Graying Of Hair, Precocious

Clinical Features

This trait is likely to have many causes. It is a feature of Book syndrome (112300), Waardenburg syndrome (193500), Lison syndrome (270750), and pernicious anemia. Probably a simple form of premature graying is inherited as a dominant. Hare (1929) described 9 affected in 5 generations, with 1 instance of male-to-male transmission. The hair began to turn at 17 or 18 years of age and was white at 25 or 26 years. In some persons with premature graying, black pigmentation of the eyebrows persists.

Pathogenesis

Steingrimsson et al. (2005) reviewed the evidence for incomplete melanocyte stem cell maintenance in hair graying, noting that the PAX3 (606597) and MITF (156845) genes encode key molecules that have been identified as helping to regulate the balance between melanocyte stem cell maintenance and differentiation.

Choi et al. (2008) presented evidence that hair graying is caused by defective migration of melanocyte stem cells into the hair bulb, which results in defective maintenance of pigmentation. RT-PCR studies showed absent or greatly reduced expression of key molecules in melanogenesis in the bulbs of human white hair compared to black hair. Downregulated genes included MITF isoform M (MITF-M), SOX10 (602229), PAX3, and tyrosinase (TYR; 606933). Since melanocyte stem cells exhibited markers for neural crest cells, such as SOX10, PAX3, and MITF-M, the results suggested that hair graying is caused by defective migration of these stem cells into the bulb area of hair, rather than loss of pigment production by these cells.

Animal Model

On the basis of studies of 'light,' a dominant mutant allele of the mouse 'brown' locus, Johnson and Jackson (1992) suggested that tyrosinase-related protein-1 (TRP1; 115501) be investigated as a candidate gene.

In horses, graying with age is an autosomal dominant trait associated with a high incidence of melanoma and vitiligo-like depigmentation. Pielberg et al. (2008) showed that the Gray phenotype is caused by a 4.6-kb duplication in intron 6 of STX17 (604204) that constitutes a cis-acting regulatory mutation. Both STX17 and the neighboring NR4A3 (600542) gene are overexpressed in melanomas from Gray horses. Gray horses carrying a loss-of-function mutation in the ASIP (600201) gene had a higher incidence of melanoma, implying that increased melanocortin-1 receptor signaling promotes melanoma development in Gray horses.