Palmoplantar keratodermas (PPKs) are a group of disorders that are diagnostically and therapeutically problematic in dermatogenetics1-3. Punctate PPKs are characterized by circumscribed hyperkeratotic lesions on palms and soles with considerable heterogeneity. In 18 families with autosomal dominant punctate PPK (OMIM #148600), we report heterozygous loss-of-function mutations in AAGAB, encoding alpha- and gamma-adaptin binding protein p34, at a previously linked locus on 15q22. p34, a cytosolic protein with a Rab-like GTPase domain, was shown to bind both clathrin adaptor protein complexes, indicative of a role in membrane traffic. Ultrastucturally, lesional epidermis showed abnormalities in intracellular vesicle biology. Immunohistochemistry showed hyperproliferation within the punctate lesions. Knockdown of p34 in keratinocytes led to increased cell division, which was linked to greatly increased epidermal growth factor receptor (EGFR) protein expression and tyrosine phosphorylation. We hypothesize that p34 deficiency may impair endocytic recycling of growth factor receptors such as EGFR, leading to increased signaling and proliferation.

Most patients with DEB have relatively mild dominantly inherited disease, only a minority suffering from severe recessive subtypes. Scarring, gastrointestinal involvement, albopapuloid lesions and a pruriginosa-like pattern each occur in both DDEB and RDEB. With increasing age, SCC is a major cause of morbidity and mortality.

The quality of life of people with epidermolysis bullosa (EB) living in Scotland was assessed by postal questionnaire using the Dermatology Life Quality Index (DLQI) and the Children's Dermatology Life Quality Index (CDLQI). There were 143 people with EB simplex (EBS) and 99 individuals with non-Hallopeau--Siemens subtypes of dystrophic EB (DEB). A further six individuals had the severe Hallopeau--Siemens subtype of DEB (RDEB-HS). The overall response was 48% (EBS 52%, DEB 40% and RDEB-HS 83%). Impairment of quality of life (QOL) was greatest in those with RDEB-HS, mean scores (adults, 18; children, 22) exceeding those of any skin disorder previously assessed. The effect on QOL of EBS and other subtypes of DEB was similar to that of moderately severe psoriasis and eczema. EBS had a greater impact on QOL than the non-Hallopeau--Siemens subtypes of DEB (EBS adults mean score, 10.7; EBS children mean score, 15; DEB adults mean score, 7.5; DEB children mean score, 11.5).

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As part of the U.K. National Epidermolysis Bullosa Register, we have systematically recorded clinical information on 130 (77%) of the 168 known Scottish epidermolysis bullosa simplex (EBS) sufferers. Three subtypes of EBS were recognized: Dowling-Meara (EBS-DM), Weber-Cockayne (EBS-WC) and Köbner (EBS-Kb), seen in 5%, 42% and 53% of patients, respectively. As there is considerable overlap between EBS-WC and EBS-Kb, with both phenotypes frequently seen within the same pedigree, EBS-WC is best regarded as a milder variant of EBS-Kb rather than a separate disorder. Improvement with age is common in all variants of EBS, but is not invariable. Pain due to acral blistering in EBS-Kb/EBS-WC has a more marked impact on life-style than the blisters of EBS-DM. Oral blistering, nail involvement and aplasia cutis congenita occur in all EBS subtypes and laryngeal involvement is a feature of EBS-DM. Seasonal variation is not seen in EBS-DM but is common in EBS-Kb/EBS-WC.