Cerebral-Cerebellar-Coloboma Syndrome, X-Linked

Clinical Features

Van Royen-Kerkhof et al. (1998) reported a nonconsanguineous family of Indonesian and white Dutch ancestry in which 2 brothers had a Joubert (see 213300)-like syndrome, and 1 of the brothers and a sister also had type I Gaucher disease (230800). Joubert syndrome was initially diagnosed in the proband based on the presence of episodic hyperpnea/apnea, agenesis of the cerebellar vermis and corpus callosum, hydrocephalus, and chorioretinal coloboma. Severely delayed psychomotor development and generalized seizures were major clinical features until death at 4 years of age. Postmortem lysosomal enzyme studies unexpectedly showed severe deficiency of glucocerebrosidase activity in cultured skin fibroblasts, and he was found to be compound heterozygous for the most common glucocerebrosidase mutations in the Netherlands, N370S (606463.0003) and L444P (606463.0001). His younger sister, who had mental retardation and autistic behavior with a normal MRI of the brain at 7 years of age, was also found to have Gaucher disease. The proband's younger brother, who 'fulfilled the diagnostic criteria' for Joubert syndrome, died at 8 months of age.

Kroes et al. (2005) restudied the family reported by Van Royen-Kerkhof et al. (1998), which then included 2 more sibs, both born after artificial donor insemination: a healthy girl and a third affected boy. The boy had hydrocephalus and a Dandy-Walker malformation on prenatal ultrasound, confirmed by MRI which also showed an abnormally smooth cortical surface; the infant died immediately after delivery. Autopsy showed macrocephaly, slight frontal bossing, and low-set, posteriorly rotated ears. Eyes were not examined. There was aberrant origin of the right subclavian artery, 13 ribs on both sides, and Meckel diverticulum. Examination of the brain showed severe hydrocephalus, absent cerebellar vermis with a cyst-like structure in the posterior fossa, and a wide fourth ventricle. There was no separation of brainstem structures, and the medulla oblongata was abnormally shaped with dorsoventral flattening and absent posterior raphe. Histologic examination showed loss of Purkinje cells in the cerebellar hemispheres and cerebellar cortical dysplasia, with focal disorganization of the upper cortical layers of the cerebral cortex and extensive leptomeningeal heterotopia. Kroes et al. (2005) stated that on the basis of brain anomalies alone, it was not certain that the 3 cases represented the same disorder, although the pedigree was suggestive of X-linked inheritance. The authors concluded that the phenotype was distinct from Joubert syndrome, citing the absence of the molar tooth sign and the presence of additional supratentorial brain malformations, and proposed the designation 'X-linked cerebral-cerebellar-coloboma syndrome.'