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Other entities represented in this entry:
SNOMEDCT: 48611009; ICD10CM: E50.8; ORPHA: 218; DO: 2734;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q24.11 | Darier disease | 124200 | Autosomal dominant | 3 | ATP2A2 | 108740 |
A number sign (#) is used with this entry because Darier-White disease (DAR) is caused by heterozygous mutation in the ATP2A2 gene (108740), which encodes the sarcoplasmic reticulum Ca(2+)-ATPase-2, on chromosome 12q24.
Darier-White disease (DAR), also known as keratosis follicularis, is an autosomal dominant skin disorder characterized by warty papules and plaques in seborrheic areas (central trunk, flexures, scalp, and forehead), palmoplantar pits, and distinctive nail abnormalities (Sakuntabhai et al., 1999). Onset is usually before the third decade, and penetrance is complete in adults, although expressivity is variable. Involvement may be severe, with widespread itchy malodorous crusted plaques, painful erosions, blistering, and mucosal lesions. Secondary infection is common. Sun, heat, and sweating exacerbate the symptoms. Darier disease never remits, but oral retinoids may reduce hyperkeratosis. Neuropsychiatric abnormalities, including mild mental retardation and epilepsy, have been described in association with Darier disease in a few families (Burge and Wilkinson, 1992); whether this is an association based on pleiotropism of the mutant gene or reflects coincidence is not clear. Histologic findings are (1) mild nonspecific perivascular infiltration in the dermis; (2) dermal villi protruding into the epidermis; (3) suprabasal detachment of the spinal layer leading to the formation of lacunae containing acantholytic cells; (4) in the more superficial epidermis, dyskeratotic round epidermal cells ('corps ronds'), the most distinctive feature; and (5) in the stratum corneum, 'grains' that resemble parakeratotic cells embedded in a hyperkeratotic horny layer. Electron microscopy reveals loss of desmosomal attachments, perinuclear aggregations of keratin filaments, and cytoplasmic vacuolization. Ultrastructural and immunologic studies suggest the disease results from an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.
Hitch et al. (1941) reported a family with affected members in 5 generations. See acrokeratosis verruciformis (101900) for discussion of phenotypic overlap with that condition. When bullous lesions are present, the condition is difficult to distinguish from benign familial pemphigus (Hailey-Hailey disease; 169600). Indeed, Niordson and Sylvest (1965) suggested that familial benign pemphigus is simply a bullous variant of Darier-White keratosis follicularis and that both may be variants of acrokeratosis verruciformis. They observed one patient with clinical and histopathologic features of all 3 entities. The father, brother, sister, and son had acrokeratosis verruciformis. Over 70 cases were observed in 1 kindred by Beck et al. (1977). Burge and Wilkinson (1992) suggested that Darier disease is associated with mild mental retardation in some families and also with an increased prevalence of epilepsy. Other mental illnesses, such as psychosis and affective disorder, have been reported in association with Darier disease.
Castori et al. (2009) reported a 14-year-old girl with an unusual combination of Darier disease and aniridia (106210) due to double de novo heterozygous mutations in the ATP2A2 and PAX6 (607108) genes, respectively. In addition to classic manifestations of both disorders, she had multiple bone cysts resulting in nontraumatic fractures of the long bones. Bone cysts were also present in the calvarium. Intelligence was normal. A review of the literature indicated that variable bone lesions had been reported in association with Darier disease, suggesting that skeletal changes may represent rare pleiotropic manifestations of ATP2A2 mutations.
Darier Disease, Acral Hemorrhagic Type
Ruiz-Perez et al. (1999) identified asn767-to-ser (108740.0004) and cys268-to-phe (108740.0004) mutations in ATP2A2 in 4 Darier disease families. Affected members in these families showed the acral hemorrhagic type of Darier disease, in which hemorrhage into acantholytic vesicles on the palms and dorsal aspects of the fingers gives rise to black macules. These findings suggested that certain mutations may be specifically disruptive to ATP2A2 function not only in keratinocytes but also in vascular endothelium cells, or that the mutant protein has a secondary effect in the blood vessels.
Segmental Darier Disease
As patients with acantholytic dyskeratotic nevi often give a history of worsening after sun exposure, and the lesions are typical of Darier disease, numerous authors have proposed that these patients have segmental Darier disease. Sakuntabhai et al. (2000) investigated the involvement of ATP2A2 in acantholytic dyskeratotic nevi following Blaschko lines in 2 patients. They identified a nonsense mutation (tyr894 to ter; 108740.0009) in the first patient and a nonconservative glycine-to-arginine mutation at codon 769 (108740.0010) in the other patient. These mutations were present in affected skin, and were not detected in unaffected skin or in leukocytes. Sakuntabhai et al. (2000) concluded that acantholytic dyskeratotic nevi can arise from a somatic mutation in ATP2A2 and suggested that the term 'acantholytic dyskeratotic nevus' might be replaced by 'segmental Darier disease induced by postzygotic mosaicism.'
The transmission pattern of DAR in the families reported by Sakuntabhai et al. (1999) was consistent with autosomal dominant inheritance.
In 2 separate studies of British families, Bashir et al. (1993) and Craddock et al. (1993) demonstrated linkage to markers in the 12q23-q24.1 region. Craddock et al. (1993) found a maximum 2-point lod score of 4.29 with marker D12S84 at theta = 0.0. Parfitt et al. (1994) defined flanking markers for the disease, namely D12S78 and D12S79, which are 12 cM apart. In addition, Parfitt et al. (1994) increased the lod score with D12S86 to 6.11 at theta = 0.0. In an additional 10 families of European and Middle Eastern ancestry, Ikeda et al. (1994) sublocalized the DAR gene to a 5-cM region in the 12q23-q24.1 region. The combined lod score was in excess of 20. The site on chromosome 12 of this disorder of keratinization is distal to that of the type II keratin gene cluster at 12q11-q13 (Buxton, 1993).
In a study of 4 large British pedigrees, Carter et al. (1994) provided further evidence for locus homogeneity by showing statistically significant linkage of all 4 families to a 4-cM region of 12q23-q24.1 between the D12S105 and D12S129 markers. In 6 Canadian families, Kennedy et al. (1995) likewise found linkage to 12q; the peak lod score on multipoint analysis was 5.5 in the interval between D12S58 and D12S84. The Canadian families were of varied European ancestry.
Using microsatellite markers, Wakem et al. (1996) localized the DAR gene to a 2-cM interval between D12S234 and D12S129. Using a polymorphic intronic marker for nitric oxide synthase-1 (163731), they excluded that gene as the Darier disease gene.
Monk et al. (1998) presented linkage analysis showing, in 4 families, key recombination events that refined the location of the DAR locus to a region of less than 1 cM in 12q24.1 and constructed a high resolution PAC.
Ikeda et al. (1998) narrowed the Darier disease locus to an interval of approximately 3.3 Mb on chromosome 12.
Craddock et al. (1993) reported a family in which Darier disease and major affective disorder cosegregated. The pedigree provided a maximum lod score of 2.1 for linkage between the Darier disease gene and a putative major dominant susceptibility locus for affective disorder.
Sakuntabhai et al. (1999) stated that the prevalence of Darier disease had been estimated at 1 in 55,000.
Monk et al. (1998) constructed a 2.4-Mb, P1-derived artificial chromosome contig spanning the DAR candidate region on 12q23-q24.1. Using a combination of EST database searching, cDNA selection, and sequence analysis of bacterial clones of the contig, Sakuntabhai et al. (1999) identified 12 genes in this interval. After screening several of these genes, they identified mutations in the ATP2A2 gene (see, e.g., 108740.0001-108740.0003), which encodes the sarco/endoplasmic reticulum Ca(2+)-ATPase type 2 isoform (SERCA2) and is highly expressed in keratinocytes. Thirteen mutations were identified, including frameshift deletions, in-frame deletions or insertions, splice site mutations, and nonconservative missense mutations in functional domains. The results demonstrated that mutations in ATP2A2 cause Darier disease and disclosed a role for the SERCA2 pump in the Ca(2+)-signaling pathway that regulates cell-to-cell adhesion and differentiation of the epidermis.
Peacocke and Christiano (1999) discussed the significance of the findings of Sakuntabhai et al. (1999). In previous years, mutations in many genes contributing to structural integrity had been shown to underlie inherited disorders of the skin. Genes encoding a variety of keratins were found to be responsible for epidermolysis bullosa simplex, epidermolytic hyperkeratosis, ichthyosis bullosa of Siemens, palmoplantar keratoderma, and pachyonychia congenita. Mutations in the LOR gene (152445), which encodes loricrin (the major component of the cornified cell envelope), had been implicated in 2 keratinizing genodermatoses, and the enzyme that crosslinks the cornified cell envelope, transglutaminase I, had been implicated in the pathogenesis of the recessively inherited lamellar ichthyosis. Plakophilin (PKP1; 601975), plectin (PLEC1; 601282), and desmoplakin (DSP; 125647) had been implicated in skin disease causation. While it seemed likely that mutations underlying Darier disease and the related disorder, Hailey-Hailey disease (169600), would affect a structural component, both disorders were mapped to chromosomal regions devoid of any known candidate genes. The first hints that the Darier disease gene might not directly concern the 'bricks and mortar' of the skin surfaced when, most unexpectedly, mutations in the connexin-31 gene (GJB3; 603324) were found to cause erythrokeratodermia variabilis. Combined with the discovery that mutations in the connexin-26 gene (GJB2; 121011) cause palmoplantar keratoderma with deafness, this finding suggested that intercellular communication is crucial for epidermal differentiation.
Sakuntabhai et al. (1999) reported an additional 24 mutations in the ATP2A2 gene (see, e.g., 108740.0007-108740.0010) among 19 DAR families and 6 sporadic cases. Over 50% of the mutations led to a premature termination codon, leading the authors to propose that haploinsufficiency is a common molecular mechanism for DAD. However, marked inter- and intrafamilial phenotypic variability of the disease was observed, suggesting that additional factors may contribute to the clinical phenotype.
In a linkage study of 2 large British kindreds segregating Darier disease, Munro et al. (1992) found a suggestion of linkage to the Duffy blood group locus (FY; 110700) at chromosome 1q21-q22. Family B showed a maximum lod of 0.807 at theta = 0.0. While the lod scores for this marker were negative in family A, a computer program showed no significant heterogeneity in the scores between the families, and the pooled data still showed positive lod scores (maximum lod = 0.218 at theta = 0.20).
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