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Alanna F Bree - One of the best experts on this subject based on the ideXlab platform.
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pathologic changes of skin and hair in ankyloblepharon ectodermal defects cleft lip palate AEC Syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Megan K Dishop, Alanna F Bree, John M HicksAbstract:Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) Syndrome is a rare disorder of hair, skin, nails, and dentition caused by mutations in the p63 gene. Pathologic changes of skin and hair in AEC Syndrome have previously been described in isolated case reports. Biopsies of normal and lesional skin from 19 patients with AEC Syndrome were examined by light microscopy. Hair samples from 18 patients were examined by light and scanning electron microscopy. Histopathologic changes identified within the skin biopsies from clinically unaffected skin include mild atrophy, focal orthokeratosis, and mild superficial perivascular lymphocytic dermatitis. Scattered melanophages in the superficial and deep dermis likely reflect post-inflammatory change. One patient with a unilateral eruption of monomorphic papulopustules on the chest and shoulder demonstrated an acneiform intraepidermal pustule. Examination of the hair shafts revealed atrophy and loss of melanin pigment in some of the patients. Structural abnormalities included pili torti, pili trianguli et canaliculi, and irregular indentation and shallow grooves. Skin and hair findings in AEC Syndrome were found to be generally similar to those described in other ectodermal dysplasia Syndromes and corroborates the few prior descriptions in AEC Syndrome specifically.
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dermatologic findings of ankyloblepharon ectodermal defects cleft lip palate AEC Syndrome
American Journal of Medical Genetics Part A, 2009Co-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 anomolies. 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. © 2009 Wiley-Liss, Inc.
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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: Reid V Sutton, Alanna F Bree, Katie Plunkett, Diane X Dang, Richard A Lewis, 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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clinical lessons learned from the international research symposium on ankyloblepharon ectodermal defects cleft lip palate AEC Syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Alanna F BreeAbstract:The International Research Symposium on ankyloblepharon-ectodermal defects-cleft lip/palate (AEC) Syndrome, that was supported by the National Foundation for Ectodermal Dysplasias (NFED) through a grant from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) and the National Institutes of Health Office of Rare Diseases (NIH-ORD), brought together physicians, scientists, and 23 individuals affected by AEC Syndrome from 13 families. Eighteen of the AEC-affected individuals were enrolled in an IRB-approved protocol through Baylor College of Medicine. Enrolled participants had clinical evaluations by multiple subspecialists, and additionally submitted blood for mutational analysis and skin specimens for pathologic evaluation. One of the goals of the conference was to define clinical and pathologic findings for improved diagnostic criteria, with the hope of determining genotype–phenotype correlations that might aid in predicting prognosis or directing therapeutics. What we found was wide interfamilial and intrafamilial variability in the manifestations of the Syndrome. We were unable to identify any specific genotype–phenotype correlations. This may relate to our small sample size or other unknown epigenetic factors that are also at play in the expression and manifestation of the Syndrome in specific individuals. © 2009 Wiley-Liss, Inc.
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facial clefting and oroauditory pathway manifestations in ankyloblepharon ectodermal defects cleft lip palate AEC Syndrome
American Journal of Medical Genetics Part A, 2009Co-Authors: Patrick Cole, Alanna F Bree, Daniel A Hatef, Yoav Kaufman, Amy Magruder, Ellen M Friedman, Raj Sindwani, Larry H HollierAbstract:Ankyloblepharon–ectodermal defects-cleft lip/palate (AEC) Syndrome is a rare disorder characterized by ectodermal dysplasia, along with other malformations such as cleft lip and palate, and various secondary issues such as chronic sinusitis, otitis media, and conductive hearing loss (CHL). The International Research Symposium for AEC Syndrome convened at Baylor College of Medicine in Houston, Texas. Patients with a suspected diagnosis of AEC Syndrome attended, and members of the dental, dermatology, plastic surgery, otolaryngology, and audiology services examined each patient. Eighteen patients with a diagnosis of AEC were evaluated. Mean age was 7.5 years (range: 4 months–30 years). Fourteen of the 15 subjects tested (93.33%) demonstrated CHL, with seven showing moderate to severe hearing deficits (41–90 dB). Nine of 13 respondents reported hoareness or voice problems; 8 were noted to display this on examination. Fourteen of 16 subjects reported speech was below average for age; 8 were in speech therapy. All 18 subjects reported a history of otitis externa or otitis media. Eleven of the subjects (61.11%) required myringotomy and pressure equalizing (PE) tubes. All patients demonstrated cleft palate defects. Of these, 16 (94.11%) presented with clefting of the soft palate, and 10 (58.82%) showed hard palate defects. Three subjects (16.67%) were noted to have submucous clefts. Our experience leads us to propose that while the oroauditory problems in those with AEC Syndrome is likely multifactorial, many issues may stem from palatal clefting. Despite this, some abnormalities persist following surgical cleft closure, which indicates other complicating factors are also involved. © 2009 Wiley-Liss, Inc.
Edward A. Ratovitski - 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, 2009Co-Authors: Mary Fete, Hans Vanbokhoven, Suzanne E Clements, Frank Mckeon, Dennis R Roop, Maranke I Koster, Caterina Missero, Laura D Attardi, 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.
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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, Hans Vanbokhoven, Suzanne E Clements, Frank Mckeon, Dennis R Roop, Maranke I Koster, Caterina Missero, Laura D Attardi, 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.
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AEC associated p63 mutations lead to alternative splicing protein stabilization of p63 and modulation of notch signaling
Cell Cycle, 2005Co-Authors: Yi-ping Huang, Alexey Fomenkov, Zhaobo Li, Tanya Fomenkov, Edward A. RatovitskiAbstract:P63, the major regulator of epithelial development/differentiation, is mutated in humanectodermal dysplasias, such as ankyloblepharon, ectodermal dysplasia and clefting (AEC). Werecently identified that p63? physically associated with mRNA processing/splicing proteins. Wepreviously showed that p63 mutations mapped to the sterile ?-motif led to disruption of theseinteractions and modulated an aberrant splicing of keratinocyte growth factor receptorcontributing into molecular mechanism underlying AEC phenotype.To further investigate the molecular mechanisms associated with AEC Syndrome weestablished the cellular model for this disorder by stable introduction of mutated allele [L514F]of p63? into immortalized keratinocyte cells. We showed that mutated ?Np63? mediated anaberrant splicing of its own p63 mRNA transcript, which in turn led to accumulation ofproteasome-resistant C- terminal truncated p63. The truncated p63 failed to associate with theC-terminal domain of RNA polymerase II through SRA4 protein and...
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p63α Mutations Lead to Aberrant Splicing of Keratinocyte Growth Factor Receptor in the Hay-Wells Syndrome
Journal of Biological Chemistry, 2003Co-Authors: Alexey Fomenkov, Ozlem Topaloglu, Anna Brechman, Motonobo Osada, Tanya Fomenkova, Eugene Yuriditsky, Barry Trink, Yi-ping Huang, David Sidransky, Edward A. RatovitskiAbstract:Abstract p63, a p53 family member, is required for craniofacial and limb development as well as proper skin differentiation. However, p63 mutations associated with the ankyloblepharon-ectodermal dysplasia-clefting (AEC) Syndrome (Hay-Wells Syndrome) were found in the p63 carboxyl-terminal region with a sterile α-motif. By two-hybrid screen we identified several proteins that interact with the p63α carboxyl terminus and its sterile α-motif, including the apobec-1-binding protein-1 (ABBP1). AEC-associated mutations completely abolished the physical interaction between ABBP1 and p63α. Moreover the physical association of p63α and ABBP1 led to a specific shift of FGFR-2 alternative splicing toward the K-SAM isoform essential for epithelial differentiation. We thus propose that a p63α-ABBP1 complex differentially regulates FGFR-2 expression by supporting alternative splicing of the K-SAM isoform of FGFR-2. The inability of mutated p63α to support this splicing likely leads to the inhibition of epithelial differentiation and, in turn, accounts for the AEC phenotype.
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, Nataliya P. Safina, Kendra Engleman, Elena Repnikova, Nikita Raje, Kristi Canty, Emily G. Farrow, Carol J. Saunders, 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, Nataliya 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.
Hans Van Bokhoven - One of the best experts on this subject based on the ideXlab platform.
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spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon ectodermal defects cleft lip palate Syndrome AEC
American Journal of Medical Genetics Part A, 2009Co-Authors: Tuula Rinne, Emine Bolat, Rowdy Meijer, H Scheffer, Hans Van BokhovenAbstract:Heterozygous mutations in the p63 gene underlie a group of at least seven allelic Syndromes, including ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (AEC) and Rapp Hodgkin Syndrome (RHS), which involves varying degrees of ectodermal dysplasia, orofacial clefting and limb malformations. Mutations in the AEC and Rapp Hodgkin Syndromes cluster in the 3' end of the p63 gene. Previously reported mutations are mainly missense and frameshift mutations in exons 13 and 14, affecting the p63alpha-specific SAM (sterile alpha motif) and TI (transactivation inhibitory) domains. A patient cohort affected by AEC Syndrome was evaluated during International Research Symposium supported by the National Foundation for Ectodermal Dysplasias. Nineteen patients underwent full clinical evaluations and 18 had findings consistent with a diagnosis of AEC Syndrome. These 19 patients, along with 5 additional relatives had genomic DNA analysis. Twenty-one of the 24 participants from 12 families were found to have mutations in the p63 gene. Eleven different mutations were identified; 10 were novel mutations. Eight were missense mutations within the coding region of the SAM domain. Three other mutations were located in exon 14 sequences, which encode the TI domain. The effects of the mutations in the SAM and TI domains are poorly understood and functional studies are required to understand the pathological mechanisms. However, AEC and RHS mutations in the 5' and 3' ends of the p63 gene point towards a critical role of the DeltaNp63alpha isoform for the AEC/RHS phenotype.
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Spectrum of p63 mutations in a selected patient cohort affected with ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (AEC).
American Journal of Medical Genetics Part A, 2009Co-Authors: Tuula Rinne, Emine Bolat, Rowdy Meijer, H Scheffer, Hans Van BokhovenAbstract:Heterozygous mutations in the p63 gene underlie a group of at least seven allelic Syndromes, including ankyloblepharon-ectodermal defects-cleft lip/palate Syndrome (AEC) and Rapp Hodgkin Syndrome (RHS), which involves varying degrees of ectodermal dysplasia, orofacial clefting and limb malformations. Mutations in the AEC and Rapp Hodgkin Syndromes cluster in the 3' end of the p63 gene. Previously reported mutations are mainly missense and frameshift mutations in exons 13 and 14, affecting the p63alpha-specific SAM (sterile alpha motif) and TI (transactivation inhibitory) domains. A patient cohort affected by AEC Syndrome was evaluated during International Research Symposium supported by the National Foundation for Ectodermal Dysplasias. Nineteen patients underwent full clinical evaluations and 18 had findings consistent with a diagnosis of AEC Syndrome. These 19 patients, along with 5 additional relatives had genomic DNA analysis. Twenty-one of the 24 participants from 12 families were found to have mutations in the p63 gene. Eleven different mutations were identified; 10 were novel mutations. Eight were missense mutations within the coding region of the SAM domain. Three other mutations were located in exon 14 sequences, which encode the TI domain. The effects of the mutations in the SAM and TI domains are poorly understood and functional studies are required to understand the pathological mechanisms. However, AEC and RHS mutations in the 5' and 3' ends of the p63 gene point towards a critical role of the DeltaNp63alpha isoform for the AEC/RHS phenotype.
Maxime Cadieux-dion - 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, Nataliya P. Safina, Kendra Engleman, Elena Repnikova, Nikita Raje, Kristi Canty, Emily G. Farrow, Carol J. Saunders, 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, Nataliya 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.