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Darier's disease (DD) is a rare, genetic skin disorder. It is an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
dominant 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
dermatologist Dermatology is the branch of medicine dealing with the skin.''Random House Webster's Unabridged Dictionary.'' Random House, Inc. 2001. Page 537. . It is a speciality with both medical and surgical aspects. A dermatologist is a specialist medi ...
Ferdinand-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 about 15 and 30 years and will vary over the lifespan in an intermittent pattern of relapse (flareups) and remit. 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
papule A papule is a small, well-defined bump in the skin lesion, skin. It may have a rounded, pointed or flat top, and may have a umbilication, dip. It can appear with a Peduncle (anatomy), stalk, be thread-like or look warty. It can be soft or firm a ...
s, keratosis follicularis, or dyskeratosis follicularis, most often appear on the arms, chest, back and legs. DD was initially studied by dermatologists. Recent research however shows DD has a whole-body effect, including cognitive (learning and intellectual) deficits, and mental health issues, particularly depression.


Diagnosis and symptoms

Diagnosis of Darier disease is often made by the appearance of the skin and nails, family history, and/or
genetic testing Genetic testing, also known as DNA testing, is used to identify changes in DNA sequence or chromosome structure. Genetic testing can also include measuring the results of genetic changes, such as RNA analysis as an output of gene expression, or ...
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. Clinical symptoms of the disease: * Fragile or poorly formed fingernails with vertical striations (as distinct from nail biting). The malformed nails often 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 an unpleasant odor. The rash can be aggravated by heat, humidity, and exposure to sunlight. * Seborrhoeic areas. 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. * Painful skin and itching (
pruritus An itch (also known as pruritus) is a sensation that causes a strong desire or reflex to scratch. Itches have resisted many attempts to be classified as any one type of sensory experience. Itches have many similarities to pain, and while both ...
). Other less common or less noticed symptoms are: * Acrokeratosis verruciformis. Acrokeratosis (AKV) is characterized by several small wart-like and flat-topped bumps that line the skin on typically the hand and feet. * Hypermelanotic macule. Dark patches on the skin that contain excess pigment. * Subungual hyperkeratotic fragments. Thickened skin that is often discolored, under nails, on either hands or feet.


Epidemiology and mental health

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, 1:36,000 in north-east England, 1:30,000 in Scotland, and 1:100,000 in Denmark. DD is seen in males and females equally. Symptoms typically arise between the ages of about 15 and 30, and vary over the lifetime in a relapse and remit pattern, 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 (skin specialists) as a purely skin disease. Recent research however suggests DD has a whole-body effect, including cognitive and mental health issues. 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%). 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. A study of 76 DD patients found that 41% reported learning difficulties, notably reading difficulties, and 74% reported a family history of learning disabilities. The full range of learning difficulties is not known.


Etiology and genetics

Skin changes in Darier's disease are related to a type of nutritional vitamin A deficiency that is caused by genetic mutations (thtat is, DD is a systemic Vitamin A deficiency). The skin displays follicular dyskeratosis (degeneration of the skin in hair follicules), which reflects as hypovitaminosis A. The skin reactions are caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.
Mutation In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, ...
s in a single
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
, ATP2A2, are the ultimate cause for the development of Darier's disease. It is an
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosomal (sex chromosome) pairs, which may have different structures. The DNA in autosome ...
dominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD.


Subtypes of Darier's disease

Subtypes of DD have been preliminarily suggested. 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
phenotypic In genetics, the phenotype () is the set of observable characteristics or traits of an organism. The term covers the organism's morphology (physical form and structure), its developmental processes, its biochemical and physiological propert ...
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
of certain mutations. One subtype is linear Darier's disease. These cases result from
somatic Somatic may refer to: * Somatic (biology), referring to the cells of the body in contrast to the germ line cells ** Somatic cell, a non-gametic cell in a multicellular organism * Somatic nervous system, the portion of the vertebrate nervous syst ...
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.


Treatment

Two recent reviews of the medical literature have evaluated treatment strategies for DD. Management and treatment of Darier disease depends on the severity of the presented clinical symptoms. Mild symptoms are often treated with moisturising creams, and more severe symptoms with topical and oral retinol or other medications (oral medications having higher strength than topical equivalents), and medical procedures. In many mild cases, DD can be managed by avoiding excessive perspiration and non-breathable and abrasive clothing (producing contact dermatitis), washing with salty water, and gentle abrasion with a gauze pad. This is supplemented by moisturising lotions and topical sunscreens. Most patients with Darier's disease can live normal healthy lives. In more severe cases of DD, application of topical and oral medications, particularly retinoids, is prescribed. Hospitalisation may be required for seriously affected individuals who display frequent relapse and remit patterns and severe infections. 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 ''Staphylococcus aureus'' is a Gram-positive spherically shaped bacterium, a member of the Bacillota, and is a usual member of the microbiota of the body, frequently found in the upper respiratory tract and on the skin. It is often posi ...
. The main viruses are
human papillomavirus Human papillomavirus infection (HPV infection) is caused by a DNA virus from the ''Papillomaviridae'' family. Many HPV infections cause no symptoms and 90% resolve spontaneously within two years. In some cases, an HPV infection persists and r ...
(HPV) and
herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2) are two members of the Herpesviridae#Human herpesvirus types, human ''Herpesviridae'' family, a set of viruses that produce Viral disease, viral infections in the majority of humans. Both HSV-1 a ...
(HSV). Infections are treated with antibiotics (for bacteria) and antiviral medications (for viruses). Treatments that have evidence-based support (though not for all persons treated) can be classified into a number of groups. Because DD is a product of systemic Vitamin A deficiency,
retinoids The retinoids are a class of chemical compounds that are natural derivatives of vitamin A or are chemically related to it. Synthetic retinoids are utilized in cosmetic formulations, clinical dermatology, and the treatment of some forms of cancer ...
, chemical compounds (molecules) that are forms of (or related to)
Vitamin A Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...
, are often recommended. Vitamin A acid compounds are often preferred as being less toxic than Vitamin A itself. 1. Topical medications: Retinoids (
Adapalene Adapalene, sold under the brand name Differin among others, is a third-generation topical retinoid primarily used in the treatment of mild-moderate acne, and is also used off-label to treat keratosis pilaris as well as other skin conditions. S ...
,
Tretinoin Tretinoin, also known as all-''trans'' retinoic acid (ATRA), is a medication used for the treatment of acne and acute promyelocytic leukemia. For acne, it is applied to the skin as a cream, gel or ointment. For acute promyelocytic leukemia, ...
, Isotretinoin, Tazarotene gel). Topical retinoids help in the reduction of hyperkeratosis. They work by causing the skin cells in the top layers to die and be shed off. * Vitamin A analogs (Calciptriol, Tacalitol). 2. Other topical medications. * 5-fluouracil, a chemotherapeutic agent. * Benzoyal peroxide 5% gel. Antibacterial effect and removes dead skin, but frequent use can cause skin irritation and other side effects, as well as bleaching of hair and clothes. * Topical
corticosteroids Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are invol ...
. 3. Oral medications: Retinoids (Acitretin, Isotretinoin). If symptoms are severe, oral retinoids have been proven to be very effective. However, there can be many adverse (and sometimes serious) side-effects associated with prolonged use. * Systemic Vitamin A analogs. 4. Medical Procedures: Surgical excision and dermabrasion, laser procedures, radiation procedures (grenz-ray, X-ray, radiology). * Dermabrasion. Removal of the top layer of skin to help smooth and stimulate new growth of the skin. *
Electrosurgery Electrosurgery is the application of a high-frequency (radio frequency) alternating polarity, electrical current to biological tissue as a means to cut, coagulate, desiccate, or fulgurate tissue.Hainer BL, "Fundamentals of electrosurgery", '' ...
. Used to help stop bleeding and remove abnormal skin growths.


Support groups

Further information on and advocacy work for Darier's disease are provided by support groups. * FIRST Skin Foundation (Foundation for Ichthyosis and Related Skin Disorders, Colmar, Pennsylvania). Ichthyosis refers to a group of skin disorders characterised by dry, scaly or thickened skin (mostly inherited, including DD).


History

Darier's disease was first described by the French dermatologist Ferdinand-Jean Darier in the journal ''Annales de dermatologie et de syphilographie''. 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. 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 DD is sometimes referred to as Darier-White disease.


Court case

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 an 82-year-old opium addict Ng Gee Seh in December 1995. Ong was
sentenced to death Capital punishment, also known as the death penalty and formerly called judicial homicide, is the state-sanctioned killing of a person as punishment for actual or supposed misconduct. The sentence ordering that an offender be punished in s ...
in August 1996 after the trial court found him guilty of murder, 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. 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 was re-sentenced to
life imprisonment Life imprisonment is any sentence (law), sentence of imprisonment under which the convicted individual is to remain incarcerated for the rest of their natural life (or until pardoned or commuted to a fixed term). Crimes that result in life impr ...
.


See also

* Linear Darier disease *
List of cutaneous conditions Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the Human body, body and composed of Human skin, skin, hair, Nail (anatomy), nails, and related muscle and glands. The major function o ...
*
Darier's sign Darier's sign is a change observed after stroking lesions on the skin of a person with systemic mastocytosis or urticaria pigmentosa. In general, the skin becomes swollen, itchy and red. This is a result of compression of mast cells, which ar ...
* Familial disseminated comedones without dyskeratosis


Notes


References


Sources

* {{Authority control Autosomal dominant disorders Conditions of the skin appendages Genodermatoses Oral mucosal pathology Papulosquamous hyperkeratotic cutaneous conditions Rare diseases Diseases named after discoverers