Sash1-mutated Pigmentary Phenotype
Zhou's group firstly screened selected genes in a 10·2-Mb region on chromosome 6q24·2-q25·2, which was once found to be responsible for a DUH-like phenotype, and then successfully identified the causal gene, SAM and SH3 domain containing 1 (SASH1), located at 6q24·3. Zhou's group further revealed that mutated SASH1 genes can upregulate expression of premelanosome and mature melanosome resident proteins (tyrosinase-related protein 1 and melanocyte protein) and melanosome transport protein to enhance the biosynthesis and transport of melanin in melanocytes. Many patients with SASH1-mutated pigmentary disorders have been reported (Table S2; see Supporting Information). Considering all these cases, SASH1 mutations appear to be associated with DUH-like or lentiginous phenotypes that are characterized by generalized lentigines predominantly on sun-exposed areas, accompanied by mottled hyper- and hypopigmentation (Figure 5).[38,39,41,42] Specifically, a homozygous SASH1 mutation can cause a new syndromic genodermatosis with multiple hypo- and hyperpigmented macules, alopecia, ungueal dystrophy, palmoplantar keratoderma and skin carcinoma.
Clinical features of a patient with SASH1-related lentiginous phenotypes. (a) Generalized lentigines predominantly present on the face and upper trunk (sun-exposed areas) and (b) can exhibit hyper- and hypopigmentation on the trunk and extremities.
DUH mostly overlaps with the SASH1-mutated phenotypes with diffuse lentigines and hypo- and hyperpigmented macules. Moreover, other lentiginous phenotypes such as late adult-onset Laugier–Hunziker syndrome, and other heritable syndromes, such as Peutz–Jeghers syndrome (OMIM 175200), LEOPARD syndrome (OMIM 151100) and Carney complex (OMIM 160980) should be included in the differential diagnosis.
Laser therapy can be considered as a treatment for lentigines in exposed areas if the patient believes the skin lesions definitely affect his or her quality of life, but the long-term benefits are not convincing. Regarding those with a homozygous SASH1 mutation, the risk of skin carcinoma should be a concern, and prenatal genetic diagnosis is an option for affected individuals.
The British Journal of Dermatology. 2017;177(4):945-959. © 2017 Blackwell Publishing