Erythrokeratodermia Variabilis et Progressiva Differential Diagnoses

Updated: May 17, 2022
  • Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD  more...
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Diagnostic Considerations

Also consider the following:

  • Progressive symmetric erythrokeratodermia (PSEK): PSEK is considered an autosomal dominant or recessive genodermatosis with a less well-defined clinical presentation than erythrokeratodermia variabilis (EKV). The disease causes fixed, slowly progressive, symmetric, and well-defined hyperkeratotic plaques, which predominantly appear on the extensor surface of the extremities, trunk, and face. In contrast to EKV, no independent, migrating red patches are present, the hyperkeratosis develops on an erythematous base, and the palms and soles are affected more often. There is considerable phenotypic variability of PSEK and erythrokeratodermia variabilis. Moreover, EKV and PSEK have been observed within the same family [6] , and the same disease-causing GJB4 (Connexin 30.3) mutation (p.Gly12Asp) has been reported in patients diagnosed with EKV or PSEK. [47] These findings indicate that a subset of PSEK cases belong to the clinical spectrum of EKV. However, many other PSEK cases do not have identifiable mutations in the connexin genes and likely represent a heterogeneous group of other disorders that remain to be better defined on a clinical and molecular level. [42, 43, 44] A frameshift mutation in the LOR gene encoding loricrin (ie, 709insC) on band 1q was identified in a Japanese family with PSEK-like features and mutilating palmoplantar keratoderma (ie, pseudo-ainhum), which is usually not seen in PSEK. This observation is consistent with other LOR gene mutations in mutilating palmoplantar keratoderma with ichthyosis (Camisa-type of palmoplantar keratoderma; Vohwinkel syndrome with ichthyosis, OMIM 603324) and these disorders are now classified as loricrin keratoderma, an entity distinct from PSEK. [48, 49] In 2006, a genetic locus for PSEK has been suggested on 21q11.2-q21.2. [50] An autosomal recessive form of PSEK has been reported in 4 affected members of a Pakistani family who had symmetric hyperkeratotic plaques without sharp borders, palmoplantar keratoderma, hyperkeratotic pads over interdigital joints, thick nails but normal hair, and all were homozygous for a frameshift variant in the KRT83 gene. This keratin gene is expressed mainly in hair but also in skin, and heterozygous missense variants typically cause monilethrix, an autosomal dominant hair shaft disorder. [51]
  • Spinocerebellar ataxia and erythrokeratoderma (type Giroux-Barbeau; OMIM 133190): This disorder was originally described in a large French-Canadian pedigree. Affected individuals manifested during childhood with symmetrical, well-demarcated, fleeting erythematous patches and scaling or hyperkeratotic plaques on the dorsum of the hands and feet and on limbs. While the skin lesions disappear in the third decade of life, progressive gait ataxia due to cerebellar atrophy manifests in the fourth and fifth decades. Linkage studies and exome sequencing uncovered a pathogenic missense variant (ie, L168F) in the ELOVL4 gene that completely co-segregates with the disorder. ELOVL4 encodes an enzyme of the elongase family responsible for the elongation of very long-chain fatty acids, which are crucial for peroxisome β-oxidation and formation of the skin barrier. [1, 52]
  • Greither disease (ie, keratosis palmoplantaris transgrediens et progrediens): This is now known to be a variant of epidermolytic ichthyosis (aka epidermolytic hyperkeratosis, EHK, bullous congenital ichthyosiform erythroderma). Two unrelated families have been described with mutations in the keratin 1 ( KRT1) gene.
  • Erythrokeratolysis hiemalis (OMIM 148370, keratolytic winter erythema, Oudtshoorn skin)
  • Ichthyosis linearis circumflexa (a manifestation of Netherton syndrome)
  • Annular epidermolytic ichthyosis (as subtype of epidermolytic ichthyosis [epidermolytic hyperkeratosis, EHK, bullous ichthyosiform erythroderma])
  • NIPAL4-related autosomal recessive congenital ichthyosis (ARCI): A homozygous missense variant in the NIPAL4 gene was reported in 2 siblings from a consanguineous family, who  had typical features for EKVP but no sequence variants in GJB3 or GJB4. [53]
  • MEDNIK (mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratodermia) syndrome: Erythema and hyperkeratosis resembling erythrokeratodermia variabilis have been reported in a novel, autosomal recessive genetic syndrome observed in the Bas St-Laurent region of Quebec. Besides skin findings, patients have sensorineural hearing loss, peripheral neuropathy, psychomotor retardation, congenital chronic diarrhea, and an elevation of very long-chain fatty acids. This disorder was mapped to 7q22, and a splice site mutation in the AP1S1 gene encoding the small subunit of the AP1 complex has been identified. [54] Originally, this syndrome was reported as "EKV 3 (Kamouraska type)," although that this syndromic disorder is obviously clinically and genetically distinct from erythrokeratodermia variabilis.
  • Severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome: EKV-like skin features, such as erythematous to brown, circumscribed, well-demarcated plaques have been reported in several patients with SAM syndrome due to underlying bi-allelic desmoglein 1 ( DSG1) mutations. Other features included severe palmoplantar keratoderma and food allergies. Further studies revealed that desmoglein 1 plays a role in Cx43 stabilization and gap junction function in the epidermis, thus explaining the overlapping clinical phenotypes between EKVP and SAM syndrome. [55]

Differential Diagnoses