British Association of Dermatologists Dermatology and Genetic Medicine (BADGEM)

BG01 Novel ADAR mutations in two cases of dyschromatosis symmetrica hereditaria S. O’Sullivan, S.M. Lwin, L. Liu, J. Lai-Cheong, J.A. McGrath and J.E. Mellerio St. John’s Institute of Dermatology, King’s College, Guy’s and St. Thomas’ Hospital, London, U.K.; Viapath, St Thomas’ Hospital, London, U.K. and King Edward VII Hospital, Windsor, U.K. Dyschromatosis symmetrica hereditaria (DSH) is a rare autosomal dominant disorder characterized by hyperand hypopigmentation predominantly affecting the dorsa of the distal extremities. It results from loss-of-function mutations in the ADAR gene that encodes the enzyme responsible for doublestrand breakage of RNA through deamination of adenosines. Case 1, a 6-year-old boy of Chinese ethnicity, had depigmentation affecting the dorsa of the hands, feet, arms and knees from age 18 months within which he developed progressive darker freckling. Facial hypopigmentation with freckling on the cheeks and forehead was present along with Blaschkolinear hypopigmentation of the left scapula and anterior chest. The skin texture, nails, hair, sweating and dermatoglyphics were normal. No family members were affected. Sanger sequencing revealed a novel heterozygous ADAR mutation not present in his parents, suggesting de novo occurrence. This single nucleotide transversion, c.1601+ 1G>T, within the consensus region of a donor splice site, is predicted to compromise splicing, potentially resulting in haploinsufficiency and is therefore highly likely to be pathogenic. Case 2, a 30-year-old man of Estonian origin, had skin dyspigmentation from age 5 years. Initially, his hands had darker, blotchy pigmentation and sun-induced hand swelling, reduced sweating and corneal opacification. Examination revealed mottled hyperand hypopigmentation, reduced dermatoglyphics, general xerosis with lichenification around the ankles and mild dental anomalies. There were no oral mucosal changes, hair or nail abnormalities. His features suggested Naegeli–Franceschetti–Jadassohn syndrome; however, KRT14 gene screening was negative. The proband had a persistently borderline low vitamin B12 (43 pmol L ); however, dyspigmentation did not improve with vitamin B12 supplementation. Subsequently, whole exome sequencing of his DNA identified a new heterozygous splice site mutation in ADAR, c.15+ 10G>T which in silico modelling suggests is pathogenic, supporting a diagnosis of DSH. ADAR mutations in DSH are mainly reported in the Asian population. ADAR enzymes are involved in regulation of the immune system with both cellular and viral editing capacities. The exact mechanism of ADAR1 in causing pigmentary changes seen in DSH is not yet fully known. Autosomal recessive ADAR mutations can cause Aicardi–Goutieres syndrome although the clinical features in skin and brain are related to inflammation arising from autoimmunity. Additionally, other cutaneous dyspigmentation diseases, including dyschromatosis universalis hereditaria, reticulate acropigmentation of Kitamura and Dowling–Degos disease, result from mutations in different, distinct genes indicating that multiple cellular mechanisms can give rise to similar cutaneous pigmentary phenotypes.