Microcephaly, Cerebellar Hypoplasia, And Cardiac Conduction Defect Syndrome

Description

The Zaki-Gleeson syndrome is an autosomal recessive neurodevelopmental disorder characterized by profound mental retardation, severe microcephaly, poor growth, cerebellar hypoplasia, and second-degree cardiac conduction defects (summary by Zaki et al., 2011).

Clinical Features

Zaki et al. (2011) reported a consanguineous Egyptian family in which 3 sibs and a first cousin had a syndromic disorder apparent at birth and characterized by profound mental retardation, severe microcephaly (-8 to -11 SD), poor growth, dysmorphic facial features, cerebellar hypoplasia, and second-degree atrioventricular heart block. All showed severe psychomotor retardation, with no speech, sitting only with support, inability to grasp objects or feed themselves, and lack of sphincter control. They were hypotonic with brisk reflexes, truncal ataxia, intention tremor, and dystonic movements. The 3 older children showed autistic behavior. Dysmorphic facial features included broad forehead, thin long eyebrows, upslanting palpebral fissures, prominent nose, long philtrum, thin vermilion of the upper lip, prominent lower lip, and large ears with prominent antihelix. Hands and feet showed long fusiform fingers with bilateral campto- and clinodactyly of fifth fingers and crowded toes. Physical examination showed bradycardia and second-degree cardiac conduction defects, as well as vasomotor instability with prolonged capillary refill, skin mottling, and acrocyanosis. Brain imaging showed cerebellar hypoplasia, thin corpus callosum, simplified gyral pattern, and deep white matter abnormalities suggesting defective myelination. One child developed insulin-dependent diabetes mellitus and 2 showed impaired glucose tolerance. Molecular and linkage studies excluded the PTF1A (607194), EIF2AK3 (604032), EOMES (604615), and WDR62 (613583) genes.