchromosome 7p in a male with autistic disorder. Am J Med Genet 105:222225.

Zerres K, Schwanitz G, Gellisen K, Schroers L, Sohler R. 1989. Dup-lication of 7p de novo and literature review. Ann Genet 32:225229.

Fig. 4. FISH using (A) whole chromosome paint for chromosome 7 and (B) 7p subtelomere probe. The single signal shows that the duplication did notextend to the subtelomeric region of 7p.

TABLE I. Comparison of Spectrum of Clinical Findings in aPrevious Series and the Current Infant*

Aa (n 8) Clinical findings Bb

5 0 Mental retardation 4 1 Asymmetric skull 1 1 Brain anomalies 6 0 Large fontanelle 3 0 High forehead 6 0 Hypertelorism 2 1 Choanal/ethmoid defect 6 0 Abnormal palate 7 0 Abnormal ears 3 0 Short neck 5 2 CVS defects 2 2 GI defects 3 2 GU defects 3 0 Joint dislocations 2 0 Joint contractures 4 0 Broad digits 4 0 Foot malformations 6 0 Micrognathia *, number of patients in whom feature was described; , those in whomthe feature was described as being absent. In the remaining cases, thefeature was not commented on. Clinical findings which were present inmore than 50% of case descriptions are highlighted in bold type.aSeries reviewed by Reish et al., 1996.bCurrent infant.

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