Darier's disease

Template:Infobox medical condition (new) Darier's disease is a rare, genetic skin disorder. It is an autosomal dominant disorder, that means, if one parent has Darier’s, 50% chance if the parent is heterozygous or, very rarely, a 100% chance that a child will inherit Darier’s if that parent is homozygous. Darier's disease was initially studied by dermatologists, but recent research shows that Darier’s has a whole-body effect, including cognitive (learning and intellectual) deficits, and mental health issues, particularly depression.

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 papules, keratosis follicularis, or dyskeratosis follicularis, most often appear on the arms, chest, back and legs.<ref name="sehgal">Template:Cite journal</ref>

Diagnosis and symptoms

<ref name=":2" /> Rash associated with Darier's disease

Malformed, weak nails with V-shaped chips, a common sign of Darier's disease<ref name=":2" />

Diagnosis of Darier disease is often made by the appearance of the skin and nails, family history, and/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.

Clinical symptoms of the disease:Template:Citation needed

• 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).

Other less common or less noticed symptoms are:<ref>Template:Cite web</ref>

• 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.<ref>Template:Cite book</ref>
• 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,<ref name="pmid16001099">Template:Cite journal</ref> 1:36,000 in north-east England,<ref name="pmid1390140">Template:Cite journal</ref> 1:30,000 in Scotland,<ref name="pmid11841374">Template:Cite journal</ref> and 1:100,000 in Denmark.<ref name="pmid1619075">Template:Cite journal</ref>

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.<ref name="gordonsmith2010"/>

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%).<ref name="gordonsmith2010">Template:Cite journal</ref>

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.<ref>Template:Cite journal</ref>

A study of 76 DD patients found that 41% reported learning difficulties, notably reading difficulties, and 74% reported a family history of learning disabilities.<ref name="dodiuk">Template:Cite journal</ref> 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 (that 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.<ref name = vitamina>Template:Citation</ref> The skin reactions are caused by an abnormality in the desmosome-keratin filament complex leading to a breakdown in cell adhesion.<ref name=":1" /><ref name=":2">Template:Cite web</ref>

Mutations in a single gene, ATP2A2, are the ultimate cause for the development of Darier's disease. It is an autosomal dominant disorder, that is, if one parent has DD, there is a 50% chance than a child will inherit DD.Template:Efn

Subtypes of Darier's disease

Linear 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 penetrance of certain mutations.<ref>Template:Cite journal</ref>

One subtype 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.<ref>Template:Cite journal</ref>

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.<ref name="hanna">Template:Cite journal</ref><ref name="haber">Template:Cite journal</ref>

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. The main viruses are human papillomavirus (HPV) and herpes simplex virus (HSV). Infections are treated with antibiotics (for bacteria) and antiviral medications (for viruses).Template:Citation needed

Treatments that have evidence-based support (though not for all persons treated) can be classified into a number of groups.<ref name="hanna"/> Because DD is a product of systemic Vitamin A deficiency, retinoids, chemical compounds (molecules) that are forms of (or related to) Vitamin A, are often recommended. Vitamin A acid compounds are often preferred as being less toxic than Vitamin A itself.<ref name = vitamina/>

1. Topical medications: Retinoids (Adapalene, Tretinoin, 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 (5-FU), a chemotherapeutic agent.
• Benzoyal peroxide 5% gel. Antibacterial effect and removes dead skin, but long term use can cause skin irritation and other side effects, as well as bleaching of hair and clothes.Template:Citation needed
• Topical corticosteroids.Template:Citation needed

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.<ref name="hanna"/>

• 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.<ref>Template:Cite web</ref>
• Electrosurgery. Used to help stop bleeding and remove abnormal skin growths.

Support groups

Further information on Darier's disease for patients is provided by support and advocacy groups.

• B.A.D. Patient Hub (British Association of Dermatologists).<ref>Template:Citation</ref> A list of numerous British support groups for specific skin diseases, including one for Darier’s disease.

• FIRST Skin Foundation (Foundation for Ichthyosis and Related Skin Disorders, Colmar, Pennsylvania).<ref>Template:Citation</ref> 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.<ref name=Crissey2013>Template:Cite book</ref> 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 others that also bear his name.<ref>Template:Cite web</ref>

James Clarke White, a dermatologist at Harvard Medical School, 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.<ref>Template:Cite journal</ref>

Court case

In Singapore, a man escaped the death penalty for murder because 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 1995.<ref>Template:Cite news</ref><ref>Template:Cite news</ref> Ong was sentenced to death in August 1996 after the trial court found him guilty of murder,<ref>Template:Cite news</ref> and while he was appealing his conviction, Ong was hospitalized for an outbreak of Darier's disease, which was previously 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.<ref>Template:Cite news</ref> The court accepted that Ong now suffered 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.<ref>Template:Cite news</ref><ref>Template:Cite news</ref>

See also

• Linear Darier disease
• List of cutaneous conditions
• Darier's sign
• Familial disseminated comedones without dyskeratosis

Notes

Sources

• Template:Cite journal