Rare Disease Report

Two Rare Disorders Hide a Third: COMMAD Syndrome

FEBRUARY 28, 2017
Ricki Lewis, PhD
Two people in the world are known to have COMMAD syndrome, and they’re described in the December issue of the American Journal of Human Genetics.
COMMAD is an acronym for:
  • Coloboma (holes in various eye structures)
  • Osteopetrosis (abnormally dense bones)
  • Microphthalmia (small eyes)
  • Macrocephaly (large head),
  • Albinism (translucent eyes, white skin and hair)
  • Deafness
Brian P. Brooks, MD, PhD, clinical director and chief of the Pediatric, Developmental, and Genetic Ophthalmology Section of the National Eye Institute and colleagues describe two young children with the strikingly similar collection of symptoms. Tiny eyes on prenatal ultrasound were the first signs for a 5-year-old boy, and the other patient is a 9-month-old girl. They are unrelated.
Both children are compound heterozygotes – each has two different recessive mutations in a gene called MITF.
The paper calls the gene microphthalmia-associated transcription factor (MITF), but a few other sources term it melanogenesis-associated transcription factor. The latter better reflects the full phenotype, because malfunctioning melanocytes unite the manifestations. Melanocytes are simply cells that contain the pigment melanin, which is important not only in coloring the hair, skin, and eyes, but in the retina and the cochlea. Hence, the phenotype is blindness and deafness against a pale backdrop. Studies in mice, zebrafish embryos, and various cell types in culture reveal the underlying glitch in pigmentation.
What’s fascinating about COMMAD is that it is a third disease associated with one gene, and it has a different “mode of inheritance” from the other two.
The children inherited different recessive mutations from each parent, yet the parents have the same autosomal dominant condition, although they didn’t know it. The four each have Waardenburg syndrome type 2A, with very white complexions, blue eyes, premature graying, and profound sensorineural hearing loss. Some of the siblings of the two cases are fair and deaf like the parents.
A second autosomal dominant condition due to a MITF mutation is Tietz syndrome. It’s more severe than WS2A, and the few identified families might be part of a spectrum that includes both dominant disorders. Waardenburg syndrome https://ghr.nlm.nih.gov/condition/waardenburg-syndrome is also rare. The four types affect only 1 in 40,000 people, and account for only 2 to 5 percent of cases of congenital hearing loss. More than 35 mutations in MITF are known.
Team two mutations in a child, and the more severe COMMAD results. The children communicate using their sense of touch.
The practical take-away from the report is that clinicians should be alert to couples in which both people are deaf with fair skin, blue eyes and prematurely gray hair, and do a comprehensive dilated eye exam, the researchers advise. Certain ophthalmological signs will then indicate whom to follow up with genetic testing for telltale MITF mutations, and genetic counseling offered to discuss risk to offspring. 

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