Darier disease (ORPHA:218)
A rare, genetic keratinization disorder which is classically characterized by keratotic papules, acral pits, and acral wart-like lesions that can be associated with a trigger, and may occur anywhere on the body (including mucosal surfaces). Extracutaneous manifestations may include, nail anomalies, blepharitis, dry eye, neuropsychiatric illness and, recurrent parotid gland obstruction and xerostomia.
Epidemiology
The prevalence of Darier disease (DD) is estimated at around 1/30,000 in Europe.
Clinical description
Darier disease is a debilitating and chronic condition, with both cutaneous and extra-cutaneous manifestations, which can have a severe impact on patients' general health and quality of life. The cutaneous and extra-cutaneous manifestations have variable expression within and between families. Exacerbations may be triggered by summer, sweating, exposure to sunlight, mental distress, contact with wool and febrile illness. Classical lesions are characterized by keratotic papules (typically occurring on the trunk), acral pits (occurring on palms and soles) and acral wart-like lesions (typically occurring on the hands, particularly after soaking in water). Non-classical lesions may include acral keratoderma, leukodermic macules, giant comedones, vegetations and acral hemorrhagic blisters, and may co-exist with classical lesions. However, non-classical lesions are rare. Lesions can occur anywhere on the body with no specific location. Nail abnormalities include V-shaped notches at the free edge of nail, longitudinal red and white lines, ridging and splitting. Genital involvement, especially on female genitalia, is more frequent in patients with severe disease. Oral mucosal lesions may be found. Extra-cutaneous manifestations vary within and between families and may include, blepharitis, dry eye, neuropsychiatric illness, epilepsy (often only before age 20), learning disabilities, recurrent parotid gland obstruction and xerostomia. Staph aureus colonization in skin & nares is frequent and corresponds with extent of skin area affected and disease severity.
Etiology
DD is caused by mutations in the ATP2A2 gene (12q23-q24.1) encoding the sarco/endoplasmic reticulum Ca2+ ATPase isoform 2 (SERCA2), which has a central role in intracellular calcium signaling.
Diagnostic methods
The diagnosis is based on histological examination of skin lesion biopsies revealing hyperkeratosis, focal dyskeratosis and suprabasal acantholysis.
Differential diagnosis
Differential diagnoses include Hailey-Hailey disease, Grover disease (transient acantholytic dermatosis), seborrheic dermatitis, pemphigus, and warty dyskeratoma.
Antenatal diagnosis
The prenatal diagnostic tests and procedures are available for affected couples where the genetic variant has been identified.
Genetic counseling
The disorder is autosomal-dominant with complete and delayed penetrance, and variable expression. Genetic counselling is advised for affected patients to discuss identification of the mutation, the pattern of inheritance as well as the prenatal diagnostic tests and procedures available.
Management and treatment
Management and treatment are based on case reports and case series reported in the literature as well as clinical experience. The full extent of the disease should be assessed by a dermatologist and includes assessment of the skin involvement (including staph aureus colonization), the extracutaneous involvement (neuropsychiatric illness etc.), family history and triggering factors. Current treatment is symptomatic and includes topical and systemic therapy as well as minimizing exposure to triggers. For patients prone to secondary skin infections, a diluted bleach bath may be considered. Other therapies reported include injection of botulinum toxin to decrease sweating, surgical excision, electrosurgical excision, dermabrasion, laser ablation, photodynamic therapy and electron beam radiation. Extracutaneous manifestations should be treated according to standard protocols.
Prognosis
The disease is characterized by a chronic cycle with acute exacerbations and does not improve with age. In assessing the prognosis, it is very important to consider the extracutaneous manifestations of the disease. Secondary bacterial and viral infections were reported as causes of morbidity and mortality in a few cases.

                            Last update: 
                            May 2022


                            - Expert reviewer(s): 
                            Dr Roni DODIUK-GAD