Porokeratotic Eccrine Nevus May Be Caused by Somatic Connexin26 Mutations

Abstract

Porokeratotic eccrine ostial and dermal duct nevus, or porokeratotic eccrine nevus (PEN), is a hyperkeratotic epidermal nevus. Several cases of widespread involvement have been reported, including one in association with the keratitis–ichthyosis–deafness (KID) syndrome (OMIM #148210), a rare disorder caused by mutations in the GJB2 gene coding for the gap junction protein connexin26 (Cx26). The molecular cause is, as yet, unknown. We have noted that PEN histopathology is shared by KID. The clinical appearance of PEN can resemble that of KID syndrome. Furthermore, a recent report of cutaneous mosaicism for a GJB2 mutation associated with KID describes linear hyperkeratotic skin lesions that might be consistent with PEN. From this, we hypothesized that PEN might be caused by Cx26 mutations associated with KID or similar gap junction disorders. Thus, we analyzed the GJB2 gene in skin samples from two patients referred with generalized PEN. In both, we found GJB2 mutations in the PEN lesions but not in unaffected skin or peripheral blood. One mutation was already known to cause the KID syndrome, and the other had not been previously associated with skin symptoms. We provide extensive functional data to support its pathogenicity. We conclude that PEN may be caused by mosaic GJB2 mutations.

Connexin channels in congenital skin disorders

“…Porokeratotic eccrine ostial and dermal duct nevus (PEODDN) [81, 82] manifests as an epidermal nevus in a linear Blaschkoid pattern [83]. Lines of Blaschko represent the developmental path of ectodermal precursor cells, and post-zygotic somatic mutations in one of these precursors lead to a disease state in the resulting linear band of keratinocytes [84].…”

Porokeratotic Eccrine Ostial and Dermal Duct Naevus and Aberrantly Regulated Keratinization

“…We evaluated the previously reported immunofiuorescent stains for KIO and K14 in two PEODDN cases (3), and judged that Kl 0 was mostly expressed from the lower spinous layer in both two cases, and that K14 was expressed in the basal layer and suprabasal layer in one case, and in the basal layer and focally in the spinous layer in another case. In the previous and our cases of PEODDN, expression of keratins is dysregulated from early to terminal keratinization.…”

“…Porokeratotic eccrine ostial and dermal duct naevus (PEODDN) (porokeratotic eccrine naevus) is an uncommon naevus characterized by a hyperkeratotic streak or hyperkeratotic streaks following Blaschko's lines (1)(2)(3). Histopathological features include comoid lamellae protruding from dilated eccrine ducts.…”

“…Histopathological features include comoid lamellae protruding from dilated eccrine ducts. PEODDN is a mosaic form of keratitis-ichthyosis-deafness (KID) syndrome caused by a mutation in GJB2 encoding a gap junction protein connexin-26 (Cx26) (3). Connexin proteins are components of gap junctions of aqueous pores, which allow intercellular exchanges of ions and small molecules (4).…”

Erythrokeratoderma Variabilis Caused by p.Gly45Glu in Connexin 31: Importance of the First Extracellular Loop Glycine Residue for Gap Junction Function

“…PEODDN is a mosaic disorder presenting clinically as linear epidermal naevi with spiny hyperkeratosis, and with skin histology findings of hyperkeratosis, acanthosis, and porokeratotic plugs emerging from eccrine ducts. Of note, Easton et al (11) provided the first evidence that type I segmental mosaicism resulting from a single GJB2 somatic mutation can cause PEODDN. Moreover, PEODDN lesions have been identified in Blaschko-linear patterns in otherwise healthy individuals, as well as in patients with KID syndrome.…”