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Other entities represented in this entry:
SNOMEDCT: 70041004; ORPHA: 317, 495; DO: 0111195;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p34.3 | Erythrokeratodermia variabilis et progressiva 1 | 133200 | Autosomal dominant; Autosomal recessive | 3 | GJB3 | 603324 |
A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-1 (EKVP1) is caused by heterozygous mutation in the gene encoding connexin-31 (GJB3; 603324) on chromosome 1p34. One family with EKVP1 has been reported with a homozygous mutation in the GJB3 gene.
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).
Genetic Heterogeneity of Erythrokeratodermia Variabilis et Progressiva
See EKVP2 (617524), caused by mutation in the GJB4 gene (605425); EKVP3 (617525), caused by mutation in the GJA1 gene (121014); EKVP4 (617526), caused by mutation in the KDSR gene (136440); EKVP5 (617756), caused by mutation in the KRT83 gene (602765); EKVP6 (618531), caused by mutation in the TRPM4 gene (606936); and EKPV7 (619209), caused by mutation in the PERP gene (609301).
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.
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.
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). Wollina et al. (1989) reported a 5-generation family in which 4 individuals, including a mother, son, the mother's brother, and his daughter, exhibited simultaneous occurrence of both erythrokeratodermia variabilis and diffuse palmoplantar hyperkeratosis of the keratosis palmoplantaris transgrediens et progrediens type. The skin lesions developed within the first month of life in all cases. Palmoplantar hyperkeratosis was a consistent feature in 10 other affected family members.
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.
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).
The transmission pattern of EKV in the families reported by Richard et al. (1998) was consistent with autosomal dominant inheritance.
Richard et al. (1998) identified heterozygous 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.
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; 603324.0010). 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.
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.
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Cowan, M. A. Erythrokeratodermia in father and daughter. Proc. Roy. Soc. Med. 55: 875-876, 1962.
Darier, J. Erythro-keratodermie verruqueuse en nappes, symetrique et progressive. Bull. Soc. Franc. Derm. Syph. 22: 252-264, 1911.
Gedde-Dahl, T., Jr., Rogde, S., Helsing, P., Gabrielsen, T., Olaisen, B. Greither's disease and erythrokeratodermia variabilis (EKV) caused by the same mutation on chromosome 1. (Abstract) Human Genome Mapping Workshop 93, Kobe, Japan 1993. P. 1.
Gottfried, I., Landau, M., Glaser, F., Di, W.-L., Ophir, J., Mevorah, B., Ben-Tal, N., Kelsell, D. P., Avraham, K. B. A mutation in GJB3 is associated with recessive erythrokeratodermia variabilis (EKV) and leads to defective trafficking of the connexin 31 protein. Hum. Molec. Genet. 11: 1311-1316, 2002. [PubMed: 12019212] [Full Text: https://doi.org/10.1093/hmg/11.11.1311]
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van Steensel, M. A. M., Oranje, A. P., van der Schroeff, J. G., Wagner, A., van Geel, M. The missense mutation G12D in connexin30.3 can cause both erythrokeratodermia variabilis of Mendes da Costa and progressive symmetric erythrokeratodermia of Gottron. Am. J. Med. Genet. 149A: 657-661, 2009. [PubMed: 19291775] [Full Text: https://doi.org/10.1002/ajmg.a.32744]
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