Erythrokeratoderma variabilis progressiva (ORPHA:308166)
Erythrokeratoderma variabilis progressiva (EKVP) is a type of erythrokeratoderma characterized by the association of hyperkeratosis and erythema in persistent, although sometimes variable, circumscribed lesions. Progressive symmetric erythrokeratoderma (PSEK) and erythrokeratoderma variabilis (EKV) are probably no longer two distinctive diseases but rather the two clinical manifestations of a same disease, now known as EKVP.
Epidemiology
Erythrokeratoderma is a rare skin disease whose prevalence has recently been estimated at around 1/ 2, 000,000 people. Both sexes are affected equally.
Clinical description
The disease usually starts in the early months of life or later in infancy. Erythema at birth has been described. Patients present with well-demarcated, erythematous patches and hyperkeratotic plaques that are arranged symmetrically. The lesions favor the extensor surface of the upper and lower extremities, buttocks and face. The plaques tend to progress during childhood, with lesions stabilizing thereafter. Considerable clinical overlap exists between PSEK and EKV, the main distinguishing feature being the presence of migratory erythema in patients with EKV. The migratory aspects of the lesions may also change over time, according to lifetime periods. The palms and soles are usually normal but some patients may have palmoplantar keratoderma. Minimal pruritus may be noted. Improvement has rarely been reported.
Etiology
EKVP is caused by mutations in the connexin genes GJB4 (1p35-p34), coding for connexin-30.3 or GJB3 (1p34), coding for connexin-31. Connexins are proteins that form gap junctions that allow the transport and signaling between neighboring cells in the epidermis. Since other unrelated multiethnic patients were negative for connexin genes, new causal genes are yet to be discovered. De novo mutations in GJA1 (6q22.31) were also reporting as causing EKVP.
Diagnostic methods
Diagnosis is based on the presence of characteristic clinical features. The histopathological features are non-specific. Light microscopy, in the case of EKV, reveals orthokeratotic basket-weave hyperkeratosis, moderate to severe acanthosis with prominent granular layer, and papillomatosis; and in the case of PSEK, there is acanthosis of the epidermis with basket-weave and often patchy parakeratotic hyperkeratosis. The granular layer is prominent and sometimes shows intracellular vacuolization. Follicular plugging is not uncommon. Electron microscopy reveals, in the case of EKV, a reduced number of keratinosomes within the stratum granulosum and sometimes clumped tonofilaments; and in the case of PSEK, perinuclear vacuolization and lipid-like vacuoles or laminated inclusions in the stratum corneum, but these features are not diagnostic.
Differential diagnosis
Differential diagnosis includes other diseases with erythematous and hyperkeratotic lesions such as KID syndrome, keratoderma hereditarium mutilans with ichthyosis, pityriasis rubra pilaris and psoriasis.
Genetic counseling
The majority of cases follow an autosomal dominant mode of inheritance but approximately 40% occur sporadically. Autosomal recessive inheritance has also been described and should be considered when providing genetic counseling, especially in consanguineous families.
Management and treatment
Treatment is symptomatic. Emollients are often used but their efficacy is limited. Topical keratolytics or oral acitretin can reduce the thickness of the lesions. Isotretinoin has been used instead of acitretin in some cases.
Prognosis
EKVP is not a life threatening disease, but it may have an impact on the patient's quality of life and cause social handicap due to the skin's appearance. General health is unaffected.

                            Last update: 
                            October 2015


                            - Expert reviewer(s): 
                            Pr Juliette MAZEREEUW-HAUTIER  - Dr Emilie TOURNIER