R eview K E Y WORDS palmoplantar, keratoderma, hereditary, diffuse, molecular biology The diffuse palmoplantar keratodermas The dijJuse palmoplantar keratodermas S. J. Hatsell and D. P. Kelsell SUMMARY Diffuse palmoplantar keratodermas belong to a diverse group of skin disorders affecting the palms and soles. These keratodermas manifest as a diffuse thickening of the palmoplantar skin, which can often be associated with other ectodermal disorders. Classification within this group has often been difficult due to the overlapping of phenotypes between disorders and the diversity within one particular disease. During the last few years advances in the molecular characterization of many of the keratodermas has helped both in distinguishing the different diseases and increasing our understanding of skin biology. Introduction Hereditary palmoplantar keratodermas (PPKs) are a highly heterogeneous group of skin diseases, which primarily affect the palms, and soles or palmoplantar skin and involve thickening and hyperkeratosis. They can be inherited in both an autosomal dominant and recessive fashion. PPKs can be divided into three sub- groups according to their phenotype. Simple kerato- dermas manifest as lesions only on the palmoplantar skin, whereas complex keratodermas are associated with lesions of non-volar skin, hair, teeth, nails or sweat glands. Syndromic keratodermas are associated with abnormalities of other organs such as deafness, cancer, cardiomyopathy, and adrenal insufficiency. Simple keratodermas can be divided, by the clinical pattern of keratoderma, into three main groups, the diffuse, focal and punctate PPK. Syndromic forms of keratoderma are normally associated with either a diffuse or focal pattern of keratoderma, with secondary disorders including deafness and cardiomyopathy. As the name suggests , in diffuse PPK the pattern of kera- toderma is uniform across the palmoplantar skin. This compares with focal PPK, in which the keratoderma develops at pressure points or sites of trauma and pun- ctate keratoderma, which results in numerous small hy- perkeratotic nodules . Classification of the diffuse PPKs when relying on clinical findings can be ambiguous, due to the overlap of ce11ain clinical features between disorders and hete- rogeneity within the same disorder. The heterogeneity seen in phenotype throughout the diffuse PPKs is partly reflected in the diversity of genetic mutations discovered to date. However in many PPKs there can be consi- derable variation in phenotype between families and within families with the same genetic defect. Mutations Acta Dermatoven APA Vol 9, 2000, No 2 47 The dijfuse palmoplantar keratodermas so far have been found in structural, adhesion and gap junctions proteins (Figure 1), though there are other loci associated with PPK for which the specific gene defects have yet to be identified. In this review, we discuss a classification and the current molecular under- standing of the diffuse PPKs. Simple diffuse PPK Two different forms of the simple PPK showing a diffuse pattern of lesion have been described, diffuse epidermolytic PPK (EPPK) ancl diffuse non-epider- molytic PPK (NEPPK). EPPK also known as Vorner's disease, first described in 1901 and diffuse NEPPK also called Unna-Thost type, after the clinicians w ho first reported it, are often phenotypically confused (1-3). Both are present from infancy and are ch aracterized by hyperkeratos is covering the entire palms and soles. EPPK tends to have thick fissured pattern, which is borderecl with e1ythe- matous margins; compared with NEPPK (Figure 2a) which usually has a more yellow waxy appearance though the phenotype in both diseases can va1y greatly even within a family. The lesions on the skin in NEPPK are often susceptible to seconda1y dermophyte infection and hyperhidrosis is common. Spreading onto the dorsal surfaces of the hands ancl w rists with a sharp cut off is a feature ofNEPPK, though knuckles pacls can be present in EPPK. Nail ch anges may be observed in both clisorclers. Both diseases are inheritecl in an autosomal dominant fashion ancl are highly penetrant. Histologically the two cliseases can be easier to clis- tinguish, with EPPK showing keratin filament clumping in the suprabasal cells of the epidermis. Perinuclear vacuolization of keratinocytes ancl large irregularly shapecl keratohyalin granules in the granular layer are also a feature of EPPK not seen in NEPPK. NEPPK can be iclentifiecl by the presence of orthokeratotic hyper- keratosis ancl epiclermal hyperplasia. Both clisorders are linkecl to regions of the genome containing a keratin gene cluster, with EPPK linkecl to 17q12-21 harboring the type I keratin gene cluster ( 4) and NEPPK to 12ql3 where the type II keratin gene cluster maps (5, 6). Keratins are a large family ofstructu- ral proteins ancl are the major components of the cyto- skeleton of keratinocytes. These intermediate fil ament proteins fall into two groups, the type I and type II keratins which form specific heteroclimers and are expressecl in a tissue and differentiation specific pattern (7). Many clifferent epidermal diseases have been attributed to keratin mutations, which are proposed to disrupt the cytoskeleton of the cell leading to collapse of the celi ancl loss of adhesion (8). The most likely candiclate for EPPK was the type I 48 keratin, keratin 9, as the expression of this protein is restricted to the suprabasal keratinocytes in palmo- plantar epiclermis (9) . Subsequently mutations have been found in keratin 9 in patients with EPPK (10), ancl have so far been shown to be a homogeneous clisease with keratin 9 mutations being found in the majority of patients investigated (11-16). Most lie in the mutation holspot region situated in the helix initiation motif in the l A domain. This is a highly conserved prote in clomain both in keratin genes ancl other intermecliate filaments ancl is involved in the climerisation of inter- mecliate filaments. The most common mutations have been shown to change the same residue that is alterecl in keratin 14 in epiclermolysis bullosa simplex and keratin 10 in epiclermolytic hyperkeratosis respectively (17, 18). Families with NEPPK from both the UK ancl Northern Sweden have both been linkecl to 12ql3. Sequence analysis of the UK ancl Sweclish families excluclecl the type II suprabasal keratin 1 and keratin 6 which are present in palmoplantar epiclermis. Further mapping studies using more families has placecl the disease locus proximal to the keratin cluster suggesting that a keratin is not responsible for the British and Northern Swedish form ofNEPPK (19). Further studies to identify the gene is in progress, genes localized in this region include elastase 1 which bas been excluded from this disease (20) A keratin 1 mutation has been found in a family w ith NEPPK (21). This family however showed more epider- mal involvement with hyperkeratosis of the navel and areolae not seen in other families with NEPPK. This phe- notypic difference is probably a consequence of the generalized expression of keratin 1 throughout the epidermis of ali body sites with affected sites being those which may be subject to greater physical stress . Complex diffuse PPK Erythrokeratodermia Variabilis Eiythrokeratodermia variabilis (EKV) is a pheno- typically variable disease and was first clescribed in 1925 (22). It is an autosomal dominant disease, which pre- sents either at birth or within the first year as diffuse thickening of the palmoplantar epidermis with persistent generalized pigmented rough hyperkeratosis (fig. 2c) . Patients also suffer from symmetrically clistributed fixed hyperkeratotic plaques, which are sharply clemarcated and can persist for months or years. Transient erythe- matous areas occur independently to the hyperkeratosis, lasting from minutes to days, and are usually preceded by a burning sensation (fig. 2d). Both the hyperkeratosis and erythematous patches can be triggerec.l by trauma R eview Acta Dermatoven APA Vol 9, 2000, No 2 Re view Stratum corneum Suprabasal keratinocytes Basal keratinocytes Basement membrane The difjuse palmoplantar keratodermas \ celi envelope proteins / gap junction keratin filaments desmosome h emidesmosome Figure 1 . (a) Diagram showing the components of palmoplantar epidermis associated with diffuse palmoplantar keratodermas (PPK). to the skin, temperature changes, UV exposure, and emotional stress. The lesions affect the whole body but are more often found on the face, buttocks and extensor surfaces of the limbs. Histologically EKV shows no specific features, but there is generalized hyperkeratosis, acanthosis, papillomatosis, dilated capillaries and periva- scular infiltration. With increasing age the areas of the body affected by EKV become more restricted to the palmoplantar epidermis. In a number of families with EKV, the disease has been linked to lp34-p36 (23) and subsequently muta- tions have been found in the gap junction ~-3 gene (GJB3) which encodes connexin 31 (24, 25). Four muta- tions causing EKV have been identified so far in the intercellular, extracellular and transmembrane domains of connexin 31. Gap junctions are composed of co- nnexin proteins, a diverse group of proteins expressed in a tissue and differentiation specific manner of which 13 human forms have been described so far. These connexins oligomerise to form connexons which are situated in the plasma membrane and colocalise homo- typically or heterotypically with connexons on adjacent cells to form a direct inter-cytoplasmic channels (fig. lb). These channels play an important role in celi-celi communication by regulation of the transport of small molecules, such as signaling molecules and metabolites between cells. This communication is likely to control a wide range of cellular activities such as growth and differentiation. A disease phenotypically similar to EKV, progressive symmetric erythrokeratoderma (PSEK), has been des- cribed in a Japanese family. Overlapping phenotypic Figure 1. (b) Electron microscopy showing structure of desmosomes and gap junctions. desmosome g11p junction Acta Dermatoven APA Vol 9, 2000, No 2 49 The diffuse palmoplantar keratodennas 50 Figure 2. Photographs showing the different phenotypes of diffuse palmoplantar keratodermas (PPKs): (a) hyperkeratosis of the sole in non- epidermolytic palmoplantar keratoderma (NEPPK); (b) Pseudo-ainhum on the fingers in Vohwinkel's syndrome; (c) and (d) erythrodermia variabilis (EKV) with palmoplantar hyperkeratosis and erythematous keratotic patches. R ev i ew Acta Dermatoven APA Vol 9, 2000, No 2 Review characteristics with EKV inclucle cliffuse palmoplantar keratoclerma and e1ythematous plaques mainly on the buttocks ancl limb extremities though facial involvement is also common. EKV, however, shows more variable e1ythroclerma comparecl to PSEK. Genetically these two clisorclers are clistinct, with a mutation in loricrin being identified in the family w ith PSEK (26). Loricrin is a structural gene thought to be important in cross-linking in cornified envelope formation during cornification of the epidermis. Hidrotic Ectodermal Dysplasia An autosomal recessive type of hidrotic ectodermal dysplasia (HED) characterized by diffuse PPK, bliste- ring, hyperkeratotic plaques on the limbs , sweating abnormalities and sparse hair is caused by mutations in plakophilin 1, a desmosomal plaque protein (27, 28). Desmosomes are responsible for adhesion between cells in most epithelia and are made up of many clifferent proteins. The intracellular portion of the desmosome in the epidermis attaches to the keratin network of the cel! maintaining cellular integrity (Figure lb). The mutation in recessive HED causes a reduction both in the number and the size of desmosomes throughout the epidermis, which is most pronounced in the supra- basal layers. This results in a loss of adhesion between keratinocytes and consequently, histologically there are intercellular spaces in the suprabasal layers of the epidermis. Keratin networks in the cells were also disrupted presumably due to the loss of adhesion to the desmosomes. Mutations in other clesmosomal associated proteins have been linked with forms of PPK other than diffuse PPK such as clesmoplakin ancl clesmoglein 1 involve- ment in striate PPK, a form of focal PPK (29, 30). Striate PPK differs from diffuse PPK in the pattern of the lesions; inclivicluals with the striate form show linear hyper- keratosis clown the centre of each digit leacling to the palm ancl hyperkeratosis on pressure points on the so les. Desmoplakin, the most common of the clesmosomal proteins, is critical for the linking of keratin filaments to the plasma membrane. This disease shows widening of the intercellular spaces ancl an abnormal keratin filament network clue to the clisruption ofthe desmosomes and keratin filament interaction at the desmosomes. Mal de Meleda Meleda disease (Mal de Meleda) shows transgressive palmoplantar keratoclerma that occurs shortly after birth. This starts with reclness on the palms and soles sbortly followed by scaling and thickening which then spreads to tbe dorsal surfaces of the bancls and feet and to other body parts, the knees and elbows and otber sites of traumatic stress are particularly affected. Hyperbidrosis and perioral e1ythema are otber features associated with Acta Dermatoven APA Vol 9, 2000, No 2 The dijjuse palrnoplantar keratoderrnas Mal de Melecla. Tbis PPK is autosomal recessive and bas been identifiecl in a number of consanguineous families, in which linkage analysis bas placed the gene at 8qter (31). Syndromic dijfuse PPK PPK and deajness Vohwinkel's syndrome also known as keratoderma bereditaria mutilans, first described in 1929 (32) is a rare autosomal dominant disorder, which manifests as hyperkeratosis of the palrns and so les with a honeycomb appearance. Patients a lso suffer frorn constrictions of the skin around the digits (pseudo-ainhurn), which can lead to autoarnputation due to impairment of circulation ancl cleforrnity of the underlying bone (Figure 2b). Also seen in these patients are starfish shaped hyperkeratotic lesions on the dorsal surface of the hands. The bisto- pathological definition of Vohwinkel's synclrome is a tbickened stratum corneum, hypergranulosis ancl par- ticularly hyperkeratosis with round nuclei retained in the stratum corneum. There is overlap of the clinical features ofVohwinkel's syndrome and other disorders, for example, pseudo-ainhum have been seen in botb discoid lupus e1ythematosus and Mal de Meleda (33, 34). Vohwinkel's syndrome can be associated with a mild to moderate hearing loss and bas been mappecl to the cbromosome region 13qll-q12. The phenotype is due to abnormal gap junctions caused by the mutation D66H in the gene GJB2 encoding connexin 26 (35, 36). This mutation has been found in a number of unrelated Spanish, British and Italian families. Connexin 26 muta- tions, both dominant ancl recessive, have also been attri- butecl to non-syndromic sensorineural deafness (37). Mutations in connexin 31 associated with EKV do not result in any type of deafness. Other dominant and recessive mutations in connexin 31 however can cause autosomal dominant 11011-syndromic hearing loss with no epidermal involvement (38). It is not unclerstood why some mutations cause epidermal disorders and other hearing impairments, but it suggests that different domains of connexins are important in clifferent cel! types. A stmctural protein as well as a ga p junction protein defect can result in another form of Vohwinkel 's syn- drome. Tbis molecular variation of the disease sbows the characteristic mutilating keratoderma but also pre- sents generalizecl ichthyosis ancl lacks bearing ab- normalities. This form was linkecl to the epiclermal cliff- erention complex on lq21 ancl a frameshift mutation in the loricrin gene has been identifiecl in a family origi- nating in the UK (39) ancl in patients from J apan ( 40). The mutation causes loricrin to be abnormally or less .51 The d/ffuse palmoplantar keratodermas efficiently incorporated into the cornified envelope, due to impairment of the crosslinking of the protein by trans- glutaminase. HED and deajness Clouston 's hidrotic ectodermal dysplasia has been mapped to the same region as the classical form ofVoh- winkel's syndrome, 13qll-q12 (41). This autosomal dominant disorder is characterized by palmoplantar hyperkeratosis, hyperpigmentation of the skin especially over the joints, nail dystrophy and hair abnormalities ranging from brittleness to complete alopecia. Other features associated with Clouston's HED have also been described, such as sensorineural deafness and mental retardation. This regi on of the genome contains a cluster of connexin genes, which are possible candidates for this disorder. PPJ{ and cardiomyopathy A syndromic form of NEPPK, Naxos disease, which originated on the Greek island of Naxos, presents as diffuse NEPPK, arrythmogenic right ventricular cardio- myopathy and woolly hair (42). This disease is linked to 17q21 ( 43). Immunohistochemistry for plakoglobin, which maps to this region, reveals an abnormal distri- bution of the protein in affected patient skin, suggesting involvement of this gene in the disease (Hatsell and Kelsell, personal observation). ·o 'i;' l~' '!? .ri i . ..i .t· 1_,j Discussion There has recently been an increase in the under- standing of the molecular basis of the diffuse palmo- plantar keratodermas. However, confusion stili remains with regard to their clinical diagnosis due to the hetero- geneity seen in the phenotype. Diagnosis may become much easier when the molecular basis of the different PPKs is known. This understanding of a subset of skin diseases will help in the overall understanding of skin biology, by providing insights into the structure and function of the cytoskeleton, desmosomes and gap jun- ctions. Also, due to the associated involvement of other tissues in syndromic PPKs, identifying and characte- rizing the genetic abnormality will increase our know- ledge of other organs such as the ear and the heart. For example, investigation into PPK with deafness leads to the discove1y of connexin 26 as the most common cause of genetic deafness. Also with association of other forms of PPK with diseases such as esophageal cancer and neuropathy, a wide spectrum of disorders are being investigated. Acknowledgements We would like to thank Dr. Colin Munrofor supply- ing clinical photograph~~ and to Prc!f"essor Irene Leigh for discussion and reading of the manuscript. l. ThostA. Ueber erbliche Ichthyosis palmaris et plantaris cornea. Dissertation: Heidelberg (pub.) 1880. 2. Unna P. 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A mutation in the Vl end domain of keratin 1 in non-epidermolytic palmar-plantar keratoderma. J Invest Dermatol 1994;103(6):764-9. 22. Mendes da Costa S. Erythro- et keratoderrnia variabilis in a mother and a daughter. Acta Derm. Venero!. 6: 255-261, 1925 1925; 6: 255-261. 23. Richard G, LinJP, Smith L, Whyte YM, Itin P, Wollina U, et al. Linkage studies in erythrokeratodermias: fine mapping, genetic heterogeneity and analysis of candidate genes. J InvestDennatol 1997; 109(5): 666-71. 24. Richard G, Smith LE, Bailey RA, Itin P, Hohl D, Epstein EH,Jr., et al. Mutations in the human connexin gene GJB3 cause erythrokeratodermia variabilis [see comments]. Nat Genet 1998; 20(4): 366-9. 25. Wilgoss A, Leigh IM, Barnes MR, Dopping-Hepenstal P, Eady RA, Walter JM, et al. Identification of a novel mutation R42P in the gap junction protein beta-3 associated with autosomal dominant erythrokeratoderma variabilis. J Invest Dermatol 1999; 113(6): 1119-22. 26. Ishida-Yamamoto A, McGrath JA, Lam H, Iizuka H, Friedman RA, Christiana AM. The molecular pathology of progressive symmetric erythrokeratoderma: a frameshift mutation in the loricrin gene and perturbations in the cornified cell envelope. AmJ Hum Genet 1997; 61(3): 581-9. 27. McGrath JA, McMillan JR, Shemanko CS, Runswick SK, Leigh IM, Lane EB, et al. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet 1997; 17 (2): 240-4. 28. McGrathJA, Hoeger PH, Christiano AM, McMillanJR, Mellerio JE, Ashton GH, et al. Skin fragility and hypohidrotic ectodermal dysplasia resulting from ablation of plakophilin 1. Br J Dermatol 1999; 140(2): 297-307. 29. Rickman L, Simrak D, Stevens HP, Hunt DM, King IA, Bryant SP, et al. N-terminal deletion. in a desmosomal cadherin causes the autosomal dominant skin disease striate palmoplantar keratoderma. Hum Mol Genet 1999; 8(6): 971-6. 30. Armstrong DK, McKenna KE, Purkis PE, Green Ig, Eady RA, Leigh IM, et al. Haploinsufficiency of desmoplakin causes a striate subtype of palmoplantar keratoderma [published erratum appears in Hum Mol Genet 1999 May;8(5):943]. Hum Mol Genet 1999; 8(1): 143-8. Acta Dermatoven APA Vol 9, 2000, No 2 53 The difjitse palmoplantar keratodermas AUTHORS' ADDRESSES Acta Dermatoven APA Vol 9, 2000, No 2 31. Fischer J, Bouadjar B, Heilig R, Fizames C, Prud'homme JF, Weissenbach J. Genetic linkage of Meleda disease to chromosome 8qter. Eur J Hum Genet 1998; 6(6): 542-7. 32. Vohwinkel KH. Keratoma hereditarium mutilans. Arch. Derm. Syph. 1929; 158: 354-364. 33. Bergman R, Bitterman-Deutsch O, Fartasch M, Gershoni-Baruch R, Friedman-Birnbaum R. Mal de Meleda keratoderma with pseudoainhum. Br J Dermatol 1993; 128(2): 207-12. 34. Sharma RC, SharmaAK, Sharma NL. Pseudo-ainhum in discoid lupus erythematosus [letter]. J Dermatol 1998; 25 ( 4): 275-6. 35. Maestrini E, Korge BP, Ocana-Sierra J, Calzolari E, Cambiaghi S, Scudder PM, et al. A missense mu tati on in connexin26, D66H, causes mutilating keratoderma with sensorineural deafness (Vohwinkel's syndrome) in three unrelated families. Hum Mol Genet 1999; 8(7): 1237-43. 36. Kelsell DP, Wilgoss AL, Richard G, Stevens HP, Munro CS, Leigh IM. Connexin mutations associated with palmoplantar keratoderma and profound deafness in a single family. European J ournal of Human Genetics 2000; 8(2). 37. Kelsell DP, Dunlop J, Stevens HP, Len eh NJ, Llang]N, Parry G, et al. Connexin 26 mutations in hereditary non-syndromic sensorineural deafness [see comments]. Nature 1997; 387(6628): 80-3. 38. Xia JH, Llu CY, Tang BS, Pan Q, Huang L, Dai HP, et al. Mutations in the gene encoding gap junction protein beta-3 associated with autosomal dominant hearing impairment [see comments] [published erratum appears in Nat Genet 1999 Feb;21(2): 241]. Nat Genet 1998; 20(4): 370-3. 39. Maestrini E, Monaco AP, McGrath JA, Ishida-Yamamoto A, Camisa C, Hovnanian A, et al. A molecular defect in loricrin, the major component of the cornified celi envelope, underlies Vohwinkel's syndrome. Nat Genet 1996; 13(1): 70-7. 40. Takahashi H, Ishida-Yamamoto A, Kishi A, Ohara K, Iizuka H. Loricrin gene mutation in aJapanese patient of Vohwinkel's syndrome. J Dermatol Sci 1999; 19(1): 44-7. 41. Kibar Z, Der Kaloustian VM, Brais B, Hani V, Fraser FC, Rouleau GA. The gene responsible for Clouston hidrotic ectodermal dysplasia maps to the pericentromeric region of chromosome 13q. Hum Mol Genet 1996; 5(4): 543-7. 42. Protonotarios N, Tsatsopoulou A, Patsourakos P, Alexopoulos D, Gezerlis P, Simitsis S, et al. Cardiac abnormalities in familial palmoplantar keratosis. Br Heart J 1986; 56( 4): 321-6. 43. Coonar AS, Protonotarios N, Tsatsopoulou A, Needham E\V, Houlston RS, Cliff S, et al. Gene for arrhythmogenic rightventricular cardiomyopathywith diffuse nonepidermolytic palmoplantar keratoderma and woolly hair (Naxos disease) maps to 17q21. Circulation 1998; 97(20): 2049-58. Sarah J. Hatsell BSc, research scientist, Centre far Cutaneous Research, 2 Newark Street, Whitechapel, London Ei 2AT, UK DavidP. KelsellPhD, senior lecturer, same address 5.5