Diffuse palmoplantar keratoderma, Bothnian type (ORPHA:2337)
A rare isolated diffuse palmoplantar keratoderma characterized by diffuse, homogeneous, mild to thick, brown-to-yellowish palmoplantar hyperkeratosis (sometimes spreading over the dorsal aspect of fingers). Skin biopsy shows non-epidermolytic changes. There are no changes in hair, teeth or nails, and no syndromic involvement of other organs.
Epidemiology
The disease was first described in Northern Sweden, and subsequently in Denmark and in the United Kingdom. Both sexes are affected. Precise epidemiologic data are not available. A 1994 publication states a point prevalence of 0.3-0.5% in Sweden. It is possible that the prevalence was underestimated prior to the availability of genetic diagnosis.
Clinical description
Diffuse palmoplantar keratoderma, Bothnian type, presents in the first few months of life with brown-to-yellow keratoderma with an erythematous margin, and extension to dorsal aspects of hands/feet in some patients (transgrediens). Following exposure to water, the keratoderma takes a white, spongy appearance, exhibiting a margin between affected and normal skin. Hyperhidrosis is usually present. Patients can develop superinfections. Histological analysis reveals orthohyperkeratosis without epidermolysis. Superinfection by dermatophytes can be visualized with periodic acid-Schiff-staining.
Etiology
Bothnian type is due to heterozygous missense mutations in aquaporin 5 (AQP5), which encodes for a water-channel protein.
Diagnostic methods
Clinical distinction from keratoderma with associated features or syndromic forms, as well as histologic assessment (absence of epidermolysis, see above), helps to narrow down the differential diagnosis. The clinical diagnosis is confirmed by genetic testing.
Differential diagnosis
Differential diagnosis is broad for diffuse keratoderma and includes aquagenic palmoplantar keratoderma (seen in patients with cystic fibrosis, but also sporadically), KRT1-related diffuse nonepidermolytic keratoderma, epidermolytic palmoplantar keratoderma, localized forms of keratoderma (of which pachyonychia congenita due to keratin 6 mutations can sometimes present with a rather diffuse keratoderma), diffuse recessive keratoderma such as Nagashima type, mal de Meleda, Gamborg-Nielson type, and syndromes presenting with diffuse keratoderma such as palmoplantar keratoderma-esophageal carcinoma syndrome, tyrosinemia type 2, keratoderma hereditarium mutilans, Huriez syndrome, Papillon-Lefevre syndrome, loricrin keratoderma, etc.
Antenatal diagnosis
The disease is benign. Antenatal diagnosis is therefore not recommended.
Genetic counseling
This autosomal-dominant disease has a 50% risk of transmission. Genetic counseling should be offered to affected individuals informing them that there is a 50% risk of having an affected child at each pregnancy
Management and treatment
Topical medication (emollients, keratolytics, retinoids, steroids) and systemic retinoids are used, but only case series are available, and prospective studies are lacking. New targeted treatments, according to the specific mechanisms of the disease, are in development.
Prognosis
No impact on life expectancy has been documented. Disease severity is variable. The phenotype includes mild cases. More severe cases impair finger grip and walking, thus negatively affecting quality of life.

                            Last update: 
                            December 2023


                            - Expert reviewer(s): 
                            Pr Aldona PIETRZAK  - Pr Matthias SCHMUTH | ERN-Skin*


                                * European Reference Network