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Darier disease

This is part of Rare diseases.

Diagnosis: Darier disease

Synonyms: Keratosis follicularis

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Date of publication: 2013-09-18 
Version: 4.1

The disease

Darier disease (keratosis follicularis) is an inherited disorder affecting the outermost layer of the skin, the epidermis, which thickens around the hair follicles. The disease also manifests as impaired cell adhesion, meaning that the cells do not bind to each other as they should, and as a result the skin is frail. The onset of the disease usually occurs during puberty, but skin changes sometimes appear earlier.

The condition was first described in the nineteenth century by French dermatologist Jean Darier. In American literature the disease is also known as Darier-White disease.

Occurrence

Every year one to three babies in Sweden are born with the genetic trait that will later cause Darier disease. The total number of cases is estimated at 2 individuals per 100,000 (prevalence). There is also an unidentified number of people in whom only one side is affected (unilateral type), or who have a variant which manifests in patches (nevoid type).

Cause

Darier disease is caused by a mutation in the gene that codes for an enzyme known as SERCA2 (sarco-endoplasmic reticulum Ca2+-ATPase). This enzyme pumps calcium across cell membranes, for example in skin cells. The gene which controls (codes for) the synthesis of the enzyme is called ATP2A2, and is localised to chromosome 12 (12q23-q24.1).

Hailey-Hailey disease is closely related to Darier disease. In both these disorders impaired passage of calcium in the skin cells causes them to develop into horny cells prematurely, before they reach the surface of the skin.

Even if only one of the two ATP2A2 genes is affected, the disease will manifest. This means that half the normal amount of SERCA2 enzyme is not sufficient to maintain normal functionality in skin cells, at least not after puberty. It is likely that additional factors, such as an increase in certain hormones during puberty, are necessary before the shortage of the enzyme becomes apparent in the form of skin symptoms.

Figure. Cross section of skin and enlargement showing the defects typical of Darier disease of the upper layers of the epidermis

Figure. Cross section of skin

In the variant which manifests in patches (nevoid type), the ATP2A mutation has occurred in some cells during foetal development (somatic mutation), and therefore only small areas of the skin are affected.

Heredity

In many cases the pattern of inheritance is autosomal dominant. This means that one of the parents has the disease, and so has one normal gene and one mutated gene. Sons and daughters of this parent have a 50 per cent risk of inheriting the disease. Children who do not inherit the mutated gene do not have the disease and do not pass it down.

Figure. Autosomal dominant inheritance of genetic traits

In many cases the disease is caused by a new mutation. This means that the genetic mutation occurs in an individual for the first time and is not inherited from either parent. Consequently, parents with a child with a new mutation generally do not have an increased risk of having another child with the disorder. However, the new genetic mutation will be hereditary and an adult with this mutation risks passing on the mutated gene to his/her children.

The nevoid type, caused by a somatic mutation, is not hereditary, except in rare cases when isolated gametes (egg or sperm cells) are also mutated. This risk, however, is very small.
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Symptoms

Symptom onset usually occurs in adolescence, but in rare cases the disease manifests in childhood or much later in life. The severity of the condition varies, from mild skin symptoms to severe problems that may be socially debilitating. 

Symptoms start with rough pimples (papules) appearing in the outermost layer of the skin, especially around the hair follicles. The papules develop into a brownish rash, especially on the face, chest and back. Over time, the papules grow together, forming thick plaques with a moist surface. These plaques are susceptible to bacterial infections or herpes virus. Severe cystic acne may also occur. In some individuals the skin changes are limited, affecting for example the forehead and the chest, but in other cases large areas of the trunk, the lower legs, the neck, armpits and groin are affected. The severity of the disease varies among affected individuals, even within the same family. 

The severity of the disease may also vary over time. Heat and humidity tend to exacerbate the rash. UV light and minor skin injuries may also worsen the condition. Almost everyone with the disease has small, hard pits on the palms of the hands and soles of the feet, and the nails are usually cracked.

Owing to increased bacteria on the skin the lesions may have an unpleasant smell, which may be socially debilitating. The rash is often moist and occasionally bleeds. The ducts of the salivary glands in the cheeks may be obstructed, resulting in acute swelling of the parotide gland.

In the closely-related Hailey-Hailey disease, skin changes are concentrated to skin folds and the armpits. This condition causes less keratinisation (horny material), but the skin is more fragile.

Skeletal malformations sometimes occur, for example in the form of small bone cysts. These cysts rarely require treatment.

Different types of neuropsychiatric symptoms are somewhat more prevalent in individuals with Darier disease. 

Diagnosis

The diagnosis is based on the typical characteristics of skin lesions in Darier disease, and on dermatological testing. A skin biopsy will usually show characteristic degeneration of cells in the epidermis (acantholysis) and abnormally increased keratinisation (hyperkeratinisation).

DNA-based diagnosis is possible but is rarely required to establish the diagnosis. At the time of diagnosis the family should be offered genetic counselling. Carrier and prenatal diagnostics, as well as pre-implantation genetic diagnostics (PGD) in association with IVF (in vitro fertilization), are available in families where the mutation is known.

Treatment/interventions

There is currently no cure for the disorder, and efforts are directed at relieving symptoms. It is particularly important to prevent skin infections and to counteract abnormal keratinisation.

Softening creams may have an alleviating effect, but in most cases more powerful treatment options are needed to counteract thickening of the horny layer. Oral retinoids (derivatives of vitamin A) provide the most effective treatment for normalizing the keratinisation process. However, retinoids can have serious side effects and should be used restrictively. Pregnant women must never be treated with drugs containing vitamin A as retinoids cause severe birth defects. If a pregnancy is planned, treatment involving drugs containing vitamin A should be discontinued at least one year, preferably two years before the pregnancy, as retinoids may be retained in the body for a long period of time. Less harmful, but still unpleasant side effects include dry skin and mucous membranes (lips, nostrils, eyes) and minor, reversible, hair loss. Topical retinoids are sometimes applied to treat less extensive patches of skin, but they may cause irritation.

Antibacterial skin treatment is often necessary to prevent infection. Antibiotics should be administered in response to any sign of infection. Severe herpes infections are also treated with antiviral agents.
If the ducts of the salivary glands are obstructed, surgery is sometimes required.

Sweating may exacerbate problems in areas such as the groin or the armpits, and there are anti-sweating agents which may be helpful. If these are not effective, botulinum toxin injections may inhibit sweating for several months, improving the condition of the skin. In severe cases, a skin transplant may be required. Other surgical interventions that may be considered are dermabrasion (a method of smoothing the skin through surgical “scraping”) or laser treatment.

Most people with the disease should avoid exposure to sun and humid heat, as skin rashes usually become worse. However, in some cases sunlight may improve the condition.

It is important to inform those in contact with the patient that it is not contagious. The characteristic appearance of the skin may cause some people to avoid touch or direct contact with an affected child or adult. Information about the disease is an important way of counteracting isolation, and should be adapted to the age of the person with the disability.

If several family members are affected by the disease, the family will already know about how the symptoms vary over time and how to manage skincare routines. Only rarely is the condition severe enough to interfere with daily life, education and choice of occupation. In these cases psychological and social support are valuable.

Practical advice

Although frequent showering is beneficial, exaggerated scrubbing may cause weeping sores. Clothing should be loose and made of fabric that will not catch on or tear the papules/rash.

National and regional resources in Sweden

All Swedish regional hospitals and university hospitals have expertise in diagnosis and treatment. The Dermatology Clinic at Uppsala University Hospital is the national centre of excellence for a number of inherited skin diseases (genetic dermatoses).

 

Resource personnel

Professor Anders Vahlquist, Dermatology Clinic, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 30 00, fax +46 18 611 26 80, email: anders.vahlquist@medsci.uu.se.

Doctor Marie Virtanen, Dermatology Clinic, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 30 00, email: marie.virtanen@medsci.uu.se.

Courses, exchanges of experience, recreation

The Ichthyosis Association (see under “Organizations for the disabled/patient associations”) arranges annual weekend seminars, as well as regional meetings two or three times per year.

Organizations for the disabled/patient associations

Individuals with Darier disease are welcome to join the Ichthyosis Association, see address below. The symptoms of ichthyosis to some extent resemble those of Darier disease.

The Ichthyosis Association, Sturegatan 4C, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 546 404 51, www.iktyos.se.

The Ichthyosis Association is made up of 12 regions, each with its own contact person. Information about the regions and their contact people can be found on the website of the association. The newsletter of the Ichthyosis Association is published three times a year.

 

Courses, exchanges of experience for personnel

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Research and development 

Research groups in, for example, Great Britain and the US are working to increase knowledge of the interrelation between genetics and skin symptoms. Research on new therapies for Darier disease is ongoing on a worldwide basis and is currently focused on finding ways of decreasing the impact of the underlying mutation. In the long term it is hoped that it will be possible to offer better treatments with fewer side effects.

Information material

Short summaries of all the database texts are available as leaflets, in Swedish only. They can be printed out or ordered by selecting the Swedish version, and then clicking on the leaflet icon which will appear under “Mer hos oss” in the column on the right-hand side. Postage will be charged for bulk orders.

The Ågrenska Centre publishes material (in Swedish) on living with this disease as an adult: http://www.agrenska.se/Nksd/Vuxen-att-leva-med/Att-leva-med-Hudsjukdom/.

Literature

Burge SM, Wilkinson D. Darier-White disease: a review of the clinical features in 163 patients. J Am Acad Dermatol 1992; 27: 40-50.

Celli A, Mackenzie DS, Zhai Y, Tu CL, Bikle DD, Holleran WM et al. SERCA2-controlled Ca²+-dependent keratinocyte adhesion and differentiation is mediated via the sphingolipid pathway: a therapeutic target for Darier’s disease. J Invest Dermatol 2012; 132: 1188-1195.

Judge MR, Harper JI. Familial Darier’s disease with skeletal and neurological complications. Br J Dermatol 1991; 125: 51-52.

Kamijo M, Nishiyama C, Takagi A, Nakano N, Hara M, Ikeda S et al. 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 2012; 166: 1017-1022.

Leinonen PT, Hägg PM, Peltonen S, Jouhilahti EM, Melkko J, Korkiamäki T et. al. Reevaluation of the Normal Epidermal Calcium Gradient, and Analysis of Calcium Levels and ATP Receptors in Hailey-Hailey and Darier Epidermis. J Invest Dermatol 2009; 129: 1379-1387.

Macleod RI, Munro CS. The incidence and distribution of oral lesions in patients with Darier’s disease. Br Dent J 1991; 171: 133-136.

Sakuntabhai A, Ruiz-Perez V, Carter S, Jacobsen N, Burge S, Monk S et al. Mutations in ATP2A2, encoding a Ca2+ pump, cause Darier disease. Nature Genetics 1999; 21: 271-277.

Books

Vahlquist A. Chapter on skin diseases in the book Genetiska sjukdomar. Ed: Nordenskjöld M. Liber 2011; 235-236.

Database references

OMIM (Online Mendelian Inheritance in Man) 
http://www.ncbi.nlm.nih.gov/omim/
Search: Keratosis follicularis

Document information

The Swedish Information Centre for Rare Diseases produced and edited this material.

The medical expert who wrote the draft of this information material is Professor Anders Vahlquist, Uppsala University Hospital, Sweden.

The relevant organizations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

An expert group on rare diseases, affiliated with the University of Gothenburg, approved the material prior to publication.

Date of publication: 2013-09-18 
Version: 4.1 
Publication date of the Swedish version: 2012-09-19

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 422, SE-405 30 Gothenburg, Sweden. Tel: +46 31 786 55 90, email: ovanligadiagnoser@gu.se.

 

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This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.