Related Terms

• Alopecia, Clouston syndrome, connexin, ectodermal dysplasia, GJB2, GJB6, hidrotic ectodermal dysplasia, palmoplantar hyperkeratosis, palmoplantar keratoderma.

Background

• Palmoplantar hyperkeratosis and alopecia, also known as Clouston syndrome, is a form of ectodermal dysplasia. Ectodermal dysplasias are a group of syndromes with characteristic abnormalities of the ectodermal structures, including the hair, teeth, nails, sweat glands, cranial-facial structure, and hands. These genetic disorders can be inherited in an autosomal dominant or recessive manner.

• Symptoms of palmoplantar hyperkeratosis and alopecia include thickening of the skin on the palms of the hands and soles of the feet, abnormal hair loss, fingernail and toenail defects, and changes in skin coloring. Unlike most forms of ectodermal dysplasia, palmoplantar hyperkeratosis and alopecia is associated with normal teeth and a normal ability to sweat. Hearing loss has been documented in some individuals with palmoplantar hyperkeratosis and alopecia.

• Palmoplantar hyperkeratosis and alopecia is an inherited genetic disorder that is passed down among family members. Two gene candidates, the GJB6 gene and the GJB2 gene,bothon chromosome 13, have been linked to palmoplantar hyperkeratosis and alopecia in ethnically diverse populations. This disorder usually follows an autosomal dominant pattern of inheritance, meaning that only one copy of the defective GJB6 or GJB2 gene is needed for the disease to appear.

• Palmoplantar hyperkeratosis and alopecia is a rare disorder, with the exact incidence currently unknown. Cases of palmoplantar hyperkeratosis and alopecia have been found among people of French, French-Canadian, Spanish, African, Scottish-Irish, Indian, and Malaysian ancestry, and possibly others that have not been documented.

Risk Factors

• Because palmoplantar hyperkeratosis and alopecia is inherited, the only known risk factor is a family history of the disease. Palmoplantar hyperkeratosis and alopecia is caused by a mutation or defect in the GJB6 or GJB2 gene. Palmoplantar hyperkeratosis and alopecia is usually inherited, or passed down among family members, as a dominant trait, meaning that only one copy of the defective gene from either parent must be inherited for the condition to appear.

Causes

• General: Palmoplantar hyperkeratosis and alopecia is a rare inherited genetic disorder that is passed down among family members. It is caused by a mutation or defect in the GJB6 or GJB2 gene. The GJB6 gene provides instructions for making the protein connexin 30, which has been associated with some forms of deafness, and some individuals with palmoplantar hyperkeratosis and alopecia have documented hearing loss. Connexin 30 is located in the epidermis, which may explain some of the skin symptoms associated with this condition. The GJB2 gene encodes for the protein connexin 26. Connexin 26 is also associated with disorders of the skin and with deafness.

• Inheritance: Palmoplantar hyperkeratosis and alopecia is usually inherited as a dominant trait. Individuals receive two copies of most genes, one from the mother and one from the father. For a dominant disorder to appear, only one copy of the defective geneis necessary. If one parent has the disorder, there is a 50% chance that his or her child will have the disorder. If both parents have the disorder, there is a 75% chance that their child will have the disorder.

• Random occurrence: It is currently unknown whether palmoplantar hyperkeratosis and alopecia may occur as the result of a spontaneous mutation in the sperm or egg cells or in the developing embryo.

Signs and Symptoms

• Eyes: In some cases, people with palmoplantar hyperkeratosis and alopecia may have crossed eyes or may continuously squint, because of a problem with the eye muscles.

• Hair: People with palmoplantar hyperkeratosis and alopecia may experience hair loss (alopecia) or may be totally bald. Typically the eyebrows, eyelashes, and body hair are also sparse or absent.

• Nails: Depending on the severity of palmoplantar hyperkeratosis at the localized site, the nails on the fingers and toes tend to be poorly developed, discolored, grooved, ridged, and thick.

• Skin: People with palmoplantar hyperkeratosis and alopecia have thickening of the skin on the palms of the hands and soles of the feet. The skin may have extra pigment or coloring in certain areas of the body, especially over the joints. Unlike most people with ectodermal dysplasias, people with palmoplantar hyperkeratosis and alopecia can sweat normally.

• Other: Less common symptoms that have been observed in palmoplantar hyperkeratosis and alopecia include short stature, clouding of the lens of the eye (cataract), sensitivity to the sun (photophobia), inflammation of the outer layer of the eyeball and the lining of the eyelid (conjunctivitis), and clubbed fingers and toes.

Diagnosis

• General: Palmoplantar hyperkeratosis and alopecia may be suspected based on the observation of distinctive qualities of the hair, skin, and nails. In addition, a detailed family history and complete physical exam should be completed. Unlike most forms of ectodermal dysplasia, palmoplantar hyperkeratosis and alopecia is associated with normal teeth and a normal ability to sweat. Hearing loss has been documented in some individuals with palmoplantar hyperkeratosis and alopecia.

• Biopsy: In a biopsy, a small sample of tissue is taken for analysis in a lab. In palmoplantar hyperkeratosis and alopecia, a doctor may take a biopsy of the skin to assess its overall texture as well as the presence of hair follicles and sweat glands.

• Genetic testing: If palmoplantar hyperkeratosis and alopecia is suspected, DNA sequencing can be performed to determine whether a defective GJB2 or GJB6 gene exists and whether a positive diagnosis can be made.

• Prenatal DNA testing: If there is a family history of palmoplantar hyperkeratosis and alopecia, prenatal testing may be performed to determine whether the fetus has the disorder. Amniocentesis and chorionic villus sampling (CVS) can diagnose the disorder. However, because there are serious risks, such as miscarriage, associated with these tests, patients should discuss the potential health benefits and risks with a medical professional.

• During amniocentesis, a long, thin needle is inserted through the abdominal wall and into the uterus, and a small amount of amniotic fluid is removed from the sac surrounding the fetus. Cells in the fluid are then analyzed for normal and abnormal chromosomes. This test is performed after 15 weeks of pregnancy. The risk of miscarriage is about one in 200-400 patients. Some patients may experience minor complications, such as cramping, leaking fluid, or irritation where the needle was inserted.

• During chorionic villus sampling (CVS), a small piece of tissue (chorionic villi) is removed from the placenta between the ninth and 14th weeks of pregnancy. CVS may be performed through the cervix or through the abdomen. The cells in the tissue sample are then analyzed for the mutation in the keratin genes. Miscarriage occurs in about 0.5%-1% of women who undergo this procedure.

Complications

• Complications seen in palmoplantar hyperkeratosis and alopecia are not generally serious and tend to be associated with symptoms of the nails and skin, such as thickening of the skin on the palms of the hands and soles of the feet, abnormal hair loss, fingernail and toenail defects, and changes in skin coloring. These complications are generally no different from the symptoms of the condition. Hearing loss has been documented in some individuals with palmoplantar hyperkeratosis and alopecia.

Treatment

• Retinoids: Retinoids, compounds related to vitamin A, are known to soften the skin, and taken by mouth, they may improve the skin and nail symptoms seen in palmoplantar hyperkeratosis and alopecia. Minor adverse effects of retinoids include dryness and cracking of the skin, temporary hair loss, and dryness of the eyes, mouth, and nostrils. Severe adverse effects of retinoids may include liver damage, increased blood cholesterol levels, excessive bone growth, birth defects if taken by pregnant women, headache, and swelling of the brain. People taking retinoids should be regularly monitored for these adverse effects. In addition, women of childbearing age should undergo regular pregnancy tests.

• Skin softeners: Skin softeners or keratolytics, such as salicylic acid, may be used to improve the condition of the skin on the palms of the hands and soles of the feet. Skin softeners may also be used to treat the condition of the nails. Once the nails are softened, they can be cut or filed down more easily.

• Surgery: Severely affected nails may be surgically removed. Unless the entire nail bed is removed, however, the nails will grow back and problems may persist.

Integrative Therapies

• Currently, there is a lack of available scientific evidence on the use of integrative therapies for the treatment or prevention of palmoplantar hyperkeratosis and alopecia.

Prevention

• General: Because palmoplantar hyperkeratosis and alopecia is an inherited condition, there is currently no known way to prevent the disease. However, a number of options are available for prospective parents with family histories of the disorder.

• Genetic testing and counseling: Individuals who have palmoplantar hyperkeratosis and alopecia may meet with a genetic counselor to discuss the risks of having children with the disease. Genetic counselors can explain the options and the associated risks of various tests, including pre-implantation genetic diagnosis (PGD), amniocentesis, and chorionic villus sampling (CVS).

• Pre-implantation genetic diagnosis (PGD) may be used with in vitro (artificial) fertilization. In PGD, embryos are tested for the defective connexin genes, and only the embryos that are not affected may be selected for implantation. Because palmoplantar hyperkeratosis and alopecia can be detected in a fetus, parents may choose whether to continue the pregnancy. Genetic counselors may assist parents with these difficult decisions.

Author Information

• This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).

Bibliography

Natural Standard developed the above evidence-based information based on a thorough systematic review of the available scientific articles. For comprehensive information about alternative and complementary therapies on the professional level, go to www.naturalstandard.com. Selected references are listed below.

1. Ectodermal Dysplasia Society. www.ectodermaldysplasia.org.

2. Essenfelder GM, Bruzzone R, Lamartine J, et al. Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichannel activity. Hum Mol Genet. 2004 Aug 15;13(16):1703-14. View Abstract

3. Hassed SJ, Kincannon JM, Arnold GL. Clouston syndrome: an ectodermal dysplasia without significant dental findings. Am J Med Genet. 1996 Jan 22;61(3):274-6. View Abstract

4. Hayflick SJ, Taylor T, McKinnon W, et al. Clouston syndrome (hidrotic ectodermal dysplasia) is not linked to keratin gene clusters on chromosomes 12 and 17. J Invest Dermatol. 1996 Jul;107(1):11-4. View Abstract

5. Lamartine J, Laoudj D, Blanchet-Bardon C, et al. Refined localization of the gene for Clouston syndrome (hidrotic ectodermal dysplasia) in a large French family. Br J Dermatol. 2000 Feb;142(2):248-52. View Abstract

6. McNaughton PZ, Pierson DL, Rodman OG. Hidrotic ectodermal dysplasia in a black mother and daughter. Arch Dermatol. 1976 Oct;112(10):1448-50. View Abstract

7. National Foundation for Ectodermal Dysplasias. www.nfed.org.

8. Natural Standard: The Authority on Integrative Medicine. www.naturalstandard.com.

9. Parhizar N, Jones VE, McClay EF, et al. Metastatic melanoma in a patient with Clouston syndrome successfully treated with isolated hyperthermic limb perfusion. J Cutan Med Surg. 2003 Jan-Feb;7(1):43-6. View Abstract

10. Patel RR, Bixler, Norins AL. Clouston syndrome: a rare autosomal dominant trait with palmoplantar hyperkeratosis and alopecia. J Craniofac Genet Dev Biol. 1991 Jul-Sep;11(3):176-9. View Abstract

11. Smith FJ, Morley SM, McLean WH. A novel connexin 30 mutation in Clouston syndrome. J Invest Dermatol. 2002 Mar;118(3):530-2. View Abstract

12. Taylor TD, Hayflick SJ, McKinnon W, et al. Confirmation of linkage of Clouston syndrome (hidrotic ectodermal dysplasia) to 13q11-q12.1 with evidence for multiple independent mutations. J Invest Dermatol. 1998 Jul;111(1):83-5. View Abstract

13. Van Steensel MA, Steijlen PM, Bladergroen RS, et al. A phenotype resembling the Clouston syndrome with deafness is associated with a novel missense GJB2 mutation. J Invest Dermatol. 2004 Aug;123(2):291-3. View Abstract

14. Van Steensel MA, Jonkman MF, van Geel M, et al. Clouston syndrome can mimic pachyonychia congenita. J Invest Dermatol. 2003 Nov;121(5):1035-8. View Abstract