- Author: Kara N Shah, MD, PhD; Chief Editor: Dirk M Elston, MD more...
The ectodermal dysplasias (EDs) comprise a large, heterogeneous group of inherited disorders that are defined by primary defects in the development of 2 or more tissues derived from embryonic ectoderm. The tissues primarily involved are the skin and its appendages (hair follicles, eccrine glands, sebaceous glands, and, nails) and teeth. Although Thurnam published the first report of a patient with ectodermal dysplasia in 1848, the term ectodermal dysplasia was not coined until 1929 by Weech.
The ectodermal dysplasias are congenital, diffuse, and nonprogressive. To date, more than 192 distinct disorders have been described. The most common ectodermal dysplasias are X-linked recessive hypohidrotic ectodermal dysplasia (Christ-Siemens-Touraine syndrome), as shown in the image below, and hidrotic ectodermal dysplasia (Clouston syndrome).
Current classification of ectodermal dysplasias is based on clinical features. Pure ectodermal dysplasias are manifested by defects in ectodermal structures alone, while ectodermal dysplasia syndromes are defined by the combination of ectodermal defects in association with other anomalies.
Freire-Maia and Pinheiro proposed the first classification system of the ectodermal dysplasias in 1982, with additional updates in 1994 and 2001.[3, 4] Their original classification system stratified the ectodermal dysplasias into different subgroups according to the presence or absence of (1) hair anomalies or trichodysplasias, (2) dental abnormalities, (3) nail abnormalities or onychodysplasias, and (4) eccrine gland dysfunction or dyshidrosis.
Overall, the ectodermal dysplasias were classified into either group A disorders, which were manifested by defects in at least 2 of the 4 classic ectodermal structures as defined above, with or without other defects, and group B disorders, which were manifested by a defect in one classic ectodermal structure (1-4 from above) in combination with (5) a defect in one other ectodermal structure (ie, ears, lips, dermatoglyphics). Eleven group A subgroups were defined, each with a distinct combination of 2 or more ectodermal defects (eg, 2-4, 1-2-3, 1-2-3-4 from above). The group B disorders were indicated as 1-5, 2-5, 3-5, or 4-5 (from above). Visinoni tabulated a summary of the 186 defined ectodermal dysplasia syndromes classified as group A in 2009. This classification was revised in 2014 to include 163 defined ectodermal dysplasia syndromes.
With the recent identification of the causative genetic defect for a number of the ectodermal dysplasias, newer classification systems have been devised. In 2003, Lamartine reclassified the ectodermal dysplasias into the following 4 functional groups based on the underlying pathophysiologic defect: (1) cell-to-cell communication and signaling, (2) adhesion, (3) development, and (4) other. Similarly, in 2001, Priolo and Laganà reclassified the ectodermal dysplasias into 2 main functional groups: (1) defects in developmental regulation/epithelial-mesenchymal interaction and (2) defects in cytoskeleton maintenance and cell stability. Other classification systems categorize the ectodermal dysplasias based on defects in cell-cell communication and signaling, adhesion, transcription regulation, or development.
Several ectodermal dysplasia syndromes may manifest in association with midfacial defects, mainly cleft lip, cleft palate, or both. The 3 most commonly recognized entities are (1) ectodermal dysplasia, ectrodactyly, and clefting (EEC) syndrome ; (2) Hay-Wells syndrome or ankyloblepharon, ectodermal dysplasia, and cleft lip/palate (AEC) syndrome; and (3) Rapp-Hodgkin syndrome, all of which are caused by mutations in the TP63 gene. See the images below.
Ectodermal dysplasia results from the abnormal morphogenesis of cutaneous or oral embryonal ectoderm (ie, hair, nails, teeth, eccrine glands). In some forms, mesodermal abnormalities are also present. Characteristic features include the following:
Hair defects: A reduction in the number of hair follicles in conjunction with structural hair shaft abnormalities may be seen. Structural hair shaft abnormalities may result from aberrations in hair bulb formation and include longitudinal grooving, hair shaft torsion, and cuticle ruffling. Hair bulbs may be distorted, bifid, or small. 
Eccrine defects: Eccrine sweat glands may be absent or sparse and rudimentary, particularly in patients with hypohidrotic ectodermal dysplasia. [11, 12]
Other secretory gland defects: Hypoplasia of the salivary, sebaceous, and lacrimal glands may occur. In some patients, mucous glands may be absent in the upper respiratory tract and in the bronchi, esophagus, and duodenum.
Dental defects: Abnormal morphogenesis or absence of teeth as well as enamel defects may occur. 
Nail dystrophy: Abnormal nail plate formation may result in brittle, thin, ridged, or grossly deformed nails.
Although few ectodermal dysplasia syndromes have a known genetic etiology, the number of ectodermal dysplasia syndromes with an identifiable genetic basis is increasing. In 2009, 64 genes and 3 chromosomal loci were associated with 62 ectodermal dysplasias.
Key transcription factors and intracellular signaling pathways that have been implicated in the ectodermal dysplasias include the tumor necrosis factor (TNF)-like/TNV receptor signaling pathway, which involves ectodysplasin (EDA), the EDR receptor (EDAR), the EDAR-associated death domain (EDARADD); the WNT signaling pathway; the NF-kB signally pathway, which involves the NF-kB essential modulator (NEMO); and the transcription factor p63.
The frequency of the different ectodermal dysplasias in a given population is highly variable. The prevalence of hypohidrotic ectodermal dysplasia, the most common variant, is estimated to be 1 case per 100,000 births.
Collectively, the prevalence of ectodermal dysplasia is estimated at 7 cases per 10,000 births.
The ectodermal dysplasias have been reported most often in whites, but they have also been observed in persons of other races. Hidrotic ectodermal dysplasia has been reported in an extensive kindred of French-Canadian origin.
X-linked recessive hypohidrotic ectodermal dysplasia has full expression only in males. Female carriers outnumber affected men, but females show little or no signs of the condition. X-linked recessive anhidrotic ectodermal dysplasia (EDA) with immunodeficiency (EDA-ID) and the X-linked recessive syndrome of osteopetrosis, lymphedema, EDA, and immunodeficiency (OL-EDA-ID) are also seen exclusively in males. The remaining ectodermal dysplasias have no sexual predilection.
Clinical recognition of ectodermal dysplasia varies from birth to childhood depending on the severity of symptoms and the recognition of associated complications. Many patients are not diagnosed until infancy or childhood, when dental anomalies, nail abnormalities, or alopecia become apparent.
AEC or Hay-Wells syndrome may manifest at birth as ankyloblepharon in association chronic scalp erosions. Hypohidrotic ectodermal dysplasia may manifest as scaling and erythema at birth. EEC syndrome and other related ectrodactyly syndromes (eg, acro-dermato-ungual-lacrimal-tooth [ADULT] syndrome and limb-mammary syndrome) are usually recognized at birth as a result of the characteristic limb deformities. Patients with anhidrosis or hypohidrosis may present in early infancy with recurrent episodes of hyperpyrexia.
Weech AA. Hereditary ectodermal dysplasia (congenital ectodermal defect). Am J Dis Child. 1929. 37:766-90.
Pinheiro M, Freire-Maia N. The ectodermal dysplasias. Arch Dermatol. 1982 Apr. 118(4):215-6. [Medline].
Pinheiro M, Freire-Maia N. Ectodermal dysplasias: a clinical classification and a causal review. Am J Med Genet. 1994 Nov 1. 53(2):153-62. [Medline].
Freire-Maia N, Lisboa-Costa T, Pagnan NA. Ectodermal dysplasias: how many?. Am J Med Genet. 2001 Nov 15. 104(1):84. [Medline].
Visinoni AF, Lisboa-Costa T, Pagnan NA, Chautard-Freire-Maia EA. Ectodermal dysplasias: clinical and molecular review. Am J Med Genet A. 2009 Sep. 149A(9):1980-2002. [Medline].
Pagnan NA, Visinoni ÁF. Update on ectodermal dysplasias clinical classification. Am J Med Genet A. 2014 Oct. 164A (10):2415-23. [Medline].
Lamartine J. Towards a new classification of ectodermal dysplasias. Clin Exp Dermatol. 2003 Jul. 28(4):351-5. [Medline].
Priolo M, Lagana C. Ectodermal dysplasias: a new clinical-genetic classification. J Med Genet. 2001 Sep. 38(9):579-85. [Medline].
Itin PH, Fistarol SK. Ectodermal dysplasias. Am J Med Genet C Semin Med Genet. 2004 Nov 15. 131C(1):45-51. [Medline].
Okamura E, Suda N, Baba Y, Fukuoka H, Ogawa T, Ohkuma M, et al. Dental and maxillofacial characteristics in six Japanese individuals with ectrodactyly-ectodermal dysplasia-clefting (EEC)syndrome. Cleft Palate Craniofac J. 2012 Jan 11. [Medline].
Rouse C, Siegfried E, Breer W, Nahass G. Hair and sweat glands in families with hypohidrotic ectodermal dysplasia: further characterization. Arch Dermatol. 2004 Jul. 140(7):850-5. [Medline].
Berg D, Weingold DH, Abson KG, Olsen EA. Sweating in ectodermal dysplasia syndromes. A review. Arch Dermatol. 1990 Aug. 126(8):1075-9. [Medline].
Clauss F, Maniere MC, Obry F, et al. Dento-craniofacial phenotypes and underlying molecular mechanisms in hypohidrotic ectodermal dysplasia (HED): a review. J Dent Res. 2008 Dec. 87(12):1089-99. [Medline].
Priolo M. Ectodermal dysplasias: an overview and update of clinical and molecular-functional mechanisms. Am J Med Genet A. 2009 Sep. 149A(9):2003-13. [Medline].
Kaercher T. Ocular symptoms and signs in patients with ectodermal dysplasia syndromes. Graefes Arch Clin Exp Ophthalmol. 2004 Jun. 242(6):495-500. [Medline].
Nordgarden H, Storhaug K, Lyngstadaas SP, Jensen JL. Salivary gland function in persons with ectodermal dysplasias. Eur J Oral Sci. 2003 Oct. 111(5):371-6. [Medline].
Motil KJ, Fete TJ, Fraley JK, et al. Growth characteristics of children with ectodermal dysplasia syndromes. Pediatrics. 2005 Aug. 116(2):e229-34. [Medline].
Dietz J, Kaercher T, Schneider AT, Zimmermann T, Huttner K, Johnson R, et al. Early respiratory and ocular involvement in X-linked hypohidrotic ectodermal dysplasia. Eur J Pediatr. 2013 Aug. 172(8):1023-31. [Medline].
Daniel E, McCurdy EA, Shashi V, McGuirt WF Jr. Ectodermal dysplasia: otolaryngologic manifestations and management. Laryngoscope. 2002 Jun. 112(6):962-7. [Medline].
Mehta U, Brunworth J, Lewis RA, Sindwani R. Rhinologic manifestations of ectodermal dysplasia. Am J Rhinol. 2007 Jan-Feb. 21(1):55-8. [Medline].
Callea M, Teggi R, Yavuz I, Tadini G, Priolo M, Crovella S, et al. Ear nose throat manifestations in hypoidrotic ectodermal dysplasia. Int J Pediatr Otorhinolaryngol. 2013 Nov. 77(11):1801-4. [Medline].
Bergendal B. Orodental manifestations in ectodermal dysplasia-a review. Am J Med Genet A. 2014 Oct. 164A (10):2465-71. [Medline].
Fete M, Hermann J, Behrens J, Huttner KM. X-linked hypohidrotic ectodermal dysplasia (XLHED): clinical and diagnostic insights from an international patient registry. Am J Med Genet A. 2014 Oct. 164A (10):2437-42. [Medline].
Clouston HR. A hereditary ectodermal dystrophy. Can Med Assoc J. 1929. 21:18-31.
Pierard GE, Van Neste D, Letot B. Hidrotic ectodermal dysplasia. Dermatologica. 1979. 158(3):168-74. [Medline].
Reynold JM, Gold MB, Scriver CR. The characterization of hereditary abnormalities of keratin: Clouston's ectodermal dysplasia. Birth Defects Orig Artic Ser. 1971 Jun. 7(8):91-5. [Medline].
Hay RJ, Wells RS. The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: an autosomal dominant condition. Br J Dermatol. 1976 Mar. 94(3):277-89. [Medline].
Fosko SW, Stenn KS, Bolognia JL. Ectodermal dysplasias associated with clefting: significance of scalp dermatitis. J Am Acad Dermatol. 1992 Aug. 27(2 Pt 1):249-56. [Medline].
Roelfsema NM, Cobben JM. The EEC syndrome: a literature study. Clin Dysmorphol. 1996 Apr. 5(2):115-27. [Medline].
Giampietro PF, Baker MW, Basehore MJ, Jones JR, Seroogy CM. Novel mutation in TP63 associated with ectrodactyly ectodermal dysplasia and clefting syndrome and T cell lymphopenia. Am J Med Genet A. 2013 Jun. 161A(6):1432-5. [Medline].
Felding IB, Bjorklund LJ. Rapp-Hodgkin ectodermal dysplasia. Pediatr Dermatol. 1990 Jun. 7(2):126-31. [Medline].
Kere J, Srivastava AK, Montonen O, et al. X-linked anhidrotic (hypohidrotic) ectodermal dysplasia is caused by mutation in a novel transmembrane protein. Nat Genet. 1996 Aug. 13(4):409-16. [Medline].
Monreal AW, Zonana J, Ferguson B. Identification of a new splice form of the EDA1 gene permits detection of nearly all X-linked hypohidrotic ectodermal dysplasia mutations [published erratum appears in Am J Hum Genet 1998 Oct;63(4):1253-5]. Am J Hum Genet. 1998 Aug. 63(2):380-9. [Medline].
Jones KB, Goodwin AF, Landan M, Seidel K, Tran DK, Hogue J, et al. Characterization of X-linked hypohidrotic ectodermal dysplasia (XL-HED) hair and sweat gland phenotypes using phototrichogram analysis and live confocal imaging. Am J Med Genet A. 2013 Jul. 161A(7):1585-93. [Medline].
Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nat Genet. 1999 Aug. 22(4):366-9. [Medline].
Wisniewski SA, Trzeciak WH. A rare heterozygous TRAF6 variant is associated with hypohidrotic ectodermal dysplasia. Br J Dermatol. 2012 Jun. 166(6):1353-6. [Medline].
Lamartine J, Munhoz Essenfelder G, Kibar Z, et al. Mutations in GJB6 cause hidrotic ectodermal dysplasia. Nat Genet. 2000 Oct. 26(2):142-4. [Medline].
Courtois G, Smahi A, Reichenbach J, et al. A hypermorphic IkappaBalpha mutation is associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest. 2003 Oct. 112(7):1108-15. [Medline].
Doffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001 Mar. 27(3):277-85. [Medline].
Zonana J, Elder ME, Schneider LC, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000 Dec. 67(6):1555-62. [Medline].
Rinne T, Brunner HG, van Bokhoven H. p63-associated disorders. Cell Cycle. 2007 Feb 1. 6(3):262-8. [Medline].
Rinne T, Hamel B, van Bokhoven H, Brunner HG. Pattern of p63 mutations and their phenotypes--update. Am J Med Genet A. 2006 Jul 1. 140(13):1396-406. [Medline].
Richard G, Rouan F, Willoughby CE, et al. Missense mutations in GJB2 encoding connexin-26 cause the ectodermal dysplasia keratitis-ichthyosis-deafness syndrome. Am J Hum Genet. 2002 May. 70(5):1341-8. [Medline]. [Full Text].
Suzuki K, Hu D, Bustos T, et al. Mutations of PVRL1, encoding a cell-cell adhesion molecule/herpesvirus receptor, in cleft lip/palate-ectodermal dysplasia. Nat Genet. 2000 Aug. 25(4):427-30. [Medline].
McGrath JA, McMillan JR, Shemanko CS, et al. Mutations in the plakophilin 1 gene result in ectodermal dysplasia/skin fragility syndrome. Nat Genet. 1997 Oct. 17(2):240-4. [Medline].
Wang X, Reid Sutton V, Omar Peraza-Llanes J, et al. Mutations in X-linked PORCN, a putative regulator of Wnt signaling, cause focal dermal hypoplasia. Nat Genet. 2007 Jul. 39(7):836-8. [Medline].
Lugassy J, Itin P, Ishida-Yamamoto A, et al. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet. 2006 Oct. 79(4):724-30. [Medline].
Shah S, Boen M, Kenner-Bell B, Schwartz M, Rademaker A, Paller AS. Pachyonychia congenita in pediatric patients: natural history, features, and impact. JAMA Dermatol. 2014 Feb. 150 (2):146-53. [Medline].
Wilson NJ, O'Toole EA, Milstone LM, Hansen CD, Shepherd AA, Al-Asadi E, et al. The molecular genetic analysis of the expanding pachyonychia congenita case collection. Br J Dermatol. 2014 Aug. 171 (2):343-55. [Medline].
McLean WH, Hansen CD, Eliason MJ, Smith FJ. The phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011 May. 131 (5):1015-7. [Medline].
Galdzicka M, Patnala S, Hirshman MG, et al. A new gene, EVC2, is mutated in Ellis-van Creveld syndrome. Mol Genet Metab. 2002 Dec. 77(4):291-5. [Medline].
Ruiz-Perez VL, Ide SE, Strom TM, et al. Mutations in a new gene in Ellis-van Creveld syndrome and Weyers acrodental dysostosis. Nat Genet. 2000 Mar. 24(3):283-6. [Medline].
Ruiz-Perez VL, Tompson SW, Blair HJ, et al. Mutations in two nonhomologous genes in a head-to-head configuration cause Ellis-van Creveld syndrome. Am J Hum Genet. 2003 Mar. 72(3):728-32. [Medline].
Ali RH, Habib R, Ud-Din N, Khan MN, Ansar M, Ahmad W. Novel mutations in the gene HOXC13 underlying pure hair and nail ectodermal dysplasia in consanguineous families. Br J Dermatol. 2013 Aug. 169(2):478-80. [Medline].
Naeem M, Wajid M, Lee K, Leal SM, Ahmad W. A mutation in the hair matrix and cuticle keratin KRTHB5 gene causes ectodermal dysplasia of hair and nail type. J Med Genet. 2006 Mar. 43(3):274-9. [Medline]. [Full Text].
Shimomura Y, Wajid M, Kurban M, Sato N, Christiano AM. Mutations in the keratin 85 (KRT85/hHb5) gene underlie pure hair and nail ectodermal dysplasia. J Invest Dermatol. 2010 Mar. 130(3):892-5. [Medline].
Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. 2000 May 25. 405(6785):466-72. [Medline].
Bohring A, Stamm T, Spaich C, Haase C, Spree K, Hehr U, et al. 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. [Medline]. [Full Text].
Adaimy L, Chouery E, Megarbane H, Mroueh S, Delague V, Nicolas E, et al. Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia. Am J Hum Genet. 2007 Oct. 81(4):821-8. [Medline]. [Full Text].
Mues G, Bonds J, Xiang L, Vieira AR, Seymen F, Klein O, et al. The WNT10A gene in ectodermal dysplasias and selective tooth agenesis. Am J Med Genet A. 2014 Oct. 164A (10):2455-60. [Medline].
Tziotzios C, Petrof G, Liu L, Verma A, Wedgeworth EK, Mellerio JE, et al. Clinical features and WNT10A mutations in seven unrelated cases of Schöpf-Schulz-Passarge syndrome. Br J Dermatol. 2014 Nov. 171 (5):1211-4. [Medline].
Klineberg I, Cameron A, Hobkirk J, Bergendal B, Maniere MC, King N, et al. Rehabilitation of children with ectodermal dysplasia. Part 2: an international consensus meeting. Int J Oral Maxillofac Implants. 2013 Jul-Aug. 28(4):1101-9. [Medline].
Klineberg I, Cameron A, Whittle T, Hobkirk J, Bergendal B, Maniere MC, et al. Rehabilitation of children with ectodermal dysplasia. Part 1: an international Delphi study. Int J Oral Maxillofac Implants. 2013 Jul-Aug. 28(4):1090-100. [Medline].
Hickey AJ, Vergo TJ. Prosthetic treatments for patients with ectodermal dysplasia. J Prosthet Dent. 2001 Oct. 86(4):364-8. [Medline].
Imirzalioglu P, Uckan S, Haydar SG. Surgical and prosthodontic treatment alternatives for children and adolescents with ectodermal dysplasia: a clinical report. J Prosthet Dent. 2002 Dec. 88(6):569-72. [Medline].
Dhanrajani PJ, Jiffry AO. Management of ectodermal dysplasia: a literature review. Dent Update. 1998 Mar. 25(2):73-5. [Medline].
Lypka M, Yarmand D, Burstein J, Tso V, Yamashita DD. Dental implant reconstruction in a patient with ectodermal dysplasia using multiple bone grafting techniques. J Oral Maxillofac Surg. 2008 Jun. 66(6):1241-4. [Medline].
Tarjan I, Gabris K, Rozsa N. Early prosthetic treatment of patients with ectodermal dysplasia: a clinical report. J Prosthet Dent. 2005 May. 93(5):419-24. [Medline].
Al-Ibrahim HA, Al-Hadlaq SM, Abduljabbar TS, Al-Hamdan KS, Abdin HA. Surgical and implant-supported fixed prosthetic treatment of a patient with ectodermal dysplasia: a case report. Spec Care Dentist. 2012 Jan. 32(1):1-5. [Medline].
El Osta Chaiban R, Chaiban W. Ectodermal dysplasia: dental management and benefits, a case report. Eur J Paediatr Dent. 2011 Dec. 12(4):282-4. [Medline].
Aydinbelge M, Gumus HO, Sekerci AE, Demetoglu U, Etoz OA. Implants in children with hypohidrotic ectodermal dysplasia: an alternative approach to esthetic management: case report and review of the literature. Pediatr Dent. 2013 Sep-Oct. 35(5):441-6. [Medline].
Dhima M, Salinas TJ, Cofer SA, Rieck KL. Rehabilitation of medically complex ectodermal dysplasia with novel surgical and prosthodontic protocols. Int J Oral Maxillofac Surg. 2013 Sep 12. [Medline].
Lee HE, Chang IK, Im M, Seo YJ, Lee JH, Lee Y. Topical minoxidil treatment for congenital alopecia in hypohidrotic ectodermal dysplasia. J Am Acad Dermatol. 2013 Apr. 68(4):e139-40. [Medline].
Melkote S, Dhurat RS, Palav A, Jerajani HR. Alopecia in congenital hidrotic ectodermal dysplasia responding to treatment with a combination of topical minoxidil and tretinoin. Int J Dermatol. 2009 Feb. 48(2):184-5. [Medline].
Dupuis-Girod S, Cancrini C, Le Deist F, et al. Successful allogeneic hemopoietic stem cell transplantation in a child who had anhidrotic ectodermal dysplasia with immunodeficiency. Pediatrics. 2006 Jul. 118(1):e205-11. [Medline].
Fish JD, Duerst RE, Gelfand EW, Orange JS, Bunin N. Challenges in the use of allogeneic hematopoietic SCT for ectodermal dysplasia with immune deficiency. Bone Marrow Transplant. 2008 Sep 15. [Medline].