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John A. Mcgrath - One of the best experts on this subject based on the ideXlab platform.
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Ectodermal Dysplasia: Rapp-Hodgkin Syndrome and Hay-Wells Syndrome
Reference Module in Biomedical Sciences, 2020Co-Authors: Chavalit Supsrisunjai, John A. McgrathAbstract:The group of ectodermal dysplasia (ED) disorders encompasses a diverse collection of developmental anomalies affecting skin, hair, teeth, nails, and sweat glands, often with other syndromic features. Rapp-Hodgkin Syndrome and Hay-Wells Syndrome represent two eponymous forms of ED which both result from similar mutations in TP63 , encoding the transcription factor, p63. The often overlapping phenotypes and mutations in these two conditions has led to debate as to whether they are variable expressions of the same clinicopathologic entity. Nevertheless, the clinical and molecular data collectively illustrate the importance of p63 in skin and other tissue development and homeostasis.
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Rapp-Hodgkin ectodermal dysplasia Syndrome: the clinical and molecular overlap with Hay-Wells Syndrome.
American Journal of Medical Genetics Part A, 2006Co-Authors: Peter Kannu, Ravi Savarirayan, Linda Ozoemena, Susan M. White, John A. McgrathAbstract:We report on the clinical and molecular abnormalities in a 7-month-old girl and her mother with an ectodermal dysplasia disorder that most closely resembles Rapp–Hodgkin Syndrome (RHS). At birth, the child had bilateral cleft palate, a narrow pinched nose, small chin, and hypoplastic nipples, and suffered from respiratory distress, feeding difficulties, and poor weight gain, although developmental progress was normal. Her mother had a cleft palate, sparse hair, high forehead, dental anomalies, a narrow nose, dysplastic nails, and reduced sweating. Sequencing of the p63 gene in genomic DNA from both individuals revealed a heterozygous frameshift mutation, 1721delC, in exon 14. This mutation has not been described previously and is the seventh report of a pathogenic p63 gene mutation in RHS. The frameshift results in changes to the tail of p63 with the addition of 90 missense amino acids downstream and a delayed termination codon that extends the protein by 21 amino acids. This mutation is predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is considerable overlap between the molecular pathology of RHS and Hay–Wells Syndrome, with identical mutations in some cases, and that these two disorders may in fact be synonymous. © 2006 Wiley-Liss, Inc.
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Rapp-Hodgkin Syndrome and the tail of p63.
Clinical and Experimental Dermatology, 2005Co-Authors: Ien Chan, John A. Mcgrath, S. KivirikkoAbstract:Summary We report the clinical and molecular abnormalities in a 19-year-old woman with Rapp–Hodgkin ectodermal dysplasia Syndrome. The physical features include mid-facial hypoplasia, uncombable hair, cleft palate and bifid uvula, lacrimal duct obstruction and dry skin. Sequencing of the p63 gene reveals a new heterozygous frameshift mutation, 1787delG, in exon 14. The frameshift results in changes to the tail of p63 with the addition of 68 missense amino acids downstream and a delayed termination codon that extends the protein length by 21 amino acids. These changes are predicted to disrupt the normal repressive function of the transactivation inhibitory domain leading to gain-of-function for at least two isoforms of the p63 transcription factor. The expanding p63 mutation database demonstrates that there is overlap between Rapp–Hodgkin Syndrome and several other ectodermal dysplasia Syndromes, notably Hay–Wells Syndrome, and that characterization of the functional consequences of these p63 gene mutations at a molecular and cellular level is likely to provide further insight into the clinical spectrum of these developmental malformation Syndromes.
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hay wells Syndrome is caused by heterozygous missense mutations in the sam domain of p63
Human Molecular Genetics, 2001Co-Authors: John A. Mcgrath, Pascal H G Duijf, Volker Doetsch, Alan D Irvine, Robert M W De Waal, Kaate R J Vanmolkot, Vesarat Wessagowit, Alexander E Kelly, David J Atherton, Andrew W D GriffithsAbstract:Hay-Wells Syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) Syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia Syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary Syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth Syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the p63 gene are the major cause of EEC Syndrome. Linkage studies suggest that the related LMS and ADULT Syndromes are also caused by mutations in the p63 gene. Thus, it appears that p63 gene mutations have highly pleiotropic effects. We have analysed p63 in AEC Syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC Syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC Syndromes.
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Hay–Wells Syndrome is caused by heterozygous missense mutations in the SAM domain of p63
Human Molecular Genetics, 2001Co-Authors: John A. Mcgrath, Pascal H G Duijf, Volker Doetsch, Alan D Irvine, Robert M W De Waal, Kaate R J Vanmolkot, Vesarat Wessagowit, Alexander E Kelly, David J Atherton, W Andrew D GriffithsAbstract:Hay-Wells Syndrome, also known as ankyloblepharon-ectodermal dysplasia-clefting (AEC) Syndrome (OMIM 106260), is a rare autosomal dominant disorder characterized by congenital ectodermal dysplasia, including alopecia, scalp infections, dystrophic nails, hypodontia, ankyloblepharon and cleft lip and/or cleft palate. This constellation of clinical signs is unique, but some overlap can be recognized with other ectodermal dysplasia Syndromes, for example ectrodactyly--ectodermal dysplasia--cleft lip/palate (EEC; OMIM 604292), limb--mammary Syndrome (LMS; OMIM 603543), acro-dermato-ungual-lacrimal-tooth Syndrome (ADULT; OMIM 103285) and recessive cleft lip/palate--ectodermal dysplasia (CLPED1; OMIM 225060). We have recently demonstrated that heterozygous mutations in the p63 gene are the major cause of EEC Syndrome. Linkage studies suggest that the related LMS and ADULT Syndromes are also caused by mutations in the p63 gene. Thus, it appears that p63 gene mutations have highly pleiotropic effects. We have analysed p63 in AEC Syndrome patients and identified missense mutations in eight families. All mutations give rise to amino acid substitutions in the sterile alpha motif (SAM) domain, and are predicted to affect protein--protein interactions. In contrast, the vast majority of the mutations found in EEC Syndrome are amino acid substitutions in the DNA-binding domain. Thus, a clear genotype--phenotype correlation can be recognized for EEC and AEC Syndromes.
Laura D Attardi - One of the best experts on this subject based on the ideXlab platform.
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International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Frank Mckeon, Hans Vanbokhoven, Suzanne E. Clements, Dennis R. Roop, Caterina Missero, Vivian A. Lombillo, Edward RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome (Hay-Wells Syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia Syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC Syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC Syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC Syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related Syndromes.
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differential perp regulation by tp63 mutants provides insight into aec pathogenesis
American Journal of Medical Genetics Part A, 2009Co-Authors: Veronica G Beaudry, Navneeta Pathak, Maranke I. Koster, Laura D AttardiAbstract:Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay-Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell-cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia Syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC.
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International Research Symposium on Ankyloblepharon‐Ectodermal Defects‐Cleft Lip/Palate (AEC) Syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Frank Mckeon, Hans Vanbokhoven, Suzanne E. Clements, Dennis R. Roop, Caterina Missero, Vivian A. Lombillo, Edward A. RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome (Hay–Wells Syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia Syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC Syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC Syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC Syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related Syndromes. © 2009 Wiley-Liss, Inc.
Maranke I. Koster - One of the best experts on this subject based on the ideXlab platform.
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International Research Symposium on Ankyloblepharon-Ectodermal Defects-Cleft Lip/Palate (AEC) Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Frank Mckeon, Hans Vanbokhoven, Suzanne E. Clements, Dennis R. Roop, Caterina Missero, Vivian A. Lombillo, Edward RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome (Hay-Wells Syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia Syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC Syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC Syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC Syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related Syndromes.
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differential perp regulation by tp63 mutants provides insight into aec pathogenesis
American Journal of Medical Genetics Part A, 2009Co-Authors: Veronica G Beaudry, Navneeta Pathak, Maranke I. Koster, Laura D AttardiAbstract:Ankyloblepharon Ectodermal Dysplasia and Cleft Lip/Palate (AEC) or Hay-Wells Syndrome is an autosomal dominant disorder characterized by a variety of phenotypes in ectodermal derivatives, including severe skin erosions, ankyloblepharon, coarse and wiry hair, scalp dermatitis, and dystrophic nails. AEC is caused by mutations in the gene encoding the TP63 transcription factor, specifically in the Sterile Alpha Motif (SAM) domain. The exact mechanism, however, by which these specific TP63 mutations lead to the observed spectrum of phenotypes is unclear. Analysis of individual TP63 target genes provides a means to understand specific aspects of the phenotypes associated with AEC. PERP is a TP63 target critical for cell-cell adhesion due to its participation in desmosomal adhesion complexes. As PERP null mice display symptoms characteristic of ectodermal dysplasia Syndromes, we hypothesized that PERP dysfunction might contribute to AEC. Using luciferase reporter assays, we demonstrate here that PERP induction is in fact compromised with some, but not all, AEC-patient derived TP63 mutants. Through analysis of skin biopsies from AEC patients, we show further that a subset of these display aberrant PERP expression, suggesting the possibility that PERP dysregulation is involved in the pathogenesis of this disease. These findings demonstrate that distinct AEC TP63 mutants can differentially compromise expression of downstream targets, providing a rationale for the variable spectra of symptoms seen in AEC patients. Elucidating how specific TP63 target genes contribute to the pathogenesis of AEC will ultimately help design novel approaches to diagnose and treat AEC.
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International Research Symposium on Ankyloblepharon‐Ectodermal Defects‐Cleft Lip/Palate (AEC) Syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Mary Fete, Laura D Attardi, Maranke I. Koster, Frank Mckeon, Hans Vanbokhoven, Suzanne E. Clements, Dennis R. Roop, Caterina Missero, Vivian A. Lombillo, Edward A. RatovitskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome (Hay–Wells Syndrome, MIM #106220) is a rare autosomal dominant ectodermal dysplasia Syndrome. It is due to mutations in the TP63 gene, known to be a regulatory gene with many downstream gene targets. TP63 is important in the differentiation and proliferation of the epidermis, as well as many other processes including limb and facial development. It is also known that mutations in TP63 lead to skin erosions. These erosions, especially on the scalp, are defining features of AEC Syndrome and cause significant morbidity and mortality in these patients. It was this fact that led to the 2003 AEC Skin Erosion Workshop. That conference laid the groundwork for the International Research Symposium for AEC Syndrome held at Texas Children's Hospital in 2006. The conference brought together the largest cohort of individuals with AEC Syndrome, along with a multitude of physicians and scientists. The overarching goals were to define the clinical and pathologic findings for improved diagnostic criteria, to obtain tissue samples for further study and to define future research directions. The symposium was successful in accomplishing these aims as detailed in this conference report. Following our report, we also present 11 manuscripts within this special section that outline the collective clinical, pathologic, and mutational data from 18 individuals enrolled in the concurrent Baylor College of Medicine IRB-approved protocol: Characterization of AEC Syndrome. These collaborative findings will hopefully provide a stepping-stone to future translational projects of TP63 and TP63-related Syndromes. © 2009 Wiley-Liss, Inc.
Alanna F Bree - One of the best experts on this subject based on the ideXlab platform.
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Craniofacial and anthropometric phenotype in ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (Hay-Wells Syndrome) in a cohort of 17 patients.
American journal of medical genetics. Part A, 2020Co-Authors: V Reid Sutton, Katie Plunkett, Diane X Dang, Richard A Lewis, Alanna F Bree, Carlos A BacinoAbstract:Ankyloblepharon-ectodermal dysplasia-cleft lip/palate (AEC) Syndrome and Rapp-Hodgkin Syndrome are well-characterized clinical entities caused by mutations in the TP63 gene. While AEC and Rapp-Hodgkin had been thought to be clinically distinct entities, the elucidation of their molecular etiology confirmed that they are a clinical continuum as opposed to distinct disorders. We have evaluated 17 patients with AEC Syndrome using a systematic clinical approach. In our study, we have identified new features and others that were thought to occur only rarely. These include short stature and poor weight gain with preservation of head circumference in nearly all subjects, trismus in 35% and hypospadias in 78% of males. In addition, we describe the frequency of phenotypic features and demonstrate the extreme clinical variability in the largest cohort of AEC individuals reported in the literature thus far.
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Psychosocial functioning and quality of life in children and families affected by AEC Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Mariella M Lane, Alanna F Bree, William T Dalton, Sandra A Sherman, Danita I CzyzewskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome, also known as Hay-Wells Syndrome, is a rare genetic condition that results in abnormalities of the skin, hair, nails, and teeth and requires frequent self-management and medical care. We sought to describe the psychological adjustment and quality of life in children and adolescents with AEC Syndrome, as well as the impact of the child's illness on their families. The sample included 18 children and adolescents with AEC Syndrome and their parents who attended the International Research Symposium on AEC Syndrome. Parents completed standardized self-report questionnaires about child and family functioning and participated in a semi-structured interview about the child's cognitive and social functioning and the impact of AEC Syndrome on the child and family. Children completed standardized self-report questionnaires of psychosocial functioning and quality of life. Overall, results reflected a range of functioning across children and families, with some families reporting few ill effects of the condition and others describing reduced quality of life and negative impact on child and family. Identifying the domains that may be impacted should help clinicians better screen for problems in functioning of children affected by AEC Syndrome and their families.
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Dermatologic findings of ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome.
American journal of medical genetics. Part A, 2020Co-Authors: Meena R Julapalli, Virginia P. Sybert, Richard K Scher, Elaine C Siegfried, Alanna F BreeAbstract:Hay-Wells Syndrome, caused by mutations in the p63 gene, is an autosomal dominant ectodermal dysplasia with the main features of ankyloblepharon filiforme adnatum, ectodermal defects, and cleft lip/palate, from which the disorder's other name, AEC Syndrome, is derived. The National Foundation for Ectodermal Dysplasias convened the International Research Symposium for AEC Syndrome on November 8-10, 2006, at Texas Children's Hospital/Baylor College of Medicine, Houston, TX with appropriate IRB approval. This multidisciplinary conference was the largest gathering of such patients to date and allowed us to further characterize dermatologic features of AEC Syndrome, which included: sparse and wiry hair, nail changes, past or present scalp erosions, decreased sweat production, palmar/plantar changes, and unique pigmentary anomalies. Early recognition of the features of AEC Syndrome and subsequent early diagnosis is important in minimizing invasive diagnostic studies, improving morbidity and mortality, and providing genetic counseling. Skin erosions, especially those of the scalp, were identified as the most challenging cutaneous aspect of this Syndrome. Although the reasons for the skin erosions and poor healing are not known, mutations of p63 may lead to a diminished store of basal cells capable of replenishing the disrupted barrier. Therapeutic strategies currently under exploration include gene therapy, as well as epidermal stem cell therapy. Until then, gentle wound care and limiting further trauma seem to be the most prudent treatment modalities.
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Craniofacial and anthropometric phenotype in ankyloblepharon–ectodermal defects–cleft lip/palate Syndrome (Hay–Wells Syndrome) in a cohort of 17 patients†
American Journal of Medical Genetics Part A, 2009Co-Authors: V Reid Sutton, Katie Plunkett, Diane X Dang, Richard A Lewis, Alanna F Bree, Carlos A BacinoAbstract:Ankyloblepharon–ectodermal dysplasia–cleft lip/palate (AEC) Syndrome and Rapp–Hodgkin Syndrome are well-characterized clinical entities caused by mutations in the TP63 gene. While AEC and Rapp–Hodgkin had been thought to be clinically distinct entities, the elucidation of their molecular etiology confirmed that they are a clinical continuum as opposed to distinct disorders. We have evaluated 17 patients with AEC Syndrome using a systematic clinical approach. In our study, we have identified new features and others that were thought to occur only rarely. These include short stature and poor weight gain with preservation of head circumference in nearly all subjects, trismus in 35% and hypospadias in 78% of males. In addition, we describe the frequency of phenotypic features and demonstrate the extreme clinical variability in the largest cohort of AEC individuals reported in the literature thus far. © 2009 Wiley-Liss, Inc.
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Psychosocial functioning and quality of life in children and families affected by AEC Syndrome.
American Journal of Medical Genetics Part A, 2009Co-Authors: Mariella Lane, Alanna F Bree, William T Dalton, Sandra A Sherman, Danita I CzyzewskiAbstract:Ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome, also known as Hay–Wells Syndrome, is a rare genetic condition that results in abnormalities of the skin, hair, nails, and teeth and requires frequent self-management and medical care. We sought to describe the psychological adjustment and quality of life in children and adolescents with AEC Syndrome, as well as the impact of the child's illness on their families. The sample included 18 children and adolescents with AEC Syndrome and their parents who attended the International Research Symposium on AEC Syndrome. Parents completed standardized self-report questionnaires about child and family functioning and participated in a semi-structured interview about the child's cognitive and social functioning and the impact of AEC Syndrome on the child and family. Children completed standardized self-report questionnaires of psychosocial functioning and quality of life. Overall, results reflected a range of functioning across children and families, with some families reporting few ill effects of the condition and others describing reduced quality of life and negative impact on child and family. Identifying the domains that may be impacted should help clinicians better screen for problems in functioning of children affected by AEC Syndrome and their families. © 2009 Wiley-Liss, Inc.
Lee Zellmer - One of the best experts on this subject based on the ideXlab platform.
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Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion Syndrome: a case report.
BMC Medical Genetics, 2018Co-Authors: Maxime Cadieux-dion, Nicole P. Safina, Kendra Engleman, Carol J. Saunders, Elena Repnikova, Nikita Raje, Kristi Canty, Emily G. Farrow, Neil A. Miller, Lee ZellmerAbstract:Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (AEC or Hay-Wells Syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis. We describe a patient presenting clinical features reminiscent of AEC Syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63, IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele. To our knowledge, this is the fourth family reported with CHUK-deficiency and the second patient with immune abnormalities. This is the first case of CHUK-deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo. In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.
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Novel heterozygous pathogenic variants in CHUK in a patient with AEC-like phenotype, immune deficiencies and 1q21.1 microdeletion Syndrome: a case report
BMC Medical Genetics, 2018Co-Authors: Maxime Cadieux-dion, Nicole P. Safina, Kendra Engleman, Elena Repnikova, Nikita Raje, Kristi Canty, Carol Saunders, Emily Farrow, Neil Miller, Lee ZellmerAbstract:Background Ectodermal dysplasias (ED) are a group of diseases that affects the development or function of the teeth, hair, nails and exocrine and sebaceous glands. One type of ED, ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (AEC or Hay-Wells Syndrome), is an autosomal dominant disease characterized by the presence of skin erosions affecting the palms, soles and scalp. Other clinical manifestations include ankyloblepharon filiforme adnatum, cleft lip, cleft palate, craniofacial abnormalities and ectodermal defects such as sparse wiry hair, nail changes, dental changes, and subjective hypohydrosis. Case presentation We describe a patient presenting clinical features reminiscent of AEC Syndrome in addition to recurrent infections suggestive of immune deficiency. Genetic testing for TP63 , IRF6 and RIPK4 was negative. Microarray analysis revealed a 2 MB deletion on chromosome 1 (1q21.1q21.2). Clinical exome sequencing uncovered compound heterozygous variants in CHUK ; a maternally-inherited frameshift variant (c.1365del, p.Arg457Aspfs*6) and a de novo missense variant (c.1388C > A, p.Thr463Lys) on the paternal allele. Conclusions To our knowledge, this is the fourth family reported with CHUK -deficiency and the second patient with immune abnormalities. This is the first case of CHUK -deficiency with compound heterozygous pathogenic variants, including one variant that arose de novo . In comparison to cases found in the literature, this patient demonstrates a less severe phenotype than previously described.
