Impact of anatomical abnormalities on velopharyngeal insufficiency in patients with submucous cleft palate.

BACKGROUND: Submucous cleft palate (SMCP) is a congenital anomaly characterized by the presence of Calnan's triad. However, in clinical practice, it is common for individuals to exhibit one or two anatomical abnormalities within the triad. Furthermore, the definition of SMCP has been diverse and ambiguous in literature. Therefore, this study aimed to analyze the correlation between anatomical abnormalities and development of velopharyngeal insufficiency (VPI). METHODS: We conducted a retrospective analysis of 99 patients referred to our clinic for speech issues or anatomical abnormalities identified during routine oral examinations from January 2012 to June 2023. A single surgeon performed all physical examinations. We evaluated the presence of bony notch, zona pellucida, and bifid uvula, assigned a score to each abnormality, and analyzed their correlation with VPI. The correlation of each of the abnormalities with VPI development was examined, along with the relationship between the number of abnormalities and VPI. RESULTS: Among the 99 patients, 27 were diagnosed with VPI. Only the bony notch had a significant correlation with VPI development. The incidence of VPI tended to increase with the presence of more anatomical abnormalities. VPI occurred in approximately 40% of patients exhibiting all three anatomical abnormalities. CONCLUSION: The study findings highlight the importance of meticulous intraoral examinations in patients with SMCP and careful monitoring of patients with a bony notch or two or more anatomical abnormalities.

Panhypopituitarism and bifid uvula / Journal of the ASEAN Federation of Endocrine Societies

@#A 20-year-old male was referred to the Endocrinology Clinic in view of abnormal thyroid function test result and poor development of secondary sexual characteristics. He was born out of non-consanguineous marriage and had a history of breech delivery at term. He had perinatal complications in the form of delayed cry and lower respiratory tract infection. Developmental delay was also present (delayed motor, speech and social milestones). His scholastic performance was below average and he reported being the shortest child in class from kindergarten.

Loeys-Dietz syndrome: Case report and review of the literature.

Loeyz-Dietz syndrome (LDS) is a genetic connective tissue disorder characterized by various clinical manifestations, most notably vasculopathies and skeletal abnormalities. The disease is rare, and has multiple overlapping features with other connective tissue disorders. As such, many radiologists remain unfamiliar with the imaging and clinical findings in LDS. Here, we describe the case of a 14-year-old male without previous diagnosis of LDS who presented with aortic root aneurysm and acute type A aortic dissection. Further workup revealed numerous abnormalities, including marked tortuosity of the cervical arterial system, a bifid uvula, hypertelorism, and a superior mesenteric artery aneurysm. Genetic testing ultimately revealed a mutation in Transforming Growth Factor Beta Receptor 1.

Loeys-Dietz Syndrome.

Loeys-Dietz syndrome is an autosomal dominant aortic aneurysm syndrome characterized by multisystemic involvement. The most typical clinical triad includes hypertelorism, bifid uvula or cleft palate and aortic aneurysm with tortuosity. Natural history is significant for aortic dissection at smaller aortic diameter and arterial aneurysms throughout the arterial tree. The genetic cause is heterogeneous and includes mutations in genes encoding for components of the transforming growth factor beta (TGFß) signalling pathway: TGFBR1, TGFBR2, SMAD2, SMAD3, TGFB2 and TGFB3. Despite the loss of function nature of these mutations, the patient-derived aortic tissues show evidence of increased (rather than decreased) TGFß signalling. These insights offer new options for therapeutic interventions.

Incidence of Symptomatic Submucous Cleft Palate in the Netherlands: A Retrospective Cohort Study Over a Period of 22 Years.

OBJECTIVE: To analyze the incidence of submucous cleft palate (SMCP) in a large national database and raise awareness among referring providers: pediatricians, speech pathologists, and dentists to minimize delay in diagnosis. DESIGN: Retrospective cohort study. SETTING: Tertiary setting. PATIENTS: Patients were extracted from the "Dutch Association for Cleft and Craniofacial Anomalies" database. A total of 6916 patients were included from 1997 until 2018 and divided into 2 groups (ie, SMCP versus cleft palate [CP]). Patients born before 1997 and adopted patients were excluded. INTERVENTIONS: Clefts were classified as either hard of soft palatal involvement based on anatomical landmarks at first consultation. MAIN OUTCOME MEASURES: Primary outcomes were the patient characteristics in both groups (ie, gender, birth weight, gestational age, and additional anomalies). Secondary outcome was the time of diagnosis among subgroups. RESULTS: In total, 532 patients were diagnosed with SMCP (7.7%). Birth weight, gestational age, and additional anomalies did not differ between subgroups, but there were more males in the SMCP group (P < .001). The median age of diagnosis of the SMCP group was significantly higher than of the CP group (987 vs 27 days; P < .001). Over the course of 22 years, the time of diagnosis for SMCP did not decrease. CONCLUSION: Submucous cleft palate represents <10% of the Dutch cleft population and 19.4% of all CP. Time of diagnosis for SMCP is significantly longer when compared with time of diagnosis of CP, and this has not changed over the study period of 22 years.

Prevalence of bifid uvula in primary school children.

BACKGROUND: A bifid uvula is an anatomic variation that can be predictive of sub-mucous cleft palate, which may cause velopharyngeal insufficiency (VPI). Bifid uvula prevalence in the literature ranges from 0.18% to 10.3%, depending on the population studied. The aim of this study is to determine the prevalence of bifid uvula in the Geneva's school children population. METHODS: A cross-sectional study was conducted in Geneva's primary school children, from September 2014 to June 2015. An examination of the uvula was performed by dentists working for the Scholastic Dental Service, after a specific training in diagnosing bifid uvulas. The dentists recorded their findings on a standardized form. RESULTS: The total number of school children in Geneva in the school year 2014-2015 was 30,375. 23,961 children had their uvula examined, representing 79% of the total population of school children. Among them, a hundred school children had a cleft uvula. One schoolgirl had no uvula. The prevalence of bifid uvula is 0.42%. Sex ratio (M/F) is 0.96. DISCUSSION: This large study, the second in literature for number of patients examined, identified a prevalence of bifid uvula of 0.42%. This result is in agreement with previous studies.

Incidence of bifid uvula and its relationship to submucous cleft palate and a family history of oral cleft in the Brazilian population / Incidence of bifid uvula and its relationship to submucous cleft palate and a family history of oral cleft in the Brazilian population

Abstract Introduction: Bifid uvula is a frequently observed anomaly in the general population and can be regarded as a marker for submucous cleft palate. Objective: In this study aimed to determine the frequency of bifid uvula and submucous cleft palate and their relationship with oral clefts in a Brazilian population. Methods: We conducted a transversal, descriptive and quantitative study of 1206 children between August 2014 and December 2015. A clinical examination of the children was conducted by means of inspection of the oral cavity with the aid of a tongue depressor and directed light. After the clinical examination in children, parents answered a questionnaire with questions about basic demographic information and their family history of oral clefts in their first-degree relatives. After application of the questionnaires, the information collected was archived in a database and analyzed by the statistical program SPSS® version 19.0, by applying Chi-Square tests. Values with p < 0.05 were considered statistically significant. Results: Of the 1206 children included in this study, 608 (50.40%) were female and 598 (49.60%) were male (p = 0.773). The average age of children was 3.75 years (standard deviation ± 3.78 years). Of the 1206 children studied, 6 (0.5%) presented with bifid uvula. Submucosal cleft palate was not found in any child. When the family histories of children were examined for the presence of nonsyndromic cleft lip and/or cleft palate, no first degree relatives presented with the congenital anomaly. Conclusion: This study revealed that the incidence of bifid uvula and submucous cleft palate in this population was quite similar to previously reported incidence rates. Our study suggests an intensification of new reviews, with broader and diverse populations, seeking to associate the occurrence of bifid uvula, submucous cleft palate and oral clefts.

Resumo: Introdução: A úvula bífida é uma anomalia frequentemente observada na população em geral e pode ser considerada como um marcador de fissura palatina submucosa. Objetivo: Determinar a frequência de úvula bífida e fissura palatina submucosa e sua relação com fissura orais em uma população brasileira. Método: Realizamos um estudo transversal, descritivo e quantitativo de 1.206 crianças entre agosto de 2014 e dezembro de 2015. O exame clínico das crianças foi realizado por meio da inspeção da cavidade oral com auxílio de um abaixador de língua e luz direcionada. Após o exame clínico nas crianças, os pais responderam a um questionário com perguntas sobre informações demográficas básicas e antecedentes de fendas orais em familiares de primeiro grau. As informações coletadas foram arquivadas em um banco de dados e analisadas pelo programa estatístico SPSS® versão 19.0, aplicando testes de Qui-Quadrado. Os valores com p < 0,05 foram considerados estatisticamente significativos. Resultados: Das 1.206 crianças incluídas neste estudo, 608 (50,40%) eram do gênero feminino e 598 (49,60%) do masculino (p = 0,773). A idade média das crianças foi de 3,75 anos (desvio-padrão ± 3,78 anos). Das 1.206 crianças estudadas, seis (0,5%) apresentavam úvula bífida. A fissura palatina submucosa não foi encontrada em nenhuma criança. Quando as histórias familiares de crianças foram examinadas quanto à presença de fissura de lábio e/ou palato não sindrômica, nenhum parente de primeiro grau apresentava esta anomalia congênita. Conclusão: Este estudo revelou que a incidência de úvula bífida e fissura palatina submucosa nesta população é bastante semelhante às taxas de incidência previamente relatadas. Nosso estudo sugere uma intensificação de novas revisões, com populações mais amplas e diversas, buscando associar a ocorrência de úvula bífida, fissura palatina submucosa e fissura orais.

Haploinsufficiency of NCOR1 associated with autism spectrum disorder, scoliosis, and abnormal palatogenesis.

NCOR1 (nuclear receptor corepressor 1) is a transcriptional coregulatory protein that regulates the balance between histone acetylation and histone deacetylation. NCOR1 is listed as one of the 3,230 dose-sensitive genes which very rarely show truncating mutations in the pediatric population without severe diseases, even in a heterozygous state. In a large cohort study of intellectual disability/autism spectrum disorder, splicing mutations were identified in two individuals, however, the truncating effects of these splicing mutations have not been examined at the transcription level. We describe a 3-year-old girl who had behavior consistent with autism spectrum disorder, a bifid uvula, and early-onset scoliosis. Trio exome analysis showed a de novo heterozygous mutation at the splice donor site in exon 19 of NCOR1, c.2182 + 1G > T (NM_00190440.1). Reverse transcription polymerase chain reaction assay confirmed that the splicing mutation results in skipping of exon 19, a shift in the reading frame and then to nonsense-mediated mRNA decay. This patient represents the first patient who has had unequivocal documentation of haploinsufficient for the NCOR1 gene. Based on our observations, we conclude that NCOR1 is indeed a human disease-causing gene. We further suggest that bifid uvula, a micro form of cleft palate, may well be causally related to de novo NCOR1 haploinsufficiency, in that a previously reported deletion mapping study of atypical Smith-Magenis syndrome patients with large deletions and cleft palate identified that NCOR1, the only loss-of-function-intolerant gene within the region, is located in the smallest region of overlap.

Deletion of the T-box transcription factor gene, Tbx1, in mice induces differential expression of genes associated with cleft palate in humans.

OBJECTIVE: We examined the function of the T-box transcription factor 1 (TBX1) in palatogenesis. DESIGN: Tbx1-knockout mice were histologically examined by hematoxylin and eosin staining. Next, secondary palatal shelves dissected from wild type or Tbx1-knockout mice embryos at embryonic day 13.5 were investigated with microarray analysis, gene ontology analysis, and real-time quantitative polymerase chain reaction. We performed gene profiling of developing palatal shelves from wild type and Tbx1-knockout embryos. We also analyzed the association of mouse genes linked to cleft palate with biological processes and compared the results with those of our ontology analysis of dysregulated genes in Tbx1-knockout palatal shelves. RESULTS: Histological analysis of Tbx1-knockout palate with complete cleft palate at postnatal day 1 showed aplasia of secondary palates associated with a small mandible and a small tongue compared to wild type littermates. Gene ontology analysis indicated that genes associated with development of the nervous system, muscle, and biomineral tissue were dysregulated in Tbx1-knockout palatal shelves. Furthermore, in Tbx1-knockout palatal shelves, genes associated with human cleft palate, specifically, myosin heavy chain 3 (Myh3) and nebulin (Neb), were downregulated and gamma-aminobutyric acid type A receptor beta 3 subunit (Gabrb3) was upregulated. CONCLUSIONS: Our findings demonstrate that TBX1 maintains normal growth and development of palatal shelves, mediated through the regulation of genes involved in muscle cell differentiation, nervous system development, and biomineral tissue development. Multiple factors in Tbx1-knockout mice may lead to various subtypes of cleft palate.

Incidence of bifid uvula and its relationship to submucous cleft palate and a family history of oral cleft in the Brazilian population.

INTRODUCTION: Bifid uvula is a frequently observed anomaly in the general population and can be regarded as a marker for submucous cleft palate. OBJECTIVE: In this study aimed to determine the frequency of bifid uvula and submucous cleft palate and their relationship with oral clefts in a Brazilian population. METHODS: We conducted a transversal, descriptive and quantitative study of 1206 children between August 2014 and December 2015. A clinical examination of the children was conducted by means of inspection of the oral cavity with the aid of a tongue depressor and directed light. After the clinical examination in children, parents answered a questionnaire with questions about basic demographic information and their family history of oral clefts in their first-degree relatives. After application of the questionnaires, the information collected was archived in a database and analyzed by the statistical program SPSS® version 19.0, by applying Chi-Square tests. Values with p<0.05 were considered statistically significant. RESULTS: Of the 1206 children included in this study, 608 (50.40%) were female and 598 (49.60%) were male (p=0.773). The average age of children was 3.75 years (standard deviation±3.78 years). Of the 1206 children studied, 6 (0.5%) presented with bifid uvula. Submucosal cleft palate was not found in any child. When the family histories of children were examined for the presence of nonsyndromic cleft lip and/or cleft palate, no first degree relatives presented with the congenital anomaly. CONCLUSION: This study revealed that the incidence of bifid uvula and submucous cleft palate in this population was quite similar to previously reported incidence rates. Our study suggests an intensification of new reviews, with broader and diverse populations, seeking to associate the occurrence of bifid uvula, submucous cleft palate and oral clefts.

Congenital Curved Nail of the Fourth Toe Associated with Oral Disorders.

Congenital curved nail of the fourth toe represents an unusual deformity in which the nail of the fourth toe curves in a plantar direction. It is unknown why only this toe is affected; however, the initial descriptions suggest that this is a mesodermal defect. We describe a case of congenital curved nail of the fourth toe associated with bifid uvula. There are only 2 reports mentioning the association of this nail abnormality with cleft palate and/or lip. In our patient, there was an association with bifid uvula that is considered a minor form of palatine fissure. There seems to be an association of congenital curved nail of the fourth toe with cleft palate to different degrees; however, the pathogenesis of the deformity remains unknown.

Familial Gordon syndrome associated with a PIEZO2 mutation.

Gordon syndrome or distal arthrogryposis type 3 is a rare autosomal dominant disorder characterized by contractures of upper and lower limbs. It is distinguishable from other forms of distal arthrogryposis by cleft palate and short stature. Recently, Gordon syndrome has been associated to heterozygous mutations in the piezo-type mechanosensitive ion channel component 2 gene (PIEZO2). Different mutations of this gene also cause distal arthrogryposis type 5 and Marden-Walker syndrome. Dysfunction of this ion channel provides pleiotropic effects on joints, ocular muscles, and bone development. Here, we present a family with three affected individuals exhibiting multiple contractures (metacarpo-phalangeal and interphalangeal joints as well as elbow, shoulder, knee, and ankle joints), clubfeet, short stature, bifid uvula/cleft palate, and a distinct facial phenotype including ptosis. In addition, mild intellectual disability and delay in psychomotor development are obvious. The multigenerational phenotypic spectrum of Gordon syndrome is present in the 37-year-old father, his 4-year-old son and a male neonate showing typical signs of arthrogryposis in the prenatal ultrasound examination already seen at 13 week of gestation. In all affected family members, we identified the PIEZO2 mutation c.8057G>A (p.Arg2686His) by Sanger sequencing. Our analysis indicated that mild delay in psychomotor development and intellectual disability could be part of the phenotypic spectrum of Gordon syndrome. © 2016 Wiley Periodicals, Inc.

Defining the Phenotype and Assessing Severity in Phosphoglucomutase-1 Deficiency.

OBJECTIVE: To define phenotypic groups and identify predictors of disease severity in patients with phosphoglucomutase-1 deficiency (PGM1-CDG). STUDY DESIGN: We evaluated 27 patients with PGM1-CDG who were divided into 3 phenotypic groups, and group assignment was validated by a scoring system, the Tulane PGM1-CDG Rating Scale (TPCRS). This scale evaluates measurable clinical features of PGM1-CDG. We examined the relationship between genotype, enzyme activity, and TPCRS score by using regression analysis. Associations between the most common clinical features and disease severity were evaluated by principal component analysis. RESULTS: We found a statistically significant stratification of the TPCRS scores among the phenotypic groups (P < .001). Regression analysis showed that there is no significant correlation between genotype, enzyme activity, and TPCRS score. Principal component analysis identified 5 variables that contributed to 54% variance in the cohort and are predictive of disease severity: congenital malformation, cardiac involvement, endocrine deficiency, myopathy, and growth. CONCLUSIONS: We established a scoring algorithm to reliably evaluate disease severity in patients with PGM1-CDG on the basis of their clinical history and presentation. We also identified 5 clinical features that are predictors of disease severity; 2 of these features can be evaluated by physical examination, without the need for specific diagnostic testing and thus allow for rapid assessment and initiation of therapy.

Exome sequencing identifies a novel heterozygous TGFB3 mutation in a disorder overlapping with Marfan and Loeys-Dietz syndrome.

Marfan syndrome (MFS) and Loeys-Dietz syndrome (LDS) are clinically related autosomal dominant systemic connective tissue disorders. Although mutations in several genes of the TGF-beta signalling and related pathways have been identified in the past (e.g. FBN1, TGFBR1, TGFBR2, SMAD3, TGFB2), there are still many individuals with "marfanoid" phenotypes in whom no causative mutations are identified. We performed whole exome sequencing in two of three affected individuals from a family with phenotypic features overlapping MFS and LDS. The two affected children and their affected father had tall stature, arachnodactyly, hyperextensible joints, hypertelorism, bifid uvula, but no cardiac involvement, aortic dilation or eye involvement. We detected a novel heterozygous mutation in TGFB3, c.898C>G, predicting the missense substitution p.Arg300Gly. Sanger sequencing confirmed the mutation and its segregation with the phenotype. The first two TGFB3 mutations were reported previously in two unrelated individuals with marfanoid features: one individual with growth retardation carried a heterozygous loss-of-function mutation (c.1226G>A; p.Cys409Tyr; Rienhoff et al., 2013), whereas a child with overgrowth carried a mutation in the same codon as the mutation identified in the three affected individuals reported here (c.899G>A; p.Arg300Gln; Matyas et al., 2014). The mutations at codon Arg300 presumably lead to increased TGF-beta signalling, suggesting that the short or tall stature seen in patients with TGFB3 mutations may result from opposing effects of mutations on TGF-beta signalling. Thus, we add a novel human TGFB3 mutation, contribute to the clinical delineation of the emerging connective tissue disorder tentatively called Rienhoff syndrome and compare the data with a very recent report (Bertoli-Avella et al., 2015) on TGFB3 mutations associated with aortic aneurysms or dissections.

Nuevas manifestaciones orales del síndrome branquio-óculo-facial: Caso clínico / New oral manifestations of Branchio-oculo-facial syndrome: Case report

El síndrome branquio-óculo-facial es una condición autosómica dominante con expresividad variable y que afecta particularmente las estructuras de la cara y cuello por un desarrollo inadecuado del primero y segundo arco branquial; presenta malformaciones de los ojos y oídos, con características faciales distintivas. Está asociado con alteraciones en el gen TFAP2A. Se presenta una paciente de 9 años con fenotipo de síndrome branquio-óculo-facial y la presencia de dos nuevas manifestaciones orales, la úvula bifida y la lengua con hendidura central parcial, no descritas hasta ahora en esta condición clínica.

The branchio-oculo-facial syndrome is a dominant autosomic condition with variable expressivity that affects particularly the facial and neck structures by an inadequate development of the first and second branchial arch. It is characterized by malformations of eyes and ears, with distinct facial characteristics. It is associated with alterations in TFAP2A gene. We present a patient with 9 years of age with phenotype of the branchio-oculo-facial syndrome and the presence of 2 new oral manifestations, the bifid uvula and the tongue with partial central cleft, not yet described in this clinical condition.

Nuevas manifestaciones orales del síndrome branquio-óculo-facial: Caso clínico / New oral manifestations of Branchio-oculo-facial syndrome: Case report

El síndrome branquio-óculo-facial es una condición autosómica dominante con expresividad variable y que afecta particularmente las estructuras de la cara y cuello por un desarrollo inadecuado del primero y segundo arco branquial; presenta malformaciones de los ojos y oídos, con características faciales distintivas. Está asociado con alteraciones en el gen TFAP2A. Se presenta una paciente de 9 años con fenotipo de síndrome branquio-óculo-facial y la presencia de dos nuevas manifestaciones orales, la úvula bifida y la lengua con hendidura central parcial, no descritas hasta ahora en esta condición clínica.(AU)

The branchio-oculo-facial syndrome is a dominant autosomic condition with variable expressivity that affects particularly the facial and neck structures by an inadequate development of the first and second branchial arch. It is characterized by malformations of eyes and ears, with distinct facial characteristics. It is associated with alterations in TFAP2A gene. We present a patient with 9 years of age with phenotype of the branchio-oculo-facial syndrome and the presence of 2 new oral manifestations, the bifid uvula and the tongue with partial central cleft, not yet described in this clinical condition.(AU)

Nuevas manifestaciones orales del síndrome branquio-óculo-facial: Caso clínico / New oral manifestations of Branchio-oculo-facial syndrome: Case report

El síndrome branquio-óculo-facial es una condición autosómica dominante con expresividad variable y que afecta particularmente las estructuras de la cara y cuello por un desarrollo inadecuado del primero y segundo arco branquial; presenta malformaciones de los ojos y oídos, con características faciales distintivas. Está asociado con alteraciones en el gen TFAP2A. Se presenta una paciente de 9 años con fenotipo de síndrome branquio-óculo-facial y la presencia de dos nuevas manifestaciones orales, la úvula bifida y la lengua con hendidura central parcial, no descritas hasta ahora en esta condición clínica.(AU)

The branchio-oculo-facial syndrome is a dominant autosomic condition with variable expressivity that affects particularly the facial and neck structures by an inadequate development of the first and second branchial arch. It is characterized by malformations of eyes and ears, with distinct facial characteristics. It is associated with alterations in TFAP2A gene. We present a patient with 9 years of age with phenotype of the branchio-oculo-facial syndrome and the presence of 2 new oral manifestations, the bifid uvula and the tongue with partial central cleft, not yet described in this clinical condition.(AU)

A mutation in TGFB3 associated with a syndrome of low muscle mass, growth retardation, distal arthrogryposis and clinical features overlapping with Marfan and Loeys-Dietz syndrome.

The transforming growth factor ß (TGF-ß) family of growth factors are key regulators of mammalian development and their dysregulation is implicated in human disease, notably, heritable vasculopathies including Marfan (MFS, OMIM #154700) and Loeys-Dietz syndromes (LDS, OMIM #609192). We described a syndrome presenting at birth with distal arthrogryposis, hypotonia, bifid uvula, a failure of normal post-natal muscle development but no evidence of vascular disease; some of these features overlap with MFS and LDS. A de novo mutation in TGFB3 was identified by exome sequencing. Several lines of evidence indicate the mutation is hypomorphic suggesting that decreased TGF-ß signaling from a loss of TGFB3 activity is likely responsible for the clinical phenotype. This is the first example of a mutation in the coding portion of TGFB3 implicated in a clinical syndrome suggesting TGFB3 is essential for both human palatogenesis and normal muscle growth.

Submucous cleft palate: variations in bony defects of the hard palate.

We have analysed bony defects of the hard palate in patients with submucous cleft palate to find out whether velopharyngeal insufficiency (VPI) is dependent on the extent of these defects. We evaluated the maxillofacial structures associated with cleft palate by 3-dimensional computed tomography (CT) in 23 children diagnosed with submucous cleft palate. Bony defects of the hard palate were divided into Type I, defined as absent posterior nasal spine (n=12), Type II, V-shaped bony notch (moderate, n=7), and Type III, as bony defect extending into the incisive foramen (severe, n=4) defects, respectively. VPI was found in 10, 3, and 4 patients, respectively. Neither VPI nor the degree of bifid uvula was significantly associated with the types of bony defects.