Incontinentia pigmenti (IP) is a disorder of the skin and its appendages, the eyes, and central nervous system (CNS) that occurs primarily in females and on occasion in males. IP is inherited in an X-linked manner. About 65% of affected individuals have IP as a result of a de novo pathogenic variant. Heterozygous, affected women have a 50% chance of transmitting the IKBKG pathogenic variant at conception; however, male conceptuses with an IKBKG loss-of-function variant miscarry. To date, the few cases of males with IP reported have had either a 47,XXY karyotype or somatic mosaicism for the IKBKG/NEMO pathogenic variant. A male with somatic and germline mosaicism may transmit the IKBKG/NEMO pathogenic variant to daughters. Disease pathophysiology is strictly dependent from a condition of cellular mosaicism due to the random X chromosome inactivation in female with IP and the cellular mosaicism in male with IP. In addition, it must be noticed that small hypomorphic mutations of the IKBKG/NEMO gene (missense, in-frame deletions, frameshifts, and splicing) that result in impaired, but not absent IKBKG/NEMO gene function, cause the Hypoidrotic Ectodermal Dysplasia with Immunodeficiency (EDA-ID, OMIM #300291) disease in hemizygous male patients and mild form IP in their heterozygous mother. EDA-ID and IP are allelic diseases. The largest cohort of individuals with IP in whom the clinical and molecular diagnosis has been confirmed is reported in the publication from Fusco et al. (2014). Prevalence at birth is estimated to be of 1.2 in 100,000 in the European Union (Orphanet Report Series 2017).
IKBKG/NEMO