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Hypohidrotic ectodermal dysplasia

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Description

Hypohidrotic ectodermal dysplasia is one of more than 100 types of ectodermal dysplasia. Starting before birth, these disorders result in the abnormal development of ectodermal tissues, particularly the skin, hair, nails, teeth, and sweat glands.

Most people with hypohidrotic ectodermal dysplasia have a reduced ability to sweat (hypohidrosis) because they have fewer sweat glands than normal or their sweat glands do not function properly. Sweating is a major way that the body controls its temperature; as sweat evaporates from the skin, it cools the body. Reduced sweating can lead to a dangerously high body temperature (hyperthermia), particularly in hot weather. In some cases, hyperthermia can cause life-threatening health problems.

Affected individuals tend to have sparse scalp and body hair (hypotrichosis). The hair is often light-colored, brittle, and slow-growing. Hypohidrotic ectodermal dysplasia is also characterized by several missing teeth (hypodontia) or teeth that are malformed. The teeth that are present erupt from the gums later than usual and are frequently small and pointed.

Some people with hypohidrotic ectodermal dysplasia have distinctive facial features, including a prominent forehead, thick lips, and a flattened bridge of the nose. Additional features of this condition can include thin, wrinkled, and dark-colored skin around the eyes; chronic skin problems such as eczema; and a bad-smelling discharge from the nostrils (ozena).

Intellectual ability and growth are typically normal in people with hypohidrotic ectodermal dysplasia.

Frequency

Hypohidrotic ectodermal dysplasia is the most common form of ectodermal dysplasia. It is estimated to occur in 1 in 20,000 newborns worldwide.

Causes

Hypohidrotic ectodermal dysplasia is a genetic condition that can result from mutations in one of several genes. These include EDA, EDAR, EDARADD, and WNT10A. EDA gene mutations are the most common cause of the disorder, accounting for more than half of all cases. EDAR, EDARADD, and WNT10A gene mutations each account for a smaller percentage of cases. In about 10 percent of people with hypohidrotic ectodermal dysplasia, the genetic cause is unknown.

The EDA, EDAR, and EDARADD genes provide instructions for making proteins that work together during embryonic development. These proteins form part of a signaling pathway that is critical for the interaction between two cell layers, the ectoderm and the mesoderm. In the early embryo, these cell layers form the basis for many of the body's organs and tissues. Ectoderm-mesoderm interactions are essential for the formation of several structures that arise from the ectoderm, including the skin, hair, nails, teeth, and sweat glands.

Mutations in the EDA, EDAR, or EDARADD gene prevent normal interactions between the ectoderm and the mesoderm, which impairs the normal development of skin, hair, nails, teeth, and sweat glands. Mutations in any of these three genes lead to the major signs and symptoms of hypohidrotic ectodermal dysplasia described above.

The WNT10A gene provides instructions for making a protein that is part of a different signaling pathway known as Wnt signaling. Wnt signaling controls the activity of certain genes and regulates the interactions between cells during embryonic development. Signaling involving the WNT10A protein is critical for the development of ectodermal structures, particularly the teeth. The WNT10A gene mutations that cause hypohidrotic ectodermal dysplasia impair the protein's function, which disrupts the development of teeth and other structures that arise from the ectodermal cell layer.

When hypohidrotic ectodermal dysplasia results from WNT10A gene mutations, its features are more variable than when the condition is caused by mutations in the EDA, EDAR, or EDARADD gene. Signs and symptoms range from mild to severe, and mutations in the WNT10A gene are more likely to cause all of the permanent (adult) teeth to be missing.

Inheritance

Hypohidrotic ectodermal dysplasia has several different inheritance patterns. Most cases are inherited in an X-linked pattern and are caused by mutations in the EDA gene. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females, who have two copies of the X chromosome, one altered copy of the gene in each cell often leads to less severe features of the condition. Signs and symptoms can include a few missing or abnormal teeth, sparse hair, and mild problems with sweat gland function. However, some females with one copy of the mutated gene have more severe features of this disorder.

Less commonly, hypohidrotic ectodermal dysplasia has an autosomal dominant or autosomal recessive pattern of inheritance. Mutations in the EDAR, EDARADD, or WNT10A gene can cause either autosomal dominant or autosomal recessive hypohidrotic ectodermal dysplasia.

Autosomal dominant inheritance means one copy of the altered gene in each cell is sufficient to cause the disorder. Some affected individuals inherit the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.

Autosomal recessive inheritance means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene. Some mutation carriers have mild signs and symptoms of hypohidrotic ectodermal dysplasia, including a somewhat reduced ability to sweat and less severe dental abnormalities.

Other Names for This Condition

  • anhidrotic ectodermal dysplasia
  • Christ-Siemens-Touraine syndrome
  • CST syndrome
  • HED

References

  • Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, Hoffmann M, Ledig S, Sel S, Wieacker P, Röpke A. WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. Am J Hum Genet. 2009 Jul;85(1):97-105. doi: 10.1016/j.ajhg.2009.06.001. Epub 2009 Jun 25. Citation on PubMed or Free article on PubMed Central
  • Cluzeau C, Hadj-Rabia S, Jambou M, Mansour S, Guigue P, Masmoudi S, Bal E, Chassaing N, Vincent MC, Viot G, Clauss F, Manière MC, Toupenay S, Le Merrer M, Lyonnet S, Cormier-Daire V, Amiel J, Faivre L, de Prost Y, Munnich A, Bonnefont JP, Bodemer C, Smahi A. Only four genes (EDA1, EDAR, EDARADD, and WNT10A) account for 90% of hypohidrotic/anhidrotic ectodermal dysplasia cases. Hum Mutat. 2011 Jan;32(1):70-2. doi: 10.1002/humu.21384. Citation on PubMed
  • Mikkola ML. Molecular aspects of hypohidrotic ectodermal dysplasia. Am J Med Genet A. 2009 Sep;149A(9):2031-6. doi: 10.1002/ajmg.a.32855. Review. Citation on PubMed
  • Nguyen-Nielsen M, Skovbo S, Svaneby D, Pedersen L, Fryzek J. The prevalence of X-linked hypohidrotic ectodermal dysplasia (XLHED) in Denmark, 1995-2010. Eur J Med Genet. 2013 May;56(5):236-42. doi: 10.1016/j.ejmg.2013.01.012. Epub 2013 Feb 14. Citation on PubMed
  • Trzeciak WH, Koczorowski R. Molecular basis of hypohidrotic ectodermal dysplasia: an update. J Appl Genet. 2016 Feb;57(1):51-61. doi: 10.1007/s13353-015-0307-4. Epub 2015 Aug 21. Review. Citation on PubMed or Free article on PubMed Central
  • van der Hout AH, Oudesluijs GG, Venema A, Verheij JB, Mol BG, Rump P, Brunner HG, Vos YJ, van Essen AJ. Mutation screening of the Ectodysplasin-A receptor gene EDAR in hypohidrotic ectodermal dysplasia. Eur J Hum Genet. 2008 Jun;16(6):673-9. doi: 10.1038/sj.ejhg.5202012. Epub 2008 Jan 30. Citation on PubMed
  • Wiśniewski SA, Kobielak A, Trzeciak WH, Kobielak K. Recent advances in understanding of the molecular basis of anhidrotic ectodermal dysplasia: discovery of a ligand, ectodysplasin A and its two receptors. J Appl Genet. 2002;43(1):97-107. Review. Citation on PubMed
  • Wright JT, Grange DK, Fete M. Hypohidrotic Ectodermal Dysplasia. 2003 Apr 28 [updated 2017 Jun 1]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1112/ Citation on PubMed
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