Keratosis follicularis, also known as Darier disease, is a rare, genetic skin disorder. Affected individuals develop skin lesions that consist of thickened, rough bumps (papules) or plaques that may also be greasy or have a brown or yellow crust. These hardened, scaly lesions are progressive and may gradually grow bigger or spread. The nails and mucous membranes are also affected in many cases. Additional symptoms may be present in some cases. Individuals may have periods of time when signs improve (remission), but the lesions usually recur (relapse). The specific problems vary from one individual to another. Keratosis follicularis is inherited as an autosomal dominant trait.
The symptoms of keratosis follicularis usually become apparent during the teen-age years often around puberty. Symptoms may develop in older individuals, but rarely develop after the third or fourth decade of life. In rare cases, symptoms have become apparent in children under 10. The severity of the disorder and the specific symptoms that develop vary, even among individuals within the same family.
The initial lesions in keratosis follicularis are usually small, firm, greasy bumps (papules) that are often skin-colored, brown or yellow-brown in color. The lesions usually affect the areas of the body near sebaceous glands (sehorrheic areas) including the chest, back, forehead, scalp and groin. The area just behind the ears is a common initial site for the development of characteristic skin lesions. The sebaceous glands secrete an oily, fatty substance known as sebum that helps protect the skin from infection and helps the skin retain water. The sebaceous glands are found in the skin throughout the body except on the palms and the soles.
The skin lesions associated with keratosis follicularis generally develop a brown, greasy crust and become thickened (hyperkeratosis), scaly and darkened. The lesions will slowly grow bigger eventually coming together (coalescing) to form large discolored, warty plaques that may cover significant portions of the body. In extremely rare, severe cases, almost the entire body may be affected. The lesions may cause persistent itchiness (pruritus) and blistering. Pain in the affected areas is uncommon, but has occurred.
The skin lesions associated with keratosis follicularis may develop bacterial, viral or fungal infections (secondary infections) that worsen (exacerbate) the condition. Infected skin lesions may give off a distinct, unpleasant (malodorous) smell. The herpes simplex virus may be prone to infecting the lesions. Heat, exercise and sunlight may also worsen keratosis follicularis or cause a new outbreak of lesions.
Individuals with keratosis follicularis have periods where no lesions are present (remission). However, the lesions tend to recur (relapse). Keratosis follicularis is usually worse in the summer and improves in the winter. Severe sunburn often causes an outbreak.
Another common finding associated with keratosis follicularis is the development of multiple, small, yellow-brown, flattened wart-like (verrucous) bumps (papules) on the palms of the hands and the soles of the feet. These lesions may sometimes be the first symptom of keratosis follicularis to develop. Many affected individuals may also develop small horny bumps called punctate keratoses or depressions (pits) on the palms and soles.
Most individuals with keratosis follicularis have abnormalities affecting the nails including thin, brittle nails that frequently splinter or become notched at the tip, thickening and hardening of the skin underneath the nails (subungual hyperkeratosis), and the presence of red or white streaks that run up and down the nail.
In many cases, the mucous membranes within the mouth may develop multiple, small white bumps (papules) that form a cobblestone pattern. The roof of the mouth (palate) is most often affected. The gums, larynx and esophagus may also be affected. These lesions can also affect the salivary glands potentially causing salivary gland obstruction. In some cases, these lesions have developed on the mucous membranes of the anus and rectum.
Although in most cases the skin is predominantly affected, additional symptoms have been reported in some cases of keratosis follicularis including a variety of neurological findings including seizures, bipolar disorder, and learning disabilities.
In some cases, only one small area of the body is affected and the disease does not spread (localized keratosis follicularis). Keratosis follicularis can also affect only adjacent areas of the body (segmental keratosis follicularis) or may appear as a band-like line of affected skin usually on one side of the body (linear keratosis follicularis).
Keratosis follicularis is a genetic disorder that occurs randomly as the result of a spontaneous genetic change (i.e., new mutation) or is inherited as an autosomal dominant trait.
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. 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 percent for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that keratosis follicularis occurs due to mutations of the ATP2A2 gene located on the long arm (q) of chromosome 12 (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 sub-divided into many bands that are numbered. For example, "chromosome 12q23-q24.1" refers to bands 23-24.1 on the long arm of chromosome 12. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The ATP2A2 gene contains instructions for creating (encoding) a protein that acts as a calcium pump in the cell. This protein known as SERCA2, is responsible for carrying calcium ions from the semi-transparent fluid (cytoplasm) found in the interior of a cell to the extensive membrane network of a cell (endoplasmic reticulum). Calcium ions play an essential role in cell-to-cell adhesion and, if the calcium pump fails, affected cells will not adhere or stick together (acantholysis). The exact process by which loss or improper function of the SERCA2 protein causes keratosis follicularis is unknown. The protein is most active (expressed) in keratinocytes, the main cell type of the outermost layer of the skin (epidermis). Failure of keratinocytes to stick together results in the abnormal formation of keratin tissue (keratinization). Keratin is the tough, structural protein that is a major component of the skin. For this reason, keratosis follicularis is sometimes referred to as a disorder of abnormal keratinization or dyskeratosis.
The linear and segmental forms of keratosis follicularis may represent genetic mosaicism. Mosaicism is a condition in which the genetic mutation that causes keratosis follicularis occurs in some of the cells of the body, but not in others. The severity of the disease in these cases depends on the percentage of cells affected, but is less severe than in individuals who have the mutation in all of their cells. Mosaicism causing keratosis follicularis is believed to result from a mutation of the ATP2A2 that occurs after fertilization (postzygotic) and is not inherited.
Keratosis follicularis affects males and females in equal numbers. It is estimated to occur in 1 in 36,000 to 100,000 individuals in the general population. The disorder usually becomes apparent during the second decade in life, but has developed in individuals as young 4 and older than 70. Keratosis follicularis was first described in the medical literature in 1889.
Symptoms of the following disorders can be similar to those of keratosis follicularis. Comparisons may be useful for a differential diagnosis.
Hailey-Hailey disease, also known as benign familial chronic pemphigus, is a rare genetic skin disorder. Hailey-Hailey disease is characterized by blistering, erosive skin lesions that most often form on the neck, chest, armpits and groin. The lesion may itch or cause a burning sensation. Secondary infection of the lesions may also occur. Most individuals develop symptoms in the third or fourth decade of life, but symptoms can develop at any age. The lesions may disappear on their own, but can recur. Heart, friction, sunlight and trauma may cause an outbreak or worsen existing symptoms. Hailey-Hailey disease is caused by mutations of the ATP2C1 gene and is inherited as an autosomal dominant trait. (For more information on this disorder, choose "Hailey-Hailey" as your search term in the Rare Disease Database.)
Acrokeratosis verruciformis of Hopf is a rare genetic 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 the 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). The nails may be opaque and brittle. Acrokeratosis verruciformis of Hopf is allelic to keratosis follicularis, which means the two disorders are caused by different mutations of the same gene (ATP2A2 ). Some researchers believe that acrokeratosis verruciformis of Hopf is a localized form of keratosis follicularis.
Grover's disease, also known as transient acantholytic dermatosis, is a rare skin disorder characterized by the sudden appearance of small, firm, raised red lesions, most often on the skin of the chest and back. Diagnosis of this disorder becomes apparent under microscopic examination when a loss of "cement" that holds the cells of the skin together is observed. Over time, as the skin loses the "cement," the cells separate (lysis). Small blisters containing a watery liquid are present. These blisters tend to group and have a swollen red border around them. The skin lesions may itch (pruritis). The lesions usually disappear after a period of six to 12 months. Grover's disease is mainly seen in males older than forty or fifty. Its cause is unknown but it is thought to be related to trauma to sun damaged skin. (For more information on this disorder, choose "Grover's disease" as your search term in the Rare Disease Database.)
Ichthyosis is a general term for a family of rare genetic skin diseases characterized by dry, thickened, scaling skin. The various forms are distinguished from one another by: 1) extent of the scaling and how widely and where the scaling is scattered over the body; 2) the presence or absence and intensity of reddening of the skin (erythroderma); 3) the mode of inheritance; and 4) the character of associated abnormalities. (For more information on this disorder, choose "ichthyosis" as your search term in the Rare Disease Database.)
Diagnosis A diagnosis of keratosis follicularis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests in the surgical removal and microscopic examination (biopsy) of affected skin tissue. A biopsy may reveal abnormal formation of keratin tissue (keratinization) and failure of cell-to-cell adhesion (acantholysis).
Treatment The treatment of keratosis follicularis is directed toward the specific symptoms that are apparent in each individual. For some individuals, sunscreen, loose clothing, moisturizing creams and avoiding excessive heat may help prevent outbreaks.
Synthetic derivatives of vitamin A (retinoids) applied directly to the affected areas (topically) may help reduce scaly thickening of the skin (hyperkeratosis). Therapy that helps soften and shed hardened, abnormal skin (keratolytics) such as treatment with salicylic acid in propylene glycol gel may also help treat hyperkeratosis. Topical corticosteroids and substances that soothe and soften the skin (emollients) have also been used to alleviate inflammation in localized keratosis follicularis.
Retinoids taken by mouth (orally) have been effective in treating individuals with keratosis follicularis and are the drugs mot often used to treat severe cases. Oral retinoids such as tretinoin and acitretin affect the entire body (systemic therapy). Long-term use of oral retinoids can be associated with side effects and should only be used under the supervision of a physician.
Antibiotics may be necessary to treat individuals with secondary bacterial infection. Antiviral agents such as acyclovir have been used to treat associated infection with the herpes simplex virus.
Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
Additional therapies have been used to treat affected individuals including erbium:YAG laser resurfacing, in which physicians use a laser to destroy the damage cells that make up the characteristic skin lesion of keratosis follicularis. This form of laser therapy has led to a remission in two affected individuals. More research is necessary to determine the long-term safety and effectiveness of the erbium:YAG laser for individuals with keratosis follicularis.
Photodynamic therapy, a procedure in which a drug known as a photosensitizer is used along with a special type light, has been used to treat some individuals with keratosis follicularis. During photodynamic therapy, the drug is administered to an affected individual and absorbed by the affected cells. A specific wavelength of light is used to active the drug which binds with oxygen creating a chemical that destroys the affected cell. More research is necessary to determine the long-term safety and effectiveness of photodynamic therapy for individuals with keratosis follicularis.
Additional therapies have been reported in the medical literature as being used for the treatment of individuals with keratosis follicularis including topic 5-fluorouracil and cyclosporin. Controlled surgical scraping (dermabrasion) has also been used to treat some affected individuals.
James WD, Berger TG, Elston DM. Eds. Andrew's Diseases of the Skin: Clinical Dermatology. 10th ed. Saunders. 2005:567-568.
Ringfeil F. Darier Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:101.
Rimoin D, Connor JM, Pyeritz RP, Korf BR. Eds. Emory and Rimoin's Principles and Practice of Medical Genetics. 4th ed. Churchill Livingstone. New York, NY; 2002:3913-3915.
JOURNAL ARTICLES Sanderson EA, Killoran CE, Pdevis-Leftick A, Wilkel CS. Localized Darier's disease in a Blaschloid distribution: two cases of phenotypic mosaicism and a review of mosaic Darier's disease. J Dermatol. 2007;34:761-764.
Cardoso CL, Freitas P, Taveira LA, Consolaro A. Darier disease: case report with oral manifestations. Med Oral Pathol Oral Cir Bucal. 2006;11:E404-406.
Yoon TY, Kim JW, Kim MK. Successful treatment of Darier disease with topical 5-fluorouracil. Br J Dermatol. 2006;156:1210-1212.
Dhitavat J, Fairclough RJ, Hovnanian A, Burge SM. Calcium pumpts and keratinocytes: lessons from Darier's disease and Hailey-Hailey disease. Br J Dermatol. 2004;50:821-828.
Dhitavat J, Dode L, Leslie N, Sakuntabhai A, Lorette G, Hovnanian A. Mutations in the sarcoplasmic/endplasmic reticulum CA2+ ATPase isoform cause Darier disease. J Invest Dermatol. 2003b;121:486-489.
Dhitavat J, Macfarlane S, Dode L, et al. Acrokeratosis verruciformis of Hopf is cause by mutation in ATP2A2: evidence that it is allelic to Darier's disease. J Invest Dermatol. 2003c;120:229-232.
Exadaktylou D, Kurwa HA, Calonje E, Barlow RJ. Treatment of Darier's disease with photodynamic therapy. Br J Dermatol. 2003;149:606-10.
Hulatt L, Burge S. Darier's disease: hopes and challenges. J R Soc Med. 2003;96:439-441.
Sakuntabhai A, Dhitavat J, Burge S, Hovnanian A. Mosaicism for ATP2A2 mutations causes segmental Darier's disease. J Invest Dermatol. 2000;115:1144-1147.
Beier C, Kaufmann R. Efficacy of erbium:YAG laser ablation in Darier disease and Hailey-Hailey disease. Arch Dermatol. 1999;135:423-427.
Burge S. Darier's disease – the clinical features and pathogenesis. Clin Exp Dermatol. 1994;19:193-205.
FROM THE INTERNET Kwok PY. Liao W. Keratosis Follicularis (Darier Disease). Emedicine Journal, February 28 2007. Available at: http://www.emedicine.com/DERM/topic209.htm Accessed on: February 16, 2008.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:124200; Last Update:02/12/2003. Available at: http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=124200 Accessed on: February 16, 2008.
March of Dimes Birth Defects Foundation 1275 Mamaroneck Avenue White Plains, NY 10605 Tel: (914)428-7100 Fax: (914)997-4763 Tel: (888)663-4637 Email: Askus@marchofdimes.com Internet: http://www.marchofdimes.com
Foundation for Ichthyosis & Related Skin Types 1364 Welsh Road G2 North Wales, PA 19454 Tel: (215)619-0670 Fax: (215)619-0780 Tel: (800)545-3286 Email: info@scalyskin.org Internet: http://www.scalyskin.org
NIH/National Arthritis and Musculoskeletal and Skin Diseases Information Clearinghouse 1 AMS Circle Bethesda, MD 20892-3675 USA Tel: (301)495-4484 Fax: (301)718-6366 Tel: (877)226-4267 TDD: (301)565-2966 Email: NIAMSinfo@mail.nih.gov Internet: http://www.niams.nih.gov/Health_Info
National Registry for Ichthyosis and Related Disorders University of Washington Dermatology Department, Box 356524 1959 N.E. Pacific Seattle, WA 98195-6524 Tel: (206)616-3179 Fax: (206)616-6793 Tel: (800)595-1265 Email: ichreg@u.washington.edu Internet: http://www.skinregistry.org
Genetic and Rare Diseases (GARD) Information Center PO Box 8126 Gaithersburg, MD 20898-8126 Tel: (301)519-3194 Fax: (240)632-9164 Tel: (888)205-2311 TDD: (888)205-3223 Email: gardinfo@nih.gov Internet: http://www.genome.gov/10000409
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