Clinical heterogeneity in recessive epidermolysis bullosa due to mutations in the keratin 14 gene, KRT14

Abstract

Summary Background. Epidermolysis bullosa simplex (EBS), the most common subtype of EB, is usually inherited as an autosomal dominant trait caused by mutations in either the keratin 5 (KRT5) or keratin 14 (KRT14) genes. Recessive EBS (R‐EBS) is extremely rare. Methods. We present the first Australian patient diagnosed with R‐EBS, to our knowledge, and a comprehensive review of genotypes and phenotypes of R‐EBS reported cases. Results. The female proband, of Turkish descent with consanguineous parentage, was referred to us at the age of 8 years. Clinically, she had a severe phenotype including generalized blisters, mucosal involvement and EB naevi. Immunofluorescence mapping and electron microscopy were consistent with a diagnosis of EBS. Staining for Keratin 14 (K14) was negative. The basal layer, however, reacted with monoclonal antibodies to keratins 6 (K6) and 16 (K16). Mutation screening from genomic DNA showed that the proband was homozygous for the truncation mutation Y204X in exon 3 of KRT14, and both unaffected parents were heterozygous for a single KRT14 Y204X mutation. The phenotype of our patient is reported in more detail and with longer follow‐up than those of others published in the literature. Discussion. The proband’s phenotype was severe as an infant but improved with age, suggesting that an alternative keratin is pairing with K5 in her skin to compensate for the loss of K14 – a novel biological compensatory mechanism. It is interesting that K6 and K16 were expressed, as these are normally positive in hyperproliferative skin disorders.

Immunofluorescence mapping in inherited epidermolysis bullosa: a study of 86 cases from India

“…In general, the expression of the above proteins and keratin 14 are normal in all subtypes of EBS except in the autosomal recessive type, where there is an absence of keratin 14 staining. 10 However, our study showed abnormal patterns in 12 of 32 cases. These cases did not necessarily belong to the autosomal recessive subtype, although molecular analysis was not done to confirm the pattern of inheritance.…”

“…The immunofluorescence findings in all but one case correlated well with those described by Cepeda‐Valdés et al ., in that the staining of type IV collagen, laminin 332 and type VII collagen was observed to the floor of the blister. In general, the expression of the above proteins and keratin 14 are normal in all subtypes of EBS except in the autosomal recessive type, where there is an absence of keratin 14 staining . However, our study showed abnormal patterns in 12 of 32 cases.…”

Immunofluorescence antigen mapping for hereditary epidermolysis bullosa

“…Additional EBS-specific antibodies (keratin 5 and 14, plectin and α6β4 integrin) may be employed; in general, expression of proteins are normal, except in autosomal recessive EBS, when patients may have absent keratin 14 staining. [20] In patients with EBSmuscular dystrophy (EBS-MD), plectin is mostly absent, and in the rare case of EBS Ogna, it is markedly reduced. [21] In EB subtypes with pyloric atresia (either EBS or JEB), plectin or, α6β4 integrin are reduced or absent.…”

Epidermolysis Bullosa Simplex

“…75,76 Regular immunohistochemistry can be used in recessive cases to demonstrate absence of keratin intermediate filaments. 18, 77 Molecular diagnosis is generally conducted in a stepwise fashion, with screening beginning by mutation analysis of KRT5 and KRT14 conserved regions; data collected in Western populations have shown that more than 40% of EBS cases are caused by a mutation affecting the KRT14 R125 residue. 78,79 The existence of KRT14 pseudogenes requires the use of special techniques to avoid amplification of nonrelevant sequences.…”