Darier's disease (DD) is a rare, genetic skin disorder. It is an autosomaldominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD. It was first reported by French dermatologistFerdinand-Jean Darier in 1889.
Mild forms of the disease are the most common, consisting of skin rashes that flare up under conditions such as high humidity, high stress, or tight-fitting clothes. Short stature, combined with poorly-formed fingernails that contain vertical striations, is diagnostic even for mild forms. Symptoms usually appear in late childhood or early adulthood between the ages of 15 and 30 years and will vary over the lifespan, mainly from flareups.
More severe cases are characterized by dark crusty patches on the skin that are mildly greasy and that can emit a strong odor. These patches, also known as keratotic papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the arms, chest, back and legs.[4]
DD was initially studied by dermatologists. Recent research however suggests DD has a whole-body effect, including cognitive (learning and intellectual) deficits, and mental health issues, particularly depression.
[5] Rash associated with Darier's diseaseMalformed, weak nails with V-shaped chips, a common sign of Darier's disease[5]Linear Darier's disease
Diagnosis of Darier disease is often made by the appearance of the skin, family history, or genetic testing for the mutation in the ATP2A2 gene. However, many individuals are never diagnosed because of the mildness of their symptoms. Mild cases present clinically as minor rashes (without odor) that can become exacerbated by heat, humidity, stress, and sunlight.
The symptoms of the disease are thought to be caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.[6][5]
Fragile or poorly formed fingernails (as distinct from nail biting). The malformed nails have V-shaped nicks at the edge of the nail.
Rash that covers many areas of the body, sometimes with weeping. In severe cases, it is often associated with a strong unpleasant odor. The rash can be aggravated by heat, humidity, and exposure to sunlight.
Seborrhoeic areas. This is defined as areas where excess oil and sebum is released. Overall greasy or scaly skin either in the central chest and back or in the folds of the skin.
Acrokeratosis verruciformis.[5] Acrokeratosis is characterized by several small wart-like and flat-topped bumps that line the skin on typically the hand and feet.[8]
Hypermelanotic macule. Patches on the skin that contain excess pigment, they often appear as dark patches in the skin.
Worldwide prevalence of DD is estimated as between 1:30,000 and 1:100,000. Case studies have shown estimated prevalence by country to be 3.8:100,000 in Slovenia,[9] 1:36,000 in north-east England,[10] 1:30,000 in Scotland,[11] and 1:100,000 in Denmark.[12]
DD is seen in males and females equally. Symptoms typically arise between the ages of 15 and 30, and vary over the lifetime, in particular flareups that need to be managed. DD is inherited (genetic), and in particular can be traced in family groups in specific geographic localities.
Darier's disease is a non-communicable disorder, but secondary infections by bacteria and viruses can be spread to others.
DD was initially identified and studied by dermatologists as a purely skin disease. Recent research however suggests DD has a whole-body effect, including cognitive and mental health issues.[13]
A study of 100 British individuals diagnosed with Darier's disease reported that affected individuals display elevated frequencies of neuropsychiatric conditions. They had high lifetime rates for mood disorders (50%), including depression (30%), bipolar disorder (4%), suicidal thoughts (31%), and suicide attempts (13%).[13]
A Swedish study of 770 individuals with DD showed a six-fold risk of being diagnosed with an intellectual disability, compared to matched Swedish population controls.[14]
A study of 76 DD patients found that 41% reported learning difficulties, notably reading difficulties, and 74% reported a familiy history of learning disabilities.[15]
Mutations in a single gene, ATP2A2, are responsible for the development of Darier's disease. It is an autosomaldominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD.
The gene ATP2A2 encodes the SERCA2 protein, which is a calcium pump localized to the membranes of the endoplasmic reticulum (ER) in nearly all cells and the sarcoplasmic reticulum (SR) in muscle cells. The ER is where protein processing and transport begins for proteins targeted for secretion. The SR is a specialized form of ER found in muscle cells that sequesters calcium, the regulated efflux of which into the cytosol stimulates muscle fiber contraction. Calcium acts as a second messenger in many cellular signal transduction pathways. SERCA2 is required for Ca2+ signaling in cells by removing nearly all Ca2+ ions from the cytoplasm and storing them in the ER/SR compartments.[16][17][6][18]
Darier's disease has an autosomal dominant pattern of inheritance.
A large number of mutant alleles of ATP2A2 have been identified in association with Darier's Disease. One study of 19 families and 6 sporadic cases found 24 specific, novel mutations associated with DD symptoms. This study reported a loose, imperfect correlation between the severity of ATP2A2 mutations with the severity of the condition. Significant variability in disease severity between members of the same family carrying the same mutation was also reported by this study, suggesting that genetic modifiers contribute to the phenotypicpenetrance of certain mutations.[19]
The mutation is inherited in an autosomal dominant pattern. This means that only one allele needs to be mutated in order to express the trait. This also means that someone who is born to one parent with DD has a 50% chance of inheriting the mutant allele and having the disease. Loss-of-function mutations typically display recessive inheritance while the gain-of-function or hyperactive function of proteins is characteristic of dominant mutations. The observation that only one mutated allele of the SERCA2 is sufficient to produce clinical symptoms suggests that proper "gene dosage" is necessary for maintaining Ca2+ homeostasis in cells.[17] This means that two wild type copies of ATP2A2 are needed for proper cell function, which provides a logical basis for dominant phenotypes arising from loss-of-function alleles. Most ATP2A2 mutations are haploinsufficiency mutations, which means that only having only one functional copy of the functional gene results in a reduced level of protein expression that is not sufficient for wild type function for making enough of the coded protein for the cell to function properly. However, there is significant variability in disease severity in how the mutations are expressed even within families that have the same mutation. It is currently unclear in the current research why a reduction in SERCA2 expression/activity causes clinical symptoms restricted to the epidermis. One hypothesis that some researchers have given is that other cell types express additional "back-up" Ca2+ pumps that can compensate for the reduced function or expression of the SERCA2 protein, while skin cells rely exclusively on the SERCA2 gene for calcium sequestration, meaning only they are affected by its reduction in expression.[6]
Subtypes of DD have been preliminarily suggested. One of these is "linear Darier's disease". These cases result from somatic mutations to ATP2A2 in epidermal stem cells. Such individuals display phenotypic mosaicism, where the Darier's phenotype only affects the subset of epidermal tissue arising from the mutated progenitor cell. Somatic mutations are not inherited by the offspring of such individuals.[20]
Management and treatment of Darier disease depends on the severity of the presented clinical symptoms.[21][22]
In most minor cases, the disorder can be managed using sunscreen, moisturizing lotions, avoidance of non-breathable clothing, and excessive perspiration. In mild cases, signs and symptoms may clear up completely through hygienic interventions. Most patients with Darier's disease live normal, healthy lives.
In more severe cases of Darier's disease, hospitalisation may be required to heal affected individuals who display frequent relapse and remit patterns.
Rapid resolution of rash symptoms can be complicated by the increased vulnerability of affected skin surfaces to secondary bacterial or viral infections. Bacterial overgrowth can produce an odour. The main bacteria is epidermal Staphylococcus aureus. The main viruses are human papillomavirus (HPV) and herpes simplex virus (HSV). In these cases, topical and/or oral antibiotics (for bacteria) and antiviral medications (for viruses) may need to be prescribed.[23]
If Darier's is more localized, common treatments include:[citation needed]
Topical retinoids: used to help in the reduction of hyperkeratosis, retinoids work by causing the skin cells in the top layers to die and be shed off. The common retinoids used for this disorder are: Adapalene,Tazarotene gel and Tretinoin.
Dermabrasion. Removal of the top layer of skin to help smooth and stimulate new growth of the skin.[27]
Electrosurgery. Used to help stop bleeding and remove abnormal skin growths.
If symptoms are severe, oral retinoids are prescribed and have been proven to be 90% effective. However, there can be many adverse side-effects associated with prolonged use.[28] Common oral retinoids include acitretin, isotretinoin, and cyclosporine.
Some patients are able to prevent flares with use of topical sunscreens and oral vitamin C.[29]
Further information on and advocacy work for Darier's disease are provided by the FIRST Skin Foundation.[30]
Darier's disease was first described by the Frech dermatologist Ferdinand-Jean Darier in the journal Annales de dermatologie et de syphilographie.[31] Darier was a well-regarded dermatologist of the time who was the head of the medical department at the Hôpital Saint-Louis. Darier was an early proponent of histopathology, or the examination of samples of diseased flesh under a microscope to determine the cause of illnesses. Using this technique, he was able to uncover the origins of Darier's disease and a host of others that also bear his name.[32]
James Clarke White, a dermatologist at Harvard Medical School, independently characterized and published his observations on this dermatological disorder in the same year as Darier (1889), which is why the condition is sometimes referred to as Darier-White disease.[33]
In Singapore, a man escaped the death penalty for murder as a result of Darier's disease. Ong Teng Siew, a Malaysian chicken slaughterer aged 27, was charged with murdering a 82-year-old opium addict Ng Gee Seh in December 1995.[34][35] Ong was sentenced to death in August 1996 after the trial court found him guilty of murder,[36] and while he was appealing against his conviction, Ong was hospitalized in September 1996 for an outbreak of Darier's disease, which had previously went undiagnosed. After his lawyer discovered that the disease had a causal link to psychiatric disorders, this new evidence enabled Ong to successfully apply for a re-trial.[37] The court accepted the new evidence and that Ong was suffering from diminished responsibility as a result of Darier's disease, and therefore he was found guilty of a lesser offence of manslaughter and he was re-sentenced to life imprisonment.[38][39]
^Godic A, Miljkovic J, Kansky A, Vidmar G (June 2005). "Epidemiology of Darier's Disease in Slovenia". Acta Dermatovenerol Alp Pannonica Adriat. 14 (2): 43–8. PMID16001099.
^Burge SM, Wilkinson JD (July 1992). "Darier-White disease: a review of the clinical features in 163 patients". J. Am. Acad. Dermatol. 27 (1): 40–50. doi:10.1016/0190-9622(92)70154-8. PMID1619075.
^Cederlof M, Karlsson R, et al. (July 2015). "Intellectual disability and cognitive ability in Darier disease: Swedish nation-wide study". Br. J. Dermatol. 173 (1): 155–8. doi:10.1111/bjd.13740. PMID25704118.
^Dodiuk-Gad M, Lerner Z, et al. (2014). "Learning disabilities in Darier's disease patients". J. Eur. Acad. Dermat. Vener. 28 (3): 314–319. doi:10.1111/jdv.12103. PMID23410204.
^Haber RM, Dib NG (Jan–Feb 2021). "Management of Darier disease: A review of the literature and update". Indian J. Dermatol. Venereol. Leprol. 87 (1): 14–21. doi:10.25259/IJDVL_963_19. PMID33580925.
^Kamijo M, Nishiyama C, Takagi A, Nakano N, Hara M, Ikeda S, Okumura K, Ogawa H (May 2012). "Cyclooxygenase-2 inhibition restores ultraviolet B-induced downregulation of ATP2A2/SERCA2 in keratinocytes: possible therapeutic approach of cyclooxygenase-2 inhibition for treatment of Darier disease". Br. J. Dermatol. 166 (5): 1017–22. doi:10.1111/j.1365-2133.2011.10789.x. PMID22413864. S2CID42918432.
