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Ectodermal Dysplasias
Ectodermal Dysplasias AJ Clarke, Cardiff University, Cardiff, UK
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by FM Pope, volume 2, pp 599–601, © 2001, Elsevier Inc.
Hypohidrotic Reduced sweating. Hypotrichosis Sparse hair. Oligodontia Having few teeth.
Glossary Anhidrotic Absent sweating. HED Hypohidrotic ectodermal dysplasia.
Introduction The ectodermal dysplasias (EDs) comprise a diverse group of >170 genetic disorders that have in common the abnormal development of the ectodermal appendages: the hair, teeth, nails, and sweat glands, and sometimes also salivary and lacri mal glands and other related structures. The skin itself may also be distinctive: there may be reduced dermal fat and thickened palms and soles. There have been several attempts to classify the EDs. The best-known classification, a landmark, took the form of a book by Freire-Maia and Pinheiro (1984), in which the four key appendages of hair, teeth, nails, and sweat glands were num bered 1–4; each type of ED was grouped together in the appropriate numerical category (e.g., 1–2–3–4 if all four appendages were involed). Several attempts have been made since then to classify by both clinical features and on a rational, causal basis. In this article, we describe three of the major EDs, caused by mechanisms of three distinct categories, and refer to several other EDs. There are animal (mammalian) models for several of the human disorders.
X-Linked Hypohidrotic Ectodermal Dysplasia: The Role of a Signaling Pathway (OMIM 305100) This is much the commonest of the EDs and, although he was not the first, Charles Darwin did give a description of the condition. Affected males have hypotrichosis, oligodontia (usually conical, ‘peg-shaped’), reduced or absent sweat glands in the skin (resulting in hypo- or an-hidrosis) and mucus glands in the respiratory and colonic mucosa, reduced lacrimal and salivary gland activity, and (in some) dysplastic or hypotrophic nails. Infancy is hazardous with a mortality of 25–30% in the first 2 years even in the temperate United Kingdom, usually associated with chest infections and high fevers. Mortality is lower if the diagnosis is suspected early as knowl edge of the diagnosis helps to improve care. About half of the affected boys have recurrent infections and/or failure to thrive in early childhood. Medical problems then subside, although dental treatment assumes major impor tance and there is a need for temperature control throughout life. The management of physical, especially facial, appearance also becomes important and can dominate the lives of some affected individuals because of stigmatization leading to social isolation. Female carriers will often show few signs of the condition, perhaps none, although a small number with an
448
unfavorable pattern of X-chromosome inactivation manifest very clear signs; most note a few missing teeth but little else. The term ‘ectodermal dysplasia’ is misleading in relation to X-linked hypohidrotic ectodermal dysplasia (XHED), in that the endoderm is involved too – in particular, the mucus cells in the respiratory tact and the intestine. XHED, therefore, may be regarded as a failure of epithelial function – more generally of epithelial–mesenchymal interaction, not merely of ectodermal development or ecto-mesodermal interaction. The molecular basis is mutation in the ectodysplasin gene, EDA1, at chromosome Xq12–13.1, leading to alterations in the predominant protein isoform ectodysplasin A-1. This is a trans membrane protein including a short collagenous doman with 19 Gly-X-Y repeats (where the amino acids X and Y may vary, while Glycine is present as every third amino acid). The C-terminal extracellular segment contains the tumor necrosis factor (TNF) domain and can be released by enzymatic cleavage and allowed to diffuse to act at a distance. The ectodysplasin ligand binds to the cell-surface ectodysplasin-A receptor (EDAR), the protein product of the EDAR gene located on chromosome 2q. The phenotype of mutations in the ligand (EDA1) and its receptor (EDAR) is essentially the same, although some EDAR mutations lead to recessive phenotypes and others to a dominant phenotype. A similar appearance also results from mutations in the EDARADD gene, encoding a cytosolic adaptor protein; the three proteins function as a TNF family signaling pathway within the ectoderm, in that both EDA1 and EDAR are expressed within the ectoderm and not the mesoderm, although the resulting phenotype includes sec ondary changes to the mesodermal components of the ‘ectodermal’ appendages because hair, teeth, and sweat glands include mesodermal elements. The downstream actions of ectodysplasin are mediated at least in part by the inhibition of bone morphogenetic protein (BMP) and the upregulation of sonic hedgehog (Shh) activity. Although there is reason to believe that EDA1 has continu ing functions in tissue maintenance and the cycles of hair growth, its primary task of tissue development only requires its presence for a brief period in early development. This was demonstrated in the mouse by the administration of a recom binant fusion protein, of ectodysplasin with the Fc portion of IgG1, to pregnant female carriers of the Tabby mutation (the murine ortholog of EDA1). The Fc element ensured transport of the fusion protein across the placenta. Administration both prenatally or shortly after birth was effective at largely correct ing the features of ED in hemizygous (and therefore affected) Tabby male progeny; postnatal treatment in a canine model
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 2
doi:10.1016/B978-0-12-374984-0.00462-9
Ectodermal Dysplasias also resulted in substantial improvement. Efforts are underway to develop these methods for use in the human, for the ther apeutic reversal of XHED in an affected male infant or, perhaps more likely, fetus. If it is not effective given in the newborn period, as seems probable, the question would arise of how to establish the safety of administering such a protein at �20 weeks (halfway) through a human pregnancy. The upstream factors involved in the synthesis of ectodys plasin and its receptor include the Wnt signaling pathway. The ectoderm is stimulated to produce ectodysplasin by Wnt sig naling, and to produce the EDAR by the transforming growth factor β (TGFβ) signal, activin βA. The involvement of Wnt is especially interesting as mutations in the gene WNT10A account for a substantial proportion of cases of ED, which can lead to a wide range of phenotypes including sparse hair, few teeth, increased or decreased sweating, palmoplantar hyperkeratosis, eyelid cysts, and a range of other effects on the skin and nails. Mutations in WNT10A have been associated with �10% of cases of ED and �15% of cases of HED. One of the uncommon associated phenotypes includes a predispo sition to malignancy in the skin, which is otherwise unusual in the EDs. Another related type of ED is the ED with immunodefo ciency caused by mutation in exon 10 of the IKBKG (formerly NEMO) gene at Xq28. These mutations cause the general phy sical and facial phenotype of hypohidrotic ED but with more severe immune dysfunction than is usual in XHED and, in particular, an impaired production of antibodies in response to bacterial cell wall polysaccharides. The mutations do not completely inactivate the protein and there is some residual function. Other mutations in IKBKG, often frameshift or non sense mutations, cause a very different phenotype – that of incontinentia pigmenti. In this X-linked but apparently domi nant condition, families have a deficit of males with a 1:1:1 ratio of healthy males:unaffected females:affected females; the affected male conceptions miscarry. Affected females usually develop a blistering skin eruption in the neonatal period, occa sionally before birth, that then heals but leaves pigmented scars in whorls and streaks. The pigmentation in these scars fades with age, leaving smooth, hairless, and nonsweating patches of skin. The teeth and eyes, and sometimes other organs, may also show a number of features of ED.
Clouston’s Hidrotic Ectodermal Dysplasia: The Role of Structural Proteins (OMIM 129500) One of the less common types of ED, although the second to be described, is that of hidrotic ED (with sweating intact). A founder effect means that it is relatively common in the French Canadian population. There is very little hair, palmo plantar thickening with hyperkeratosis, and severely dystrophic nails. This is an autosomal dominant disorder caused by mis sense mutations in the gene GJB6, which encodes the connexin 30 gap junction protein. The mechanism through which the mutant protein causes its effects is not entirely clear as the protein is distributed normally in patients with this condition, although it shows altered electrochemical properties in the gap junctions between cells, resulting in leaks of adenosine tripho sphate (ATP) into the medium.
449
It is interesting that other mutations in this gene – usually deletions – contribute to genetic deafness when present in conjunction with mutations in connexin 26, another gap junc tion protein. A few GJB6 mutations give a phenotype with overlapping features – some effects on hearing and some der matological manifestations. There are several other EDs that are caused by mutations in other structural proteins. These include pachyonychia conge nita, with several features in common with Clouston’s hidrotic ED but caused by heterozygous mutation in one of the keratin proteins KRT16 or KRT17, or their expression partners KRT6A and KRT6B.
Ectrodactyly–Ectodermal Dysplasia–Clefting Syndrome and the p63 gene: The Role of a Transcription Factor (OMIM 129900) There is a family of conditions with overlapping phenotypes that include features of ED, orofacial clefting, and ectrodactyly (‘split hand/split foot’) (see Glossary); the eyes are also frequently involved. The ‘core’ condition is the ‘ectrodactyly– ED–clefting’ (EEC) syndrome, and affected individuals often show lacrimal duct atresia. While the phenotypes are often highly variable in degree, the pattern of tissues involved is usually the same within a family, depending upon the mutation. Distinct phenotypic clusters within this group include the ankyloblepharon–ectodermal dysplasia–clefting (AEC) syn drome and the Rapp–Hodgkin syndrome of ED and orofacial clefting. The whole set of such disorders has now been shown to result from different mutations within the same gene, TP63. This protein is a transcription factor related to the tumor sup pressor protein, p53. Another ED associated with transcription factor gene muta tions is the tricho-rhino-phalangeal (TRP) syndrome. In this condition, mutations affecting the TRPS1 zinc-finger transcrip tion factor gene result in sparse scalp hair, a distinctive facial appearance (including a bulbous nasal tip and a long, flat philtrum), and some skeletal anomalies (including cone-shaped epiphyses of the phalanges and short stature). When this arises from a large deletion of chromosome 8q24 as part of a contiguous gene deletion syndrome, these features are accompanied by substantial learning difficulties and the condition is known as the Langer–Giedion syndrome.
See also: Metabolic Disorders, Mutants.
Further Reading Barrow LL, Van Bokhoeven H, Daack-Hirsch S, et al. (2002) Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. Journal of Medical Genetics 39: 559–566. Bohring A, Stamm T, Spaich C, et al. (2009) WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. American Journal of Human Genetics 85: 1–9. Clarke A, Phillips DIM, Brown R, and Harper PS (1987) Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Archives of Disease in Childhood 62: 989–996. Essenfelder GM, Bruzzone R, Lamartine J, et al. (2004) Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichemical activity. Human Molecular Genetics 13(16): 1703–1714.
450
Ectodermal Dysplasias
Freire-Maia N and Pinheiro M (1984) Ectodermal Dysplasias: A Clinical and Genetic Study. New York: Alan R Liss Inc. Gaide O and Schneider P (2003) Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nature Medicine 9(5): 614–618. Irvine AD (2006) Ectodermal dysplasias. In: Harper J, Prange A, and Prose N (eds.) Textbook of Pediatric Dermatology, 2nd edn., ch. 19.12, pp. 1412–1466. Oxford, UK: Blackwell Publishers. Mikkola ML (2008) Molecular aspects of hypohidrotic ectodermal dysplasia. American Journal of Medical Genetics Part A 149A: 2031–2036. Priolo M and Lagana C (2001) Ectodermal dysplasias: A new clinical-genetic classification. Journal of Medical Genetics 38: 579–585. Zonana J, Elder ME, Schneider LC, et al. (2000) 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). American Journal of Human Genetics 67: 1555–1562.
Relevant Websites http://www.ectodermaldysplasia.org – Ectodermal Dysplasia Society; UK patient support group. http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information; Ectodermal dysplasia: Simple definition. http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information; GeneReviews: search for descriptions of both hypohidrotic and hidrotic ectodermal dysplasias. http://www.nfed.org – National Foundation for Ectodermal Dysplasias; US patient support group. http://www.omim.org – Online Mendelian Inheritance in Man (OMIM): search for detailed account of any gene associated with a distinct genetic condition.
© 2013 Elsevier Inc. All rights reserved.
This article is a revision of the previous edition article by FM Pope, volume 2, pp 599–601, © 2001, Elsevier Inc.
Hypohidrotic Reduced sweating. Hypotrichosis Sparse hair. Oligodontia Having few teeth.
Glossary Anhidrotic Absent sweating. HED Hypohidrotic ectodermal dysplasia.
Introduction The ectodermal dysplasias (EDs) comprise a diverse group of >170 genetic disorders that have in common the abnormal development of the ectodermal appendages: the hair, teeth, nails, and sweat glands, and sometimes also salivary and lacri mal glands and other related structures. The skin itself may also be distinctive: there may be reduced dermal fat and thickened palms and soles. There have been several attempts to classify the EDs. The best-known classification, a landmark, took the form of a book by Freire-Maia and Pinheiro (1984), in which the four key appendages of hair, teeth, nails, and sweat glands were num bered 1–4; each type of ED was grouped together in the appropriate numerical category (e.g., 1–2–3–4 if all four appendages were involed). Several attempts have been made since then to classify by both clinical features and on a rational, causal basis. In this article, we describe three of the major EDs, caused by mechanisms of three distinct categories, and refer to several other EDs. There are animal (mammalian) models for several of the human disorders.
X-Linked Hypohidrotic Ectodermal Dysplasia: The Role of a Signaling Pathway (OMIM 305100) This is much the commonest of the EDs and, although he was not the first, Charles Darwin did give a description of the condition. Affected males have hypotrichosis, oligodontia (usually conical, ‘peg-shaped’), reduced or absent sweat glands in the skin (resulting in hypo- or an-hidrosis) and mucus glands in the respiratory and colonic mucosa, reduced lacrimal and salivary gland activity, and (in some) dysplastic or hypotrophic nails. Infancy is hazardous with a mortality of 25–30% in the first 2 years even in the temperate United Kingdom, usually associated with chest infections and high fevers. Mortality is lower if the diagnosis is suspected early as knowl edge of the diagnosis helps to improve care. About half of the affected boys have recurrent infections and/or failure to thrive in early childhood. Medical problems then subside, although dental treatment assumes major impor tance and there is a need for temperature control throughout life. The management of physical, especially facial, appearance also becomes important and can dominate the lives of some affected individuals because of stigmatization leading to social isolation. Female carriers will often show few signs of the condition, perhaps none, although a small number with an
448
unfavorable pattern of X-chromosome inactivation manifest very clear signs; most note a few missing teeth but little else. The term ‘ectodermal dysplasia’ is misleading in relation to X-linked hypohidrotic ectodermal dysplasia (XHED), in that the endoderm is involved too – in particular, the mucus cells in the respiratory tact and the intestine. XHED, therefore, may be regarded as a failure of epithelial function – more generally of epithelial–mesenchymal interaction, not merely of ectodermal development or ecto-mesodermal interaction. The molecular basis is mutation in the ectodysplasin gene, EDA1, at chromosome Xq12–13.1, leading to alterations in the predominant protein isoform ectodysplasin A-1. This is a trans membrane protein including a short collagenous doman with 19 Gly-X-Y repeats (where the amino acids X and Y may vary, while Glycine is present as every third amino acid). The C-terminal extracellular segment contains the tumor necrosis factor (TNF) domain and can be released by enzymatic cleavage and allowed to diffuse to act at a distance. The ectodysplasin ligand binds to the cell-surface ectodysplasin-A receptor (EDAR), the protein product of the EDAR gene located on chromosome 2q. The phenotype of mutations in the ligand (EDA1) and its receptor (EDAR) is essentially the same, although some EDAR mutations lead to recessive phenotypes and others to a dominant phenotype. A similar appearance also results from mutations in the EDARADD gene, encoding a cytosolic adaptor protein; the three proteins function as a TNF family signaling pathway within the ectoderm, in that both EDA1 and EDAR are expressed within the ectoderm and not the mesoderm, although the resulting phenotype includes sec ondary changes to the mesodermal components of the ‘ectodermal’ appendages because hair, teeth, and sweat glands include mesodermal elements. The downstream actions of ectodysplasin are mediated at least in part by the inhibition of bone morphogenetic protein (BMP) and the upregulation of sonic hedgehog (Shh) activity. Although there is reason to believe that EDA1 has continu ing functions in tissue maintenance and the cycles of hair growth, its primary task of tissue development only requires its presence for a brief period in early development. This was demonstrated in the mouse by the administration of a recom binant fusion protein, of ectodysplasin with the Fc portion of IgG1, to pregnant female carriers of the Tabby mutation (the murine ortholog of EDA1). The Fc element ensured transport of the fusion protein across the placenta. Administration both prenatally or shortly after birth was effective at largely correct ing the features of ED in hemizygous (and therefore affected) Tabby male progeny; postnatal treatment in a canine model
Brenner’s Encyclopedia of Genetics, 2nd edition, Volume 2
doi:10.1016/B978-0-12-374984-0.00462-9
Ectodermal Dysplasias also resulted in substantial improvement. Efforts are underway to develop these methods for use in the human, for the ther apeutic reversal of XHED in an affected male infant or, perhaps more likely, fetus. If it is not effective given in the newborn period, as seems probable, the question would arise of how to establish the safety of administering such a protein at �20 weeks (halfway) through a human pregnancy. The upstream factors involved in the synthesis of ectodys plasin and its receptor include the Wnt signaling pathway. The ectoderm is stimulated to produce ectodysplasin by Wnt sig naling, and to produce the EDAR by the transforming growth factor β (TGFβ) signal, activin βA. The involvement of Wnt is especially interesting as mutations in the gene WNT10A account for a substantial proportion of cases of ED, which can lead to a wide range of phenotypes including sparse hair, few teeth, increased or decreased sweating, palmoplantar hyperkeratosis, eyelid cysts, and a range of other effects on the skin and nails. Mutations in WNT10A have been associated with �10% of cases of ED and �15% of cases of HED. One of the uncommon associated phenotypes includes a predispo sition to malignancy in the skin, which is otherwise unusual in the EDs. Another related type of ED is the ED with immunodefo ciency caused by mutation in exon 10 of the IKBKG (formerly NEMO) gene at Xq28. These mutations cause the general phy sical and facial phenotype of hypohidrotic ED but with more severe immune dysfunction than is usual in XHED and, in particular, an impaired production of antibodies in response to bacterial cell wall polysaccharides. The mutations do not completely inactivate the protein and there is some residual function. Other mutations in IKBKG, often frameshift or non sense mutations, cause a very different phenotype – that of incontinentia pigmenti. In this X-linked but apparently domi nant condition, families have a deficit of males with a 1:1:1 ratio of healthy males:unaffected females:affected females; the affected male conceptions miscarry. Affected females usually develop a blistering skin eruption in the neonatal period, occa sionally before birth, that then heals but leaves pigmented scars in whorls and streaks. The pigmentation in these scars fades with age, leaving smooth, hairless, and nonsweating patches of skin. The teeth and eyes, and sometimes other organs, may also show a number of features of ED.
Clouston’s Hidrotic Ectodermal Dysplasia: The Role of Structural Proteins (OMIM 129500) One of the less common types of ED, although the second to be described, is that of hidrotic ED (with sweating intact). A founder effect means that it is relatively common in the French Canadian population. There is very little hair, palmo plantar thickening with hyperkeratosis, and severely dystrophic nails. This is an autosomal dominant disorder caused by mis sense mutations in the gene GJB6, which encodes the connexin 30 gap junction protein. The mechanism through which the mutant protein causes its effects is not entirely clear as the protein is distributed normally in patients with this condition, although it shows altered electrochemical properties in the gap junctions between cells, resulting in leaks of adenosine tripho sphate (ATP) into the medium.
449
It is interesting that other mutations in this gene – usually deletions – contribute to genetic deafness when present in conjunction with mutations in connexin 26, another gap junc tion protein. A few GJB6 mutations give a phenotype with overlapping features – some effects on hearing and some der matological manifestations. There are several other EDs that are caused by mutations in other structural proteins. These include pachyonychia conge nita, with several features in common with Clouston’s hidrotic ED but caused by heterozygous mutation in one of the keratin proteins KRT16 or KRT17, or their expression partners KRT6A and KRT6B.
Ectrodactyly–Ectodermal Dysplasia–Clefting Syndrome and the p63 gene: The Role of a Transcription Factor (OMIM 129900) There is a family of conditions with overlapping phenotypes that include features of ED, orofacial clefting, and ectrodactyly (‘split hand/split foot’) (see Glossary); the eyes are also frequently involved. The ‘core’ condition is the ‘ectrodactyly– ED–clefting’ (EEC) syndrome, and affected individuals often show lacrimal duct atresia. While the phenotypes are often highly variable in degree, the pattern of tissues involved is usually the same within a family, depending upon the mutation. Distinct phenotypic clusters within this group include the ankyloblepharon–ectodermal dysplasia–clefting (AEC) syn drome and the Rapp–Hodgkin syndrome of ED and orofacial clefting. The whole set of such disorders has now been shown to result from different mutations within the same gene, TP63. This protein is a transcription factor related to the tumor sup pressor protein, p53. Another ED associated with transcription factor gene muta tions is the tricho-rhino-phalangeal (TRP) syndrome. In this condition, mutations affecting the TRPS1 zinc-finger transcrip tion factor gene result in sparse scalp hair, a distinctive facial appearance (including a bulbous nasal tip and a long, flat philtrum), and some skeletal anomalies (including cone-shaped epiphyses of the phalanges and short stature). When this arises from a large deletion of chromosome 8q24 as part of a contiguous gene deletion syndrome, these features are accompanied by substantial learning difficulties and the condition is known as the Langer–Giedion syndrome.
See also: Metabolic Disorders, Mutants.
Further Reading Barrow LL, Van Bokhoeven H, Daack-Hirsch S, et al. (2002) Analysis of the p63 gene in classical EEC syndrome, related syndromes, and non-syndromic orofacial clefts. Journal of Medical Genetics 39: 559–566. Bohring A, Stamm T, Spaich C, et al. (2009) WNT10A mutations are a frequent cause of a broad spectrum of ectodermal dysplasias with sex-biased manifestation pattern in heterozygotes. American Journal of Human Genetics 85: 1–9. Clarke A, Phillips DIM, Brown R, and Harper PS (1987) Clinical aspects of X-linked hypohidrotic ectodermal dysplasia. Archives of Disease in Childhood 62: 989–996. Essenfelder GM, Bruzzone R, Lamartine J, et al. (2004) Connexin30 mutations responsible for hidrotic ectodermal dysplasia cause abnormal hemichemical activity. Human Molecular Genetics 13(16): 1703–1714.
450
Ectodermal Dysplasias
Freire-Maia N and Pinheiro M (1984) Ectodermal Dysplasias: A Clinical and Genetic Study. New York: Alan R Liss Inc. Gaide O and Schneider P (2003) Permanent correction of an inherited ectodermal dysplasia with recombinant EDA. Nature Medicine 9(5): 614–618. Irvine AD (2006) Ectodermal dysplasias. In: Harper J, Prange A, and Prose N (eds.) Textbook of Pediatric Dermatology, 2nd edn., ch. 19.12, pp. 1412–1466. Oxford, UK: Blackwell Publishers. Mikkola ML (2008) Molecular aspects of hypohidrotic ectodermal dysplasia. American Journal of Medical Genetics Part A 149A: 2031–2036. Priolo M and Lagana C (2001) Ectodermal dysplasias: A new clinical-genetic classification. Journal of Medical Genetics 38: 579–585. Zonana J, Elder ME, Schneider LC, et al. (2000) 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). American Journal of Human Genetics 67: 1555–1562.
Relevant Websites http://www.ectodermaldysplasia.org – Ectodermal Dysplasia Society; UK patient support group. http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information; Ectodermal dysplasia: Simple definition. http://www.ncbi.nlm.nih.gov – National Center for Biotechnology Information; GeneReviews: search for descriptions of both hypohidrotic and hidrotic ectodermal dysplasias. http://www.nfed.org – National Foundation for Ectodermal Dysplasias; US patient support group. http://www.omim.org – Online Mendelian Inheritance in Man (OMIM): search for detailed account of any gene associated with a distinct genetic condition.