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Genetic and Clinical Heterogeneity in Transgressive Palmoplantar Keratoderma

2001; Elsevier BV; Volume: 116; Issue: 5 Linguagem: Inglês

10.1046/j.1523-1747.2001.01346-3.x

1523-1747

Gilles G. Lestringant, Philippe M. Frossard, Katja‐Martina Eckl, André Reis, Hans Christian Hennies,

Contact Dermatitis and Allergies

To the Editor Transgressive hyperkeratosis is a phenomenon that may occur in various forms of palmoplantar keratoderma (PPK). It consists of hyperkeratosis spreading from the palms and soles across the line of transgredience onto the dorsa of the fingers, the toes, the hands and the feet, the flexor aspects of the wrists and the heels. In particular, transgressive PPK is a feature of autosomal recessively inherited disorders such as Naxos disease (PPK with cardiac abnormalities, OMIM #601214), Papillon–Lefèvre syndrome (PPK with periodontopathia, OMIM #245000), and Mal de Meleda (OMIM #248300). Mal de Meleda (MDM), or keratosis palmoplantaris transgrediens of Siemens, was first reported in 1826 on the island of Meleda, now Mljet, in Croatia. It has since been reported in patients from other European countries, North Africa, the Near and the Middle East, Chile, India, Laos, and Taiwan. Onset of the disorder is in early infancy before 1 y of age with diffuse PPK and transgressive keratosis. There is no associated involvement of other organs. Histopathologically, hyperorthokeratosis and acanthosis are seen as well as foci of parakeratosis (Frenk et al., 1996Frenk E. Guggisberg D. Mevorah B. Hohl D. Meleda disease: report of two cases investigated by electron microscopy.Dermatology. 1996; 193: 358-361Crossref PubMed Scopus (16) Google Scholar). Some other features, in which environmental factors may play a role, are facultative and variable. They are hyperkeratotic scaly lesions of cobblestone appearance over the knees and elbows called ‘lichenoid plaques’, nail abnormalities, knuckle-pads, perioral erythema, hyperhidrosis, and pseudo-ainhum. Some but not all patients show a marked progression of most features of the disease. A rather broad spectrum of clinical presentations is characteristic of MDM and it has been argued that the disorder may be genetically heterogeneous (Frenk et al., 1996Frenk E. Guggisberg D. Mevorah B. Hohl D. Meleda disease: report of two cases investigated by electron microscopy.Dermatology. 1996; 193: 358-361Crossref PubMed Scopus (16) Google Scholar;Lestringant et al., 1997Lestringant G.G. Frossard P.M. Adeghate E. Qayed K.I. Mal de Meleda: a report of four cases from the United Arab Emirates.Pediatr Dermatol. 1997; 14: 186-191Crossref PubMed Scopus (29) Google Scholar). In 1998, a locus for MDM was described on chromosome 8q24-qter in two consanguineous families from Algeria (Fischer et al., 1998Fischer 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: 542-547Crossref PubMed Scopus (47) Google Scholar). By homozygosity mapping, the authors localized the gene to a 5 cM interval telomeric to D8S1727 (Figure 1). Since then, a third Algerian family mapping to the same region has been reported (Bouadjar et al., 2000Bouadjar B. Benmazouzia S. Prud'Homme J.F. Cure S. Fischer J. Clinical and genetic studies of 3 large, consanguineous, algerian families with mal de meleda.Arch Dermatol. 2000; 136: 1247-1252Crossref PubMed Scopus (38) Google Scholar). Recently, we have confirmed and refined the localization of a gene for MDM on chromosome 8q24-qter in one Palestinian family and two families from the United Arab Emirates. 1Hennies HC, Lestringant GG, Stevens HP, Hinz B, Frossard PM, Leigh IM, Reis A: Mal de Meleda: Candidate gene analysis on chromosome 8q24.3 and identification of genetic and clinical heterogeneity. Am J Hum Genet 67:378, 2000 (abstr.)1Hennies HC, Lestringant GG, Stevens HP, Hinz B, Frossard PM, Leigh IM, Reis A: Mal de Meleda: Candidate gene analysis on chromosome 8q24.3 and identification of genetic and clinical heterogeneity. Am J Hum Genet 67:378, 2000 (abstr.) We present here five patients from three consanguineous Arab families with autosomal recessive transgressive PPK that is not linked either to the region on chromosome 8q24-qter or to a number of further candidate regions for PPK, namely the type-I and -II keratin gene clusters on chromosomes 12q12 and 17q21, respectively, the region of the plakoglobin gene on chromosome 17q21, which is mutated in Naxos disease (McKoy et al., 2000McKoy G. Protonotarios N. Crosby A. et al.Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease).Lancet. 2000; 355: 2119-2124https://doi.org/10.1016/s0140-6736(00)02379-5Abstract Full Text Full Text PDF PubMed Google Scholar), and the epidermal differentiation complex on chromosome 1q21 that harbors, among other genes, the one for loricrin, which carries mutations in a mutilating form of PPK (Maestrini et al., 1996Maestrini E. Monaco A.P. McGrath J.A. et al.A molecular defect in loricrin, the major component of the cornified cell envelope, underlies Vohwinkel’s syndrome.Nat Genet. 1996; 13: 70-77Crossref PubMed Scopus (201) Google Scholar). All three families, which originate from Yemen (families A and B) and Oman (family C), are highly consanguineous and demonstrate an autosomal recessive inheritance of the disorder (Figure 2).Figure 2Pedigrees of three families with transgressive palmoplantar keratoderma and haplotypes on telomeric chromosome 8q. All parents are double first- or second-degree relatives. Genotyping at D8S272, D8S1741, D8S1751, D8S1836, D8S1925, and D8S2334 revealed exclusion of linkage to 8q24-qter by lack of homozygosity and obligatory recombination events (family C). Likely haplotypes were constructed in family C.View Large Image Figure ViewerDownload (PPT) In family A, the 5-y-old boy presented with lesions consisting of diffuse erythrodermic PPK and well-delineated transgressive erythrodermic keratosis, often with scaly borders, on the flexor aspects of the wrists, the dorsa of the feet and toes and of the hands and fingers, and over the malleoli. On both knees there were plaques of moderate erythrodermic keratosis 8–10 cm in diameter with accentuated skin markings. Lesions had started on palms and soles at about 6 mo of age. The patient was first examined at 3 y of age and subsequently there were several follow-up visits during which various transient lesions were noted, such as perioral erythema, knuckle-pads, and erythema of the buttocks with scaly edges. The affected girl was examined at the age of 7 mo. She presented with mild diffuse erythrodermic PPK, erythroderma with thickened and increased skin markings on the sides of the feet, and mild skin thickening with erythema on the dorsa of several fingers. The patient of family B was examined at the age of 3½ y. He presented with diffuse erythrodermic PPK and with mild erythematous transgressive hyperkeratosis. There were areas of accentuated skin markings with scaly borders on the toes, on the sides of the feet, on the malleoli, on both thumbs and fifth fingers, on the distal phalanx of the other fingers, over the knuckles, and on the flexor aspects of the wrists. There were ill-defined plaques of erythrodermic keratosis on the knees. The boy and the girl of family C were examined at the ages of 4 and 2 y, respectively. They presented grossly with lesions similar to those already described in the previous patients. All patients presented with red nails with preserved lunulae. Their hair, teeth, eyes, mucosae, and mental development were normal. There was no hyperhidrosis. None of the parents and ancestors were affected or reported affected. Skin biopsies were denied. To test whether or not the autosomal recessive transgressive PPK present in our families was linked to the MDM interval on chromosome 8q described byFischer et al., 1998Fischer 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: 542-547Crossref PubMed Scopus (47) Google Scholar, we analyzed six microsatellite markers from that region. Besides markers at D8S272, D8S1741, D8S1751, and D8S1836 (Dib et al., 1996Dib C. Fauré S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar), we additionally examined markers at D8S1925 and D8S2334 (Rosenberg et al., 1997Rosenberg M. Hui L. Ma J. et al.Characterization of short tandem repeats from thirty-one human telomeres.Genome Res. 1997; 7: 917-923PubMed Google Scholar) from the subtelomeric structure of chromosome 8q Figure 1), distally to D8S1836, the most telomeric marker in the Généthon map (Dib et al., 1996Dib C. Fauré S. Fizames C. et al.A comprehensive genetic map of the human genome based on 5,264 microsatellites.Nature. 1996; 380: 152-154Crossref PubMed Scopus (2668) Google Scholar). Moreover, markers at D1S252, D1S498, D1S1664, and D1S305 in the region of the epidermal differentiation complex, at D12S368, D12S96, and D12S83 in the type-II keratin gene region, and at D17S946, D17S1787, and D17S791 in the region containing type-I keratin genes and the plakoglobin gene were analyzed. DNA was extracted from blood drawn after informed consent of the probands. A blood sample from the little girl of family A (6–2) was not available. Markers were amplified individually by polymerase chain reaction with one primer of each pair end-labeled with fluorescent dye. Reaction products were electrophoresed either on an ABI 377 or on a MegaBace 1000 automatic DNA sequencer. Data were analyzed using the computer programmes Genescan v2.1 and Genotyper v2.5 (Applied Biosystems, Foster City, CA), or Genetic Profiler v1.1 (Amersham Pharmacia Biotech, Uppsala, Sweden). Two-point LOD score calculation was performed with the LINKAGE v5.2 programme package (Lathrop and Lalouel, 1984Lathrop G.M. Lalouel J.M. Easy calculations of lod scores and genetic risks on small computers.Am J Hum Genet. 1984; 36: 460-465PubMed Google Scholar), and multipoint LOD scores were calculated with GENEHUNTER-plus (Kruglyak et al., 1996Kruglyak L. Daly M.J. Reeve-Daly M.P. Lander E.S. Parametric and nonparametric linkage analysis: a unified multipoint approach.Am J Hum Genet. 1996; 58: 1347-1363PubMed Google Scholar). A LOD score ≤ 2 was considered significant against linkage. In MDM family C, with two affected siblings, we observed obligatory recombination events between the phenotype and each of the loci analyzed on chromosome 8q, except for the marker at D8S1925 which is uninformative in the family (Figure 2). Because parents of affected individuals are double first cousins (family C), double second cousins (B), or second cousins and first cousins once removed (A), homozygosity by descent for the underlying mutation is highly expected. The patients from all three families, however, are heterozygous at each of the informative marker loci (Figure 2). Therefore, the MDM interval on chromosome 8q could be effectively excluded in all families by homozygosity mapping. Two-point linkage analysis (data not shown) and multipoint analysis clearly ruled out linkage to the chromosomal region distal to D8S272 (Figure 3). Similarly, linkage to the other candidate gene regions was excluded by homozygosity mapping and multipoint linkage analysis (data not shown). We report here on five members of three unrelated families from the United Arab Emirates who presented with autosomal recessive transgressive PPK. The disorder did not map either to the chromosomal region described in three Algerian and in three Palestinian and Emirati Arab families with MDM, or to several further regions of known candidate genes for keratoderma. MDM belongs to a group of severe diffuse autosomal recessive PPK with transgredience but without associated involvement of other organs. The variability of additional facultative features, however, does not concur with a well-defined phenotype. Incidentally, the patients of family A have already been reported as having MDM (Lestringant et al., 1997Lestringant G.G. Frossard P.M. Adeghate E. Qayed K.I. Mal de Meleda: a report of four cases from the United Arab Emirates.Pediatr Dermatol. 1997; 14: 186-191Crossref PubMed Scopus (29) Google Scholar). Moreover, although most cases of MDM have been reported in individuals originating grossly from the same geographical area, the Mediterranean region, other cases have been described in patients from various ethnic groups and distant geographic origins. These observations are consistent with the existence of genetic heterogeneity in patients with transgressive PPK without associated features, which we demonstrate here. Nevertheless, the underlying erythroderma, a trait also present in some genuine MDM patients (Franceschetti et al., 1972Franceschetti A.T. Reinhart V. Schnyder U.W. La Maladie de Meleda.J Genet Hum. 1972; 20: 267-296PubMed Google Scholar;Salamon et al., 1982Salamon T. Cezarovic B. Nardelli-Kovacici M. Schnyder U.W. Die Meleda-Krankheit – eine Akroerythrokeratodermie.Z Hautkr. 1982; 57: 580-586PubMed Google Scholar), that was prominent in the patients reported here, has already been described (Lestringant et al., 1997Lestringant G.G. Frossard P.M. Adeghate E. Qayed K.I. Mal de Meleda: a report of four cases from the United Arab Emirates.Pediatr Dermatol. 1997; 14: 186-191Crossref PubMed Scopus (29) Google Scholar) in a patient mapping to chromosome 8q24-qter (data not shown). Hence there are currently no consistent diagnostic criteria clearly correlating with the genetic etiology of the disease. Genes underlying a number of different autosomal dominantly inherited palmoplantar keratodermas have been described in recent years (reviewed inChristiano, 1997Christiano A.M. Frontiers in keratodermas: pushing the envelope.Trends Genet. 1997; 13: 227-233https://doi.org/10.1016/s0168-9525(97)01104-9Abstract Full Text PDF PubMed Scopus (0) Google Scholar;Irvine and McLean, 1999Irvine A.D. McLean W.H. Human keratin diseases: the increasing spectrum of disease and subtlety of the phenotype-genotype correlation.Br J Dermatol. 1999; 140: 815-828https://doi.org/10.1046/j.1365-2133.1999.140004815.xCrossref PubMed Scopus (0) Google Scholar;Kelsell and Stevens, 1999Kelsell D.P. Stevens H.P. The palmoplantar keratodermas: much more than palms and soles.Mol Med Today. 1999; 5: 107-113https://doi.org/10.1016/s1357-4310(98)01428-2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The identification of those mutations showed that functionally rather different proteins may be involved in the etiology of very similar phenotypes and provided further insight into the complex process of epidermal differentiation; however, there are only few autosomal recessive palmoplantar keratodermas. Mutations in the tyrosine aminotransferase gene were identified in Richner–Hanhart syndrome, or palmoplantar keratoderma with corneal dystrophy (Natt et al., 1987Natt E. Westphal E.M. Toth-Fejel S.E. Magenis R.E. Buist N.R. Rettenmeier R. Scherer G. Inherited and de novo deletion of the tyrosine aminotransferase gene locus at 16q22.1-q22.3 in a patient with tyrosinemia type II.Hum Genet. 1987; 77: 352-358Crossref PubMed Scopus (53) Google Scholar,Natt et al., 1992Natt E. Kida K. Odievre M. Di Rocco M. Scherer G. Point mutations in the tyrosine aminotransferase gene in tyrosinemia type II.Proc Natl Acad Sci USA. 1992; 89: 9297-9301Crossref PubMed Scopus (62) Google Scholar), and mutations in the gene for cathepsin C were only recently found in patients with Papillon–Lefèvre syndrome (Hart et al., 1999Hart T.C. Hart P.S. Bowden D.W. et al.Mutations of the cathepsin C gene are responsible for Papillon–Lefèvre syndrome.J Med Genet. 1999; 36: 881-887PubMed Google Scholar;Toomes et al., 1999Toomes C. James J. Wood A.J. et al.Loss-of-function mutations in the cathepsin C gene result in periodontal disease and palmoplantar keratosis.Nat Genet. 1999; 23: 421-424https://doi.org/10.1038/70525Crossref PubMed Scopus (373) Google Scholar). It appears that the MDM phenotype is due to at least two different genotypes. The identification of the genes underlying MDM and the phenotype described here will show whether both (or more) MDM subgroups are caused by mutations in functionally related proteins and could hence reveal further, as yet unknown, interactions of components of the epidermis. A genome-wide search for the locus of the present phenotype is probably necessary as a first step to identify the gene mutated in this disorder. We are grateful to all family members who participated in this study. We wish to thank Fabienne Trotier for excellent technical assistance. The Gene Mapping Center is funded by a grant in aid of the German Human Genome Project to A.R.