Alternative titles; symbolsCOLOBOMA, OCULAR, WITH ICHTHYOSIS, BRAIN MALFORMATIONS, AND ENDOCRINE ABNORMALITIESCDG Iq; CDGIq▼ Clinical FeaturesAl-Gazali et al. (2...
Alternative titles; symbols
▼ Clinical Features
Al-Gazali et al. (2008) reported an inbred Emirati family of Baluch origin with ocular colobomas, ichthyosis, and endocrine abnormalities associated with midline brain malformations and mental retardation. All 4 affected children had ocular colobomas, developmental delay, and midline brain malformations. Hypoplasia of the pituitary gland was found in the 3 children who underwent brain MRI, and ichthyosiform dermatitis appeared in infancy in 3 surviving children. Variable features included congenital heart defects, hypertrichosis, and dark skin of the dorsum of hands and feet associated with a mild degree of palmoplantar keratoderma. This phenotype overlaps that of the CHIME syndrome (280000), but the authors noted several features present in CHIME that were not present in these patients, including deafness, seizures, oligodontia, and hair abnormalities. There is also some overlap with septooptic dysplasia (182230), but only 1 child in this family had optic nerve hypoplasia, which is mandatory for that diagnosis. Al-Gazali et al. (2008) suggested that this family's phenotype represented a distinct autosomal recessive syndrome of ocular coloboma and ichthyosis.
Cantagrel et al. (2010) identified 6 additional families with the same phenotype described by Al-Gazali et al. (2008). The most striking features were congenital eye malformations, such as ocular coloboma or hypoplasia of the optic disc, variable visual loss, nystagmus, hypotonia, motor delay, mental retardation, and facial dysmorphism. Brain abnormalities included cerebellar atrophy or vermis malformations. Some patients had ichthyosiform erythroderma or congenital heart defects. Nine patients who were evaluated had microcytic anemia, increased liver enzymes, coagulation abnormalities, and decreased antithrombin III (SERPINC1; 107300).
▼ Biochemical Features
Using laboratory studies of transferrin, Cantagrel et al. (2010) demonstrated a type 1 glycosylation defect in affected individuals of the family reported by Al-Gazali et al. (2008). Biochemical analysis of this and other affected families showed that the metabolic block occurred early in the N-glycosylation pathway, altering synthesis or transfer of the glycan part of lipid-linked oligosaccharide (LLO) to recipient proteins. In vitro assays indicated that the amount of the lipid carrier dolichol-phosphate (Dol-P) was limited.
By genomewide linkage analysis of the family reported by Al-Gazali et al. (2008), Cantagrel et al. (2010) mapped the disease locus to a 53.8- to 57.4-Mb interval on chromosome 4q12 (lod score of 4.2) encompassing 42 genes.
▼ Molecular Genetics
By linkage analysis followed by candidate gene sequencing of a family reported by Al-Gazali et al. (2008), Cantagrel et al. (2010) identified a homozygous mutation in the SRD5A3 gene (611715.0001). Analysis of similarly affected families identified 6 others with homozygous or compound heterozygous SRD5A3 mutations (see, e.g., 611715.0002-611715.0005). Altogether, there were 11 affected children from 7 families. The mutation spectrum was consistent with a loss of function of SRD5A3. Four families with the CHIME syndrome tested negative for SRD5A3 mutations.