Information on the following diseases can be found in the Related Disorders section of this report:

• Acrokeratosis Verruciformis of Hopf
• Hyperkeratosis Follicularis in Cutem Penetrans (Kyrle Disease)
• Keratosis Pilaris (Follicular Ichthyosis)
• Psoriasis

In most instances, the symptoms of Keratosis follicularis begin slowly, with the appearance of skin lesions that worsen gradually. In a few cases, lesions appear and spread rapidly (fulminant form). The affected skin is usually itchy with a burning sensation. Firm spots (papules) become larger and darker; these papules may be covered with grayish-brown scales or crusts. Skin lesions may increase in size and grow together into patches (vegetative plaques). These lesions may appear anywhere on the body but most commonly affect the scalp, ears, area behind the ears, face, neck, upper chest, and back. Scalp hair is usually unaffected. The areas under the breasts and the arms as well the groin may also become involved.

Most individuals with this disorder present with unusual nails; the nails are unusually thick and have white or red, longitudinal streaks. The underlying skin may be unusually dry. In most cases, the delicate membranes that line the mouth (oral mucosa) may also be involved. The inside of the mouth may have an unusual "cobblestone" texture (especially on the tongue, palate, and alveolar ridges). In some individuals, the symptoms of Keratosis follicularis may be limited to the nails and mouth. In others, symptoms may not be apparent until adulthood. Some individuals experience extended periods of remission (no symptoms).

Keratosis follicularis is most often gradually progressive and tends to become more severe with exposure to sunshine and/or emotional stress. Symptoms may improve during the winter months. It is, however, a chronic disorder.
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Keratosis follicularis is inherited as an autosomal dominant genetic trait. The faulty gene has been tracked to Gene Map Locus: 12q23-q24.1.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further subdivided into many bands that are numbered. For example, "chromosome 12q23-q24.1" refers to a region between bands 23 and 24.1 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

All individuals carry 4-5 abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.

Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.

Recent studies indicate that the faulty gene (ATP2A2) fails to code properly for an essential protein that acts as a calcium pump in the cell. This calcium pump is responsible for carrying the calcium ions in the cytoplasm of the cell from the interior of the cell to the cell wall. At the cell wall, the calcium ions play an essential role in cell-to-cell adhesion. If the calcium pump fails, the skin cells fail to adhere or stick together and the disease process unfolds. In some cases, acute sunburn is thought to "trigger" the onset of the disease.
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Keratosis follicularis usually begins during childhood, but it may appear as late as the 7th decade of life. Most cases are diagnosed between the ages of eight and 15 years. Males are affected in greater numbers than females. In Denmark, the incidence of this disorder is estimated at 1 in 10,000 persons. In the United States, Keratosis follicularis affects about 1 in 50,000 persons or 20 per million of population. There are, probably, a total of about 5,000 individuals affected by this disorder, and approximately 75 infants are born with this disease each year in the United States.
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Symptoms of the following disorders may be similar to those of Keratosis follicularis. Comparisons may be useful for differential diagnosis:

Acrokeratosis verruciformis of Hopf is a dominant hereditary skin disorder which tends to occur in members of families affected by dermatological conditions characterized by hardened skin. Symptoms of the disorder include flat-topped or slightly convex, smooth, firm, elevated spots (papules) usually distributed symmetrically on the back of both hands, feet, wrists and/or ankles. Spots may be few or numerous; they may range in size from 1/16 to 1/4 inch. Spots are mostly flesh-colored, some are light brown. The palms of the hands and the soles of the feet may be hardened (hyperkeratotic). Nails are opaque and brittle.

Hyperkeratosis vollicularis in cutem penetrans (Kyrle disease) is a rare skin disease occurring mostly in female adults. It is characterized by painful, scattered eruptions with horn-like cone-shaped plugs. Usually only the extremities, buttocks and cheeks are involved.

Keratosis pilaris (follicular ichthyosis) is a common skin disorder occurring during adolescence. It is characterized by mild redness of the skin with elevated hardened spots (keratotic papules) in irregular distribution, and the appearance of goose flesh, especially on thighs and arms. (To locate information about other types of Ichthyosis, choose "Ichthyosis" as your search term in the Rare Disease Database.)

Psoriasis is a common chronic and recurrent skin disease characterized by dry, well circumscribed, silvery, scaling elevated spots (papules) and plaques of various sizes. Psoriasis varies in severity from mild to severe. (For more information on this disorder, choose "Psoriasis" as your search term in the Rare Disease Database.)
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Diagnosis
Keratosis follicularis can be diagnosed by examining nail tissue and testing for the faulty gene.

Treatment
The disorder is usually treated with the retinoic acid (Retin-A) and corticosteroids. Severe episodes may, with caution, be treated with the retinoid drug etretinate or isotretinoin (Accutane). Prolonged use of retinoids is to be avoided. Surgical removal of diseased tissue from skin lesions (debridement) may also be helpful.
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Some years ago, the National Cancer Institute sponsored a study of the long-term safety and efficacy of acitretin, a vitamin A derivative, on diseases involving hardening of the skin (keratinization). It was found that after several months of treatment, mild improvement in the symptoms occurred. The drug has substantial and severe side-effects, and should be taken only upon the advice of a physician and careful watch of the patient.

McKusick VA, Ed. ONLINE MENDELIAN INHERITANCE IN MAN (OMIM). The Johns Hopkins University. Darier-White Disease; DAR. Entry Number; 124200: Last Edit Date; 2/12/2003.

TEXTBOOKS
Behrman RE, Kliegman RM, Arvin AM, eds. Nelson Textbook of Pediatrics. 15th ed. W.B. Saunder Company. Philadelphia, PA; 1996:1867, 1877.

Champion RH, Burton JL, Ebling FJG. eds. Textbook of Dermatology. 5th ed. Blackwell Scientific Publications. London, UK; 1992:1362-65.

REVIEW ARTICLES
Cooper SM, Burge SM. Darier’s disease: epidemiology, pathophysiology, and management. Am J Clin Dermatol. 2003;4:97-105.

Kitajima Y. Mechanisms of desmosome assembly and disassembly. Clin Exp Dermatol. 2002;27:684-90

McMillan JR, Shimizu H. Desmosomes: structure and function in normal and diseased epidermis. J Dermatol. 2001;28:291-98.

JOURNAL ARTICLES
Gilaberte M, Puig L, Vidal D, et al. Acantholytic dyskeratotic naevi following Blaschko’s Lines: a mosaic form of Darier’s disease. J Eur Acad. Dermatol Venereol. 2003;17:196-99.

Barfield RL, Barrett KR, Moon CM, et al. Pruritic linear papules on a 75 year-old woman: a case of localized Darier-White disease. Cutis. 2002;70:225-28.

Sheridan AT, Hollowood K, Sakuntabhai A, et al. Expression of sarco/endo-plasmic reticulum Ca2+-ATPase type 2 isoforms (SERCA2) in normal human skin and mucosa, and darier’s disease skin. Br J Derrmatol. 2002;147:670-74.

Jones I, Jacobsen N, Green EK, et al. Evidence for familial cosegregation of major affective disorder and genetic markers flanking the gene for Darier’s disease. Mol Psychiatry. 2002;7:424-27.

von Eiff C, Becker K, Metze D, et al. Intracellular persistence Of Staphylococcus aureus small-colony variants within keratinocytes: a cause for antibiotic treatment failure in a patient with darier’s disease. Clin Infect Dis. 2001;32:1643-47.

Jacobsen NJ, Franks EK, Elvidge G, et al. Exclusion of the Darier’s disease gene, ATP2A2, as a common susceptibility gene for bipolar disorder. Mol Psychiatry. 2001;6:92-97.

Bale SJ, Toro JR. Genetic basis of Darier-White disease: bad pumps cause bumps. J Cutan Med Surg. 2000;4:103-06.

FROM THE INTERNET
Kwok P-Y, Hsu T. Keratosis Follicularis (Darier Disease). emedicine. Last Updated: August 21, 2003. 8pp.
www.emedicine.com/derm/topic209.htm

Darier Disease. About Ichthyosis. Foundation for Ichthyosis & Related Skin Types (FIRST). ©2003. 2pp.
www.scalyskin.org/content.cfm?ContentID=96&ColumnID=14

Darier’s disease: Clinical Features, Differential Diagnosis, Hayley-Hayley disease, Treatment, Keratinization disorders. GPNotebook. nd. Multiple pages.
www.gpnotebook.co.uksimplepage.cfm?ID=-892338152
www.gpnotebook.co.uksimplepage.cfm?ID=-879099880
www.gpnotebook.co.uksimplepage.cfm?ID=-838467560&linkID=11639&cook=yes
www.gpnotebook.co.uksimplepage.cfm?ID=1429536829&linkID=11637&cook=yes
www.gpnotebook.co.uksimplepage.cfm?ID=-905576399&linkID=11638&cook=yes
www.gpnotebook.co.uksimplepage.cfm?ID=912982048&linkID=11640&cook=yes

Darier’s Disease. nd. 2pp.
www.show.scot.nhs.uk/monklands/ClinicalServices/MedicalDirectorate/derminfo/DARIER.htm

Lie DA. Response to Question. Darier’s Disease. Posted: 05/24/2001. 3pp.
www.medscape.com/viewarticle/413860

Darier’s Disease. British Association of Dermatologists. ©2001. 2pp.
www.bad.org.uk/patients/skin_disease_info/dariers/