Mal de Meleda: A Focused Review

Caroline Perez; Amor Khachemoune


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

In This Article

Differential Diagnoses

There are presently over 25 identified hereditary PPK diseases that can be separated into five basic categories: (1) diffuse PPK; (2) diffuse mutilating PPK; (3) focal PPK; (4) ectodermal dysplasia with PPK; and (5) syndromic PPK.[45] Of these, at least seven PPK diseases show AR inheritance. As indicated in Sect. 5, Gamborg-Nielsen-type PPK has recently been identified by Zhao et al. to be a phenotypic variant of Mal de Meleda, due to a mutation in the SLURP-1 gene. Clinically, the phenotype of Gamborg-Nielsen-type PPK is milder than Mal de Meleda, with less severe hyperkeratosis, lack of nail involvement, and no distant keratoses. The transgredient pattern of hyperkeratosis to the dorsum of the hands and feet and knuckle pad formation are variably present.[46] Naxos syndrome and Carvajal syndrome are both syndromic PPK diseases attributable to AR-inherited mutations of desmosome proteins and should be ruled out because of concern for congenital cardiomyopathy. Papillion-Lefevre syndrome (PLS) is another AR PPK with skin lesion patterns nearly identical to Mal de Meleda. PLS, however, is typically notable for the additional clinical sign of periodontitis and early tooth loss. A rare phenotypic variation of PLS demonstrates late-onset periodontitis, so differentiating between this variant of PLS and Mal de Meleda may prove difficult.[47] In situations where the family history is unremarkable or unknown, genetic testing would allow for definitive diagnosis, as the gene mutation in PLS is cathepsin C on chromosome 11q14.[48] Oculocutaneous tyrosinemia displays AR inheritance but features focal PPK with painful ocular inflammation. Nagashima-type PPK is also AR but is a milder disease and can be differentiated from Mal de Meleda clinically based on the non-progressive nature of the hyperkeratosis, which usually terminates at puberty. The genetic mutation in Nagashima-type is SERPINB7 rather than SLURP-1..[49] Greither's disease can present very similarly to Mal de Meleda but is mostly differentiated based on its autosomal dominant inheritance pattern as well as the fact that presentation can be later in childhood.[50] Olmsted syndrome presents in early childhood with bilateral transgredient PPK but is thought to have an autosomal dominant pattern of inheritance and is a mutilating-type PPK with a tendency to involve the perioral area.[51] There are also RASopathies that can present with cutaneous symptoms similar to those seen in the PPK, such as Costello syndrome.[52] Table 1 [48,50,53–68] provides a broad overview of PPK diseases that may be included in the differential diagnosis of Mal de Meleda.

Mal de Meleda and Gamborg-Nielsen-type PPK (as its own clinical entity or as a variant of Mal de Meleda) are the only PPKs with SLURP-1 gene mutations. The National Center for Biotechnology Information's Genetic Testing Registry reports there are currently seven laboratories worldwide that offer genetic testing specifically for SLURP-1 gene mutations in suspected Mal de Meleda cases.[69]