Darier-White Disease

Alternative Names

  • DAR
  • Keratosis Follicularis
  • Darier Disease
  • DD
  • Darier Disease, Acral Hemorrhagic Type
  • Darier Disease, Segmental,
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WHO-ICD-10 version:2010

Congenital malformations, deformations and chromosomal abnormalities

Other congenital malformations

OMIM Number

124200

Mode of Inheritance

Autosomal dominant

Gene Map Locus

12q24.11

Description

Darier disease (DD) or Darier-White disease, also known as Keratosis follicularis, is an autosomal dominantly inherited genodermatosis disorder characterized by the development of keratotic papules in seborrheic areas and specific nail anomalies.  The worldwide prevalence of Darier disease is estimated at around 1/50,000.  Onset of skin changes is usually in adolescence, but in rare cases the disease manifests in childhood or much later in life.  The severity of the disease varies, from mild skin symptoms to severe problems that may be socially debilitating.  Symptoms start with papules appearing in the outermost layer of the skin; the papules develop into a brownish rash, especially on the scalp, forehead, upper arms, chest, back, knees, elbows, and behind the ear.  The diagnosis is based on the typical characteristics of skin lesions in Darier disease, and on histological examination of skin lesion biopsies revealing hyperkeratosis, focal dyskeratosis and suprabasal acantholysis.  To date, there is no cure for the disorder, and efforts are directed at relieving symptoms.  For patients with mild form of the disease, simple moisturisers, sun protection and selection of the right clothing to avoid heat and sweating are usually sufficient.

Mutations in the gene ATP2A2 are the cause of Darier disease.  ATP2A2 was mapped to 12q23-q24.1; it encodes the sarcoplasmic/endoplasmic reticulum Ca2+ -ATP isoform 2 protein (SERCA2), which is a calcium pump highly expressed in keratinocytes. SERCA2 maintains a low cytoplasmic Ca2+ level by actively transporting calcium ions from the cytosol into the lumen of the endoplasmic reticulum, where Ca2+ is stored. 

Over 130 mutations have been detected in patients with Darier disease; the majority of which are missense mutations, in-frame deletions or insertions.  Additionally, premature termination codons and abnormal splicing were also observed. Defects in the SERCA2 enzyme reduce calcium levels in the endoplasmic reticulum, and therefore result in severe disruption of Ca2+ transport function. This elucidates the role of SERCA2 pump in the Ca2+ signaling pathway and its involvement in cell adhesion and differentiation of the epidermis.

Epidemiology in the Arab World

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Other Reports

Saudi Arabia

Al Robaee et al. (2004) described a 41-year-old Saudi male with Darier’s disease with esophageal involvement.  At the age of 10 years he was hospitalized due to a coffee-ground vomitus for three days.  Skin examination showed diffuse dirty hyperkeratotic papules and plaques covering 90% of his body.  Also nail examination revealed extensive subungual hyperkeratosis, nail fragility and longitudinal striation.  There were 50% hyperkeratotic plagues in the scalp, resulting in a patchy scarring alopecia.  In addition, there was diffuse involvement of esophageal mucosa by multiple hyperkeratotic in the upper gastrointestinal tract.  The patient was on acitretin and topical therapy.

Tunisia

Bchetnia et al. (2009) studied mutational spectrum and phenotype-genotype correlation of Darier disease (DD) in 8 Tunisian families, comprising a total of 23 patients and 9 unaffected family members.  Although phenotypic variation was repeatedly observed, the typical clinical features of DD were constantly present.  In five of the studied families, different neuropsychiatric disorders were noticed.  Molecular analysis of the ATP2A2 gene revealed 3 recurrent mutations (119-120delAG, R677X, and D702N) and 4 novel variations: 2 missense mutations (G217A and L900R), one microinsertion (2772-2779 ins C), and one microdeletion (1747-1749 del 2T).

Cheour et al. (2009) presented the results of psychiatric examination that was carried out in 13 patients with Darier's disease.  Eight of the patients had neuropsychiatric symptoms; two patients presented mild mental retardation and six patients had mood disorders, three of them belonged to the same family.

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