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(A~D) Well-demarcated hyperkeratotic plaque, involving the palms and soles. Note the hyperkeratosis of the dorsa of the hands and feet. Constricting band-like lesions around digits, particularly the 2nd to 4th fingers in both hands, are shown.
Source publication
Mal de Meleda (MDM), also known as keratoderma palmoplantaris transgrediens, is a rare inherited form of palmoplantar keratoderma. It is characterized by erythema and hyperkeratosis of the palms and soles, extending to the dorsal aspects of the hands and feet. A 15-year-old Korean female presented with sharply demarcated hyperkeratotic plaques on t...
Context in source publication
Context 1
... 15-year-old female presented with diffuse palmoplantar thickening that had been present from birth. In the beginning, the lesions were limited to only her fingertips. However, with age, they progressively spread to the dorsal surfaces of the hands and feet. Since the age of ten, old, waxy ivory-yellow, palmoplantar hyperkeratotic pla- ques, with well-demarcated margins, accompanied with nail change, have been present. On cutaneous exami- nation, we observed extensive diffuse hyperkeratosis of the palms and soles, which extended to the dorsal surfaces of the hands and feet (Fig. 1). She had knuckle pads on several interphalangeal joints and on both elbows. Conical tapering of the fingers and nail changes included thickening of the nail and hypercurvature. She also had a thin tongue, with several furrows at the distal portions of the tongue. The palmoplantar skin revealed an unpleasant smell, and maceration with hyperhidrosis, especially during the summer months. Teeth, hair, and general physical examination were unremarkable. None of the family members were affected and no consan- guineous relationship was found (Fig. 2). The potassium hydroxide (KOH) mounts from the hyperkeratotic lesions of the palm, sole, dorsa of hands and feet, fingernail, and toenail, were all positive. Other laboratory work up was normal. Histopathologic findings of the sole, as well as the dorsa of the hand and foot, showed marked hyper- keratosis, acanthosis, and normogranulosis, without epi- dermolysis (Fig. 3A). PAS-positive spores and hyphae were present in the stratum corneum (Fig. 3B). Her genetic study detected mutations in SLURP-1 (Table 1). From these findings, she was diagnosed as MDM. She was topically treated with a mixture of 50% salicylic acid and steroid ointments, and systemically with oral antifungal and antibiotic agents. After combined treatments, the hyperkeratotic plaques showed some improvement, in- cluding reduction in thickness, especially in the erythe- matous dorsal borders, and the malodorous smell dis- ...
Citations
... In the present study, we detected for the first time the compound heterozygous mutation c.243C > A (Asp81Glu) and c.256G > A (Gly86Arg). Only four rare types of compound heterozygous mutations have been reported to date [21,[29][30][31], but none was found in a Chinese individual. In previous studies, 4 patients in 3 Chinese families from mainland China were reported to have MdM due to the same homozygous mutation (c.256G > A). ...
Background
Mal de Meleda is an autosomal recessive palmoplantar keratoderma, with SLURP1 identified as the pathogenic gene responsible. Although over 20 mutations in SLURP1 have been reported, only the mutation c.256G > A (p.G87R) has been detected in Chinese patients. Here, we report a novel heterozygous SLURP1 mutation in a Chinese family.
Methods
We assessed the clinical manifestations of two Chinese patients with Mal de Meleda and collected specimens from the patients and other family members for whole-exome and Sanger sequencing. We used algorithms (MutationTaster, SIFT, PolyPhen-2, PROVEAN, PANTHER, FATHMM, mCSM, SDM and DUET) to predict the pathogenetic potential of the mutation detected. We also employed AlphaFold2 and PyMOL for protein structure analysis.
Results
Both patients displayed the typical manifestation of palmoplantar keratoderma. In Proband 1, we detected a novel compound heterozygous mutation (c.243C > A and c.256G > A) in exon 3 of SLURP1. Proband 2 was an adult female born to a consanguineous family and carried a homozygous mutation (c.211C > T). Algorithms indicated both mutations to be probably disease causing. We used AlphaFold2 to predict the protein structure of these mutations and found that they cause instability, as shown by PyMOL.
Conclusions
Our study identified a novel compound heterozygous mutation (c.243C > A and c.256G > A) in a Chinese patient with Mal de Meleda that has the potential to cause instability in protein structure. Moreover, this study expands on the existing knowledge of SLURP1 mutations and contributes to knowledge of Mal de Meleda.
... Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma [1]. It was first described in 1826 in a patient from Mljet, formerly known as the Meleda Island in the Adriatic Sea. ...
... In addition to its role as a neuromodulator regulating epidermal homeostasis, the SLURP1 protein is also known to inhibit the secretion of tumor necrosis factor alpha from macrophages during wound healing. These roles also explain the hyperproliferative and inflammatory processes reflected in the clinical manifestation of mal de Meleda [1]. Examination of the DNA material obtained from patient' s blood sample revealed a p.Arg 96 Pro (c.287 CGA>CCA) homozygous missense mutation in the SLURP1 gene. ...
... However, the symptoms may resurface when treatment is discontinued. Treatment should be supplemented with antibacterial and antifungal medication due to an increased risk of bacterial and fungal infections in these patients [1]. Topical antifungal therapy was administered in our case because hyphae and spores were observed upon a direct KOH analysis prepared from the palms and soles of the feet, and also from the nails. ...
Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma. A 19-year-old male presented with a congenital yellowish discoloration and thickening of both palms and soles of the feet. His family history revealed that there was no consanguinity between the mother and the father and that the patient had three healthy brothers. The second- and third-degree relatives, five females and one male, also exhibited similar skin findings. From the isolated DNA samples, the extrinsic regions of the SLURP1 gene were screened using the sequence analysis and the Sanger sequencing was performed with the 3130 Sequence Analyzer. Results of this analysis show that a p.Arg 96 Pro (R96P) (c.287 CGA>CCA) homozygous missense point mutation was detected on the SLURP 1 (a secreted toxin-like mammalian lymphocyte antigen 6/urokinase-type plasminogen activator receptor-related protein 1) gene of the patients, while heterozygous p.Arg 96 Pro (R96P) (c.287 CGA>CCA) mutation was detected in the mother, father, and brothers. Our search of the Human Genome Mutation Database and previous literature revealed no reports of this mutation in mal de Meleda. We report this case due to the identification of a novel gene mutation in a patient with mal de Meleda, a palmoplantar keratoderma.
... 9,12 The mal de Meleda gene has been mapped to chromosome 8q24.3, 1 with mutations in ARS (component B)-81/s gene (LY6LS), also known as SLURP1, encoding secreted Ly-6/uPAR related protein 1 (SLURP1). 1,13 Cases of mal de Meleda with SLURP1 mutations have been reported in Algerian, 1 Bedouin, 14 Chinese, 15 Croatian, 1 Dutch, 16,17 German, 14,16,18 Indian, 19 Indonesian, 20 Italian, 21 Japanese, 6,22 Korean, 23 Kurdish, 2 Libyan, 24 Pakistani, 25 Palestinian, 14 Scottish, 18 Swedish, 26 Taiwanese 27,28 Tunisian, 18,21,29 and Turkish descents. 14,[30][31][32][33] To date no cases has been reported from a Javanese family, though the mutation has been reported in Indonesian woman who live in Australia. ...
Background:
Mal de Meleda (OMIM# 248300; keratosis palmoplantaris transgrediens) is an autosomal recessive form of palmoplantar keratoderma, clinically characterized by sharp demarcated erythema and hyperkeratosis of the palms and soles that progress with age and extend to the dorsal aspects of the hands and feet. The mal de Meleda is caused by mutations in the SLURP1 gene that encodes secreted lymphocyte antigen 6/urokinase-type plasminogen receptor-related protein 1 (SLURP1). To date no reported cases from Indonesia. The aims of the study were to describe the typical features of mal de Meleda cases in a Javanese family in Indonesia and identify the mutation in the ARS B gene which encodes SLURP1.
Patients and methods:
In this study, three Javanese patients, siblings from nonconsanguineous nonaffected parents, presented with classical symptoms of mal de Meleda. Genetic analysis screening SLURP1 gene was conducted for the specimens from the patients and other family members.
Results:
A novel homozygous three-nucleotide deletion in exon 3, i.e. c.271-273TCTdel, was identified in the patients. Subcloning and sequencing revealed both parents (I.2 and I.3) and one of the father's siblings (I.1) carry heterozygous c.271-273TCTdel, while the other father's sibling (I.2), the mother's sister (I.4), and a healthy control matched the ethnicity of the family, showing normal sequence of the entire SLURP1.
Conclusion:
This is the first mal de Meleda case of Javanese ethnicity to be documented, and the unique mutation has not previously been reported. The finding supports the notion that despite the rarity, SLURP1 mutation causing mal de Meleda is ubiquitous.
... Subsequent to its initial description in 1826, the disease has been reported in at least 19 countries outside of Croatia including Algeria, Chile, China, Germany, India, Indonesia, Italy, Japan, Korea, Laos, Libya, The Netherlands, Pakistan, Saudi Arabia, Scotland, Sweden, Tunisia, Turkey, and the United Arab Emirates [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19]. ...
... Some samples exhibit parakeratosis, while others show orthokeratosis [29]. There is also variation with respect to findings in the stratum granulosum, as both hypergranulosis and normogranulosis have been recorded [6,30,31]. Further, there is histologic involvement beyond the epidermis into the upper dermis with a perivascular lymphocytic dermal infiltrate [30][31][32]. ...
Mal de Meleda is a rare autosomal recessive palmoplantar keratoderma (PPK) disease with an estimated prevalence of 1:100,000. Clinically, the onset of the disease is typically soon after birth and features a transgrediens (plantar surface progressing to dorsal surface) and progrediens (worsening with age) pattern of hyperkeratosis of the palms and soles. The disease can feature other potentially disfiguring effects on the hands and feet that can severely impact function. Histologically, the lesions show hyperkeratosis and acanthosis without epidermolysis in the epidermis, accompanied by perivascular lymphocytic infiltrate in the dermis. Secreted LY6/urokinase-type plasminogen activator receptor (uPAR)-related protein-1 (SLURP-1) genetic mutations are implicated in Mal de Meleda. SLURP-1 is involved in mediation of inflammation as well as keratinocyte apoptosis regulation. Because the disease is so rare, there are no set guidelines for management, but the accepted approach tends to include oral acitretin plus topical keratolytic therapy. Genetic counseling should also be offered. This focused review highlights the clinical and histological features, differential diagnoses, genetic background, and the current thoughts on management of Mal de Meleda.
... Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma [1]. It was first described in 1826 in a patient from Mljet, formerly known as the Meleda Island in the Adriatic Sea. ...
... In addition to its role as a neuromodulator regulating epidermal homeostasis, the SLURP1 protein is also known to inhibit the secretion of tumor necrosis factor alpha from macrophages during wound healing. These roles also explain the hyperproliferative and inflammatory processes reflected in the clinical manifestation of mal de Meleda [1]. Examination of the DNA material obtained from patient' s blood sample revealed a p.Arg 96 Pro (c.287 CGA>CCA) homozygous missense mutation in the SLURP1 gene. ...
... However, the symptoms may resurface when treatment is discontinued. Treatment should be supplemented with antibacterial and antifungal medication due to an increased risk of bacterial and fungal infections in these patients [1]. Topical antifungal therapy was administered in our case because hyphae and spores were observed upon a direct KOH analysis prepared from the palms and soles of the feet, and also from the nails. ...
... Mal de Meleda, also known as keratoderma palmoplantaris transgrediens, is a rare type of autosomal recessive palmoplantar keratoderma [1]. It was first described in 1826 in a patient from Mljet, formerly known as the Meleda Island in the Adriatic Sea. ...
... In addition to its role as a neuromodulator regulating epidermal homeostasis, the SLURP1 protein is also known to inhibit the secretion of tumor necrosis factor alpha from macrophages during wound healing. These roles also explain the hyperproliferative and inflammatory processes reflected in the clinical manifestation of mal de Meleda [1]. Examination of the DNA material obtained from patient' s blood sample revealed a p.Arg 96 Pro (c.287 CGA>CCA) homozygous missense mutation in the SLURP1 gene. ...
... However, the symptoms may resurface when treatment is discontinued. Treatment should be supplemented with antibacterial and antifungal medication due to an increased risk of bacterial and fungal infections in these patients [1]. Topical antifungal therapy was administered in our case because hyphae and spores were observed upon a direct KOH analysis prepared from the palms and soles of the feet, and also from the nails. ...
... In the past few decades, several cases of this disease have also been reported in some Mediterranean countries and in the Middle East, in places that were on the trade routes of the medieval Republic of Dubrovnik which incorporated the island (28)(29)(30)(31)(32)(33). However, Meleda disease has been recently observed in more distant countries such as in Chinese families in Taiwan, in Pakistan, or in Korea, currently the farthest country from the endemic areas and with no connection in history (34)(35)(36). ...
Meleda disease is an indigenous dermatological disease classified as a hereditary palmoplantar keratoderma. The disease was first described on the island of Mljet, Croatia, by Luko Stulli in 1826. We present a historical review of the literature data throughout the centuries till today. Recently, the gene responsible for the disease has been identified on chromosome 8qter within the cluster of Ly-6 homologous human genes. Various mutations in the secreted LY6/PLAUR-related protein1 gene (SLURP1) located on the aforementioned chromosome were identified as the cause of the disease. Due to similarity between the islands of Malta and Mljet, we are proud of the fact that, to the credit of Croatian researchers and scientists, Mal de Meleda entered the international scientific literature under that very name and has preserved it until today.
... Mal de Meleda, a severe form of palmoplantar keratoderma (PPK), is caused by mutations in SLURP1 (Fischer et al., 2001;Eckl et al., 2003;Marrakchi et al., 2003). The disease is very rare and there are relatively few thorough descriptions of disease phenotypes (Fischer et al., 2001;Charfeddine et al., 2003;Eckl et al., 2003;Marrakchi et al., 2003;Oh et al., 2011). Affected patients have thickening of the skin on the palms and soles, occasionally with pseudoainhum formation and autoamputation of digits. ...
... Our findings are relevant to clinical dermatology. The discovery of a defective water barrier in SLURP1-deficient skin, along with increased neutral lipids in the stratum corneum, could help explain malodorous skin in mal de Meleda (Oh et al., 2011). Leakage of interstitial fluids into the stratum corneum along with the accumulation of triglyceride droplets would favor the growth of microorganisms, and bacterial lipases are known to release malodorous aldehydes, alcohols, and ketones (Chung and Seok, 2012). ...
Mutations in SLURP1 cause mal de Meleda, a rare palmoplantar keratoderma (PPK). SLURP1 is a secreted protein that is expressed highly in keratinocytes but has also been identified elsewhere (e.g., spinal cord neurons). Here, we examined Slurp1-deficient mice (Slurp1(-/-)) created by replacing exon 2 with β-gal and neo cassettes. Slurp1(-/-) mice developed severe PPK characterized by increased keratinocyte proliferation, an accumulation of lipid droplets in the stratum corneum, and a water barrier defect. In addition, Slurp1(-/-) mice exhibited reduced adiposity, protection from obesity on a high-fat diet, low plasma lipid levels, and a neuromuscular abnormality (hind-limb clasping). Initially, it was unclear whether the metabolic and neuromuscular phenotypes were due to Slurp1 deficiency, because we found that the targeted Slurp1 mutation reduced the expression of several neighboring genes (e.g., Slurp2, Lypd2). We therefore created a new line of knockout mice (Slurp1X(-/-) mice) with a simple nonsense mutation in exon 2. The Slurp1X mutation did not reduce the expression of adjacent genes, but Slurp1X(-/-) mice exhibited all of the phenotypes observed in the original line of knockout mice. Thus, Slurp1 deficiency in mice elicits metabolic and neuromuscular abnormalities in addition to PPK.Journal of Investigative Dermatology advance online publication, 6 February 2014; doi:10.1038/jid.2014.19.
... We found the 82delT variation commonly in families MDM-12 and MDM-13. This frame shift mutation results in truncated, misfolded, and therefore [15]); Ivs1 + 1G > A (Pakistani [16]); Trp15Arg (German [15], Scottish [3], and Dutch [17]); 82delT (Tunisian [3], Scottish [3], Algerian [3], Croatian [9], Kurdish [10], and Italian [11]); Ivs2 + 1G > A (Algerian [3]); Cys43Stop (Turkish [18]); Arg71Pro (Dutch [17]); Cys77Ala (Tunisian [4]); Pro82Ser (Turkish [19]); Gly86Arg (Palestinian [15], Turkish [15]), and Pakistani [16]), Korean [20], Taiwanese [21]); Arg96Stop (Croatian [9], Turkish [10], Korean [20], and Pakistani [16]); Lys98Pro (Turkish [22]); Cys99Tyr (Tunisian [12]); and Arg71His (patient was reported in a study from France, and the origin is not reported [23]). nonfunctional protein. ...
... We found the 82delT variation commonly in families MDM-12 and MDM-13. This frame shift mutation results in truncated, misfolded, and therefore [15]); Ivs1 + 1G > A (Pakistani [16]); Trp15Arg (German [15], Scottish [3], and Dutch [17]); 82delT (Tunisian [3], Scottish [3], Algerian [3], Croatian [9], Kurdish [10], and Italian [11]); Ivs2 + 1G > A (Algerian [3]); Cys43Stop (Turkish [18]); Arg71Pro (Dutch [17]); Cys77Ala (Tunisian [4]); Pro82Ser (Turkish [19]); Gly86Arg (Palestinian [15], Turkish [15]), and Pakistani [16]), Korean [20], Taiwanese [21]); Arg96Stop (Croatian [9], Turkish [10], Korean [20], and Pakistani [16]); Lys98Pro (Turkish [22]); Cys99Tyr (Tunisian [12]); and Arg71His (patient was reported in a study from France, and the origin is not reported [23]). nonfunctional protein. ...
Mal de Meleda (MDM) is a rare, autosomal recessive form of palmoplantar keratoderma. It is characterized by erythema and hyperkeratosis of the palms and soles that progressively extend to the dorsal surface of the hands and feet. It is caused by mutations in SLURP-1 gene encoding for secreted mammalian Ly-6/uPAR-related protein 1 (SLURP-1). We performed mutational analysis by direct sequencing of SLURP-1 gene in order to identify the genetic defect in three unrelated families (families MDM-12, MDM-13, and MDM-14) variably affected with transgressive palmoplantar keratoderma. A spectrum of clinical presentations with variable features has been observed from the pronounced to the transparent hyperkeratosis. We identified the 82delT frame shift mutation in the SLURP-1 gene in both families MDM-12 and MDM-13 and the missense variation p.Cys99Tyr in family MDM-14. To date, the 82delT variation is the most frequent cause of MDM in the world which is in favour of a recurrent molecular defect. The p.Cys99Tyr variation is only described in Tunisian families making evidence of founder effect mutation of likely Tunisian origin. Our patients presented with very severe to relatively mild phenotypes, including multiple keratolytic pits observed for one patient in the hyperkeratotic area which was not previously reported. The phenotypic variability may reflect the influence of additional factors on disease characteristics.
This report further expands the spectrum of clinical phenotypes associated with mutations in SLURP1 in the Mediterranean population.
Résumé
Les kératodermies palmoplantaires (KPP) sont un ensemble hétérogène de maladies dermatologiques rares qui se caractérisent par une hyperkératose palmaire et plantaire. Les KPP peuvent être considérées comme acquises ou héréditaires. Les KPP héréditaires (KPPH) peuvent être classées en 3 groupes : 1) les KPPH non syndromiques isolées ; 2) les KPPH non syndromiques complexes associées à d’autres manifestations cutanées focales, à distance des paumes et des plantes avec ou sans atteinte phanérienne et 3) les KPPH syndromiques associées à des manifestations extracutanées. Le développement du séquençage de nouvelle génération a permis d’identifier, au cours des dix dernières années, de nombreux nouveaux gènes et variants impliqués dans les KPPH. Ces travaux ont notamment montré que des affections, apparemment distinctes, étaient causées par des variants d’un même gène, et que des phénotypes apparemment similaires étaient, au contraire, dus à des variants dans des gènes distincts. Cette revue décrit les différentes causes génétiques des kératodermies palmoplantaires héréditaires non syndromiques isolées pour lesquelles les gènes ont pu être identifiés.
