Cerebellar, Ocular, Craniofacial, And Genital Syndrome

A number sign (#) is used with this entry because of evidence that cerebellar, ocular, craniofacial, and genital syndrome (COFG) is caused by homozygous mutation in the MAB21L1 gene (601280) on chromosome 13q13.

Description

Cerebellar, ocular, craniofacial, and genital syndrome (COFG) is characterized by moderate to severe developmental delay and impaired intellectual development, severe cerebellar hypoplasia, a noticeably short forehead, medially sparse/flared and laterally extended eyebrows, corneal dystrophy, underdeveloped labioscrotal folds, and tufts of hair extruding from the lactiferous ducts with breast and nipple underdevelopment. Additional features such as pontine involvement, retinal degeneration, anteverted nares, and low-set ears have been variably observed (Rad et al., 2019).

Clinical Features

Silay et al. (2013) reported a 7-year-old Turkish boy, born of consanguineous parents, who had bilateral undescended testes and agenesis of the scrotum. His 16-year-old and 6-month-old sisters had complete agenesis of the labia majora. All 3 sibs had visual impairment and moderate hearing loss, and the boy was reported to have various dysmorphic features, significant cognitive impairment, and corneal dystrophy. Endocrinologic evaluation was normal in the sibs. The authors stated that this was the first report of sibs with absence of scrotum and labia majora, and noted that the additional findings suggested the presence of a genetic syndrome.

Kayserili et al. (2016) restudied the 3 Turkish sibs reported by Silay et al. (2013) and described a similarly affected 19-year-old Turkish man. All 4 patients exhibited microcephaly with distinctive facial features, including short forehead and laterally extended, medially flared eyebrows, as well as central corneal opacities, underdevelopment of labioscrotal folds, and nonprogressive pontocerebellar hypoplasia. In addition, the patients exhibited the unusual finding of hair extruding from the lactiferous ducts.

Bruel et al. (2017) described an 8-year-old Algerian boy with scrotal agenesis, dysmorphic facial features, corneal dystrophy, Dandy-Walker malformation, and global developmental delay.

Molecular Genetics

In an 8-year-old Algerian boy with cerebellar malformation, ocular anomalies, facial dysmorphism, and scrotal agenesis, Bruel et al. (2017) identified homozygosity for a 1-bp duplication in the MAB21L1 gene (601280.0001) that was present in heterozygosity in his unaffected first-cousin parents and not carried by his unaffected sisters.

Rad et al. (2019) studied 10 patients from 5 unrelated families with a strikingly similar syndromic labioscrotal aplasia phenotype, including the 2 Turkish families (families 4 and 5) reported by Kayserili et al. (2016), who were all homozygous for mutations in the MAB21L1 gene (see, e.g., 601280.0002-601280.0005) that were inherited from unaffected consanguineous parents. Rad et al. (2019) designated the disorder 'cerebellar, ocular, craniofacial, and genital syndrome (COFG).'