SG17 Familial progressive hyper- and hypopigmentation due to a novel variant in KITLG

Abstract

Familial progressive hyper- and hypopigmentation (FPHH) is a rare autosomal dominant condition caused by pathogenic variants in the KIT ligand gene (KITLG). Here, we report an 8-year-old girl who was noted in infancy to have an increasing number of café au lait patches. On examination, she also had multiple macular depigmented lesions. Her initial presentation was thought likely to represent neurofibromatosis type 1; however, no abnormalities were detected in NF1, SPRED1 or mismatch repair genes (MLH1, MSH2, MSH6, PMS2). Further investigation of 79 genes associated with pigmentary disorders identified a variant in KITLG, c.325G>A, p.Asp109Asn, not previously reported in association with FPHH. Parental testing confirmed this was a de novo variant. Following multidisciplinary team discussion, this variant was considered highly likely to be disease causing. Our patient has since developed further pigmentary changes, with no other medical issues, including extracutaneous involvement or hearing loss. To date, 10 pathogenic variants in KITLG have been associated with FPHH. Most lie within a beta-strand in the N-terminal domain of stem cell factor (SCF), which interacts with the c-KIT receptor tyrosine kinase. The variant identified in our patient lies adjacent to this beta-strand. Additional KITLG mutations are associated with Waardenburg syndrome and nonsyndromic hearing loss. While pathogenic variants causing FPHH are thought to enhance SCF activity, leading to increased melanocyte production and survival, the mechanism underlying hypo­pigmentation remains unclear. No fertility issues or other extracutaneous manifestations have been reported in association with FPHH. This report broadens the spectrum of mutations associated with FPHH. In this case, molecular diagnosis positively influenced management by clarifying reproductive and familial risk. The presentation in our patient suggests that FPHH may be underdiagnosed and should be considered in individuals investigated for NF1 presenting with early-onset pigmentary mosaicism.