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Erythrokeratodermia Variabilis et Progressiva  Differential Diagnoses

  • Author: Gabriele Richard, MD, FACMG; Chief Editor: Dirk M Elston, MD  more...
Updated: Nov 04, 2015

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.[35] 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.[30, 31, 32] 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.[36, 37] In 2006, a genetic locus for PSEK has been suggested on 21q11.2-q21.2.[38]
  • 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, 39]
  • 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])
  • 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.[40] Originally, this syndrome was reported as "EKV 3 (Kamouraska type)," although that this syndromic disorder is obviously clinically and genetically distinct from erythrokeratodermia variabilis.

Differential Diagnoses

Contributor Information and Disclosures

Gabriele Richard, MD, FACMG Chief Medical Officer, GeneDx, Inc

Gabriele Richard, MD, FACMG is a member of the following medical societies: American Society of Human Genetics, Society for Pediatric Dermatology

Disclosure: Receive salary for employment from GeneDx, a wholly owned subsidiary of BioReference Labs, a wholly owned subsidiary of Opko Health.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Harry Dao, Jr, MD Assistant Professor, Department of Dermatology, Baylor College of Medicine

Harry Dao, Jr, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine

Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Mark W Cobb, MD Consulting Staff, WNC Dermatological Associates

Mark W Cobb, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Society of Dermatopathology

Disclosure: Nothing to disclose.

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Figurate erythema. Courtesy of M. King and J. Crawford.
Targetlike erythema. Courtesy of M. King and J. Crawford.
Generalized hyperkeratosis with scaling, accentuated skin lines, and figurate erythema. Courtesy of M. King and J. Crawford.
Thick hyperkeratotic plates with hystrixlike spines. Courtesy of M. King and J. Crawford.
Sharply demarcated, figurate, hyperkeratotic plaques in a symmetric distribution. Courtesy of M. King and J. Crawford.
Figurate hyperkeratotic plaque with erythematous patches. Courtesy of M. King and J. Crawford.
Plantar keratoderma with peeling. Courtesy of M. King and J. Crawford.
Diffuse glovelike palmar keratoderma. Courtesy of M. King and J. Crawford.
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