Mal De Meleda: a Report of Two Cases in One Family

CASE REPORT Mal de Meleda: A report of two cases in one family

A. Prohić, E. Kasumagić-Halilović, M.Kantor

Department of Dermatovenerology, The University Clinical Center in Sarajevo, Bosnia and Herzegovina

ABSTRACT Mal de Meleda is a rare autosomal recessive skin disorder, characterized by transgressive palmoplantar keratoderma, lichenoid skin lesions, perioral erythema, brachydactyly and nail abnormalities. We are reporting two cases of a clinically typical disease in a family. No consanguineous relationship between the parents was known and cases could not be detected in three generations of the patient’s family. Key words: genodermatosis, Mal de Meleda, palmoplantar keratoderma

INTRODUCTION We are reporting two cases of a clinically typical disease in a sister and a brother from Herzegovina. No consanguineous relationship between the parents was Mal de Meleda, also known as keratosis palmoplantaris known, none of the family members were affected. transgrediens of Siemens, is a very rare genodermatosis with the prevalence in the general population of 1 in 100,000. CASE REPORT The disease was first observed and described in 1826 by Dubrovnik’s state-physician Luca Stulli on the Dal- Case 1 A thirty-nine year old male was seen for evalua- matian island of Mljet (Meleda) (1). For more than a tion of a palmoplantar thickening that had been present half of the century it was mistaken for leprosy, until from birth. Erythema of the palms and soles was the Hovorka and Ehlers (2) realized that it was a noninfec- first manifestation followed rapidly by roughening and tious disease and used the term Mal de Meleda, the top- thickening of the skin. At first the lesions were restrict- onym utilized today. Many researches studied this very ed only on his palms and soles and than extended to the particular disease but it was the dermatologist Kogoj sides and the dorsa of the hands and feet. Transgressive who performed the first extensive epidemiologic study pahyderma was noted in pubertal period. (3). The autosomal recessive mode of inheritance was described in 1938 (4), and the linkage of the disorder to On physical examination, the patient was noted to have the 8qter locus was reported in 1998 (5). yellowish coloured, diffuse keratoderma in the glove- and-sock distribution. It was delineated by prominent The main clinical characteristics are palmoplantar kera- erythematous border of desquamatiom from uninvolved toderma and transgressive pachyderma, which extend skin (Figure 1). Nail abnormalities were also observed on the dorsal surfaces of the hands and feet (glove- and consisted of hyperconvexity and dystrophy. and-stocking distribution), hyperhidrosis and perioral erythema. Other features of the disorder such as brachydactyly, contractures of the fingers, conical dis- Case 2 A thirty-five year old female complained of tal phalanges, nail abnormalities and lichenoid plaques thickening of the palms and soles that had been present were also reported (6-8). since birth. At the beginning, the lesions were confirmed only to her palms and soles with dominated erythematous component, but later they became more hyperkera- Corresponding author: A.Prohić, Department of Dermatovenerology, The University totic and extended to the dorsal aspects of the hands and Clinical Center in Sarajevo, Bosnia and Herzegovina, Bolnička 25, Tel/Fax: + 387 33 213 490, e-mail: [email protected]

73 Medicinski glasnik, Volume 3, Number 2, August 2006

and apart from for described symptoms they were in good health. The palmoplantar keratodermas are a heterogeneous group of keratinization disorders characterized by erythema and hyperkeratosis of the palms and soles. More than 40 different types of palmoplantar keratodermas have been described (9). The clinical picture in both patients is compatible with the diagnosis of Mal de Meleda. Both patients showed the main clinical features of this genodermatosis ac- cording to the criteria of Schnyder et al (10): diffuse thickening of the palms and soles appearing before the age of 5 months and transgressive pachyderma with onset usually before the age of 2 years. Other features of the disorder were also seen: contractures of the fingers; conical distal phalanges and nail abnormalities. Keratotic plaques on the elbows and knees and perioral erythema were noted only at female patient. Associated hyperhydrosis that cause malodorous maceration were noted in none of them. The variable frequencies of clinical symptoms probably reflect individual variation in the presentation of the disease. Progressiveness of the lesions was seen in both patients; this has been reported previously in a series of patients from the United Arab Figure 1 Case 1: Diffuse yellowish coloured keratoderma in glove-sock Emirates (7) and Algeria (6), where an age-related pro- distribution (upper); palmar hyperkeratosis with red border of desquamation delimiting the hyperkeratotic region (down) gression in the extension of the lesions was mentioned. feet and involved the ankles. Transgressive pahyderma Mal de Meleda must be differentiated from other forms was also noted in pubertal period at the same time with of palmoplantar keratodermas. They are sometimes dif- keratotic plaques on elbows and knees. Physical exam- ficult to distinguish clinically, and diagnoses are made ination revealed massive, yellowish palmoplantar hy- on the basis of morphologic features, distribution of perkeratosis with extension to the dorsal aspects of the hyperkeratosis, the presence or absence of associated hands, sharply outlined with brownish red scaly border anomalies and inheritance pattern. Papillon-Lefèvre from normal skin. There has been conical thickening in syndrom, which was localized to chromosome 11q distal parts of her fingers and contracture deformities at (11), is an autosomal recessive palmoplantar keratoder- fingers (Figure 2). The nails showed subungual hyper- ma that is typically associated with gingivitis, periostal keratosis and pahyonychia and koilonychias. Keratotic changes in alveolar bones and intracranial calcifica- plaques on elbows and knees become less prominent tion (12). Richner Hanhart syndrome has an autosomal and infiltrated under the local therapy. Slightly- pro recessive inheritance pattern in which palmoplantar nounced perioral erythema was also noted. keratoderma is associated with mental retardation and corneal dystrophy. Molecular biology includes defi- Both patients were under acitretine treatment with 20 ciency of the enzyme tyrosine aminotransferase, lead- mg daily over a period of two years which led to im- ing to increased levels of serum tyrosine and phenolic provement in hyperkeratosis and reduction of contrac- acid metabolites of tyrosin (13). Vohwinkel syndrome tures of the hands; however, there was little effect on is a diffuse mutilating keratoderma, characterized by erythema. Relapses were observed when acitretine was ainhum, which cause spontaneous amputations. Alo- discontinued. In both patients the progressive character pecia, deafness, myopathy and paraplegia may also be of the lesions has become obvious in the last few years, associated (14). Mutations have been identified in connexin 26 (15). Diffuse nonepidermolytic palmoplantar

74 Case report

The efficacy of the aromatic retinoids in the treatment of disorders of keratinization is well established (21,22). Acitritin treatment in our cases resulted in marked reduction of the hyperkeratosis but had no effect on erythema. Relapses were observed when the dose was re- duced or acitretine was discontinued. Since the first description of Mal de Meleda in 1826 the disorder has also been reported from Europe (23-25), Africa (6,26), Asia (7,27,28) and America (29). This case report characterizes Mal de Meleda in the Mediter- ranean setting and shows that the sporadic cases found elsewhere in the regions out of the medieval trade routes carry the same mutation as the patients from Mljet Is- land. However, environmental and individual factors may also play a role in the broad clinical presentation of this rare genodermatosis.

REFERENCES: 1. Kogoj F. Die Krankheit von Mljet (Mal de Meleda). Acta Derm Venereol 1934; 15: 264-299. 2. Hovorka O, Ehlers E. Mal de Meleda. Arch Derm Syph (Berlin) 1897; 40: 251-256. 3. Kogoj F. Mljetska bolest. Zagreb: Yugoslavian Academy of Sciences and Arts, 1963. 4. Bosnjakovic S. Vererbungverhaltnisse bei der sog Krankheit von Mljet (mal de Meleda). Acta Derm Venereol 1938;19:88-122. 5. Fischer J, Bouadjar B, Heilig R, Fizames C, Prud’homme J-F, Weissenbach J. Genetic linkage of Meleda disease to chromosome 8qter. Eur J Hum Genet 1998; 6: 542-547. 6. Bouadjar B, Benmazouzia S, Prud’homme JF, Cure S, Fischer J. Clinical and genetic studies of 3 large, consanguineous, Algerian families with mal de Meleda. Arch. Dermatol. 2000; 136: 1247–1252. 7. Lestringant GG, Frossard PM, Adeghate E, Qayed KI. Figure 2 Case 2: Pronounced, transparent, yellowish palmoplantar hyper- Mal de Meleda: a report of four cases from the United keratosis (upper); extension of hyperkeratosis to the dorsal aspects of the Arab Emirates. Pediatr Dermatol 1997; 14:186-191. hands (midst); hyperkeratosis leading to contractures of the hands (down) 8. Fatovic-Ferencic S. Mal de Meleda. J Invest Dermatol keratoderma, Thost-Unna syndrome, is inherited in an 2003; 121: 433. autosomal dominant fashion, does not progress to the 9. Itin PH, Fistarol SK. Palmoplantar keratodermas. Clin Dermatol 2005; 23:15-22. glove-and-stocking distribution (16) and mutations 10. Schnyder UW, Franceschetti AT, Ceszarovic B, Sege- have been found in keratin 9 (17). Mal de Naxos is also din J. La maladie de Meleda autochtone. Ann Dermatol an autosomal recessive disorder of palmplantar kerat- Syphiligr (Paris) 1969; 96: 517-530. inisation characterized by additional cardiac anomalies 11. Fischer J, Blanchet-Bardon C, Prud’homme JF, Pavek and woolly hair (18). The gene locus has been mapped S, Steijlen PM, Dubertret L, et al. Mapping of Papillon- to chromosome 17q21 (19). Recently reported heredi- Lefèvre syndrome to the chromosome 11q14 region. Eur J Hum Genet 1997; 5: 156-160. tary palmoplantar keratosis of the Gamborg Nielsen 12. Hart TC, Shapira L. Papillon-Lefèvre syndrome. Period- type is a possible subtle variant form of keratosis pal- ontol 2000; 1994; 6: 88-100. moplantaris transgrediens (20).

75 Medicinski glasnik, Volume 3, Number 2, August 2006

13. Minami-Hori M, Ishida-Yamamoto A, Katoh N, Taka- 21. Happle R, van de Kerhof PCM, Traupe H. Retinoids in hashi H, Iizuka H. Richner-Hanhart syndrome: report of a disorders of keratinization: their use in adults. Dermato- case with a novel mutation of tyrosine aminotransferase. logica 1987; 175(Suppl 1): 107-124. J Dermatol Sci. 2006; 41: 82-84. 22. Blanchet-Bardon C, Nazzaro V, Rognin C, Geiger JM, 14. Sensi A, Bettoli V, Zampino MR, Gandini E, Calzolari Puissant A, et al. Acitretin in the treatment of severe dis- E. Vohwinkel syndrome (mutilating keratoderma) associ- orders of keratinization. J Am Acad Dermatol 1991; 24: ated with craniofacial anomalies. Am J Med Genet 1994; 982-986. 50: 201-203. 23. Niles HD, Klump MM. Mal de Meleda: review of the 15. Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, literature and report of four cases. Arch Dermatol Syph Cambiaghi S, Scudder PM, et al. A missense mutation in 1939; 39: 409-421. connexin 26, D66H, causes mutilating keratoderma with 24. Blum P, Marlingue G. Type sclerodermiforme de la sensorineural deafness (Vohwinkel’s syndrome) in three maladie de Meleda. Bull Soc Fr Dermatol Syphil 1939; unrelated families. Hum Mol Genet 1999; 8:1237-1243. 46:643-666. 16. Menni S, Saleh F, Piccinno R, Corbetta C, Melotti D. Pal- 25. Camarasa JG, Garcia Flores A. Recessive keratosis palmoplantar keratoderma of Unna-Thost: response to biotin moplantaris progrediens (Meleda’s disease). Med Cutan in one family. Clin Exp Dermatol. 1992; 17: 337-338. Ibero Lat Am 1987; 15: 24-28. 17. Reis A, Hennies HC, Langbein L, Digweed M, Mischke 26. Zahaf A, Charfi C, Bakhlouti A. La kératodermie palmo- D, Drechsler M, et al. Keratin 9 gene mutations in epider- plantaire type Meleda. Semaine Hop Paris 1987; 63:1043- molytic palmoplantar keratoderma (EPPK). Nat Genet 1046. 1994; 6:174-179. 27. Chotzen VA, Starr JC, Mauro TM. Mal de Meleda in a 18. Protonotarios N, Tsatsopoulou A, Fontaine G. Naxos dis- Laotian family. Int J Dermatol 1993; 32: 602-604. ease: keratoderma, scalp modifications, and cardiomy- 28. Jee SH, Lee YY, Wu YC, Lu YC, Pan CC. Report of a opathy. J Am Acad Dermatol. 2001 Feb; 44: 309-311. family with mal de Meleda in Taïwan: a clinical, his- 19. Coonar AS, Protonotarios N, Tsatsopoulu A, Needham topathological and immunological study. Dermatologica EW, Houlston RS, Cliff S, et al. Gene for arrhythmogenic 1985; 171: 30-37. right ventricular cardiomyopathy with diffuse nonepi- 29. Reed ML, Stanley J, Stengel F, Shupack JL, Benjamin dermolytic palmoplantar keratoderma and woolly hair DM. Mal de Meleda treated with 13-cis retinoic acid. (Naxos disease) maps to 17q21. Circulation 1998; 97: Arch Dermatol 1979; 115: 605-608. 2049-2058. 30. Urbina F, Cristobal MC, Sandoval R. Mal de Meleda. 20. Kastl I, Anton-Lamprecht I, Nielsen P. Hereditary palmo- Cutis 1995; 56: 235-238. plantar keratosis of the Gamborg Nielsen type: clinical and ultrastructural characteristics of a new type of autosomal recessive palmoplantar keratosis. Arch Dermatol Res 1990; 282:363-370.