J Pediatr (Rio J). 2015;91(5):485---492 www.jped.com.br ORIGINAL ARTICLE Diagnostic implications of associated defects in ଝ,ଝଝ patients with typical orofacial clefts a,∗ b c Isabella L. Monlleó , Amanda G.R. de Barros , Marshall I.B. Fontes , b b d Ana K.M. de Andrade , Gisele de M. Brito , Diogo L.L. do Nascimento , e Vera L. Gil-da-Silva-Lopes a School of Medicine, Clinical Genetics Service, Hospital Universitário Prof. Alberto Antunes, Universidade Federal de Alagoas (UFAL), Maceió, AL, Brazil b School of Medicine, Universidade Federal de Alagoas (UFAL), Maceió, AL, Brazil c Maternal-Child and Adolescent Health Department, Universidade Estadual de Ciências da Saúde de Alagoas (UNCISAL), Maceió, AL, Brazil d Laboratory of Human Cytogenetics (LCH), Universidade Estadual de Ciências da Saúde de Alagoas (UNCISAL), Maceió, AL, Brazil e Department of Medical Genetics, Faculdade de Ciências Médicas (FCM), Universidade Estadual de Campinas (UNICAMP), Campinas, SP, Brazil Received 10 October 2014; accepted 16 December 2014 Available online 4 June 2015 KEYWORDS Abstract Objectives: To describe prevalence of associated defects and clinical---genetic characteristics Cleft lip; of patients with typical orofacial clefts seen at a reference genetic service. Cleft palate; Congenital Methods: Descriptive study conducted between September of 2009 and July of 2014. Tw o abnormalities; experienced dysmorphologists personally collected and coded clinical data using a validated, Phenotype standard multicenter protocol. Syndromic cases were defined by the presence of four or more minor defects, one or more major defects, or recognition of a specific syndrome. Fisher’s exact and Kruskal---Wallis tests were used for statistics. Results: Among 141 subjects, associated defects were found in 133 (93%), and 84 (59.5%) were assigned as syndromic. Cleft palate was statistically associated with a greater num- ber of minor defects (p < 0.0012) and syndromic assignment (p < 0.001). Syndromic group was associated with low birth weight (p < 0.04) and less access to surgical treatment (p < 0.002). There was no statistical difference between syndromic and non-syndromic groups regarding gender (p < 0.55), maternal age of 35 years and above (p < 0.50), alcohol (p < 0.50) and tobacco consumption (p < 0.11), consanguinity (p < 0.59), recurrence (p < 0.08), average number of preg- nancies (p < 0.32), and offspring (p < 0.35). ଝ Please cite this article as: Monlleó IL, de Barros AG, Fontes MI, de Andrade AK, Brito GM, do Nascimento DL, et al. Diagnostic implications of associated defects in patients with typical orofacial clefts. J Pediatr (Rio J). 2015;91:485---92. ଝଝ Study conducted at the School of Medicine, Clinical Genetics Service, Hospital Universitário Prof. Alberto Antunes, Universidade Federal de Alagoas (UFAL), Maceió, AL, Brazil. ∗ Corresponding author. E-mail: [email protected] (I.L. Monlleó). http://dx.doi.org/10.1016/j.jped.2014.12.001 0021-7557/© 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved. 486 Monlleó IL et al. Conclusions: There is a lack of information on syndromic clefts. The classification system for phenotype assignment adopted in this study has facilitated recognition of high prevalence of associated defects and syndromic cases. This system may be a useful strategy to gather homogeneous samples, to elect appropriate technologies for etiologic and genotype---phenotype approaches, and to assist with multiprofessional care and genetic counseling. © 2015 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved. PALAVRAS-CHAVE Implicac¸ões diagnósticas de defeitos associados em pacientes com fendas orofaciais típicas Fenda de lábio; Fenda de palato; Anomalias Resumo Congênitas; Objetivos: descrever a prevalência de defeitos associados e as características genético-clínicas Fenótipo de pacientes com fendas orofaciais típicas (FOT) em um servic¸o de referência em genética. Métodos: Estudo descritivo realizado entre setembro/2009 a julho/2014. Os dados foram col- hidos e codificados por dois observadores clínicos com experiência em dismorfologia, utilizando protocolo validado em estudo multicêntrico. Presenc¸a de 4 ou mais defeitos minor, um ou mais defeitos major e diagnóstico de síndrome reconhecida foram critérios utilizados para classificar o caso como sindrômico. Utilizou-se Teste Exato de Fisher para análise de variáveis categóricas e Kruskal-Wallis para igualdade de médias. Resultados: Entre 141 sujeitos, 133 (93%) apresentavam ao menos um defeito minor ou major associado, sendo 84 (59,5%) classificados como sindrômicos. As fendas de palato estiveram associadas com maior número de defeitos minor (p < 0,0012) e com a classificac¸ão sindrômica (p < 0,01). O grupo sindrômico apresentou maior taxa de baixo peso (p < 0,04) e menor acesso a tratamento cirúrgico (p < 0,02). Não houve diferenc¸as entre os grupos quanto ao gênero (p < 0,55), idade materna ≥ 35 anos (p < 0,50), ingestão de álcool (p < 0,50) e tabagismo (p < 0,11), consanguinidade (p < 0,59), recorrência familial (p < 0,08) e média de gestac¸ões (p < 0,32) e de filhos nascidos vivos (p < 0,35). Conclusões: Existe escassez de informac¸ões sobre fendas sindrômicas. O método de classificac¸ão fenotípica utilizado possibilitou a identificac¸ão de alta prevalência de defeitos associados e de casos sindrômicos. Este método seria uma alternativa para homogeneizar amostras, determinar tecnologias visando investigac¸ão etiológica e estudos de correlac¸ão genótipo-fenótipo, além de colaborar para intervenc¸ão multiprofissional e aconselhamento genético. © 2015 Sociedade Brasileira de Pediatria. Publicado por Elsevier Editora Ltda. Todos os direitos reservados. Introduction In Brazil, there are problems regarding the epidemiolog- ical registry of birth defects. In spite of that fact, a recently published estimate predicted the birth of 2900---4000 chil- The scientific interest in the typical orofacial clefts (OFCs), 6 dren with OFCs in the country in 2011. Considering the represented by paramedian fissures affecting the lip, palate 1,2 maintenance of the birth rate in the country and taking or both, dates back to the mid-eighteenth century. The into account that the treatment of an individual with OFCs development of technological tools in the genomic era has extends into adulthood, this estimate of new cases/year has allowed the expansion of knowledge on their etiology, nat- an important economic impact on the health care system. ural history, and risk factors. However, the understanding Surgical repair of the cleft is usually perceived by the of overlapping gene---gene and gene---environment associa- family as the only treatment required. However, a patient tions and their effects on phenotype remains an important with a typical OFC requires continued speech therapy, den- challenge. This knowledge forms the theoretical basis upon tal, otorhinolaryngological, and psychological support into which cost-effective treatment and prevention proposals 1 --- 4 adulthood, and usually requires more than one surgical should be built. intervention.1 --- 4 Typical OFCs are congenital malformations with large epi- Longitudinal studies have disclosed other important demiological, social, psychological, and economic impact. health-related aspects, highlighting higher mortality rate The prevalence ranges from one case to every 500---2500 at any age, higher prevalence of psychiatric disorders, and births. This variation reflects the interference of genetic increased risk for breast, brain, and colon cancer in the indi- and environmental factors related to ethnic background, viduals and their families. In the United States, a cost of US$ geographic region, and nutritional and health status of the population.2 --- 5 200,000 per capita has been estimated in the lifelong care of Defects associated with typical orofacial clefts 487 individuals with OFCs, considering specific treatment, con- abnormality) or strongly suspected based on their recur- 2,3,5 trol, and prevention of comorbidities. rence in a number of cases. The prevalence of the association of OFCs with other - MCDs: any combination of OFCs with one or more major birth defects is a controversial area in the literature. The defects for which no etiological factor has been demon- fact is that, in the presence of associated defects, the strated or suspected. OFC is no longer considered an isolated malformation (non- syndromic OFC) with multifactorial etiology, and is then The outcome variable, dependent, was the presence of classified as syndromic. It is estimated that it occurs in 30% morphological abnormalities associated with OFCs, with the of cases with cleft lip with or without cleft palate (CL/P) sample being regrouped according to the phenotypic classi- 2,3,5,7 and in 50% of cases of cleft palate (CP). fication of cases of non-syndromic OFCs (presence of up to Syndromic OFCs may present a known etiology, classified three minor defects) and cases of syndromic OFCs (presence as a monogenic, chromosomal, or teratogenic syndrome, of four or more minor defects, diagnosis of the syndrome, or may present an unknown etiology, constituting cases and of MCDs). Independent variables and their respective with multiple malformation, often called multiple congeni- categories were: 2,3,5,7,8 tal defects (MCDs). The classification of OFCs as syndromic and non- Demographic characteristics: age, gender. syndromic and the recognition of associated defects and Maternal, newborn, and family characteristics: