LAUSR

DEAR EDITOR, Ectodermal dysplasia–skin fragility syndrome (EDSFS) is an autosomal recessive genodermatosis characterized by skin fragility, chronic cheilitis, palmoplantar keratoderma, abnormal hair growth and nail dystrophy. ED-SFS is caused by mutations in the PKP1 gene encoding plakophilin 1, which result in desmosomal abnormality and poor intercellular cohesion between epidermal cells. A 2-year-old girl presented with asymptomatic cutaneous lesions that were first noted some months after birth. She was the first child of healthy unrelated white parents, and had no familial or personal medical antecedents. Cutaneous examination showed slightly scaly hypopigmented plaques with crusted erosions and some erythematous patches segmentally distributed throughout her left arm and leg (Fig. 1a). A band of prominent linear hyperkeratosis involved her left sole. The first left toenail and fingernail showed linear subungual hyperkeratosis and yellowish discoloration (Fig. 1b). Teeth, scalp hair and sweating were normal. A skin biopsy from the left thigh showed orthokeratosis, acanthosis and focal hypergranulosis. Wide intercellular spaces with scattered foci of acantholysis were noted in the spiny layer. Isolated dyskeratotic cells were seen within the upper epidermal layers. Striking paranuclear eosinophilic masses were seen in the keratinocytes (Fig. 1c). Because these histopathological features are characteristic of ED-SFS, mutational analysis of PKP1 (NM_001005337) was carried out on the patient’s skin and blood. This revealed in exon 3 the mutation c.638delT, p.V213Gfs*33 in a heterozygous state (Fig. S1; see Supporting Information). To the best of our knowledge this mutation has not been reported before (Human Gene Mutation Database Professional). It leads to a premature termination codon and truncation of the plakophilin 1 polypeptide, and presumably to mRNA decay. The mutation was paternally inherited, but the second disease-causing mutation remained elusive. To identify the molecular basis of the postzygotic mosaicism underlying the cutaneous phenotype in the index case, keratinocytes were isolated from affected skin by use of standard methods. DNA was extracted from the cultured keratinocytes and submitted to Sanger sequencing of PKP1. Interestingly, in keratinocytes derived from affected skin, c.638delT was detected in a homozygous state (Fig. S1b), and no additional second mutation was found. These results suggest that loss of heterozygosity is the most probable mechanism explaining the mosaic lesions in our patient. By quantitative polymerase chain reaction (PCR), we found no evidence for a large deletion in one allele (not shown), and therefore we propose that a recombination event is the most probable mechanism underlying homozygosity in the lesional skin of our patient. Quantitative real-time PCR showed that PKP1 cDNA was strongly reduced in keratinocytes from the