Hay–Wells syndrome
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Hay–Wells syndrome (also known as AEC syndrome; see ''
Naming Naming is assigning a name to something. Naming may refer to: * Naming (parliamentary procedure), a procedure in certain parliamentary bodies * Naming ceremony, an event at which an infant is named * Product naming, the discipline of deciding wha ...
'') is one of at least 150 known types of
ectodermal dysplasia Ectodermal dysplasia (ED) is a group of genetic syndromes all deriving from abnormalities of the ectodermal structures.James, William; Berger, Timothy; Elston, Dirk (2005). ''Andrews' Diseases of the Skin: Clinical Dermatology''. (10th ed.). Sau ...
. These disorders affect tissues that arise from the
ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from t ...
al
germ layer A germ layer is a primary layer of cells that forms during embryonic development. The three germ layers in vertebrates are particularly pronounced; however, all eumetazoans (animals that are sister taxa to the sponges) produce two or three pr ...
, such as skin, hair, and nails.


Genetics

Hay–Wells syndrome is
autosomal An autosome is any chromosome that is not a sex chromosome. The members of an autosome pair in a diploid cell have the same morphology, unlike those in allosome, allosomal (sex chromosome) pairs, which may have different structures. The DNA in au ...
dominant, caused by a
missense mutation In genetics, a missense mutation is a point mutation in which a single nucleotide change results in a codon that codes for a different amino acid. It is a type of nonsynonymous substitution. Substitution of protein from DNA mutations Missense m ...
in the
Sterile alpha motif In molecular biology, the protein domain Sterile alpha motif (or SAM) is a putative protein interaction module present in a wide variety of proteins involved in many biological processes. The SAM domain that spreads over around 70 residues is fo ...
(SAM) of the ''
TP73L Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the ''TP63'' (also known as the '' p63'') gene. The ''TP63'' gene was discovered 20 years after the discove ...
'' (p63)
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
which encodes for a protein-protein interaction domain. It is a very rare disorder. Hay–Wells syndrome is an autosomal dominant pattern of inheritance. 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. Specifically, mutations within the Tumor Protein 63 gene have been implicated in Hay–Wells syndrome. Residing on the long-arm of chromosome 3, the Tumor Protein 63 (TP63) gene is critical for proper development and homeostasis of stratified epithelia. 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. Although 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.


Proteomics

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. 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. 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. 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. Most notably, Hay-Wells-type p63 mutations cause irregular repression of 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.


Phenotype

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. 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.


Diagnosis

In HWS, the hair is coarse and sparse,
eyelash An eyelash (also called lash) (Latin: ''Cilia'') is one of the hairs that grows at the edge of the eyelids. It grows in one layer on the edge of the upper and lower eyelids. Eyelashes protect the eye from debris, dust, and small particles and p ...
es 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 Hypohidrosis is a disorder in which a person exhibits diminished sweating in response to appropriate stimuli. In contrast with hyp''er''hidrosis, which is a socially troubling yet often benign condition, the consequences of untreated hypohidrosi ...
. Chronic inflammatory dermatitis of the
scalp The scalp is the anatomical area bordered by the human face at the front, and by the neck at the sides and back. Structure The scalp is usually described as having five layers, which can conveniently be remembered as a mnemonic: * S: The ski ...
is a common symptom. Two features differentiate HWS from other ectodermal displasias. First, the syndrome is associated with
cleft palate A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
, and, less often,
cleft lip A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
. Second, the edges of the upper and lower
eyelid An eyelid is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. The human eyel ...
grow bands of fibrous tissue, often causing them to be fused together. This condition in the eyelids is called ''
ankyloblepharon filiforme adnatum Ankyloblepharon is defined as the adhesion of the edges of the upper eyelid with the lower eyelid. Ankyloblepharon must be differentiated from blepharophimosis, in which palpebral aperture is reduced and there is telecanthus, but the eyelid margins ...
''.


Management


Etymology

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", "ankyloblepharon–ectodermal defects–cleft lip/palate (AEC) syndrome", "ankyloblepharon–ectodermal defect–cleft lip and/or palate syndrome", or "ankyloblepharon ectodermal dysplasia and clefting". Hay–Wells syndrome, or Ankyloblepharon-Ectodermal Dysplasia-Clefting (AEC) syndrome, is one of the least known form of ectodermal dysplasia; a collection of inherited diseases that cause atypical development of nails, glands, teeth, and hair. Fewer than 100 affected individuals have been described in the medical literature. Males and females are equally affected by Hay–Wells syndrome. No demographic has been shown to be especially susceptible to the syndrome. Symptoms are apparent at birth, or become apparent when atypical development of teeth occurs. 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. Therefore, a diagnosis of Hay–Wells syndrome is largely based upon the physical clinical presentation of the patient.


See also

*
TP73L Tumor protein p63, typically referred to as p63, also known as transformation-related protein 63 is a protein that in humans is encoded by the ''TP63'' (also known as the '' p63'') gene. The ''TP63'' gene was discovered 20 years after the discove ...
*
List of cutaneous conditions Many skin conditions affect the human integumentary system—the organ system covering the entire surface of the body and composed of skin, hair, nails, and related muscle and glands. The major function of this system is as a barrier against t ...
*
List of dental abnormalities associated with cutaneous conditions Many conditions of or affecting the human integumentary system have associated abnormalities of the teeth. See also * List of cutaneous conditions * List of contact allergens * List of cutaneous conditions associated with internal malignan ...


References


Further reading

* * *
GeneReviews/NCBI/NIH/UW entry on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate Syndrome or AEC Syndrome, Hay-Wells Syndrome. Includes: Rapp–Hodgkin Syndrome
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External links


OMIM entries on AEC
{{DEFAULTSORT:Hay-Wells syndrome Genodermatoses Rare syndromes Autosomal dominant disorders Syndromes affecting the skin