Cerebral Dysgenesis, Neuropathy, Ichthyosis, And Palmoplantar Keratoderma Syndrome

A number sign (#) is used with this entry because cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome (CEDNIK syndrome) is caused by homozygous mutation in the SNAP29 gene (604202) on chromosome 22q11.

Description

CEDNIK (cerebral dysgenesis, neuropathy, ichthyosis, and keratoderma) syndrome refers to a unique constellation of clinical manifestations including microcephaly, severe neurologic impairment, psychomotor retardation, failure to thrive, and facial dysmorphism, as well as palmoplantar keratoderma and late-onset ichthyosis. Brain magnetic resonance imaging (MRI) shows various degrees of cerebral dysgenesis including absence of corpus callosum and cortical dysplasia. The syndrome has been found to be uniformly fatal between the ages of 5 and 12 years (Fuchs-Telem et al., 2011).

Clinical Features

Sprecher et al. (2005) described a clinical syndrome in 7 individuals from 2 unrelated consanguineous Arab Muslim families living in northern Israel. After a normal birth, the patients presented during the first 4 months of life with failure to thrive, roving eye movements, and poor head and trunk control. All patients had progressive microcephaly and facial dysmorphism consisting of elongated facies, downward-slanting palpebral fissures, mild hypertelorism, and flat, broad nasal root. Palmoplantar keratosis and ichthyosis appeared between 5 and 11 months of age. By 8 to 15 months, major developmental milestones were not achieved, and all patients had severe psychomotor retardation. Other features included hypoplastic optic discs and sensorineural deafness. MRI showed defects of the corpus callosum and cortical dysplasia with pachygyria and polymicrogyria. Skin biopsy showed clear vesicles in the spinous, granular, and stratum corneum layers, with retained glucosylceramides, suggesting abnormal lamellar granule maturation. Sprecher et al. (2005) concluded that this neurocutaneous syndrome results from abnormal vesicle trafficking, vesicle maturation, and vesicle fusion.

Fuchs-Telem et al. (2011) reported a brother and sister from a consanguineous Pakistani family who both required neonatal tube feeding and had dysmorphic facies with small fontanels, long pointed nose, and small chin, as well as ichthyosis, palmoplantar keratoderma, hearing loss, and severe developmental delay. Brain MRI revealed a small corpus callosum in both sibs as well as other abnormalities, including ventricular asymmetry and frontal cortical dysplasia in the sister and perisylvian polymicrogyria with extensive cortical malformation in the brother.

Mapping

By linkage analysis of families with CEDNIK syndrome, Sprecher et al. (2005) mapped the disorder to a 4-Mb region on chromosome 22q11.2 (maximum multipoint lod score of 4.85 at D22S446).

Molecular Genetics

In affected patients with CEDNIK syndrome, Sprecher et al. (2005) identified a homozygous mutation in the SNAP29 gene (604202.0001).

In a brother and sister from a consanguineous Pakistani family who had features consistent with CEDNIK syndrome, Fuchs-Telem et al. (2011) identified homozygosity for a 1-bp insertion in the SNAP29 gene (604202.0002) that was not found in 200 control chromosomes. DNA from other family members was not available.