#133200
ICD+
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| ERYTHROKERATODERMIA VARIABILIS ET PROGRESSIVA; EKVP | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ERYTHROKERATODERMIA VARIABILIS; EKV ERYTHROKERATODERMIA, PROGRESSIVE SYMMETRIC; PSEK ERYTHROKERATODERMIA FIGURATA, CONGENITAL FAMILIAL, IN PLAQUES ERYTHROKERATODERMIA VARIABILIS WITH ERYTHEMA GYRATUM REPENS | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Other entities represented in this entry: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| GREITHER DISEASE, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| KERATOSIS PALMOPLANTARIS TRANSGREDIENS ET PROGREDIENS, INCLUDED | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Phenotype Gene Relationships | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Clinical Synopsis | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva (EKVP) can be caused by heterozygous mutation in the genes encoding connexin-31 (GJB3; 603324) and connexin-30.3 (GJB4; 605425). There is also evidence for an autosomal recessive form of EKVP, caused by homozygous mutation in the GJB3 gene. A form of EKVP associated with erythema gyratum repens has also been found to be caused by mutation in the GJB4 gene. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Description | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The erythrokeratodermias are a clinically variable and genetically heterogeneous group of inherited disorders characterized by widespread erythematous plaques, stationary or migratory, associated with nonmigratory hyperkeratoses (summary by Ishida-Yamamoto et al., 1997). The condition is usually present at birth or occurs during the first year but may begin later in childhood or even in early adulthood. Lesions preferentially affect the face, buttocks, and extensor surfaces of the limbs. Palmoplantar keratoderma occurs in about half the cases, but hair, nails, and teeth are not affected (summary by Macfarlane et al., 1991). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Nomenclature | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Patients with migratory erythematous plaques were formerly designated as having erythrokeratodermia variabilis (EKV), whereas patients with stationary erythrokeratotic plaques were reported to have a separate entity, designated progressive symmetric erythrokeratodermia (PSEK). However, both forms of erythrokeratodermia were observed within a single family, with biopsies that were ultrastructurally indistinguishable (Macfarlane et al., 1991). The suspicion that PSEK was not genetically distinct from EKV was later confirmed when the same mutation was identified in unrelated Dutch patients, some of whom had been diagnosed with EKV (Richard et al., 2003) and others with PSEK (van Steensel et al., 2009). Van Steensel et al. (2009) proposed the designation 'erythrokeratodermia variabilis et progressiva' to indicate the protean nature of the disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clinical Features | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mendes da Costa (1925) described this condition in a mother and daughter and assigned the designation erythrokeratodermia variabilis (EKV). The patients showed relatively fixed patches of hyperkeratosis and erythematous areas 'characterized by capriciously formed outlines, like the boundary lines of seacoasts on maps.' In contrast to the hyperkeratotic areas, the erythematous areas moved from hour to hour. Noordhoek (1950) reported a particularly striking Dutch EKV pedigree. Cowan (1962) described a father and daughter with erythrokeratodermia. From early childhood the father had lesions on the face, hands, forearms, legs, and feet. Marked hyperkeratosis, hyperpigmentation, and hypertrichosis were some of the features as well as erythema which varied from time to time and in site. The cardinal feature is the presence almost from birth of sharply outlined geographic areas of erythrokeratodermia. This was probably the condition present in the extensively affected kindred reported by Kelly and Kocsard (1970). Ishida-Yamamoto et al. (1997) stated that only approximately 30 cases of the progressive, symmetric form of erythrokeratodermia (PSEK) had been reported since the initial description by Darier (1911). Hopsu-Havu and Tuohimaa (1971) reported that epidermal cell proliferation is increased in PSEK. Macfarlane et al. (1991) reported 2 sisters, aged 5 years and 8 years, each with a different form of erythrokeratodermia. The younger sister developed expanding, migrating erythematous annular lesions at 17 months of age. The lesions, which lasted from several hours to 2 days, often appeared at times of marked environmental temperature change or when febrile. At 3 years of age, she developed scaly, slightly pigmented patches on the cheeks and ears, pigmented and hyperkeratotic plaques distributed symmetrically on the posterior thighs, and palmoplantar keratoderma, and was clinically diagnosed as having EKV. Her older sister had no skin lesions before 6 years of age, then developed pigmented, scaly plaques on the cheeks and chin, with erythema and peeling of the pinnae. Pigmented scaly plaques were also present in a remarkably symmetrical distribution on the medial thighs, knees, and elbows, and there was keratoderma of the palms and soles. She had no migrating areas of erythema, but from the age of 8 years, the fixed patches and skin around them often became redder in extremes of environmental temperature. The authors noted that the clinical appearance in this sister corresponded to PSEK. There was no other family history of erythrokeratodermia and the parents were not consanguineous. Ultrastructural findings in both cases were identical, and Macfarlane et al. (1991) suggested that EKV and PSEK were different manifestations of the same inherited condition. Richard et al. (2000) restudied the PSEK family originally reported by Macfarlane et al. (1991) as well as 5 additional probands with PSEK who had extensive, symmetrically distributed hyperkeratotic plaques with variable degrees of underlying erythema involving the extremities, trunk, and face, often with sparing of skin folds. Four of the 6 patients also had diffuse palmoplantar keratoderma, and 4 patients required systemic treatment with retinoids. None of these affected individuals had transient, migrating erythema or reported hearing impairment or other associated symptoms. Macari et al. (2000) studied 8 affected and 3 healthy individuals over 3 generations of an Israeli family of Kurdish origin with the migratory form of EKVP, originally described by Hacham-Zadeh and Even-Paz (1978). The dermatosis started at birth or shortly thereafter, but the patients were usually in good general health. Migratory erythematous lesions tended to turn gradually into more or less fixed keratotic plaques. In some patients, these erythematous lesions appeared as erythema gyratum repens, characterized by rapidly migrating figurata erythema 1 to 2 cm wide in an annular, garland, or spiral arrangement (Braun-Falco et al., 1991), which Macari et al. (2000) stated had not previously been reported in EKV. Generally, the palms and soles were spared. Lesions started to become worse in summer and to improve in winter. In 1 patient, lesions worsened during pregnancy. Audiograms in 2 affected patients were normal. Richard et al. (2003) studied 57 patients with the migratory form of EKVP from 13 unrelated families. The hyperkeratosis was confined to localized plaques in 10 families, and individuals from the remaining 3 families had more widespread involvement. In 3 families, patchy or diffuse glove-like palmoplantar keratoderma (PPK; see 144200) was observed. In 2 families, children but not adults displayed rapidly changing erythematous patches with prominent circinate or gyrate borders (erythema gyratum repens). Richard et al. (2003) observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors. Keratosis Palmoplantaris Transgrediens et Progrediens Greither disease, also known as keratosis palmoplantaris transgrediens et progrediens, is characterized by nonbullous desquamation of erythematous palms and soles, with hyperhidrosis (Greither, 1952). Gedde-Dahl et al. (1993) showed that manifestations of EKV and of Greither disease coexisted in a Norwegian family. Furthermore, linkage indicated that the disorder was determined by a mutation at the same site on chromosome 1 as EKV. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a linkage study of a Dutch kindred, part of which was studied by Noordhoek (1950), van der Schroeff et al. (1984) found close linkage with Rh (111700), which is located at 1p36.2-p34. Only one recombinant was found among 27 informative persons (maximum lod = 5.55 at recombination fraction of 0.044). With linkage information from another large kindred, van der Schroeff et al. (1988) brought the maximum lod score to 9.93 at a recombination fraction of 0.03 (95% CI, 0.008-0.11). Macari et al. (2000) performed linkage analysis in an Israeli family of Kurdish origin with the migratory form of EKVP, associated with erythema gyratum repens in some patients, originally described by Hacham-Zadeh and Even-Paz (1978). Macari et al. (2000) mapped the disorder to chromosome 1p35-p34, obtaining a maximum 2-point lod score of 2.343 (theta = 0) with marker D1S472, and noted that all affected individuals shared a common allele. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Heterozygous Mutation in the GJB3 Gene Richard et al. (1998) identified mutations in the connexin gene GJB3 (603324.0001-603324.0003) as the cause of the migratory form of erythrokeratodermia variabilis (EKV) in 4 families. No mutation in GJB3 was found in 8 other EKV families. Wilgoss et al. (1999) identified heterozygosity for a missense mutation in the GJB3 gene (R42P; 603324.0008) in affected members of a family with EKV. Richard et al. (2000) analyzed the GJB3 gene in 2 families and 3 sporadic patients with EKV and in 2 families and 4 sporadic patients with the progressive, symmetric form (PSEK) of erythrokeratodermia, including a family previously described by Macfarlane et al. (1991) in which 1 sister had features of EKV and the other of PSEK. Richard et al. (2000) identified 3 heterozygous mutations in GJB3, including R42P, in EKV probands, but detected no mutations in the PSEK patients. Homozygous Mutation in the GJB3 Gene In a brother and sister from an Israeli family segregating autosomal recessive erythrokeratodermia variabilis, Gottfried et al. (2002) identified homozygosity for a missense mutation in the GJB3 gene (L34P; 603342.0010). The unaffected parents were heterozygous for the mutation, which was not found in 208 control chromosomes. Gottfried et al. (2002) suggested that the missense mutation might not be able to exert a dominant-negative effect in the heterozygote form, thus manifesting itself clinically only in the homozygote. Heterozygous Mutation in the GJB4 Gene In affected members of an Israeli family of Kurdish origin with the migratory form of erythrokeratodermia (EKV), originally described by Hacham-Zadeh and Even-Paz (1978), in which some patients displayed erythema gyratum repens, Macari et al. (2000) identified heterozygosity for a missense mutation in the GJB4 gene (F137L; 605425.0001). Richard et al. (2003) analyzed the GJB4 gene in 13 unrelated families with EKV who were known to be negative for mutation in GJB3, and identified 6 distinct mutations (605425.0001-605425.0006) in 5 families and a sporadic patient. The F137L substitution, previously identified in an Israeli family of Kurdish origin with EKV and erythema gyratum repens by Macari et al. (2000), was found in 2 families: the identical 409T-C transition was detected in a family with typical EKV, whereas in a 2-year-old boy with EKV and erythema gyratum repens, a 411C-A transversion that also resulted in the F137L substitution was identified (605425.0002). No mutations were found in the remaining 7 families; Richard et al. (2003) stated that they did not observe any discriminatory or consistently deviant clinical features of EKV that would allow clinical differentiation of these patients from others harboring mutations in the GJB3 or GJB4 genes. In 2 unrelated Dutch patients with PSEK, van Steensel et al. (2009) identified heterozygosity for the G12D mutation in the GJB4 gene (605425.0004) that had previously been found in affected members of a Dutch family with typical EKV by Richard et al. (2003). Haplotype analysis of the 2 PSEK patients and 3 patients from the EKV family showed a shared haplotype extending over 2 Mb including the GJB4 gene. Van Steensel et al. (2009) concluded that PSEK and EKV can be manifestations of the same genetic defect and proposed the designation 'erythrokeratodermia variabilis et progressiva' to indicate the protean nature of the disorder. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Schnichels et al. (2007) generated a conditional mouse model of EKV using the human F137L mutation in the Cx31 gene. Although homozygosity for the mutation was embryonic lethal, heterozygous mice were fertile and showed no obvious abnormalities. In vitro cellular functional expression studies showed that the heterozygous mutant channel had approximately 30% decreased neurobiotin transfer activity, probably due to a dominant-negative effect. Heterozygous mutant mice showed a decreased healing time of tail incision wounds by 1 day, similar to mice with decreased expression of Cx43 (GJA1; 121014) in the epidermis. These findings suggested again that the Cx31 and Cx43 proteins functionally interact. No erythema was detected in young mice before 2 weeks of age, and only about 5% of the skin area of mutant mice showed hyperproliferation of the stratum germinativum. In addition, heterozygous Cx31 mutant mice showed normal epidermal expression patterns and levels of other connexin proteins. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| See Also: | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Brown and Kierland (1966); Schnyder and Sommacal-Schopf (1957) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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