Shaheen Syndrome

A number sign (#) is used with this entry because of evidence that Shaheen syndrome (SHNS) is caused by homozygous mutation in the COG6 gene (606977) on chromosome 13q14.

Biallelic mutation in the COG6 gene can also cause congenital disorder of glycosylation type IIl (CDG2L; 614576), which has overlapping features.

Description

Shaheen syndrome is an autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly (summary by Shaheen et al., 2013).

Clinical Features

Shaheen et al. (2013) reported a large multiple consanguineous Saudi family in which 8 individuals had mental retardation associated with variable abnormalities suggestive of ectodermal dysplasia, including hypohidrosis with normal numbers of sweat glands resulting in episodic hyperthermia, enamel hypoplasia, and hyperkeratosis of the palms and soles. Hair and nails were normal. Two patients had borderline microcephaly (-2 SD). Isoelectric focusing of transferrin was normal. Four additional patients from 2 unrelated consanguineous families that shared the same tribal origin of the first family were subsequently identified. These 4 patients also had mental retardation, anhidrosis, palmoplantar keratosis, and acquired microcephaly. One of the 4 patients had normal dentition, and 2 had nonspecific hepatitis with mild to moderate elevation of liver enzymes and negative serology.

Haijes et al. (2014) suggested that the phenotype described by Shaheen et al. (2013) was a mild variant of CDG2L, and that the normal isoelectric focusing of transferrin may have resulted from residual COG6 enzyme activity. Alkuraya and Shaheen (2014) responded that the disorder described by them was 'significantly different' from that described in CDG2L, but agreed that allele specific pathogenicity may be a possible mechanism that explains the phenotypic difference.

Inheritance

The transmission pattern of mental retardation and hypohidrosis in the families reported by Shaheen et al. (2013) was consistent with autosomal recessive inheritance.

Mapping

By autozygosity mapping of a large consanguineous Saudi family with mental retardation and hypohidrosis, Shaheen et al. (2013) found linkage to a locus on chromosome 13q13.3-q13.11.

Molecular Genetics

In 12 patients from 3 consanguineous Saudi families with mental retardation and hypohidrosis, Shaheen et al. (2013) identified a homozygous splice site mutation in the COG6 gene (606977.0001), resulting in decreased levels of the COG6 and STX6 (603944) proteins. The mutation, which was identified by homozygosity mapping and exome sequencing, segregated with the disorder. Immunohistochemical analysis showed that COG6 is expressed in sweat glands, but skin biopsy from a patient showed normal structure and density, suggesting a functional defect. Isoelectric focusing of serum transferrin was repeatedly normal, showing no glycosylation defects.