Coloboma, Osteopetrosis, Microphthalmia, Macrocephaly, Albinism, And Deafness

A number sign (#) is used with this entry because of evidence that a syndrome involving coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness (COMMAD) is caused by compound heterozygous mutation in the MITF gene (156845) on chromosome 3p13.

Clinical Features

George et al. (2016) reported an unrelated boy and girl born with severe microphthalmia, profound congenital sensorineural hearing loss, and lack of pigment in hair, skin, and eyes. Both also exhibited macrocephaly, and skeletal survey showed osteopetrosis, particularly of the anterior ribs and femoral heads. Additional features in the boy included coloboma, microcornea with pannus, dense bilateral cataracts, and translucent irides. Craniofacial dysmorphism included frontal bossing, shallow orbits, preauricular pits, and posteriorly rotated ears; the girl also had micrognathia and wide palatine ridges. MRI confirmed severe microphthalmia and showed hypoplasia of the optic nerves and chiasm. George et al. (2016) called the disorder COMMAD (coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness). The parents in both families had congenital sensorineural hearing loss, blue irides, fair skin, and premature graying of the hair, but did not display dystopia canthorum, consistent with Waardenburg syndrome type 2A (WS2A; 193500); the boy had 1 brother and the girl had 3 sibs who were affected similarly to the parents.

Molecular Genetics

In 2 unrelated children with COMMAD, born of parents who exhibited features consistent with MITF-associated Waardenburg syndrome type 2A, George et al. (2016) sequenced the MITF gene and identified compound heterozygous mutations in both children (156845.0003 and 156845.0010-156845.0012). The parents in both families were each heterozygous for 1 of the mutations, as were the probands' sibs who showed features similar to those of the parents. None of the heterozygous individuals exhibited osteopetrosis, macrocephaly, microphthalmia, or colobomata.