Genetics Underlying Rare Syndrome Identified

Ricki Lewis, PhD

February 28, 2017

A newly identified severe congenital syndrome of deafness, blindness, albinism, and dense fragile bones can arise when two people, each of whom have a rare, specific form of deafness, have children, according to a report published in the American Journal of Human Genetics.

Aman George, PhD, from the Ophthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, Maryland, and colleagues call the syndrome COMMAD, which stands for coloboma (ocular holes), osteopetrosis (dense bones), microphthalmia (small eyes), macrocephaly (large head), albinism, and deafness.

Each of the two children in whom the syndrome was identified has two different recessive mutations of the gene that encodes microphthalmia-associated transcription factor (MITF). Researchers previously knew that mice with two recessive mutations in the MITF gene have impaired development of melanocytes, retinal pigment epithelium, mast cells, and osteoclasts, but human cases had not been seen before.

Mutations in MITF are known to cause two dominant conditions in humans with "highly overlapping" symptoms. Waardenburg syndrome type 2A (WS2A) is associated with abnormal hair, skin, and eye color and congenital sensorineural hearing loss. A different dominant mutation in MITF causes Tietz syndrome, which also causes incomplete albinism and hearing loss, as well as lack of eyebrows. The dominant mutations affect melanocytes in the skin and the cochlea.

The first patient, a 5-year-old boy, is blind as a result of colobomatous microphthalmia (small eyes missing some structures), small corneas covered with fibers, and cataracts. He also has translucent irides, profound sensorineural hearing loss, and no pigment in the eyes, skin, or hair. He has facial anomalies (shallow orbits, posteriorly rotated ears, preauricular pits, and frontal bossing), macrocephaly, and osteopetrosis. The small eyes were detected on ultrasound, but the pregnancy was uneventful.

The boy's parents each have blue irides, a fair complexion, premature graying, and sensorineural hearing loss. One sibling resembles the parents, and another is unaffected.

The second patient, a 9-month-old girl, has the same symptoms as the boy. Her three siblings resemble her parents, who, like the boy's parents, have blue irides, a fair complexion, and sensorineural hearing loss. Both sets of parents are nonconsanguineous, although that is not an issue because each child has two different mutations.

The researchers sequenced the MITF genes in both children because of the severity of symptoms and the similarity to mice that are homozygous recessive for mutations in the gene, and because the parents' phenotype matched that for individuals with one mutation in the gene. The parents do not have osteopetrosis, macrocephaly, microphthalmia, or colobomata, nor did they know that they had WS2A.

Cell culture experiments that tagged the MITF protein from the boy with green fluorescent protein revealed that the abnormal form could not enter nuclei, nor could it bind DNA. Experiments using zebrafish embryos demonstrated that the disabled transcription factor impairs melanocyte migration, differentiation, and survival, which is consistent with the complete albinism seen in the two children.

The severe ocular anomalies could result from effects on the retinal pigment epithelium and the neural retina. "Our study provides evidence that MITFmutations can cause colobomatous microphthalmia in humans," the researchers conclude.

The identification of these two cases of COMMAD should alert clinicians to the risk for children whose parents have partial albinism and hearing loss, although all three conditions are extremely rare.

"Description of this syndrome is perhaps particularly important, given that intermarriage within the deaf community is relatively common, and neither set of parents in this study recognized they had WS2A prior to having their child with COMMAD," the researchers conclude.

A comprehensive dilated eye exam can reveal the ocular developmental anomalies that would suggest genetic testing to rule out either WS2A or Tietz syndrome. They advise genotyping individuals who might have either syndrome and providing genetic counseling on risks to offspring if heterozygotes plan to have children together.

The paper was published in the December 2016 issue of the journal but is being highlighted this week by the National Eye Institute in honor of Rare Disease Day.

The authors have disclosed no relevant financial relationships.

Am J Hum Genet. 2016;99:1388-1394. Abstract

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