Clinical Genetics 1991: 39 386-390 Case Report

Interstitial deletion of chromosome 2q associated with ovarian dysgenesis

EVERETT DAVIS'. M. CRAFE', CHRISTOPHER cUNNIFF*, KENNETH LYONS JONES' AND MARK % C A R +

Departments of 'Pathology and 'Medicine and 'Division of Dysmorphology, Department of Pediatrics, University of California, San Diego, USA

In the present report we describe a girl with mental retardation, Dandy-Walker malformation, craniofacial anomalies, cardiac defect, and ovarian dysgenesis associated with an interstitial deletion of chromosome 2. The interstitial deletion in the proband was associated with an apparently balanced translocation involving chromosomes 2 and 7 in the father.

Received 9 July, revised I7 December, accepted for publication 19 December 1990

Key words: deletion 2q; ovarian dysgenesis.

Improved banding techniques for cytogen- etic analysis of individuals with suspected chromosomal abnormalities now allow for precise characterization of chromosomal re- arrangements and, by extension, the pheno- typic findings which occur as a result of these rearrangements. The purposes of this report are to present the case of a child with an interstitial deletion of chromosome 2, associated with ovarian dysgenesis, and to document the unusual karyotypic findings in the child and her father.

Case Report

This was the second pregnancy of a healthy 23-year-old mother and a 30-year-old father. The mother had a first trimester spon- taneous abortion 1 year previously. An ul- trasound examination at 32 weeks of ges- tation demonstrated a posterior fossa cyst, suggestive of a Dandy-Walker malfor- mation. The karyotype was 46,XX, del(2)(q13;-q21) (Fig. Ib and 2).

The pregnancy proceeded to term and was complicated by mild polyhydramnios.

Birthweight was 2790 g (20th centile), length 46 cm (10th centile) and head circumference 36 cm (>95th centile). Physical examin- ation revealed poorly developed auricles, bi- lateral epicanthal folds, generalized hyper- extensibility, loose skin, a short proximal phalanx of the fifth finger, and an abnormal palmar crease on the left. An echocardio- gram demonstrated a large atrial septa1 de- fect, and an echoencephalogram demon- strated a Dandy-Walker malformation and an absent corpus callosum.

Her postnatal course was marked by fail- ure to thrive and recurrent unexplained fe- brile episodes. At age 5 months, she had a ventriculo-peritonedl shunt placed to allevi- ate progressive hydrocephalus. She was placed on phenobarbital to control seizures. Neurodevelopmental examinations consist- ently demonstrated global hypotonia and severe generalized developmental delay. She died suddenly at the age of 29 months from aspiration of gastric contents.

At autopsy, she had two strictures in the small intestine and one in the large intestine which may have been the result of amoebia-

P A R T I A L 2 q M O N O S O M Y 387

3

7 7

Fig. 1. Chromosomes no. 2 and 7 of the fathsr (A) and the proband (B). A)46,XY, inv(9). t(2:7) (q32.2;pll). B) 46,XX. dei(2)(q13;q21).

sis. Staining and immunodiflusion tech- niques to demonstrate amoebae were unsuc- cessful.

There were bilateral pulmonary artery thrombi, and the lungs had two lobes on the right and one on the left. The heart had a large atrial septa1 defect.

The brain demonstrated a Dandy-Walker malformation, with partial agenesis of the cerebellar vermis, dilatation of the fourth ventricle, and an overlying 3-cm cyst. The cerebellar vermis was absent inferiorly, but present superiorly. The foramina of Lusch- ka and Magendie were patent. The corpus callosum was entirely absent and the third

Fig. 2 Chromosome no. 2 of proband with breakpoints indicated by arrows.

losum. The lateral ventricles were not en- larged at the time of autopsy. Microscopic examination revealed a small subacute cere- bellar infarct, but no heterotopias or other developmental anomalies.

Microscopic sections of the ovaries dem- onstrated a connective tissue layer with underlying ovarian stroma (Fig. 3). There were tubules and morula-like structures with a single layer of follicular epithelium; there were also a few scattered structures reminiscent of ovarian follicles. Some of these had a double layer of follicular epithe- lium and contained eosinophilic material, suggestive of degenerated ova. There were no viable primary follicles.

ventricle was dilated. The lateral ventricles were turned upwards at the lateral comers and there were prominent Probst’s bundles, characteristic of agenesis of the corpus cal-

Cytogenetfc Findings

Chromosomal analysis was performed on the proband and her parents. The proband

388 D A V I S E T A L .

Fig. 3. Photomicrograph of rtreek ovaries showing stroma. as well as several structures rernlniscent of ovarian follicles. No viable oocytee are present. (Magnification 9350X).

was found to have an interstitial deletion of chromosome no. 2 (Fig. 1 b). Her karyotype is 46,XX,de1(2)(q13q21).

The father’s karyotype is 46,XY, inv(g),t(2;7)(q32.2;~11) (Fig. la). In ad- dition to the balanced translocation involv- ing chromosomes 2 and 7, there is also a pencentric inversion of chromosome 9, which is a normal variant observed in ap- proximately 2% of individuals who have karyotype analysis (Hsu 1986).

The mother has a normal 46,XX karyo- type.

Dlrcussion

Interstial deletions of the long arm of chro- mosome 2 are rare cytogenetic abnormali- ties. The paucity of reported cases could be due to their low frequency, their lethality, or both. We are aware of two other patients

described previously who had the same breakpoints as the child reported here (Ger- man et al. 1973, Lucas et al. 1987). The infant reported by Lucas et al. had craniosy- nostosis, frontal bossing, hypcrtelorism, downslanting palpebral fissures, low-set cars, and a short nose with a broad, de- pressed nasal bridge. Karyotype was 46,XX,de1(2)(q 14q21). The child reported by German et al. was described as mildly retarded, microcephalic, dysmorphic, and having an abnormal gait. There are several previous reports of individuals with more proximal (Antich et al. 1983) and more dis- tal deletions (Al-Awadi et al. 1983, Benson et al. 1986, Fryns et al. 1977, Taysi et al. 1981), but the clinical features of these re- ported cases do not allow for recognition of a distinctive pattern of anomalies. A recent review details the cytogenetic findings in cases of chromosome 2 deletion (Palmer et al. 1990).

P A R T I A L 2 q M O N O S O M Y 389

Ovarian dysgenesis has not been reported previously in patients with interstitial de; letions of chromosome 2. This finding is common in individuals with trisomy for chromosomes 13, 18, (Kennedy et al. 1977) and 21 (Hojager et al. 1978), as well as for individuals with the 45,X karyotype. Inves- tigations of meiotic pairing in the ovaries of patients with trisomy 21 (Speed 1986) and with 45,X (Speed 1986) suggest that abnor- malities of prophase pairing may be respon- sible for the atresia of oocytes seen in these individuals. Ovarian dysgenesis has also been reported in interspecific mammalian hybrids (Taylor & Short 1973) and in ter- tiary trisomic mice (Setterfield & Mittwoch 1986), which further suggests that chromo- somal imbalance is responsible for ovarian dysgenesis as a result of meiotic pairing ab- normalities.

The proposita has an interstitial deletion of chromosome no. 2, the breakpoints of which are not the same as the breakpoint of chromosome no. 2 involved in the trans- location observed in the father. Because the breakpoints are different between the father and the proband, a direct causal relation- ship cannot be conclusively established. The deletion may be due to an independent event, in which case the translocation in- volving the same chromosome in the father is a coincidental finding. There are reported cases of unstable translocations which result in unexpected karyotypes in the offspring of the carriers (Siffroi et al. 1988), but it is difficult to postulate a mechanism by which this might occur in the present case. It is of interest that the chromosome 2 breakpoints which are present in both the proband and her father are regarded as common fragile sites (Palmer et al. 1990), but it is contro- versial whether the association of fragile sites and sites of breakage of constitutional abnormalities represents a causal relation-

Acknowledgement

This work was supported, in part, by the NIH grant AM-07318.

References

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Address: E. Davis, M . D. U.C.S.D. Medical Center Department of Potho fogy

225 W Dickinson Street San Diego. CA 92103, USA

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