Mal de Meleda variant of palmoplantar keratoderma with reticulate pigmentation- Unveiling a novel variant in the SLURP1 gene

Dear Editor,

A 27-year-old woman, born to third-degree consanguineous parents, presented with a history of thickening of the skin of the palms and soles since birth. She reported associated hyperhidrosis and a malodorous discharge but denied any skin lesions elsewhere, generalised skin dryness, or sweating abnormalities. Family history was noncontributory. On cutaneous examination, symmetrically distributed, hyperkeratotic plaques were observed on the palms with extension on to the dorsal surfaces of hands (transgradiens pattern) with conical tapering of fingers and digital constrictions [Figure 1a and b]. symmetrically distributed hyperkeratotic plaques with deep fissures on the soles [Figure 1c]. There was a reticulate hyperpigmentation on the dorsal aspect of the feet [Figure 1d]. The rest of the mucocutaneous examination was unremarkable. Whole-exome sequencing (next generation sequencing technique) of her blood sample revealed a novel pathogenic, homozygous variant (according to the American College of Medical Genetics) in intron 1 of the SLURP1 gene (NM_020427.2 chr8: 143823745 C>A, c.58+1G>T) [Figure 2]. This variant has not been reported in the ClinVar, The Human Phenotype Ontology (HPO), 1000 genomes, or exome variant server databases. The in silico splice prediction tools suggest that this variant is likely to disrupt splicing at the junction of exon 1 and intron 1 of the SLURP1 gene. Based on the clinical features and genetic confirmation, a final diagnosis of Mal de Meleda (MDM) variant of palmoplantar keratoderma was made. Further investigations, including genetic analysis of parents could not be done due to financial constraints. She was counselled regarding the chronic course of the disease and initiated on capsule acitretin (0.5 mg/kg/day) along with topical 12% salicylic acid ointment.

Close

Figure 1:

a) Symmetrically distributed, well-demarcated hyperkeratotic plaques on the palms with conical tapering of the fingers and digital constrictions, and (b) Plaques extending onto the dorsal surfaces of the hands (transgradiens).

Export to PPT

Close

Figure 1:

(c) Symmetrically distributed, well-demarcated hyperkeratotic plaques on the soles with deep fissures. (d) Reticulate to mottled hyperpigmentation on the dorsal aspect of the feet.

Export to PPT

Close

Figure 2:

Integrative genomics viewer image depicting a pathogenic homozygous variant in the intron 1 of the SLURP1 gene (NM_020427.2 chr8: 143823745 C>A, c.58+1G>T)

Export to PPT

MDM, also known as keratosis palmoplantaris transgrediens of Siemens, is a rare autosomal recessive form of hereditary palmoplantar keratoderma (PPK) with an estimated prevalence of 1 in 100,000.^1,2 The disorder results from a homozygous variant in the SLURP1 gene located on the chromosome 8q24. SLURP-1 encodes a secreted epidermal neuromodulator that maintains epidermal homeostasis and regulates wound healing by inhibiting the release of tumour necrosis factor-alpha from macrophages. Missense variants in the SLURP1 gene lead to protein dysfunction and the development of hyperkeratosis.^1,2 The SLURP1 gene comprises three exons and two introns.³ To date, more than 21 distinct pathogenic variants have been identified in association with MDM, predominantly homozygous mutations; cases of compound heterozygosity are rare.³ In our case, the detected homozygous variant was located at the essential splice donor site within intron 1. Clinically, MDM typically manifests within the first few months of life, initially presenting as bilateral, symmetrical erythema of the palms and soles that progresses to thickened, yellow-brown hyperkeratotic plaques with sharply defined erythematous borders. A characteristic feature is the extension of hyperkeratosis onto the dorsal surfaces of the hands and feet, known as transgradiens. Complications commonly include palmoplantar hyperhidrosis, secondary bacterial and fungal infections, and offensive odour. Oral findings such as perioral erythema, high-arched palate, angular cheilitis, and lip involvement have also been described.^1-3 Nail changes are frequent and may manifest as Beau’s lines, koilonychia, subungual hyperkeratosis, and onychogryphosis. Psoriasiform or lichenoid plaques may occasionally develop on the elbows and knees.^4,5 In advanced cases, MDM may lead to the formation of constricting bands (pseudoainhum), digital autoamputation, and severe flexion contractures, particularly involving the hands, significantly impairing functional ability. Rarely reported features include syndactyly, lingua plicata, and ectopic hair growth on the palms and soles.^4,5 In our case, she had palmoplantar keratoderma, which was mutilating in the form of conical tapering of digits associated with fissuring and digital contractures. In addition, our case exhibited reticulate hyperpigmentation on the dorsum of the foot, a condition not previously described in the literature. The differential diagnosis for PPK in this case includes Greither disease (PPK with transgradiens), Olmsted syndrome (mutilating PPK, however, no periorificial keratosis was seen), and Huriez syndrome (appearance of sclerodactyly).

When evaluating reticulate pigmentation with PPK, differentiation among overlapping genodermatoses is paramount. Dyschromatosis universalis hereditaria due to SASH1 gene mutations presents with punctate PPK, noncicatricial alopecia, and onychodystrophy. Dermatopathia pigmentosa reticularis is characterised by alopecia, absent dermatoglyphics, hyperhidrosis, and mucosal pigmentation, while Naegeli-Franceschetti-Jadassohn syndrome presents with dental anomalies and nail involvement.⁵

Treatment includes topical corticosteroids, moisturisers, keratolytic agents, and topical antimicrobials. Systemic therapy with oral acitretin (0.5 mg/kg) has shown variable success in reducing hyperkeratosis.^1,3 We describe this case to highlight the identification of a novel pathogenic variant of SLURP1 and the reticulate hyperpigmentation on the dorsum of the foot, which has not been previously described in the literature.