DK Phocomelia Phenotype (von Voss-CherstvoySyndrome) Caused by Somatic Mosaicismfor del(13q)

J.S. Bamforth1* and C.C. Lin2

1Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada2Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada

DK phocomelia (von Voss-Cherstvoy syn-drome) is a rare condition characterized byradial ray defects, occipital encephalocoele,and urogenital abnormalities. Lubinsky etal. [1994: Am J Med Genet 52:272–278]pointed out similarities between this andthe del(13q) syndrome. To date, all reportedcases of DK phocomelia have been appar-ently normal chromosomally. We report on acase of DK phocomelia in which theproposita had normal lymphocyte chromo-somes, but was mosaic in fibroblasts fordel(13)(q12). Fibroblast chromosomes stud-ies on other cases of DK phocomelia havenot been reported: this raises the possibilitythat some cases of DK phocomelia may besomatic mosaics for del(13)(q12). Am. J.Med. Genet. 73:408–411, 1997.© 1997 Wiley-Liss, Inc.

KEY WORDS: DK phocomelia; del(13q)

INTRODUCTION

DK phocomelia syndrome is a rare condition com-prising radial ray defects, occipital encephalocoele, andurogenital abnormalities. It is usually lethal neona-tally, although long term survivors have been de-scribed [Urioste et al., 1994]. The pathogenesis andcause of this condition is not known. Nearly all caseshave been sporadic.

CLINICAL REPORT

The proposita was 8 years old. She was the secondchild of a nonconsanguineous Caucasian couple. Thepaternal age at birth was 33 and the maternal age was29 years.

The pregnancy was complicated by intrauterine

growth retardation in the third trimester. Delivery wasby Cesarean section for fetal distress.

The birth weight at 41 weeks of gestation was 2,150g (−3 SD), length 45 cm (−2 SD) and the OFC 30 cm (−4SD). There was a small parieto-occipital encephalo-coele in the midline. The face was asymmetric withflattening of the right side and elevation of the rightear. The left palpebral fissure appeared shorter thanthe right. The ears were posteriorly angulated. In theupper limb, there was absence of the right fifth finger,

*Correspondence to: J.S. Bamforth, B-139 CSB, 8440-114Street, Edmonton, Alberta, Canada, T6G 2B7.

Received 14 November 1996; Accepted 16 June 1997Fig. 1. Frontal view of face. Note low anterior hair line, mild midface

hypoplasia, wide gap between incisors, and open mouth.

American Journal of Medical Genetics 73:408–411 (1997)

© 1997 Wiley-Liss, Inc.

hypoplasia of the thumb, and a single palmar crease.On the right, there was hypoplasia of the fifth fingerwith dislocation. The right thumb was of normal size.The nasal bridge was broad. The hips were dislocated.The feet were narrow with long vertical creases on thesoles. The anus was displaced anteriorly.

During the first year, she fed poorly and regurgitatedconstantly. She developed renal pelvi-ureteric junctionobstruction that required surgical relief. By 15 monthsof age, the facial asymmetry had resolved. When herhair started to grow, she had bald patches.

At age 9 years, the child developed seizures. She canwalk with assistance indoors, but requires a wheel-chair outdoors. She is not able to speak nor is she bowelor bladder trained. She is very sociable and able todistinguish her parents from other persons. She has aboisterous sense of humor toward people with whomshe is familiar. She manages to make her likes anddislikes known through various gestures and will per-mit or refuse physical examination depending on herlike or dislike of the physician. On examination she hada low anterior hairline, mild midface hypoplasia, hairwhich extended onto the lateral side of the face, and awide gap between the central incisors (Figs. 1,2). Therewas thinning of the hair over the scalp (Fig. 3). Thehand and foot anomalies were unchanged (Figs. 4,5).

INVESTIGATIONS

Blood karyotype was normal on routine and highresolution G banding analysis. At 7 years, chromosome

analysis was undertaken on a skin biopsy. A total of 50cells was analyzed. In 5 cells, 1 normal chromosome 13was replaced by a small marker chromosome with akayotype of 46,XX,−13,+mar. The remaining 45 cellshad a normal female karyotype. A repeat cytogeneticstudy from a skin biopsy of a different site showed all2 0 c e l l s e x a m i n e d h a v i n g t h e k a r y o t y p e46,XX,−13,+mar (Fig. 6A). The marker chromosomeappeared to be derived from an acrocentric chromo-some, but was negative with Ag-NOR staining (Fig.6B). FISH study with a chromosome specific total chro-mosome painting probe revealed strong hybridizationsignal on the normal chromosome 13 and the markerchromosome (Fig. 6C,D). The marker chromosome wastherefore identified as a deleted chromosome 13 with abreak point at q12. We thus conclude that the patienthas somatic mosaicism 46,XX/46,XX,−13,+del(13)(q12)expressed predominantly in the mesoderm line.

DISCUSSION

Twelve cases of von Voss-Cherstvoy syndrome werereported [von Voss et al., 1979; Cherstvoy et al., 1980;Kunze et al., 1992; Froster-Iskenius and Meinecke,1992; Lubinsky et al., 1994; Urioste et al., 1994]. Thecases of Kunze et al. [1992] and Froster-Iskenius andMeinecke [1992] were not published as DK phocomelia,but are considered to be cases of this condition by Lu-binsky et al. [1994].

The condition is listed under presumed autosomalrecessive inheritance in OMIM. This supposition is

Fig. 2. Lateral of face. Note midface hypoplasia, hair extending ontolateral side of face, posteriorly rotated ears, and thinning of hair overtemples.

Fig. 3. View of crown showing thinning of hair over scalp.

DK Phocomelia and del(13q) 409

based on parental consanguinity in 2 cases, togetherwith a recurrence in 1 of these cases. However, 10 of 12published cases did not report consanguinity or bonafide recurrence. New dominant mutation of a putativegene remains a possibility that is difficult to prove,although there is no supporting evidence from tradi-tional indicators such as advanced paternal age or go-nadal mosaicism.

The cause of DK phocomelia has been elusive. Lu-binsky et al. [1994] commented on the overlap of theDK phocomelia phenotype with the phenotype of dele-tion of critical region of 13q32 [Brown et al., 1993]. The

conditions share the propensity toward neural tube de-fects; similar limb defects with a preponderance for ra-dial defects; genito-urinary defects of various kinds.

We are not aware that fibroblast karyotyping hasbeen performed in any previously reported cases of DKphocomelia. It is tempting to suggest that at least someof these cases may be due to somatic mosaicism fordel(13q) confined to a mesodermal line. Such ananomaly would likely arise spontaneously as a postzy-gotic event by a mechanism similar to that causingPallister-Killian syndrome (mosaic tetrasomy 12p)[Pallister et al., 1977]. We suggest fibroblast karyotyp-

Fig. 4. View of hands showing ab-sent fifth finger on the right, and re-duction of left fifth finger.

Fig. 5. View of feet showing pesplanus. Note vertical groove on rightsole.

410 Bamforth and Lin

ing of suspected DK phocomelia cases in order to see ifthis observation is confirmed.

REFERENCES

Brown S, Gerson S, Anyane-Yeboa K, Warburton D (1993): Preliminarydefinition of a ‘‘critical region’’ of chromosome 13 in q32: Report of 14cases with 13q deletions and review of the literature. Am J Med Genet45:52–59.

Cherstvoy E, Lazjuk G, Lurie O, Ostrovskaya T, Shevd O (1980): Syndromeof multiple congenital malformations including phocomelia, thrombo-cytopaenia, encephalocoele and urogenital abnormalities. Lancet ii:485.

Froster-Iskenius U, Meinecke P (1992): Encephalocele, radial defects, car-diac, gestational, anal and renal anomalies: A new multiple congenitalanomaly (MCA) syndrome? Clin Dysmorphol 1:37–41.

Kunze J, Huber-Schmacher S, Vogel M (1992): VACTERL plus hydroceph-alus: A monogenic lethal condition. Eur J Pediatr 151:467–468.

Lubinsky MS, Kahler SG, Speer IE, Hoyme E, Kirillova IA, Lurie IE(1994): von Voss-Cherstvoy syndrome: A variable perinatally lethalsyndrome of multiple congenital anomalies. Am J Med Genet 52:272–278.

Pallister PD, Meisner LF, Elejalde BR, Francke U, Herrmann J, SprangerJ, Tiddy W, Inhorn SL, Opitz JM (1977): The Pallister Mosaic Syn-drome. New York: Alan R. Liss Inc., for the National Foundation–March of Dimes. BD:OAS XIII (3B):103–110.

Urioste M, Paisan L, Martı́nez-Frı́as M (1994): DK-phocomelia syndromein a child with a long standing follow up. Am J Med Genet 52:269–271.

von Voss H, Kramer HG, Gobel U, Kemperdick H (1979): Phocomelie,Menigoenzephalozele und hypoplatische Thrombocytopenie, ein neuesSyndrom? In ‘‘Klinische Genetik in der Pädiatrie.’’ I. Symposion Kiel,Juli 1978: George Thieme, pp 70–74.

Fig. 6. Chromosome analysis using trypsin G-banding, Ag-NOR staining and FISH with chromosome 13 total chromosome DNA painting probe. A:G-banded karyotype shows that one of the chromosome 13 is replaced by a small marker chromosome (indicated by an arrow). B: Metaphase withAG-NOR staining. The marker chromosome is AG-NOR negative (indicated by an arrow). C,D: FISH study with digoxigenin-labelled COATASOME 13total chromosome probes from ONCOR. A metaphase spread was stained with a mixture of DAPI and propidium iodide following the hybridizationprocedure and observed under the filter combinations suitable for each of these fluorochromes. The marker chromosome is clearly observed (indicated byan arrow) with DAPI fluorescence (C). Both the marker chromosome and the chromosome 13 (indicated by arrows) show strong hybridization signals withFITC fluorescence in the same metaphase (D).

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