Oculocerebral svndrome with hypopigmentat[on (Cross syndrome): report of a new case

Lerone M, Pessagno A, Taccone A, Poggi G, Romeo G, Silengo MC. Oculocerebral syndrome with hypopigmentation (Cross syndrome): re- port of a new case. Clin Genet 1992: 41: 87-89.

A syndrome of ocular and cutaneous hypopigmentation, severe mental retardation with spastic tetraplegia and athetosis was first observed by Cross in three siblings of an inbred Amish family. Since then, seven other patients, three.sporadic and four with familial recurrence, have been reported in the literature, confirming the autosomal recessive inheritance. The clinical spectrum of the syndrome has been expanded to include true developmental defects of the CNS such as cystic malformation of the posterior fossa of the Dandy-Walker type. We report a new case of Cross syndrome.

In 1967, Cross et a]. reported three siblings born to consanguineous parents and affected with a unique oculocerebral syndrome characterized by cu- taneous hypopigmentation resembling albinism, ocular anomalies, mental retardation and spastic tetraplegia. Since then, only five other reports deal- ing with this syndrome have been published (Pas- sarge & Fuchs-Reche 1975, Preus et a]. 1983, Pat- ton et al. 1987, Fryns et a]. 1988, Courtens et al. 1989). We report here a new sporadic case.

Case report

L.A. is a 20-month-old infant male, with an unre- markable family history. Both parents are healthy and consanguinity is denied. No common ancestor could be traced up to the fourth generation. A 12- year-old brother is in good health.

L.A. was the full-term product of an uncom- plicated pregnancy and delivery. Birth weight was 3580 g, length 51 cm, and OCF 33 cm. He was in good health until 3 months of age when seizures began and early signs of developmental retardation were first detected.

Physical examination at 20 months of age showed: weight 10.2 kg (10th-25th percentile), height 80 cm (3rd-10th percentile), and head cir- cumference 43 cm (below 3rd percentile). The fol- lowing findings were observed: hypopigmentation

M. Lsrons', A Psssagno', A T a c c ~ n a ~ , 6. Poggi', 6. ROIU~O' and M. C. Silsngo' 'Ambutatorio di Genetim Medica, *Divisione di Neuropsichiatrii Infantile and %rvbio di Radiologia, lstituto G. Gaslini. Genova Italy

Key words: autosomal recessive inheritance - Cross syndrome - Dandy-Walker malformation - mental retardation - owlocutaneous hypopig- mentation Dr. M. C. Silengo, Laboratorio di Genetica Moleco- lare, lstituto G. Gaslini, largo G. Gaslini, 5, 1-1 61 48 Genova, Italy Received 22 April, revised 22 July, accepted for publication 24 July 1991

of hair manifested by the presence of strands of white hair mingled with normal colored hair all through the scalp (Fig. l), microcephaly, hypertro- phied gingivae and oral frenula, high-arched pal- ate, and microdontia. Psychomotor development was severely retarded; normal milestones have never been achieved. Infantile myoclonic seizures were not controlled by anti-convulsant therapy. Spastic tetraparesis with hyperactive tendon re- flexes was observed. Both thumbs were adducted and the hands showed distal tapering of fingers and bilateral simian creases. Ophthalmological examination revealed intermittent strabismus and nystagmus. An albinoid aspect of the retina was observed at fundoscopy, a finding which has been confirmed by three ophthalmologists who have examined the child at different ages. Visual evoked potentials and an electroretinogram showed mark- edly reduced voltages.

Electroencephalography showed a generalized hypsarrhythmic pattern. Electromyography showed aspecific neurogenic signs. The sensory and motor conduction velocities were normal. Mag- netic resonance imaging of the brain demonstrated ventricular dilatation and a posterior fossa cyst with cerebellar hypoplasia, consistent with Dandy- Walker malformation (Fig. 2).

Skeletal survey revealed generalized, severe oste- oporosis.

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Fig. 1. Phenotype of the patient, illustrating the microcephaly and the dyschromic changes of the hair.

Fig. 2. MRI of the brain demonstrating cortical atrophy, cere- beIlar hypoplasia with posterior fossa cyst and hydrocephalus.

Plasma and urine aminoacids, lysosomal en- zymes, urinary excretion of mucopolysaccharides and oligosaccharides, tests for intrauterine infec- tions, and blood karyotype were normal or nega- tive. The parents refused permission for a skin biopsy. Microscopic examination of the hair showed aspecific reduction of the pigment (Fig. 3).

Discussion

Our patient presents all the major features of the oculocerebral syndrome with hypopigmentation, first described by Cross et al. (1967) in three sib- lings of an inbred Amish family. Such characteristic features are: hypopigmentation manifested by the albinoid fundus and by the presence of a few strands of white hair, severe mental retardation, spastic tetraparesis, cerebellar hypoplasia with Dandy-Walker malformation, abnormalities of the tongue and the gingivae, microdontia and general- ized osteoporosis.

Since the first report by Cross et al. in 1967, only five other reports dealing with this syndrome have been published; three of the reported patients were

sporadic cases, four were familial and included two set of siblings of consanguineous parents, support- ing an autosomal recessive mode of inheritance. Including our patient, a total of 11 patients are known; three of them are Italian. The scarcity of these reports and the high rate of parental consan- guinity indicate that the Cross syndrome is rare. However, a bias of ascertainment of patients with severe hypopigmentation might play a significant role. The normal skin pigmentation and the mild dyschromic changes in the scalp hair observed in our patient, suggest the existence of wide clinical variability with regard to the severity of hypopig- mentation.

The presence of development malformations of the central nervous system, such as cerebellar hypo- plasia and the Dandy-Walker anomaly, revealed by the CT scan of the brain in the cases reported by Fryns and Preus, seem to indicate that the Cross syndrome is a true multiple congenital anomalies/ mental retardation syndrome. Our case further supports this hypothesis. Neurones and melano- cytes are embryologically derived from the same origin in the neuroectoderm. Abnormalities in the

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process of neural crest migration might be the cause for both the CNS malformations and the pigmentary changes.

Referencss Courtens W, Broeckx W, Ledoux M, Vamos E. Oculocerebral

hypopigmentation syndrome (Cross syndrome) in a Gipsy child. Acta Paediatr Scand 1989: 78: 806-810.

Cross HE, McKusick VA, Breen W. A new oculocerebral sYn- drome with hypopigmentation. I Pediatr 1967: 70: 398406.

Fryns JP, Dereymaeker AM, Heremann G, Marien J, Hauwaert J van, Turner G, Hockney A. Berghe H van den. Oculocereb- ral syndrome with hypopigmentation (Cross syndrome). Re- port of two siblings born to consanguineous parents. Clin Genet 1988: 34: 81-84.

Passarge E. Fuchs-Reche S. Oculocerebml syndrome with hy- popigmentation. Birth Defects: Original Article Series 1975: XI: 466-467.

Patton RA, Baraitser R, Heagherty AMR, Eddy RAJ. An oculocerebral hypopigmentation syndrome: a case report with clinical, histochemical and ultrastructural findings. 1 Med Genet 1987: 24: 118-122.

Preus M, Fraser FC, Wingleswort FW. An oculocerebral hypo- pigmentation syndrome. J Genet Hum 1983: 31: 323-328.

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