185 GJB2 mutations in patients with ichthyosis follicularis and histopathology of porokeratotic adnexal ostial nevus

Abstract

Ichthyosis follicularis (IF) is a distinct cutaneous entity reported in combination with atrichia and photophobia. Mutations in SREBF1 and MBTPS2 have been associated with IF. We sought the genetic cause of IF in two distinct families from a cohort of 180 patients with clinical manifestation of Mendelian disorders of cornification (MeDOC) or ichthyosis. In Family 1, the proband presented with IF, bilateral sensorineural hearing loss (SNHL), and keratitis was found to have a de novo heterozygous GJB2: c.148G>A, p.Asp50Asn in genomic DNA extracted from the peripheral blood lymphocytes. In Family 2, manifested by IF, bilateral SNHL, and punctate palmoplantar keratoderma, compound heterozygous mutations in the GJB2 were discovered: a pathogenic c.526A>G; p.Asn176Asp, and a common frameshift mutation, c.35delG; p.Gly12Valfs*2. Histopathology from both patients was compatible with porokeratotic adnexal ostial nevus (PAON). Interestingly previously, somatic mutations in the GJB2 were shown in association with PAON. Due to shared histopathology between segmental and mosaic PAON and the PAON in association with ichthyosis syndromes such as Keratitis-ichthyosis-deafness (KID) syndrome, it was suggested that KID syndrome is the constitutional form of PAON. Accordingly, our finding supports this hypothesis by finding GJB2 mutations in the DNA of lymphocytes in MeDOC patients with PAON histopathology. These findings attest to the complexity of the clinical consequences of different mutations in GJB2.