Oral cleft prevention program (OCPP)

Background Oral clefts are one of the most common birth defects with significant medical, psychosocial, and economic ramifications. Oral clefts have a complex etiology with genetic and environmental risk factors. There are suggestive results for decreased risks of cleft occurrence and recurrence with folic acid supplements taken at preconception and during pregnancy with a stronger evidence for higher than lower doses in preventing recurrence. Yet previous studies have suffered from considerable design limitations particularly non-randomization into treatment. There is also well-documented effectiveness for folic acid in preventing neural tube defect occurrence at 0.4 mg and recurrence with 4 mg. Given the substantial burden of clefting on the individual and the family and the supportive data for the effectiveness of folic acid supplementation as well as its low cost, a randomized clinical trial of the effectiveness of high versus low dose folic acid for prevention of cleft recurrence is warranted. Methods/design This study will assess the effect of 4 mg and 0.4 mg doses of folic acid, taken on a daily basis during preconception and up to 3 months of pregnancy by women who are at risk of having a child with nonsyndromic cleft lip with/without palate (NSCL/P), on the recurrence of NSCL/P. The total sample will include about 6,000 women (that either have NSCL/P or that have at least one child with NSCL/P) randomly assigned to the 4 mg and the 0.4 mg folic acid study groups. The study will also compare the recurrence rates of NSCL/P in the total sample of subjects, as well as the two study groups (4mg, 0.4 mg) to that of a historical control group. The study has been approved by IRBs (ethics committees) of all involved sites. Results will be disseminated through publications and presentations at scientific meetings. Discussion The costs related to oral clefts are high, including long term psychological and socio-economic effects. This study provides an opportunity for huge savings in not only money but the overall quality of life. This may help establish more specific clinical guidelines for oral cleft prevention so that the intervention can be better tailored for at-risk women. ClinicalTrials.gov Identifier NCT00397917

Benzodiazepine use in pregnancy and major malformations or oral cleft: meta-analysis of cohort and case-control studies

Objective: To determine if exposure to benzodiazepines during the first trimester of pregnancy increases risk of major malformations or cleft lip or palate.

Functional outcomes in the Cleft Care UK study - Part 3:oral health and audiology

OBJECTIVES: To compare oral health and hearing outcomes from the Clinical Standards Advisory Group (CSAG, 1998) and the Cleft Care UK (CCUK, 2013) studies. SETTING AND SAMPLE POPULATION: Two UK-based cross-sectional studies of 5-year-olds born with non-syndromic unilateral cleft lip and palate undertaken 15 years apart. CSAG children were treated in a dispersed model of care with low-volume operators. CCUK children were treated in a centralized, high volume operator system. MATERIALS AND METHODS: Oral health data were collected using a standardized proforma. Hearing was assessed using pure tone audiometry and middle ear status by otoscopy and tympanometry. ENT and hearing history were collected from medical notes and parental report. RESULTS: Oral health was assessed in 264 of 268 children (98.5%). The mean dmft was 2.3, 48% were caries free, and 44.7% had untreated caries. There was no evidence this had changed since the CSAG survey. Oral hygiene was generally good, 96% were enrolled with a dentist. Audiology was assessed in 227 of 268 children (84.7%). Forty-three per cent of children received at least one set of grommets--a 17.6% reduction compared to CSAG. Abnormal middle ear status was apparent in 50.7% of children. There was no change in hearing levels, but more children with hearing loss were managed with hearing aids. CONCLUSIONS: Outcomes for dental caries and hearing were no better in CCUK than in CSAG, although there was reduced use of grommets and increased use of hearing aids. The service specifications and recommendations should be scrutinized and implemented.

Centralization of cleft care in the UK. Part 6:a tale of two studies

OBJECTIVES: We summarize and critique the methodology and outcomes from a substantial study which has investigated the impact of reconfigured cleft care in the United Kingdom (UK) 15 years after the UK government started to implement the centralization of cleft care in response to an earlier survey in 1998, the Clinical Standards Advisory Group (CSAG). SETTING AND SAMPLE POPULATION: A UK multicentre cross-sectional study of 5-year-olds born with non-syndromic unilateral cleft lip and palate. Data were collected from children born in the UK with a unilateral cleft lip and palate between 1 April 2005 and 31 March 2007. MATERIALS AND METHODS: We discuss and contextualize the outcomes from speech recordings, hearing, photographs, models, oral health and psychosocial factors in the current study. We refer to the earlier survey and other relevant studies. RESULTS: We present arguments for centralization of cleft care in healthcare systems, and we evidence this with improvements seen over a period of 15 years in the UK. We also make recommendations on how future audit and research may configure. CONCLUSIONS: Outcomes for children with a unilateral cleft lip and palate have improved after the introduction of a centralized multidisciplinary service, and other countries may benefit from this model. Predictors of early outcomes are still needed, and repeated cross-sectional studies, larger longitudinal studies and adequately powered trials are required to create a research-led evidence-based (centralized) service.

Investigation Of Genetic Factors Underlying Typical Orofacial Clefts: Mutational Screening And Copy Number Variation.

Typical orofacial clefts (OFCs) comprise cleft lip, cleft palate and cleft lip and palate. The complex etiology has been postulated to involve chromosome rearrangements, gene mutations and environmental factors. A group of genes including IRF6, FOXE1, GLI2, MSX2, SKI, SATB2, MSX1 and FGF has been implicated in the etiology of OFCs. Recently, the role of the copy number variations (CNVs) has been studied in genetic defects and diseases. CNVs act by modifying gene expression, disrupting gene sequence or altering gene dosage. The aims of this study were to screen the above-mentioned genes and to investigate CNVs in patients with OFCs. The sample was composed of 23 unrelated individuals who were grouped according to phenotype (associated with other anomalies or isolated) and familial recurrence. New sequence variants in GLI2, MSX1 and FGF8 were detected in patients, but not in their parents, as well as in 200 control chromosomes, indicating that these were rare variants. CNV screening identified new genes that can influence OFC pathogenesis, particularly highlighting TCEB3 and KIF7, that could be further analyzed. The findings of the present study suggest that the mechanism underlying CNV associated with sequence variants may play a role in the etiology of OFC.

Hábitos de sucção não nutritiva em crianças pré-escolares

OBJETIVO: Verificar a prevalência e os fatores associados aos hábitos de sucção não nutritiva em crianças pré-escolares matriculadas em creches e pré-escolas de Natal (RN). MÉTODOS: Foi conduzido um estudo transversal com 1.190 crianças de ambos os sexos na faixa etária de 3 a 5 anos, matriculadas em creches e pré-escolas de Natal. Não foram incluídas no estudo crianças com fendas labiopalatinas, desordens temporomandibulares, ou aquelas submetidas a tratamento ortodôntico e/ou ortopédico; também não fizeram parte da amostra instituições de ensino especializadas em crianças portadoras de deficiência. Utilizou-se um questionário estruturado, respondido pelos pais ou responsável, com dados sobre a instituição, sexo e idade das crianças, escolaridade dos pais e questões relacionadas aos hábitos. A análise dos dados foi realizada através do teste do qui-quadrado e a regressão logística. RESULTADOS: Obteve-se prevalência de 40,2% de hábitos de sucção não nutritiva, dos quais 27,7% eram de sucção de chupeta e 12,5% de dedo. Os hábitos de sucção apresentaram maior percentual para o sexo feminino, destacando-se a sucção de dedo (p = 0,02); em crianças com menos idade destacou-se a sucção de chupeta (p = 0,0006). Observou-se maior frequência de sucção de chupeta e de dedo, respectivamente, para o nível superior (p < 0,05) e fundamental (p < 0,05) de escolaridade dos pais. A regressão logística demonstrou que a menor idade dos indivíduos (p = 0,033) e o nível médio de escolaridade dos pais (p = 0,035) são fatores independentes para a persistência dos hábitos. CONCLUSÃO: Verificou-se uma alta prevalência de realização dos hábitos de sucção não nutritiva, apresentando como fatores de destaque a menor idade das crianças e o nível médio de escolaridade dos pais.

Comparação dos resultados da fala após as cirurgias de retalho faríngeo e veloplastia intravelar para correção da disfunção velofaríngea

OBJETIVO: Comparar a fala e o funcionamento velofaríngeo após as técnicas de retalho faríngeo e veloplastia intravelar para a correção da disfunção velofaríngea residual. MÉTODOS: Foi realizado um estudo retrospectivo com análise de 148 casos com fissura labiopalatina operada e submetidos à correção cirúrgica da disfunção velofaríngea, sendo 77 com retalho faríngeo (média de idade: 20,4 anos) e 71 com veloplastia intravelar (média de idade: 16,2 anos). Foram avaliadas a ressonância da fala, a presença de articulações compensatórias, a emissão de ar nasal e a extensão da falha no fechamento velofaríngeo antes e após as duas técnicas. RESULTADOS: Dos 77 casos submetidos ao retalho faríngeo 64 (83%) apresentaram melhora na ressonância, enquanto que dos 71 casos com veloplastia intravelar 48 (68%) revelaram melhora, havendo diferença significativa entre os grupos. No grupo com retalho faríngeo, seis (8%) apresentaram melhora na articulação compensatória e dois (3%) no grupo veloplastia intravelar, enquanto a emissão de ar nasal melhorou em 17 (22%) casos com retalho faríngeo e em 18 (26%) com veloplastia intravelar. Não houve diferença entre os grupos quanto à articulação compensatória e emissão de ar nasal. A falha no fechamento velofaríngeo reduziu em 75 (96%) casos com retalho faríngeo e 46 (66%) com a veloplastia intravelar, havendo diferença entre os grupos. CONCLUSÃO: A técnica de retalho faríngeo mostrou-se mais efetiva na melhora da ressonância e no fechamento velofaríngeo quando comparada à veloplastia intravelar.

Caracterização da fala de indivíduos submetidos à palatoplastia primária

OBJETIVOS: Descrever as características de fala de indivíduos submetidos à palatoplastia primária; relacioná-las com tipo de fissura, técnica cirúrgica e idade na ocasião da cirurgia; e descrever as condutas fonoaudiológicas após a cirurgia. MÉTODOS: Estudo retrospectivo de 167 casos, de ambos os gêneros, com fissura labiopalatina, submetidos à palatoplastia primária. Foram coletadas informações relativas ao tipo de fissura, idade na palatoplastia, técnica cirúrgica, e as análises subjetivas sobre as características da fala, realizadas por fonoaudiólogas. RESULTADOS: Na avaliação perceptiva da fala após a cirurgia, encontrou-se inteligibilidade de fala alterada (46%), ressonância hipernasal (33%), articulações compensatórias (26%), emissão de ar nasal (14%), mímica facial (11%) e fraca pressão aérea intra-oral (8%). Na associação entre a ressonância e as articulações compensatórias com tipo de fissura, técnica cirúrgica e faixa etária, não houve diferença significativa. A conduta mais frequentemente tomada foi a de terapia fonoaudiológica (38%), para correção das articulações compensatórias e/ou outras alterações. CONCLUSÃO: A maioria dos indivíduos apresentou ressonância equilibrada ou hipernasalidade aceitável e ausência de articulações compensatória, independente do tipo de fissura, da técnica cirúrgica e da faixa etária, embora não tenha ocorrido diferença significativa. Dentre as condutas adotadas após a primeira avaliação pós-palatoplastia primária, a terapia fonoaudiológica foi a mais frequente.

Avaliação audiológica pré-cirurgia otológica de indivíduos com fissura labiopalatina operada

OBJETIVO: descrever as características audiológicas de indivíduos com fissura labiopalatina operada (FLP) e indicação de cirurgia otológica, comparando os grupos quanto ao tipo e grau da perda auditiva, bem como a curva timpanométrica. MÉTODOS: análise de 150 prontuários, ambos os gêneros, idade igual ou superior a 4 anos, FLP e indicação de cirurgia otológica, divididos em 3 grupos: I - Tubo de ventilação (TV), II - Timpanoplastia e III - Timpanomastoidectomia, analisando aspectos quanto a entrevista audiológica, audiometria tonal limiar e imitanciometria. RESULTADOS: o grupo I apresentou porcentagem maior de cirurgia bilateral (86%), o que não ocorreu nos demais grupos. Na entrevista audiológica, 83% apresentou algum tipo de queixa auditiva, sendo a mais frequente a perda auditiva (64%) com p<0,05 entre os grupos I e II; I e III. O tipo de perda auditiva de maior ocorrência foi condutivo bilateral (56%) seguido de unilateral (35%), com p<0,05 entre os grupos I e II; I e III. A perda de grau leve unilateral foi a de maior ocorrência (41%), seguida de grau leve a moderada bilateral (20%), com p<0,05 entre os três grupos. A curva timpanométrica mais frequente foi a do tipo B bilateral (39%) com p<0,05 entre os três grupos. CONCLUSÃO: a maioria dos indivíduos apresentou algum tipo de queixa na entrevista audiológica e alterações na audiometria tonal limiar e imitanciometria. A maioria dessas alterações foi compatível com problemas de orelha média, com perda auditiva do tipo condutiva, de grau leve e bilateral, independentemente da indicação cirúrgica.

As atividades expressivas e recreativas em crianças com fissura labiopalatina hospitalizadas: visão dos familiares

Este estudo teve por objetivo verificar a visão dos familiares a respeito da importância das atividades expressivas e recreativas na hospitalização e recuperação cirúrgica de crianças com fissura labiopalatina (FLP), procurando identificar os benefícios dessas atividades nos períodos pré e pós-operatório. Foram entrevistados 138 familiares de crianças com FLP, na faixa etária de sete a 12 anos, hospitalizados no Hospital de Reabilitação de Anomalias Craniofaciais (HRAC/USP). Os resultados mostraram que a grande maioria dos entrevistados preferia desenvolver alguma atividade com a criança enquanto aguardava a cirurgia, tendo expressado sentimentos positivos durante esse período. Segundo os entrevistados, as atividades expressivas e recreativas no período pré-operatório deixam a criança mais calma, observando melhora na condição emocional da mesma. Essas atividades distraem, divertem, acalmam e contribuem para o desenvolvimento da criança, sendo importantes para a recuperação cirúrgica, amenizando os efeitos negativos da hospitalização. As atividades na brinquedoteca foram as preferidas pelas crianças e pelos familiares. Na visão dos familiares, as atividades expressivas e recreativas favorecem a criança e os pais, reduzindo o estresse, proporcionando sentimentos positivos a ambos e auxiliando a adaptação e o restabelecimento físico e emocional. Evidenciam a importância do brincar durante a hospitalização, contribuindo para um atendimento humanizado, principalmente no caso de crianças com fissura labiopalatina, sujeitas a um grande número de procedimentos cirúrgicos e hospitalizações.

Novel Heterozygous Nonsense GLI2 Mutations in Patients with Hypopituitarism and Ectopic Posterior Pituitary Lobe without Holoprosencephaly

Context: GLI2 is a transcription factor downstream in Sonic Hedgehog signaling, acting early in ventral forebrain and pituitary development. GLI2 mutations were reported in patients with holoprosencephaly (HPE) and pituitary abnormalities. Objective: The aim was to report three novel frameshift/nonsense GLI2 mutations and the phenotypic variability in the three families. Setting: The study was conducted at a university hospital. Patients and Methods: The GLI2 coding region of patients with isolated GH deficiency (IGHD) or combined pituitary hormone deficiency was amplified by PCR using intronic primers and sequenced. Results: Three novel heterozygous GLI2 mutations were identified: c. 2362_2368del p. L788fsX794 (family 1), c. 2081_2084del p. L694fsX722 (family 2), and c. 1138 G > T p. E380X (family 3). All predict a truncated protein with loss of the C-terminal activator domain. The index case of family 1 had polydactyly, hypoglycemia, and seizures, and GH, TSH, prolactin, ACTH, LH, and FSH deficiencies. Her mother and seven relatives harboring the same mutation had polydactyly, including two uncles with IGHD and one cousin with GH, TSH, LH, and FSH deficiencies. In family 2, a boy had cryptorchidism, cleft lip and palate, and GH deficiency. In family 3, a girl had hypoglycemia, seizures, excessive thirst and polyuria, and GH, ACTH, TSH, and antidiuretic hormone deficiencies. Magnetic resonance imaging of four patients with GLI2 mutations and hypopituitarism showed a hypoplastic anterior pituitary and an ectopic posterior pituitary lobe without HPE. Conclusion: We describe three novel heterozygous frameshift or nonsense GLI2 mutations, predicting truncated proteins lacking the activator domain, associated with IGHD or combined pituitary hormone deficiency and ectopic posterior pituitary lobe without HPE. These phenotypes support partial penetrance, variable polydactyly, midline facial defects, and pituitary hormone deficiencies, including diabetes insipidus, conferred by heterozygous frameshift or nonsense GLI2 mutations. (J Clin Endocrinol Metab 95: E384-E391, 2010)

Nonsense Mutations in FGF8 Gene Causing Different Degrees of Human Gonadotropin-Releasing Deficiency

Context: FGFR1 mutations cause isolated hypogonadotropic hypogonadism (IHH) with or without olfactory abnormalities, Kallmann syndrome, and normosmic IHH respectively. Recently, missense mutations in FGF8, a key ligand for fibroblast growth factor receptor (FGFR) 1 in the ontogenesis of GnRH, were identified in IHH patients, thus establishing FGF8 as a novel locus for human GnRH deficiency. Objective: Our objective was to analyze the clinical, hormonal, and molecular findings of two familial IHH patients due to FGF8 gene mutations. Methods and Patients: The entire coding region of the FGF8 gene was amplified and sequenced in two well-phenotyped IHH probands and their relatives. Results: Two unique heterozygous nonsense mutations in FGF8(p.R127X and p.R129X) were identified in two unrelated IHH probands, which were absent in 150 control individuals. These two mutations, mapped to the core domain of FGF8, impact all four human FGF8 isoforms, and lead to the deletion of a large portion of the protein, generating nonfunctional FGF8 ligands. The p.R127X mutation was identified in an 18-yr-old Kallmann syndrome female. Her four affected siblings with normosmic IHH or delayed puberty also carried the p.R127X mutation. Additional developmental anomalies, including cleft lip and palate and neurosensorial deafness, were also present in this family. The p.R129X mutation was identified in a 30-yr-old man with familial normosmic IHH and severe GnRH deficiency. Conclusions: We identified the first nonsense mutations in the FGF8 gene in familial IHH with variable degrees of GnRH deficiency and olfactory phenotypes, confirming that loss-of-function mutations in FGF8 cause human GnRH deficiency. (J Clin Endocrinol Metab 95: 3491-3496, 2010)

Dental Evaluation of Kabuki Syndrome Patients

Kabuki syndrome is a genetic disorder of unknown etiology characterized by mental retardation, growth deficiency, and peculiar face (i.e., long palpebral fissures, eversion of the lateral third of the lower eyelids, prominent ears, and broad and depressed nasal tip). Oral manifestations commonly observed in Kabuki syndrome may comprise cleft lip/palate, bifid tongue and uvula, malocclusion, and dental abnormalities. We evaluated the dental findings of eight patients with Kabuki syndrome. One presented cleft palate; three presented caries; and seven had missing teeth, with the upper lateral incisors and inferior central incisors being the most commonly absent. All missing teeth were permanent, and there was no alteration of dental chronology or morphology. Because most patients had mixed dentition, the presence or absence of primary teeth was assessed through the parents` reports. One patient presented an absent upper canine, which had not been reported previously in the literature. Dental findings may be helpful for clinical diagnosis, or they may be an additional finding to substantiate the diagnosis of Kabuki syndrome in children with mild phenotype.

Clinical and Fiberoptic Endoscopic Evaluation of Swallowing in Robin Sequence Treated With Nasopharyngeal lntubation: The Importance of Feeding Facilitating Techniques

Objective: To evaluate oral feeding capacity, the swallowing process, and risk for aspiration, both clinically and during fiberoptic endoscopic evaluation of swallowing, in infants with isolated Robin sequence treated exclusively with nasopharyngeal intubation and feeding facilitating techniques. Design: Longitudinal and prospective study. Setting: Hospital de Reabilitacao de Anomalies Craniofaciais, University of Sao Paulo, Bauru, Brazil. Patients: Eleven infants with isolated Robin sequence, under 2 months of age, treated with nasopharyngeal intubation. Interventions: Feeding facilitating techniques were applied in all infants throughout the study period. The infants were evaluated clinically and through fiberoptic endoscopic evaluation of swallowing at first, second, and, if necessary, third week of hospitalization (T1, T2, T3). The mean volume of ingested milk was registered during clinical evaluation, and events were registered during feeding. Results: The respiratory status of all infants was improved after nasopharyngeal intubation; 72% of them presented risk for aspiration during fiberoptic endoscopic evaluation of swallowing at T1. This risk was less frequent when thickened milk was given to the infants and at subsequent evaluations (T2 and T3). Conclusions: Nasopharyngeal intubation aids in stabilizing the airway in isolated Robin sequence, but it does not relate directly to feeding. The risk for aspiration was present in most of the infants, mainly during the first week of hospitalization, and improved within a few weeks, after the use of feeding facilitating techniques.

Tooth abnormalities and soft tissue alterations in patients with G/BBB syndrome

OBJECTIVE: The G/BBB syndrome is an X-linked recessive disorder characterized by eye anomalies, laryngotracheoesophageal cleft, congenital heart disease, genitourinary anomalies and gastrointestinal disorders. Patients may also present cleft lip and palate, high-arched palate and thin upper lip. This study aimed to investigate the occurrence of tooth abnormalities and soft tissue changes in patients with G/BBB syndrome. DESIGN: Cross-sectional. SUBJECTS AND METHODS: Twenty-one patients with G/BBB syndrome were analyzed as to the presence of tooth abnormalities and soft tissue alterations. MAIN OUTCOME MEASURES: The prevalence of tooth agenesis and supernumerary teeth was compared to patients without morphofunctional alterations, matched for gender and age. RESULTS: All patients had complete cleft lip and palate; 95.23% of patients presented tooth abnormalities, mainly hypoplastic alterations, with predominance of alterations of number, followed by alterations of structure, shape and position. The frequency of tooth agenesis and supernumerary teeth was significantly higher compared with the control group; 11 patients presented incisiform supernumerary teeth in the mandibular anterior region. Ankyloglossia was observed in 11 of 21 patients. CONCLUSION: The presence of mandibular anterior supernumerary teeth and ankyloglossia should be investigated in the clinical evaluation of patients with suspected diagnosis of the G/BBB syndrome. Oral Diseases (2008) 14, 747-753