Mal de Meleda (ORPHA:87503)
A rare diffuse palmoplantar keratoderma characterized by symmetric palmoplantar hyperkeratosis that progressively extends to the dorsal surfaces of hands and feet (transgrediens). The disease can be associated to hyperhidrosis, lichenoid plaques and perioral erythema.
Epidemiology
The estimated worldwide prevalence is 1:100,000. About 300 patients with a molecularly confirmed pathogenic variants are described in the literature. Most of these patients were from Mediterranean countries in Europe, North Africa, the Middle East, and South Asia.
Clinical description
Onset is in the first months of life. The first symptom is erythema on the palms and soles, rapidly followed by diffuse, yellowish hyperkeratosis. Keratoderma of the dorsal surface of the distal phalanges gradually extends (sometimes in a glove/stocking-like manner) to the dorsa of the hands and feet, affecting the wrists and ankles in the majority of cases. In most patients, transgressive keratoderma also affects the apparence of the ulnar forearms. Keratoderma on the palms and soles is usually surrounded by a red, erythrodermic scale. Hyperconvexity of the nails and conical terminal phalanges are constant features of the disease, mainly in adult patients. In older patients, contractures of the hands and fingers and sclerodactyly (whitish, conical, sclerodermiform phalanges) are common. Hyperhidrosis, pseudoainhum and brachydactyly can be observed in some patients. Other features include perioral erythema, lichenoid plaques on the knees and the elbows, and nail abnormalities.
Etiology
Mal de Meleda (MDM) is caused by biallelic mutations in the gene SLURP1 (chromosome 8q24). SLURP1 mediates keratinocyte apoptosis and down-regulates tumor necrosis factors-induced inflammation. The variants are mostly missense and nonsense mutations, or, to a lesser extent, splicing substitutions or small deletions. A case of large deletion was also described in the literature. Less than 30 different pathogenic variants with an allele frequency of less than 0,001 each are described in the databases.
Diagnostic methods
The diagnosis is based on the evaluation of clinical signs and confirmed by multiplex ligation-dependent probe amplification (MLPA), quantitative PCR or DNA sequencing (e.g. Sanger sequencing, NGS).
Differential diagnosis
Differential diagnosis includes diffuse palmoplantar keratodermas such as Papillon-Lefevre-Syndrome, Greither disease, epidermolytic palmoplantar keratoderma, non-epidermolytic palmoplantar keratoderma, and palmoplantar keratodermas, Nagashima type. It also includes mild forms of pachyonychia congenita, and Vohwinkel syndrome with ichthyosis.
Antenatal diagnosis
Prenatal diagnosis is possible where the pathogenic variant has previously been identified in a family member.
Genetic counseling
MDM is an autosomal recessive transmitted disease with full penetrance. Genetic counseling should be offered to at-risk couples (both individuals are carriers of a disease-causing mutation) informing them that there is a 25% risk of having an affected child at each pregnancy.
Management and treatment
Treatment recommendations include systemic retinoids, oral retinoid acid or oral acitretin (20 mg/day), topical antimicrobial and keratolytic therapy.
Prognosis
The progressive nature of the lesions in MDM can lead to severe functional handicap with reduced mobility of hands and feet.

                            Last update: 
                            March 2023


                            - Expert reviewer(s): 
                            Pr Judith FISCHER | ERN-Skin*


                                * European Reference Network