Multiple self-healing squamous epithelioma in different ethnic groups: more than a founder mutation disorder?

Multiple self-healing squamous epithelioma (MSSE), also known as Ferguson-Smith Disease, is a rare cancer-associated genodermatosis with an autosomal dominant inheritance. Affected patients suffer from recurrent skin lesions, which clinically and histologically resemble keratoacanthomas or well-differentiated squamous cell carcinomas, but which, if left, undergo spontaneous regression, leaving pronounced scarring. The majority of MSSE cases previously described were of Scottish ancestry and all shared the same at-risk haplotype, suggesting that this disorder was caused by a founder mutation. The candidate locus for MSSE lies in a region of <4 cM in chromosome 9q22, between the markers D9S197 and D9S1809. We recently investigated MSSE families of non-Scottish origin. For every patient of these families, we obtained a detailed clinical history, with particular attention to the age of onset, distribution, and clinical course of their skin lesions. Once confirmed that they were really affected by MSSE, we performed haplotype analysis on them and their families. The haplotypes for polymorphic markers segregating with MSSE in non-Scottish and Scottish families differ, suggesting that MSSE is not caused by a founder mutation and might be more common than originally thought.

Keratin mutations of epidermolysis bullosa simplex alter the kinetics of stress response to osmotic shock.

The intermediate filament cytoskeleton is thought to confer physical resilience on tissue cells, on the basis of extrapolations from the phenotype of cell fragility that results from mutations in skin keratins. There is a need for functional cell assays in which the impact of stress on intermediate filaments can be induced and analyzed. Using osmotic shock, we have induced cytoskeleton changes that suggest protective functions for actin and intermediate filament systems. Induction of the resulting stress response has been monitored in keratinocyte cells lines carrying K5 or K14 mutations, which are associated with varying severity of epidermolysis bullosa simplex. Cells with severe mutations were more sensitive to osmotic stress and took longer to recover from it. Their stress-activated response pathways were induced faster, as seen by early activation of JNK, ATF-2 and c-Jun. We demonstrate that the speed of a cell's response to hypotonic stress, by activation of the SAPK/JNK pathway, is correlated with the clinical severity of the mutation carried. The response to hypo-osmotic shock constitutes a discriminating stress assay to distinguish between the effects of different keratin mutations and is a potentially valuable tool in developing therapeutic strategies for keratin-based skin fragility disorders.

A novel connexin 30 mutation in Clouston syndrome.

Clouston syndrome (hidrotic ectodermal dysplasia) is an autosomal dominant ectodermal dysplasia characterized by alopecia, palmoplantar hyperkeratosis, and nail dystrophy. Recently, mutations in the GJB6 gene encoding the gap junction protein connexin 30 have been shown to cause this disorder. To date, all mutations have involved two codons: G11R and A88V. Here, we report a novel mutation V37E within the first transmembrane domain of connexin 30 in a spontaneous case of Clouston syndrome. The mutation was detected in genomic DNA, confirmed in reverse transcription polymerase chain reaction products, and was excluded from 100 ethnically matched control individuals by restriction enzyme analysis.