Palmoplantar Keratoderma of the Gamborg-Nielsen Type is Caused by Mutations in the SLURP1 Gene and Represents a Variant of Mal de Meleda

Abstract

Palmoplantar keratoderma of the Gamborg-Nielsen type (PPK-GN) is a rare autosomal recessive skin disorder described in patients from Sweden. Mal de Meleda (MDM) is also a rare autosomal recessive inherited PPK first reported in 5 families from the island of Meleda. The 2 conditions phenotypically overlap and are characterised by palmoplantar erythematous hyperkeratotic plaques. The genetic background giving rise to PPK-GN has hitherto been unknown, whereas MDM is known to be caused by mutations in the gene encoding secreted Ly-6/uPAR-related protein 1, SLURP-1. In the present study we scrutinised individuals affected by PPK-GN for mutations in the SLURP1 gene and identified 2 different mutations. Fourteen Swedish patients were homozygous for a previously described mutation, c.43T>C, while one individual was a compound heterozygote with one copy of a novel mutation, c.280T>A, in addition to one copy of the c.43T>C mutation. Hereby we confirm that PPK-GN is an allelic variant of MDM.

Mal de Meleda: A Focused Review

“…Gruber et al [32] reported an additional homozygous mutation of SLURP-1 that leads to an atypical phenotype wherein the plantar surface is spared. Zhao et al [7] showed that a less severe PPK, which has historically been characterized as a hereditary PPK of the Gamborg-Nielsen type, may, in fact, more accurately be referred to as a variant of Mal de Meleda that is seen in the Swedish population. Of note, the mutation responsible for 14 of the 15 cases in the study by Zhao et al is one that has been previously described in other reports of Mal de Meleda, generally without considerable phenotypic variation [8,34].…”

“…Originally, there were three different gene mutations of SLURP-1 identified by Fischer et al: a homozygous single nucleotide deletion, a homozygous point mutation, and a homozygous splice site mutation, suggesting a founder effect from the original cases reported in Croatian and Algerian families. However, as more cases have been reported, at least 14 other mutations have been identified from families in at least 19 other countries [7,34,35]. In addition to the homozygous mutation genotype, there have also been cases showing compound heterozygous mutations with disease phenotype [36].…”

“…Zhao et al suggest it may, if only for historical reasons [37]. Figure 2 [7,11,17,[32][33][34][35][36][38][39][40][41] shows an exon/intron map of the SLURP-1 gene and lists the mutation types and their location in Mal de Meleda (as well as the Gamborg-Nielsen variant).…”

“…Subsequent to its initial description in 1826, the disease has been reported in at least 19 countries outside of Croatia including Algeria, Chile, China, Germany, India, Indonesia, Italy, Japan, Korea, Laos, Libya, The Netherlands, Pakistan, Saudi Arabia, Scotland, Sweden, Tunisia, Turkey, and the United Arab Emirates [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19].…”

“…c.1A>C (p. Met1Leu) [34] Ivs1+1G>A (alt splice site) [17] c.82delT (p.Cys28fs32X) [33] Ivs2+1G>A (alt splice site) [33] c.229T>C (p.Cys77Arg) [35] c.43T>C (p.Trp15Arg) [36] c.58+5G>T (alt splice site) [11] c.129C>A (p.C43X) [38] c.244C>T (p.Pro82Ser) [32] c.212G>A (p.Arg71His) [41] c.256G>C (p.Gly86Arg) [34] c.212G>C (p.Arg71Pro) [36] c.256G>A (p.Gly86Arg) [34] c.280T>A (p.Cys94Ser) [7] c.286C>T (p.Arg96Term) [33] c.293T>C (p.Leu98Pro) [39] c.296G>A (p.Cys99Tyr) [40] AD autosomal dominant, AR autosomal recessive, PPK palmoplantar keratoderma Reed et al [73] discussed effective treatment with oral 13-cis retinoid acid following failed treatment with corticosteroid, lactic acid, retinoid acid, and emollients. More recently, Gruber et al [32] showed effective treatment with oral acitretin 20 mg/day plus topical antimicrobial and keratolytic therapy.…”