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Mal De Meleda in a Taiwanese

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Mal De Meleda in a Taiwanese S.C. Chao, F.J. Lai, M.H. Yang, et al MAL DE MELEDA IN A TAIWANESE Sheau-Chiou Chao, Feng-Jei Lai, Mei-Hui Yang, and Julia Yu-Yun Lee Abstract: Mal de Meleda (MDM) is a rare form of recessive transgressive palmoplantar erythrokeratoderma for which mutations in the ARS gene have been identified recently. The ARS gene encodes SLURP-1, a secreted epidermal neuromodulator involved in epidermal homeostasis and inhibition of tumor necrosis factor-α release. A 27-year- old Taiwanese woman who had a history of palmoplantar keratoderma since birth presented with severe erythrokeratoderma of the hands and feet in a glove-and-stocking distribution with conical tapering of the fingers, and involvement of the skin over the major joints and thighs. There were also widespread mottled hyperpigmented macules. Mutation analysis revealed a homozygous missense mutation (G86R) in exon 3 of ARS gene of this patient. Key words: ARS protein, human; Keratoderma, palmoplantar; Mutation, missense; Neuronal nicotinic acetylcholine receptor alpha7; Taiwan J Formos Med Assoc 2005;104:276-8 Keratoderma palmoplantare transgrediens or mal de that appeared soon after birth. The family reported no Meleda (MDM) is a rare autosomal recessive inflam- known consanguinity. She was the only affected member matory keratoderma, characterized by diffuse erythema in the family. On examination, the patient had marked and hyperkeratosis of the hands and feet that appears erythema and hyperkeratosis of the hands and feet soon after birth and progressively extends to the dorsal in a glove-and-stocking distribution, accompanied by aspect of the hands and feet and around the wrist malodor (Fig.). The hyperkeratotic areas showed a and ankles. In addition, there are erythematous hyper- prominent background erythema. In addition, large keratotic plaques over the joints, perioral erythema, erythematous keratotic or scaly plaques were present brachydactyly and nail abnormalities.1 The palmo- over the joints (knees and elbows) and thighs. The plantar keratoderma (PPK) is usually associated with keratoderma of the hands was most severe and caused hyperhidrosis and superinfection resulting in mal- conical tapering of fingers with reduced mobility of the odorous maceration. The hyperkeratosis of the hands hands. The nails were thickened. Widespread mottled typically causes conical tapering and constriction of hyperpigmentation was noted symmetrically over the fingers with severe functional restriction of the hands extremities. She had normal sweating. No abnormalities and sometimes spontaneous amputation of the digits. of the eyes, teeth and hair were found. She showed no Although MDM is mainly reported from the island of signs of delayed psychomotor development. Meleda/Mljet, it has been observed in other parts of Biopsy of a hyperkeratotic lesion revealed marked the world, including the Mediterranean countries, hyperkeratosis with parakeratosis, psoriasiform middle East, Taiwan and Americas.2–5 epidermal hyperplasia with hypergranulosis and a The disease locus of MDM has been mapped to sparse superficial perivascular predominantly lympho- chromosome 8qter,6 and in recent studies, homozygous cytic infiltrate. Electron microscopy showed marked mutations in the ARS (component B) gene have been thickening of the stratum corneum with parakeratosis. identified in families with this disorder.5,7–9 In this Some corneocytes contained lipid vacuoles. Small report, we describe the clinicopathologic findings of a aggregates of lamellar bodies were noted in the inter- Taiwanese woman with MDM in whom homozygous cellular spaces in the first few layers of the corneocytes. missense mutation in the ARS gene was detected. These findings are consistent with MDM. Biopsy of a hyperpigmented macule showed slight psoriasiform hyperplasia with basal hyperpigmentation and some Case Report pigmented dendritic melanocytes in the epidermis without melanocytic proliferation. The keratoderma The proband, a 27-year-old female, presented with PPK improved after treatment with acitretin 20 mg/day. Department of Dermatology, National Cheng-Kung University Hospital, Tainan, Taiwan. Received: 9 April 2004 Revised: 11 June 2004 Accepted: 7 September 2004 Reprint requests and correspondence to: Dr. Julia Yu-Yun Lee, M.D., Department of Dermatology, National Cheng-Kung University Hospital, 138 Sheng-Li Rd. Tainan, Taiwan. 276 J Formos Med Assoc 2005 • Vol 104 • No 4 ARS Gene Mutation in Mal de Meleda Disease appear unrelated. In addition to the keratoderma, our patient manifested widespread mottled hyper- pigmented macules. Review of the clinical photos of the patients from the first pedigree revealed similar macules on the forearms in 1 of the affected sisters. Whether this pigmentary anomaly is a clinical mani- festation of MDM remains to be determined.3 The ARS (component B) gene encodes secreted lymphocyte antigen-6/urokinase-type plasminogen activator receptor-related protein-1 (SLURP-1).7 To date, 10 different mutations in the ARS gene have been reported.7–9,12 The nucleotide 256 in exon 3 may represent a mutation hot spot, since 256G>A mutation has been reported 3 times (in the present pedigree, a Palestinian pedigree and a Turkish pedigree5) and 256G>C mutation has been reported once in Turkish pedigree.5 The pathogenesis of abnormal keratinization and local inflammation in MDM is still not clear. The process of keratinization and desquamation of the epidermis is very complex and requires precise coordination and sequential regulation of multiple genes. SLURP-1 is expressed in the skin, exocervix, gums and esophagus by immunostaining.13 The protein is secreted by cultured keratinocytes, and its expression is regulated by retinoic acid, epidermal growth factor and interferon-γ. The tissue localization and the association with MDM suggest that SLURP-1 Fig. Severe erythrokeratoderma with transgrediens in a is implicated in maintaining the physiologic and typical glove-and-stocking distribution and conical tapering structural integrity of the epidermis. of the fingertips. SLURP-1 belongs to the Ly-6/uPAR superfamily of receptor and secreted proteins, which participate Genomic DNA was extracted from whole blood. in signal transduction, immune cell activation or The 3 exons of the ARS gene were amplified by cellular adhesion.14,15 SLURP-1 is structurally related polymerase chain reaction using previously described to snake neurotoxins and Lynx1 (an endogenous primers.7 Automated sequencing revealed a homo- toxin-like modulator of nicotinic acetylcholine [ACh] zygous G→A transition at nucleotide 256 in exon 3 of receptors)16 which suggests that SLURP-1 may act the proband, predicting a conversion of a glycine as a ligand for a neuronal ACh receptor. ACh is re- (GGG) to an arginine (AGG) at amino acid 86 (G86R). markably abundant in the epidermis and other types The mutation was confirmed by both forward and of surface epithelium. In keratinocytes, neuronal reverse sequencing. Both parents and 2 of the 3 sisters nicotinic ACh receptors (nAChR) have been shown of the patient were carriers of the same mutation. to control cell viability, proliferation, differentiation and motility.17 The ACh signaling through α7 nAChR channels appears essential for epidermal homeo- Discussion stasis.18 Chimienti et al reported that SLURP-1 acts as a neuromodulator of the human α7 nAChRs of The phenotypic hallmark of MDM is the presence of keratinocytes, and suggested that SLURP-1 is likely transgressive PPK. Transgressive PPK can also be to be essential for both epidermal homeostasis observed in Naxos disease (PPK with cardiac and inhibition of tumor necrosis factor-α release by abnormalities and woolly hair) and Papillon-Lefevre macrophages during wound healing.15 This may syndrome (PPK with periodonopathia). However, explain both the hyperproliferative as well as the these other forms of PPK can be distinguished from inflammatory phenotype of MDM. 15 MDM based on their associated clinical features.10,11 Further research of factors involved in regulating The present family is the second pedigree with α7 nAChR signaling pathway in the skin may facilitate MDM reported from Taiwan. These 2 pedigrees development of specific treatment to reduce the J Formos Med Assoc 2005 • Vol 104 • No 4 277 S.C. Chao, F.J. Lai, M.H. Yang, et al keratoderma and the associated inflammation in type plasminogen activator receptor-related protein-1 (SLURP- MDM. 1) and description of five ancestral haplotypes in patients with Mal de Meleda. J Invest Dermatol 2003;120:351-5. ACKNOWLEDGMENT: This study was supported by 10. McKoy G, Protonotarios N, Crosby A, et al: Identification of a grant NSC91-2314-B006-112 from the National deletion in plakoglobin in arrhythmogenic right ventricular Science Council, Taiwan. cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet 2000;355:2119-24. 11. Toomes C, James J, Wood AJ, et al: Loss-of-function mutations References in the cathepsin C gene result in periodontal disease and palmoplantar keratosis. Nat Genet 1999;23:421-4. 1. Hovorka O, Ehlers E: Mal de Meleda. Arch Derm Syph (Berlin) 12. Patel H, Nardelli M, Fenn T, et al: Homozygosity at chromosome 1897;40:251-6. 8qter in individuals affected by mal de Meleda (Meleda disease) 2. Reed ML, Stanley J, Stengel F, et al: Mal de Meleda treated with originating from the island of Meleda. Br J Dermatol 2001;144: 13-cis retinoic acid. Arch Dermatol 1979;115:605-8. 731-4. 3. Jee SH, Lee YY, Wu YC, et al: Report of a family with mal de 13. Mastrangeli R, Donini S, Kelton CA, et al: ARS Component B: Meleda in Taiwan: a clinical, histopathological and immunological structural characterization, tissue expression and regulation of study. Dermatologica 1985;171:30-7. the gene and protein (SLURP-1) associated with Mal de Meleda. 4. Lestringant GG, Frossard PM, Adeghate E, et al: Mal de Meleda: Eur J Dermatol 2003;13:560-70. a report of four cases from the United Arab Emirates. Pediatr 14. Adermann K, Wattler F, Wattler S, et al: Structural and phylo- Dermatol 1997;14:186-91. genetic characterization of human SLURP-1, the first secreted 5.
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