Laryngeal involvement in the Dowling-Meara variant of epidermolysis bullosa simplex with keratin mutations of severely disruptive potential

Abstract

The clinical features of the Dowling-Meara variant of epidermolysis bullosa simplex (EBS-DM) can, in an infant, be indistinguishable from other severe forms of epidermolysis bullosa (EB). Two unrelated infants with no family history of skin disease are described who, within hours of birth, developed extensive blistering of skin and oral mucosae and who both subsequently developed hoarse cries. Despite this superficial resemblance to other forms of EB, electron microscopy revealed a basal cell rupture and keratin aggregates characteristic of EBS-DM in the skin of both infants and in the vocal cord epithelium of one. Molecular analysis confirmed the diagnosis by identification of mis-sense point mutations in basal cell keratin genes in both cases. One patient carries a point mutation in keratin 14 (converting arginine at position 125 to histidine) and the other has a novel point mutation in keratin 5 (converting serine at position 181 to proline). Hoarseness is not a well documented feature of EBS-DM and is usually associated with junctional EB. These two patients demonstrate that the presence of a hoarse cry in an infant affected by severe EB does not necessarily indicate a poor prognosis.

Development of Allele-Specific Therapeutic siRNA for Keratin 5 Mutations in Epidermolysis Bullosa Simplex

“…The EBS-Dowling-Meara mutation p.Ser181Pro is a point mutation (c.541T4C) resulting in a serine to proline substitution in the highly conserved helix initiation motif within the 1A domain of K5 (Shemanko et al, 2000). The missense mutation p.Asn193Lys (due to DNA point mutation c.579C4G) is located in the second half of the helix 1A domain of K5, outside of the highly conserved region (Humphries et al, 1996;Rugg et al, 2007).…”

Extracutaneous manifestations and complications of inherited epidermolysis bullosa

“…134 Involvement in EBS-DM, 137,138 EBS with muscular dystropy, [139][140][141][142] and RDEB 143 is less common but may also be clinically problematic. 128,131,144,145 Airway injury in EB may appear to arise spontaneously, to follow episodes of coughing, crying, or upper respiratory tract infection, or to be precipitated or exacerbated by intubation or instrumentation of the airway. It is possible that unrecognized or untreated GERD may also trigger or exacerbate laryngeal mucosal involvement in some patients.…”

Inherited epidermolysis bullosa

“…The reason for such a phenomenon is unknown. The most notable extracutaneous complication in EBS, and one that is seen in only rare patients with EBS-DM, is tracheolaryngeal compromise, mimicking that which arises in both major subtypes of JEB [30,31]. There is also a markedly increased risk of developing basal cell carcinomas by mid-adulthood (cumulative risk of 44% by age 55) [32], a finding seen in EB only among patients with EBS-DM.…”