Keratosis Follicularis

Disease Overview

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 may gradually grow bigger or spread. The nails and mucous membranes are also affected in most patients. 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 in an autosomal dominant pattern.

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Synonyms

• Darier disease
• Darier-White disease
• dyskeratosis follicularis

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Signs & Symptoms

The symptoms of keratosis follicularis usually become apparent during the teen-age years, often around puberty. Symptoms may develop in younger or older individuals, but rarely develop after the third or fourth decade of life. 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 (sebaceous glands secrete oily grease) including the chest, back, forehead and scalp. Darier disease may also affect skin increases, e.g., groin.

The skin lesions associated with keratosis follicularis generally develop a brown, greasy crust and become thickened and warty (hyperkeratotic), scaly and darkened. The lesions will slowly grow bigger eventually coming together (coalescing) to form discolored, warty plaques that may cover extensive areas of the body particularly on the trunk. In extremely rare, severe cases, almost the entire body may be affected. The lesions may cause persistent itchiness (pruritus). Some patients have fragile skin that blisters or becomes raw (erosions) and painful.

The skin 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 and causes pain. Heat, exercise and sunlight may also worsen keratosis follicularis or cause a new outbreak of lesions.

Individuals with keratosis follicularis may have periods when few lesions are present (remission). However, the lesions tend to recur (relapse). Keratosis follicularis is usually worse in the summer and may improve in the winter. Heat or sun 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 backs of the hands or feet. These bumps may be the first sign of keratosis follicularis. Many affected individuals 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 fragile nails with splits along the length of the nail or red or white streaks that run up and down the nail with V-shaped notching at the free edge.

Sometimes the mucous membranes within the mouth develop small bumps (papules). The roof of the mouth (palate) is most often affected. The gums, larynx and esophagus may also be affected. Darier disease can also affect the ducts of the salivary glands causing salivary gland obstruction. In some people, Darier disease has developed on the mucous membranes of the anus and rectum.

Although in most people Darier disease is limited to the skin, additional symptoms have been reported in some cases including seizures, bipolar disorder, depression and learning disabilities.

Keratosis follicularis may be restricted to a band of skin on one side of the body (segmental or linear keratosis follicularis) and in these linear cases the disease is most unlikely to be passed on to the next generation.

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Causes

Keratosis follicularis is a genetic disorder that occurs randomly as the result of a spontaneous genetic change (i.e., new pathogenic variant or mutation) or the variant is inherited in an autosomal dominant pattern.

Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.

Keratosis follicularis occurs due to pathogenic variants in the ATP2A2 gene. 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 into the extensive membrane network of a cell (endoplasmic reticulum) where proteins are processed. The exact process by which loss or improper function of the SERCA2 protein causes keratosis follicularis is unknown but SERCA2 is active (expressed) in keratinocytes, the main cell type of the outermost layer of the skin (epidermis). Calcium ions in the endoplasmic reticulum play an essential role in the formation of the proteins in the sticky junctions known as a desmosomes that hold the keratinocytes together. When the calcium pumps fail, the desmosomes do not hold cells together properly and the keratinocytes separate (acantholysis). Failure of keratinocytes to stick together also leads to abnormal maturation of the keratinocytes (abnormal keratinization) with the formation of the horny bumps. For this reason, keratosis follicularis is sometimes referred to as a disorder of abnormal keratinization or dyskeratosis. SERCA2 is also active (expressed) in the neurons of the central nervous system which may explain why some people experience neuropsychiatric problems such as bipolar disorder, seizures or depression.

The linear or segmental forms of keratosis follicularis are caused by genetic mosaicism meaning that the ATP2A2 gene variant is only present in some of the cells in one part of the skin but most of the skin is not affected. Mosaicism is caused by a variant in a single cell after fertilization (postzygotic change) and is not inherited.

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Affected populations

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.

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Disorders with Similar Symptoms

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 another 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 skin may itch or burn. Secondary infection is common. Most individuals develop symptoms in the third or fourth decade of life. The lesions may disappear on their own but can recur. Heat, friction, sunlight and trauma may cause an outbreak or worsen existing symptoms. Hailey-Hailey disease is caused by variants in the ATP2C1 gene, a gene that encodes another calcium pump, and Hailey-Hailey disease is also inherited in an autosomal dominant pattern. The desmosomes do not function correctly in Hailey-Hailey disease.

Acrokeratosis verruciformis of Hopf is another rare genetic skin disorder. 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 may be allelic to keratosis follicularis, which means that the two disorders are caused by different variants of the same gene (ATP2A2).

Grover disease, also known as transient acantholytic dermatosis, is an acquired skin disorder (i.e., not inherited) characterized by the sudden appearance of small, firm, raised itchy red bumps, most often on sun-damaged skin of the chest and back. The desmosomes fail to hold the keratinocytes together in Grover disease as they do in Darier disease. The bumps may disappear after six to 12 months or persist for years. Grover disease is mainly seen in men older than forty or fifty. The cause is uncertain, but heat, sweating and sun damage seem to play a part.

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Diagnosis

A diagnosis of keratosis follicularis is made based upon a thorough clinical evaluation, a detailed history from the affected individual including the family history, identification of characteristic findings 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).

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Standard Therapies

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 reduce the severity of the disease.

Synthetic derivatives of vitamin A (retinoids) applied directly to the affected areas (topically) may help reduce scaly thickening of the skin (hyperkeratosis) but may be uncomfortable to use because they irritate the skin. 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 most often used to treat severe cases. Oral retinoids such as acitretin, alitretinoin and isotretinoin affect the entire body (systemic therapy). Oral retinoids are associated with side effects. Women must not become pregnant when taking a retinoid because these drugs could damage the baby and pregnancy should be avoided for some time after stopping the drug (the exact time depends on which retinoid was prescribed). Retinoids 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.

There have been reports about the potential benefits of drugs like dupilumab, tralokinumab and baricitinib in Darier disease but controlled clinical trials are essential to confirm the efficacy and safety of these treatments.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

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. 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 of 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.

Controlled surgical scraping (dermabrasion) has also been used to treat some affected individuals.

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 website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

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References

TEXTBOOKS
Spitz JL. Genodermatoses. 2nd ed. Lippincott Williams & Wilkins. Philadelphia, PA; 2005:42-43.

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.

Champion RH, Burton JL, Ebling FJG. Eds. Textbook of Dermatology. 5th ed. Blackwell Scientific Publications. London, UK; 1992:1362-1365.

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.

Szigeti R, Kellermayer R. Autosomal-dominant calcium ATPase Disorders. J Invest Dermatol. 2006;126:2370-2376.

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 caused 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.

INTERNET
Kwok PY., Millsop JW and Bhutani, T. Keratosis Follicularis (Darier Disease). Medscape. Updated: Oct 01, 2020. Available at: https://www.emedicine.com/DERM/topic209.htm  Accessed Dec 12, 2024.

McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University. Last Update: 07/10/2024. Entry No:124200. https://omim.org/entry/124200  Accessed Dec 12, 2024.

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