DISEASE CARD

Definition

Darier’s disease (DD) is a genetic disorder of keratinization first described by Darier and White (independently) in 1889.^{1, 2} The disease is characterized by the development of keratotic papules in seborrheic areas, with suprabasal acantholysis and dyskeratosis on histological examination of skin lesions. The underlying cause of DD are mutations in ATP2A2 gene encoding a Ca2+ pump in the endoplasmic reticulum.³

Clinical Description

Onset of the disease is usually around puberty. The majority of patients will develop the first lesions between 10 and 20 years of age. Those lesions are typically greasy, skin colored or yellow-brown keratotic papules that my coalesce into plaques. Predilection sites are the seborrhoeic areas of the trunk and face: the upper chest, back, neck, ears and scalp. Hands and fingernails are affected in nearly all patients. Flexures are also frequently involved (the groins, the axillae, the anogenital region). Skin lesions can become vegetating in the folds, are often infected, malodorous and responsible for major discomfort. They can be limited or form extensive plaques during acute phases. Careful examination of the palms and soles will frequently find small pits or punctuated keratoses which are highly suggestive, if not specific, of DD. Discrete flat, skin-coloured papules may appear on the dorsum of the hands and feet, similar to acrokeratosis verruciformis of Hopf.

Nail abnormailities are almost constant features and highly specific of the disease. The nails are fragile and split easily, they show the specific combination of red and white longitudinal stripes, have a V-shaped nick at the free margin of the nail and subungual hyperkeratosis.

Lesions of the mucous membranes have been described. The hard palate, the oral mucosa, the oesophagus, vulva and rectum may be the site where whitish small papules, often densely grouped (leucoplakia) manifest. Eye problems are frequent (blepharitis, dry eyes, eye fatigue after prolonged reading) and eyelid lesions occur in more than 50% of patients.⁴

The condition runs a chronic relapsing course, with exacerbations throughout life. Some patients will have a relatively mild disease, while others will develop a more severe form, sometimes within the same family. In particular, the skin lesions are exacerbated by exposure to sunlight or artificial UVB radiation, heat, sweating, friction and infections. Patients with Darier’s disease appear to have an increased susceptibility to herpes simplex and chronic pyogenic infections.^5-7

There is increasing evidence that DD is a multisystem disease as associations with epilepsy, neuropsychiatric disorders (e.g. intellectual disability), diabetes and heart failure have been reported.⁹

Acantholytic dyskeratotic naevi following Blaschko’s lines have been identified as mosaics for an ATP2A2 mutation with similar histologic (acantholytic dyskeratosis) and clinical (exacerbation due to heat, sweating, UV exposure; similar age of manifestation) features to Darier’s disease.⁸

Pathogenesis

ATP2A2 was identified as the defective gene by candidate positional cloning in 1999.³ ATP2A2 encodes the sarco/endoplasmic reticulum (endoplasmic reticulum) Ca2+-ATPase isoform 2 (SERCA2), a calcium pump transporting Ca2+ from the cytosol to the lumen of the endoplasmic reticulum. 
ATP2A2 spans 76 kb, is organized in 21 exons and is transcribed into three mRNAs of 4.4 kb, encoding SERCA2a, SERCA2b and SERCA2c isoforms. SERCA2b is the major isoform expressed in the human epidermis. At least 120 ATP2A2 mutations have now been reported in Darier's disease patients, the majority of which being different from family to family. Mutations are distributed across the entire molecule, with no evidence for clustering or mutation hot spots.¹⁰
The majority of the mutations are missense mutations (50%) or in-frame deletions or insertions (8%) which predict the synthesis of a structurally abnormal protein. Other mutations include nonsense mutations (12%) and frameshift mutations (23%) which lead to premature termination codon (PTC) and predict loss of protein expression through nonsense mRNA decay. The remaining mutations are splice-site mutations (7%) the consequences of which on the mutated protein remain to be documented.

Genotype-phenotype evaluation has suggested that ATP2A2 missense mutations are more frequent in severe or atypical forms. However, considerable inter- and intra-familial variability in the disease phenotype indicates that additional factors influence disease expression.
Functional analysis of ATP2A2 mutations have shown that a majority of them lead to loss of protein expression or loss of Ca2+ transport activity, supporting a disease mechanism by haploinsufficiency. However, a few mutations show evidence for a dominant negative effect. As a result, Ca2+ stores of the endoplasmic reticulum are reduced and trafficking of desmoplakin to the plasma membrane is impaired. Abnormal Ca2+ signaling is thought to have complex effects on protein post-translational modifications in the ER, on desmosome formation and gene expression leading to major defects in cellular adhesion and terminal epidermal differentiation.

Diagnosis

Histologic examination of a skin lesion shows hyperkeratosis, focal dyskeratosis (premature and abnormal keratinisation of single keratinocytes) associated with suprabasal acantholysis (cell separation above the basal layer) leading to suprabasal cleft. The rounded eosinophilic dyskeratotic cells are called “corps ronds” in the stratum spinosum, and “grains” in the upper layers of the epidermis. They are thought to correspond to apoptotic keratinocytes.

Treatment

Patients diagnosed with Darier Disease can benefit from a variety of treatments and therapies. For milder cases, regular use of moisturizers and sun protection measures, such as avoiding direct sunlight and using sunscreen, can help alleviate symptoms. Topical emollients containing urea or lactic acid can also reduce discomfort caused by crusting of the skin. Antiseptics and antibiotics can be used to prevent or treat infections, while topical retinoids may improve the appearance of hyperkeratosis. Topical steroids, calcineurin inhibitors, or vitamin D3 ointments may also be used for localized disease, though they do not alter the underlying course of the disorder. If painful skin lesions are suspected to be caused by herpes infection, antiviral treatment with acyclovir may be necessary.

For those with more severe forms of the disorder, oral retinoids and retinoid analogues, such as acitretin and isotretinoin, are considered to be the most effective treatment in reducing abnormal keratinization. However, these medications come with potential side effects, including dry lips, cheilitis, liver damage, eye complications, pancreatitis, and changes to the skeleton. If these treatments prove to be ineffective, surgical procedures such as dermabrasion, electrodessication, and ablative laser therapy may be considered.

Living with ADULT syndrome can also have a significant impact on an individual's social and emotional well-being, and psychological support may be necessary for some patients.​​​​​​^{9, 11}

References:

^{1.    Darier J. Psorospermose folliculaire végétante. Ann Dermatol Syphilol. 1889;10:597-612.
2.    White JC. A case of keratosis (icthyosis) follicularis. Cutan Genitourin Dis. 1889;7:201-209.
3.    Sakuntabhai A, Ruiz-Perez V, Carter S, et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nat Genet. 1999;21(3):271-277.
4.    Hammad H, Adler E, Yeshurun A, et al. Ophthalmic assessment in patients with Darier disease: Ophthalmic assessment in Darier disease. Am J Ophthalmol. 2021.
5.    Beck AL, Jr., Finocchio AF, White JP. Darier's disease: a kindred with a large number of cases. Br J Dermatol. 1977;97(3):335-339.
6.    Burge SM, Wilkinson JD. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol. 1992;27(1):40-50.
7.    Yeshurun A, Ziv M, Cohen-Barak E, et al. An Update on the Cutaneous Manifestations of Darier Disease. J Cutan Med Surg. 2021:1203475421999331.
8.    Sakuntabhai A, Dhitavat J, Burge S, Hovnanian A. Mosaicism for ATP2A2 mutations causes segmental Darier's disease. J Invest Dermatol. 2000;115(6):1144-1147.
9.    Bachar-Wikström E, Wikström JD. Darier Disease – A Multi-organ Condition? Acta Derm Venereol. 2021.
10.    MacLennan DH, Rice WJ, Green NM. The mechanism of Ca2+ transport by sarco(endo)plasmic reticulum Ca2+-ATPases. J Biol Chem. 1997;272(46):28815-28818.
11.    Rubegni P, Poggiali S, Sbano P, Risulo M, Fimiani M. A case of Darier's disease successfully treated with topical tacrolimus. J Eur Acad Dermatol Venereol. 2006;20(1):84-87.}