Mal de Meleda: A Focused Review

Caroline Perez; Amor Khachemoune

Disclosures

Am J Clin Dermatol. 2016;17(1):63-70. 

In This Article

Genetics and Pathophysiology

Apart from clinical and histological patterns, Mal de Meleda can be more definitively diagnosed based on family history and certainly with genetic analysis. The inheritance pattern is AR, so sporadic cases are exceedingly rare and generally there will be some clue to diagnosis in the family history.

Fischer et al.[4] first showed genetic linkage of Mal de Meleda to chromosome 8qter in 1998. In 2001, Fischer et al.[33] identified the gene responsible for the disease phenotype as that encoding the secreted LY6/urokinasetype plasminogen activator receptor (uPAR)-related protein-1 (SLURP-1). 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] Phenotypic variation exists as well. 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] It should be mentioned, however, that there is debate as to whether the distinction of Gamborg-Nielsen-type PPK as its own clinical entity may persist. Zhao et al. suggest it may, if only for historical reasons.[37] Figure 2[7,11,17,32–36,38–41] 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).

Figure 2.

Exon/intron map of SLURP-1 with known SLURP-1 mutation types and locations in Mal de Meleda. Note the predominant mutation for Gamborg-Nielsen type is a missense mutation in exon 1 c.43T>C (p.Trp15Arg) [7, 17] (adapted from Wajid et al. [17], with permission from Elsevier). bp base pairs, SLURP-1 secreted LY6/urokinase-type plasminogen activator receptor (uPAR)-related protein-1

The pathophysiology of how SLURP1 protein-encoding gene mutations lead to the phenotypic manifestations of Mal de Meleda can be better understood by reviewing the current interpretation of the function of SLURP-1. The presence of SLURP-1 has been localized to the granular layer of epidermis.[41] Here, it is thought that SLURP-1 works via nicotinic acetylcholine receptors found on keratinocyte cells as a pro-apoptotic protein.[42] Arredondo et al.[42] showed that when SLURP-1 activates keratinocytes via the nicotinic acetylcholine receptor, there is a decrease in keratinocyte cell number, suggesting the regulatory and inhibitory nature of SLURP-1. Accordingly, when the SLURP-1 protein is non-functional, as seen in Mal de Meleda, hyperkeratosis results due to improperly regulated keratinocyte apoptosis.[43]

As previously mentioned, the clinical phenotype and histology of Mal de Meleda suggest both hyperkeratosis as well as an inflammatory component to the disease. With respect to inflammation, the present literature supports the idea that the SLURP-1 gene may also function to inhibit macrophage and keratinocyte release of tumor necrosis factor (TNF)-α.[3] TNF-α release in the epidermis ultimately results in chemotaxis of dendritic cells and memory T cells through the dermis, producing generalized inflammation.[44] TNF-α release and subsequent inflammatory mediators are not regulated appropriately in Mal de Meleda, due to the lack of a functional SLURP-1 protein.

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