Hay–Wells syndrome

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Hay–Wells syndrome
Classification and external resources
ICD-10 Q82.4
OMIM 106260
DiseasesDB 33336

Hay–Wells syndrome (also known as AEC syndrome; see Naming) is one of at least 150 known types of ectodermal dysplasia.[1][2]:571

These disorders affect tissues that arise from the ectodermal germ layer, such as skin, hair, and nails.

Genetics[edit]

Hay–Wells syndrome has an autosomal dominant pattern of inheritance.

Hay–Wells syndrome is autosomal dominant,[3] caused by a missense mutation in the Sterile alpha motif (SAM) of the TP73L (p63) gene which encodes for a protein-protein interaction domain.[3] It is a very rare disorder.

Hay-Wells syndrome is represents an autosomal dominant pattern of inheritance (Nagaveni and Umashankara 2011). The syndrome is thought to arise from a missense mutation in a gene pivotal for the proper development of craniofacial structures and extremities, as well as skin differentiation (Macias et al. 2006). Specifically, mutations within the Tumor Protein 63 gene have been implicated in Hay-Wells syndrome (Rinne et al. 2009).

Residing on the long-arm of chromosome 3, the Tumor Protein 63 (TP63) gene is critical for proper development and homeostasis of stratified epithelia (Senoo et al. 2007). In Hay-Wells syndrome, and other ectodermal dysplasia disorders, a missense, nonsense, or insertion mutation has occurred in the TP63 gene. Currently, no deletion or duplication mutations have been detected in such disorders (Rinne et al. 2009). Interestingly, though ectodermal dysplasia disorders result from heterozygous mutations in TP63, compromised epidermal differentiation with epidermal decay is representative of Hay-Wells patients but is hardly observed in other syndromes. In contrast, severe abnormalities characteristic of other ectodermal dysplasia disorders (i.e. limb abnormalities in EEC) are not seen in Hay-Wells patients (Brunner et al. 2002; Julapalli et al. 2009; Zarnegar et al. 2012).


Proteomics[edit]

TP63 encodes for the p63 transcription factor, which is implicated in proliferation, differentiation, apoptosis, regular cell maintenance, and cell adhesion. Specifically, p63 is expressed within early keratinocytes and the embryonic ectodermal ridge during development. Thus, p63 is believed to play a pivotal role in the development and maintenance of the epidermis (Chan et al. 2005). Reported mutations that have resulted in Hay-Wells syndrome have occurred within the sterile alpha motif (SAM) and the transactivation inhibitory (TI) domains of the p63-coding region (Figure 1). The SAM domain of p63 is thought to be imperative for protein-protein interactions, while the TI domain may play a role in the repression of other isoforms of p63 (Koster and Roop 2004; Van Bokhoven and Brunner 2002). Recent work has shown that mutations within these domains lead to repression of other known transcriptional activators of epidermal differentiation. These transcription activators include: GRHL3, HOPX, PRDM1, KLF4, and ZNF750 (Birnbaum et al. 2006; Yang et al. 2008; Zarnegar et al. 2012). Most notably, Hay-Wells p63 mutants irregularly repress the genes that encode for ZNF750. The down-regulation of ZNF750 has been shown to hinder the expression of the other before mentioned differentiation-activators such as HOPX, PRDM1, KLF4, and GRHL3. In contrast, recapitulating the expression of ZNF750 leads to significant rescue of normal epidermal differentiation (Zarnegar et al. 2012).


Phenotype[edit]

Hay-Wells syndrome is the result of the invariant mutations of the p63 transcription factor that have been previously identified. Due to the diminished activities of p63, patients can experience a host of symptoms related to the operation of keratinocytes. In particular, the hypopigmentation observed in several Hay-Wells patients is believed to be the result of improperly developed keratinocytes not being able to properly interact with melanocytes (Seiberg et al. 2000). However, as it stands, this display of Hay-Wells syndrome has not been entirely comprehended. Most noted are the abnormal development of hair, teeth, glands, and nails (Nagaveni and Umashankara 2011; Figure 2; Figure 3; Figure 4).  


Diagnosis[edit]

In HWS the hair is coarse and sparse, eyelashes are sparse or absent, nails may be absent or malformed, and teeth may be small and malformed. There may be fewer than normal sweat glands and they may produce little sweat, a condition known generally as hypohidrosis. Chronic inflammatory dermatitis of the scalp is a common symptom.[4]

Two features differentiate HWS from other ectodermal displasias. First, the syndrome is associated with cleft palate, and, less often, cleft lip. Second, the edges of the upper and lower eyelid grow bands of fibrous tissue, often causing them to be fused together. This condition in the eyelids is called ankyloblepharon filiforme adnatum.

Naming[edit]

Hay–Wells syndrome is also known as AEC syndrome; this is short for "ankyloblepharon–ectodermal dysplasia–clefting syndrome", "ankyloblepharon filiforme adnatum–ectodermal dysplasia–cleft palate syndrome",[5]:518), "ankyloblepharon–ectodermal defects–cleft lip/palate (AEC) syndrome",[6] "ankyloblepharon–ectodermal defect–cleft lip and/or palate syndrome",[7] or "ankyloblepharon ectodermal dysplasia and clefting".[8] Hay-Wells syndrome, or Ankyloblepharon-Ectodermal Dysplasia-Clefting (AEC) syndrome, is one of over one-hundred forms of ectodermal dysplasia; a collection of inherited diseases that cause atypical development of nails, glands, teeth, and hair. Males and females are equally affected by Hay-Wells syndrome. No demographic has been shown to be especially susceptible to the syndrome. In the United States, Hay-Wells like syndromes occur in only one in 100,000 births (Motil and Fete 2009). Symptoms are apparent at birth, or become apparent when atypical development of teeth occurs (Nagaveni and Umashankara 2011). Major symptoms of Hay-Wells syndrome include: sparse hair and eyelashes, missing teeth, cleft palate, cleft lip with fusing of the upper and lower eyelids, and deformed nails (Hay and Wells 1976; Macias et al. 2006). Therefore, a diagnosis of Hay-Wells syndrome is largely based upon the physical clinical presentation of the patient (Hay and Wells 1976).

See also[edit]

References[edit]

  1. ^ Online 'Mendelian Inheritance in Man' (OMIM) 106260
  2. ^ James, William; Berger, Timothy; Elston, Dirk (2005). Andrews' Diseases of the Skin: Clinical Dermatology. (10th ed.). Saunders. ISBN 0-7216-2921-0.
  3. ^ a b Mcgrath, Ja; Duijf, Ph; Doetsch, V; Irvine, Ad; De Waal, R; Vanmolkot, Kr; Wessagowit, V; Kelly, A; Atherton, Dj; Griffiths, Wa; Orlow, Sj; Van Haeringen, A; Ausems, Mg; Yang, A; Mckeon, F; Bamshad, Ma; Brunner, Hg; Hamel, Bc; Van Bokhoven, H (February 2001). "Hay–Wells syndrome is caused by heterozygous missense mutations in the SAM domain of p63" (Free full text). Human Molecular Genetics 10 (3): 221–229. doi:10.1093/hmg/10.3.221. ISSN 0964-6906. PMID 11159940. 
  4. ^ http://emedicine.medscape.com/article/1110595-clinical#a0217
  5. ^ Freedberg, et al. (2003). Fitzpatrick's Dermatology in General Medicine. (6th ed.). McGraw-Hill. ISBN 0-07-138076-0.
  6. ^ Julapalli MR, Scher RK, Sybert VP, Siegfried EC, Bree AF. Dermatologic findings of ankyloblepharon–ectodermal defects–cleft lip/palate (AEC) syndrome. Am J Med Genet A. 2009;149A(9):1900–6. doi:10.1002/ajmg.a.32797. PMID 19681128.
  7. ^ Motil JK, Fete TJ. Growth, nutritional, and gastrointestinal aspects of ankyloblepharon–ectodermal defect–cleft lip and/or palate (AEC) syndrome. Am J Med Genet A. 2009;149A(9):1922–5. doi:10.1002/ajmg.a.32789.
  8. ^ Koster MI, Marinari B, Payne AS, Kantaputra PN, Costanzo A, Roop DR. ΔNp63 knockdown mice: A mouse model for AEC syndrome. Am J Med Genet A. 2009;149A(9):1942–7. doi:10.1002/ajmg.a.32794. PMID 19681108.

Birnbaum, R.Y., Zvulunov, A., Hallel-Halevy, D., Cagnano, E., Finer, G., Ofir, R., Geiger, D., Silberstein, E., Feferman, Y., Birk, O.S., 2006. Seborrhea-like dermatitis with psoriasiform elements caused by a mutation in ZNF750, encoding a putative C2H2 zinc finger protein. Nature Genetics. 38: 749-751. doi: 10.1038/ng1813 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=Seborrhea-like+dermatitis+with+psoriaform+elements+caused+by+a+mutation+in+ZNF750

Brunner, H.G., Hamel, B.C., and Bokhoven, H.V., 2002. The p63 gene in EEC and other syndromes. Journal of Medical Genetics. 39: 377-381. doi: 10.1136/jmg.39.6.377 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/12070241

Clements, S.E., Techanukul, T., Holden, S.T., Mellerio, J.E., Dorkins, H., Escande, F., and McGrath, J.A., 2010. Rapp-Hodgkin and Hay-Wells ectodermal dysplasia syndromes represent a variable spectrum of the same genetic disorder. British Journal of Dermatology. 163: 624-629. doi: 10.1111/j.1365-2133.2010.09859.x http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/20491771

Chan, I., McGrath, J.A., and Kivirikko, S., 2005. Rapp-Hodgkin syndrome and the tail of p63. Clinical and Experimental Dermatology. 30: 183-186. doi: 10.1111/j.1365-2230.2004.01715.x http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/15725251

Korf, B.R., 2011. Principles of Genetics. In: Goldman L, Ausiello D, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; chap 39.

Koster, M.I. and Roop, D.R., 2004. The role of p63 in development and differentiation of the epidermis: Tanioku Kihei memorial lecture. Journal of Dermatological Sciences. 34(1): 3-9. doi: 10.1016/j.jdermsci.2003.10.003 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/14757276

Hay, R.J., Wells, R.S., 1976. The syndrome of ankyloblepharon, ectodermal defects and cleft lip and palate: An autosomal dominant condition. British Journal of Dermatology. 94: 287-289. doi: 10.1111/j.1365-2133.1976.tb04384.x http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/946410

Julapalli, M.R., Scher, R.K., Sybert, V.P., Siegfried, E.C., and Bree, A.F., 2009. Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) syndrome. American Journal of Medical Genetics. 149(A): 1900-1906. doi: 10.1002/ajmg.a.32797 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=dermatologic+findings+of+ankyloblepharon-ectodermal+defects-cleft+lip%2Fpalate

Macias, E., de Carlos, F., and Cobo, J., 2006. Hay-Wells syndrome (AEC): a case report. Oral Diseases. 12(5):506-508. doi: 10.1111/j.1601-0825.2006.01227.x http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/16910923

Motil, K.J., and Fete, T.J., 2009. Growth, nutritional, and gastrointestinal aspects of ankyloblepharon-ectodermal defect-cleft lip and/or palate (AEC) syndrome. American Journal of Medical Genetics. 149(A): 1922-1925. doi: 10.1002/ajmg.a.32789 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/19676058

Nagaveni, N. B., Umashankara, K.V., 2011. Hay-Wells syndrome of ectodermal dysplasia: A rare autosomal dominant disorder. Indian Journal of Human Genetics. 17(3): 245-246. doi: 10.4103/0971-6866.92084 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/22346004

Rinne, T., Bolat, E., Meijer, R., Scheffer, H., and van Bokhoven, H., 2009. Spectrum of p63 mutations in a selected patient cohort with ankyloblepharon-ectodermal defects-cleft lip/palate syndrome. American Journal of Medical Genetics. 149(A): 1948-1951. doi: 10.1002/ajmg.a.32793 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=Spectrum+of+p63+mutations+in+a+selected+patient+cohort+with+ankyloblepharon-ectodermal+defects-cleft+lip%2Fpalate+syndrome

Sathyamurthy, A., Freund, S., Johnson, C.M., Allen, M., and Bycroft, M., 2011. Structural basis of p63-alpha SAM domain mutants involved in AEC syndrome. Federation of European Biochemical Societies. 278: 2680-2688. doi: 10.1111/j.1742-4658.2011.08194.x http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=Structural+basis+of+p63-alpha+SAM+domain+mutants+involved+in+AEC+syndrome.

Seiberg, M., Paine, C., Sharlow, E., Andrade-Gordon, P., Costanzo, M., Eisinger, M., and Shapiro, S.S., 2000. The Protease-Activated Receptor 2 Regulates Pigmentation via Keratinocyte-Melanocyte Interactions. Experimental Cell Research. 254(1): 25-32. doi: 10.1006/excr.1999.4692 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=The+protease-activated+receptor+2+regulates+pigmentation+via+keratinocyte-melanocyte+interactions

Senoo, M., Pinto, F., Crum, C.P., McKeon, F., 2007. p63 Is essential for the proliferative potential of stem cells in stratified epithelia. Cell. 129: 523-536. doi: 10.1016/j.cell.2007.02.045 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/17482546

Van Bokhoven, H., Brunner, H.G., 2002. Splitting p63. American Journal of Human Genetics. 71: 1-13. doi: 10.1086/341450 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=splitting+p63



Yang, C.F., Hwu, W.L., Yang, L.C., Chung, W.H., Chien, Y.H., Hung, C.F., Chen, H.C., Tsai, P.J., Fann, C.S., Liao, F., and Chen, Y.T., 2008. A promoter sequence variant of ZNF750 is linked with familial psoriasis. Journal of Investigatory Dermatology. 128: 1662-1668. doi: 10.1038/jid.2008.1 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=A+promoter+sequence+variant+of+ZNF750+is+linked+with+familial+psoriasis

Zarnegar, B.J., Webster, D.E., Lopez-Pajares, V., Hunt, B., Qu, K., Yan, K., Berk, D., Sen, G., and Khavan, P., 2012. Genomic profiling of a human organotypic model of AEC syndrome reveals ZNF750 as an essential downstream target of mutant TP63. American Journal of Human Genetics. 91(3): 435-443. doi: 10.1016/j.ajhg.2012.07.007 http://www.ncbi.nlm.nih.gov.www.libproxy.wvu.edu/pubmed/?term=Genomic+profiling+of+a+human+organotypic+model+of+AEC+syndrome+reveals+ZNF750+as+an+essential+downstream+target+of+mutant+TP63.  

External links[edit]