Cleft Lip and Palate in Ectodermal Dysplasia

Objective: Ectodermal dysplasia (ED) comprises multiple syndromes that affect skin, hair, nails, and teeth, and sometimes are associated with orofacial clefting. The purpose of this study is to (1) identify the prevalence and characteristics of cleft lip and/or palate (CL/P) in patients with ED and (2) describe the management and outcomes. Design: Retrospective review from 1990 to 2019. Patients: All patients with ED treated at Boston Children's Hospital. Main Outcomes Measures: Prevalence of CL/P was calculated and clinical details recorded: phenotypic anomalies, cleft type, operative treatment, and results of repair. Results: Of 170 patients with a purported diagnosis of ED, 24 (14%) had CL/P. Anatomic categories were bilateral CL/P (67%), unilateral CL/P (8%), and cleft palate only (25%). The most common ED syndrome (37%) was ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC). Pathogenic variants in TP63 were the most frequent finding in the 11 patients who had genetic testing. Aberrations from a typical clinical course included failure of presurgical dentofacial orthopedics, dehiscence of nasolabial adhesion, and total palatal absence requiring free-flap construction. Two patients had prolonged postoperative admission for respiratory infection. High fistula (8%) and velopharyngeal insufficiency (33%) rates reflected the predominance of bilateral complete forms. Conclusions: As in other types of syndromic CL/P, cleft phenotypic expression in ED is more severe than the general cleft population. Further studies are needed to correlate genotype and phenotype for the distinct syndromes included in the ED spectrum.

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Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development

10.1101/513507 ◽

2019 ◽

Author(s):

Marshall Lukacs ◽

Tia Roberts ◽

Praneet Chatuverdi ◽

Rolf W. Stottmann

Keyword(s):

Neural Crest ◽

Neural Development ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Folate Receptor ◽

Neural Crest Cell ◽

Specific Expression ◽

Hypomorphic Mutation ◽

Pathogenic Variants ◽

Cleft Lip Palate

AbstractThe glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. we identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

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CDH1 Mutation Distribution and Type Suggests Genetic Differences between the Etiology of Orofacial Clefting and Gastric Cancer

Genes ◽

10.3390/genes11040391 ◽

2020 ◽

Vol 11 (4) ◽

pp. 391

Author(s):

Arthavan Selvanathan ◽

Cheng Yee Nixon ◽

Ying Zhu ◽

Luigi Scietti ◽

Federico Forneris ◽

...

Keyword(s):

Gastric Cancer ◽

Cleft Lip ◽

Structural Characteristics ◽

Molecular Data ◽

Diffuse Gastric Cancer ◽

Pathogenic Variants ◽

Orofacial Clefting ◽

Cleft Lip Palate ◽

Cdh1 Mutation ◽

Mutation Distribution

Pathogenic variants in CDH1, encoding epithelial cadherin (E-cadherin), have been implicated in hereditary diffuse gastric cancer (HDGC), lobular breast cancer, and both syndromic and non-syndromic cleft lip/palate (CL/P). Despite the large number of CDH1 mutations described, the nature of the phenotypic consequence of such mutations is currently not able to be predicted, creating significant challenges for genetic counselling. This study collates the phenotype and molecular data for available CDH1 variants that have been classified, using the American College of Medical Genetics and Genomics criteria, as at least ‘likely pathogenic’, and correlates their molecular and structural characteristics to phenotype. We demonstrate that CDH1 variant type and location differ between HDGC and CL/P, and that there is clustering of CL/P variants within linker regions between the extracellular domains of the cadherin protein. While these differences do not provide for exact prediction of the phenotype for a given mutation, they may contribute to more accurate assessments of risk for HDGC or CL/P for individuals with specific CDH1 variants.

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Glycosylphosphatidylinositol biosynthesis and remodeling are required for neural tube closure, heart development, and cranial neural crest cell survival

eLife ◽

10.7554/elife.45248 ◽

2019 ◽

Vol 8 ◽

Cited By ~ 7

Author(s):

Marshall Lukacs ◽

Tia Roberts ◽

Praneet Chatuverdi ◽

Rolf W Stottmann

Keyword(s):

Neural Crest ◽

Heart Development ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Neural Crest Cell ◽

Neural Tube Closure ◽

Specific Expression ◽

Pathogenic Variants ◽

Median Cleft ◽

Cleft Lip Palate

Glycosylphosphatidylinositol (GPI) anchors attach nearly 150 proteins to the cell membrane. Patients with pathogenic variants in GPI biosynthesis genes develop diverse phenotypes including seizures, dysmorphic facial features and cleft palate through an unknown mechanism. We identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypo-morphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2), a component of the GPI biosynthesis pathway. The Clpex mutation decreases surface GPI expression. Surprisingly, Pgap2 showed tissue-specific expression with enrichment in the brain and face. We found the Clpex phenotype is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium. We showed folinic acid supplementation in utero can partially rescue the cleft lip phenotype. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency. These mutants developed median cleft lip and palate demonstrating a previously undocumented cell autonomous role for GPI biosynthesis in NCC development.

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Cleft Lip and Palate in CHARGE Syndrome

The Cleft Palate-Craniofacial Journal ◽

10.1177/1055665617738994 ◽

2017 ◽

Vol 55 (3) ◽

pp. 342-347 ◽

Cited By ~ 3

Author(s):

Kathryn V. Isaac ◽

Ingrid M. Ganske ◽

Stephen A. Rottgers ◽

So Young Lim ◽

John B. Mulliken

Keyword(s):

Hearing Loss ◽

Cleft Palate ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Choanal Atresia ◽

Semicircular Canals ◽

Charge Syndrome ◽

Velopharyngeal Insufficiency ◽

Feeding Difficulties ◽

Dentofacial Orthopedics

Objective: Infants with syndromic cleft lip and/or cleft palate (CL/P) often require more complex care than their nonsyndromic counterparts. Our purpose was to (1) determine the prevalence of CL/P in patients with CHARGE syndrome and (2) highlight factors that affect management in this subset of children. Design: This is a retrospective review from 1998 to 2016. Patients: Patients with CHARGE syndrome were diagnosed clinically and genetically. Main Outcomes Measures: Prevalence of CL/P was determined and clinical details tabulated: phenotypic anomalies, cleft types, operative treatment, and results of repair. Results: CHARGE syndrome was confirmed in 44 patients: 11 (25%) had cleft lip and palate and 1 had cleft palate only. Surgical treatment followed our usual protocols. Two patients with cardiac anomalies had prolonged recovery following surgical correction, necessitating palatal closure prior to nasolabial repair. One of these patients was too old for dentofacial orthopedics and underwent combined premaxillary setback and palatoplasty, prior to labial closure. Velopharyngeal insufficiency was frequent (n = 3/7). All patients had feeding difficulty and required a gastrostomy tube. All patients had neurosensory hearing loss; anomalies of the semicircular canals were frequent (n = 3/4). External auricular anomalies, colobomas, and cardiovascular anomalies were also common (n = 8/11). Other associated anomalies were choanal atresia (n = 4/11) and tracheoesophageal fistula (n = 2/11). Conclusions: CHARGE syndrome is an under-recognized genetic cause of cleft lip and palate. Hearing loss and speech and feeding difficulties often occur in these infants. Diagnosis can be delayed if the child presents with covert phenotypic features, such as chorioretinal colobomas, semicircular canal hypoplasia, and unilateral choanal atresia.

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Isoform-Specific Roles of Mutant p63 in Human Diseases

Cancers ◽

10.3390/cancers13030536 ◽

2021 ◽

Vol 13 (3) ◽

pp. 536

Author(s):

Christian Osterburg ◽

Susanne Osterburg ◽

Huiqing Zhou ◽

Caterina Missero ◽

Volker Dötsch

Keyword(s):

Cleft Lip ◽

Ectodermal Dysplasia ◽

Skin Development ◽

Disease Mechanisms ◽

Skin Fragility ◽

Cleft Lip Palate ◽

Life Threatening ◽

Functional Consequences ◽

Development And Differentiation

The p63 gene encodes a master regulator of epidermal commitment, development, and differentiation. Heterozygous mutations in the DNA binding domain cause Ectrodactyly, Ectodermal Dysplasia, characterized by limb deformation, cleft lip/palate, and ectodermal dysplasia while mutations in in the C-terminal domain of the α-isoform cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by skin fragility, severe, long-lasting skin erosions, and cleft lip/palate. The molecular disease mechanisms of these syndromes have recently become elucidated and have enhanced our understanding of the role of p63 in epidermal development. Here we review the molecular cause and functional consequences of these p63-mutations for skin development and discuss the consequences of p63 mutations for female fertility.

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Alveolar cleft and maximum cleft width as predictors for difficult laryngoscopy and intubation in patients with unilateral complete cleft lip and palate

Ain-Shams Journal of Anesthesiology ◽

10.1186/s42077-021-00137-7 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Gamal A. Abdelhameed ◽

Wael A. Ghanem ◽

Simon H. Armanios ◽

Tamer Nabil Abdelrahman

Keyword(s):

Body Weight ◽

Odds Ratio ◽

Cleft Lip ◽

Cleft Lip And Palate ◽

Difficult Laryngoscopy ◽

Secondary Outcome ◽

Pediatric Airway ◽

Alveolar Cleft ◽

Cleft Lip Palate ◽

Width Measurements

Abstract Background Cleft lip and palate is one of the commonest congenital anomalies, which have an impact on feeding, speech, and dental development away from the significant psychosocial sequel. Early surgical repair aims to restore appearance and function, and the modern techniques can leave many defects undetectable. Therefore, the anesthetic challenge facing the pediatric airway with such abnormalities is still of a great impact. The aim of our study among 189 patients enrolled is to correlate alveolar gap and maximum cleft width measurements as predictors of difficult laryngoscopy and intubation in infants with unilateral complete cleft lip/palate aging from 1 to 6 months. As a secondary outcome, their weight is to be correlated too as another parameter. Results The alveolar gap and maximum cleft width are both of equal high predictive power (p value ≤ 0.001) with 100% sensitivity for both and specificity of 76.10% and 82.39% respectively, with a cut off value of ≤ 10 mm and 11 mm for these dimensions respectively, and odds ratio of incidence of difficult intubation is 4.18 and 5.68 respectively, while body weight ≤ 5.75 kg has an odds ratio of 2.32. Conclusion Alveolar cleft and maximum cleft width can be used as predictors for anticipation of difficult laryngoscopy and intubation infant patients with unilateral complete cleft lip and palate, while body weight ≤ 5.75 kg increases the risk more than twice.

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The syndrome of ectrodactyly, ectodermal dysplasia and cleft lip and palate: report of a family demonstrating a dominant inheritance pattern

Clinical Genetics ◽

10.1111/j.1399-0004.1972.tb01461.x ◽

2008 ◽

Vol 3 (5) ◽

pp. 295-302 ◽

Cited By ~ 35

Author(s):

C. B. Brill ◽

L. Y. F. Hsu ◽

K. Hirschhorn

Keyword(s):

Cleft Lip ◽

Cleft Lip And Palate ◽

Ectodermal Dysplasia ◽

Inheritance Pattern ◽

Dominant Inheritance

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How is the face formed and when it goes wrong: In relation to Cleft Lip/Palate

Manchester Medical Journal ◽

10.7227//mmj.0035 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Fozia Khan

Keyword(s):

Cleft Lip ◽

Normal Development ◽

Cleft Lip And Palate ◽

Complex Structure ◽

First Trimester ◽

Facial Defect ◽

Facial Defects ◽

The Face ◽

Embryonic Life ◽

Cleft Lip Palate

The normal development of the face relies upon the correct morphogenesis of structures in utero that usually occurs within the first trimester of embryonic life. The face is a very complex structure involving many genes and factors and with it being such a crucial part of life, both physically and aesthetically and therefore mentally, its important for everything to be just right. However, when the normal process doesn’t go to plan this results in dysmorphogenesis, which cleft lip and palate (CLP) is an example of as the lip/palate doesn’t fuse together and the infant is left with a gap. Although the exact cause of CLP is unknown, it is thought to be a mixture of genetics, environment and the teratogens the mothers are exposed to within the environment. This report will demonstrate the normal development of the face for the purpose of understanding how it goes wrong, resulting in CLP. Since there is still a lot to be understood about CLP it will also shed light on recent advances in relating SHH and certain genes as a possible cause for this dysmorphogenesis. The report will also briefly look at the relation of CLP with the genes associated with syndromic and non-syndromic diseases and the different types of CLP. There are many other facial defects that are a result of dysmorphogenesis, however as CLP is one of the most common yet poorly understood facial defect, it will be the main focus of this report.

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