Mal De Meleda

A number sign (#) is used with this entry because mal de Meleda is caused by homozygous mutation in the SLURP1 gene (606119) on chromosome 8q24.

Clinical Features

Congenital symmetrical cornification of the palms and soles, with ichthyotic changes elsewhere, characterizes this disorder which derives its name from its relatively high frequency among inhabitants of the Island of Meleda, Dalmatia, Yugoslavia. Bosnjakovic (1938) studied the family in Mljet (or Meleda). Schnyder et al. (1969) provided more recent observations. Hyperhidrosis, perioral erythema, and lichenoid plaques were also noted. Franceschetti et al. (1972) reported on Meleda disease and stated that Neumann (1898) was the first to report the disorder, in 5 families from Meleda. Fischer et al. (1998) described the clinical characteristics of Meleda disease as transgressive palmoplantar keratoderma, hyperhidrosis, and perioral erythema.

During clinical assessment of MDM families in Tunisia, Mokni et al. (2004) detected minor clinical signs in the palms and soles of women who were obligate carriers of this autosomal recessive disorder. They illustrated cobblestone changes in the skin of the palms of 2 women, each of whom was heterozygous for a mutation in the SLURP1 gene (see 606119.0008-606119.0009). Two women heterozygous for the 82delT mutation (606119.0001) were also described; both had mild palmoplantar keratodermas, and one had interdigital fissures.

Mapping

Fischer et al. (1998) performed linkage analysis of 2 large consanguineous families from Algeria, including 10 affected individuals, and found strong evidence for localization of a gene for Meleda disease on 8qter with a maximum 2-point lod score for D8S1751 of 8.21 at theta = 0.0. Analysis of homozygosity regions and recombination events placed the gene in a region of at least 3 cM, telomeric to D8S1727. A common haplotype was observed in the 2 families, suggesting a founder effect.

Molecular Genetics

Fischer et al. (2001) refined the critical region on chromosome 8qter and identified mutations in affected individuals in the ARS component B gene, encoding a protein named SLURP1 (606119), for secreted Ly6/uPAR related protein-1. Three different homozygous mutations (82delT, 606119.0001; 178G+1G-A, 606119.0002; and R96X, 606119.0003) were detected in 19 families of Algerian and Croatian origin, suggesting founder effects. Moreover, one of the common haplotypes presenting the same mutation was shared by families from both populations.

Charfeddine et al. (2003) identified homozygous mutations in the SLURP1 gene (606119.0001; 606119.0008-606119.0009) in 17 affected members of 8 consanguineous families segregating mal de Meleda from northern Tunisia.

Heterogeneity

Lestringant et al. (2001) examined 5 patients with autosomal recessive mal de Meleda from 3 unrelated consanguineous families from the United Arab Emirates. The patients had diffuse erythrodermic PPK and transgressive erythrodermic keratosis, often with scaly borders, plaques of erythrodermic keratosis on the knees, and red nails with preserved lunulae; none had hyperhidrosis. The MDM interval on chromosome 8q was excluded by homozygosity mapping in all 3 families. Lestringant et al. (2001) concluded that the MDM phenotype is due to at least 2 different genotypes.

Van Steensel et al. (2002) reported a 7-year-old Dutch girl with MDM, born of nonconsanguineous parents, who had transgredient erythroderma and hyperkeratosis of the palms and soles with slight scaling, hyperhidrosis, brachydactyly, and beginning pseudoainhum of the right middle finger. Sequence analysis of exons and intron-exon junctions of the SLURP1, E48 (LY6D; 606204), and GML (602370) genes showed no deviation from wildtype sequence. Van Steensel et al. (2002) suggested that genetic heterogeneity exists in Meleda disease.

Charfeddine et al. (2006) studied 3 affected and 4 unaffected members of a 6-generation consanguineous Tunisian family with MDM. Screening the SLURP1 gene in 1 of the patients revealed no mutations, and multipoint haplotype analysis excluded linkage to the MDM interval on chromosome 8 in this family. Charfeddine et al. (2006) noted that the keratoderma in these patients was cracked rather than waxy yellow as seen in classic MDM, and concluded that MDM is a clinically and genetically heterogeneous disease.

Pathogenesis

The high degree of structural similarity between SLURP1 and the 3-finger motif of snake neurotoxins and LYNX1 (606110) suggested that SLURP1 may interact with neuronal acetylcholine receptors. Chimienti et al. (2003) found that SLURP1 potentiated the human alpha-7 nicotinic acetylcholine receptors (CHRNA7; 118511) present in keratinocytes. The authors concluded that SLURP1 acts as a secreted epidermal neuromodulator that may be essential for both epidermal homeostasis and inhibition of TNF-alpha (191160) release by macrophages during wound healing. This may explain both the hyperproliferative as well as the inflammatory clinical phenotype of mal de Meleda.