Genetic, chromosomal, and syndromic causes of neural tube defects.
ABSTRACT: OBJECTIVE:To ascertain the incidence, and describe the various forms of neural tube defects (NTDs) due to genetic, chromosomal, and syndromic causes. METHODS:We carried out a retrospective analysis of data retrieved from the medical records of newborn infants admitted to the Neonatal Intensive Care Unit with NTDs and their mothers spanning 14 years (1996-2009) at the Security Forces Hospital, Riyadh, Saudi Arabia. The cases were ascertained by a perinatologist, neonatologist, geneticist, radiologist, and neurologist. The literature was reviewed via a MEDLINE search. Only liveborn babies were included. Permission from the Educational Committee at the Security Forces Hospital was obtained prior to the collection of data. RESULTS:Out of 103 infants with NTDs admitted during this period, 20 (19.4%) were found to have an underlying genetic syndromic, chromosomal and/or other anomalies. There were 5 cases of Meckel-Gruber syndrome, 2 Joubert syndrome, one Waardenburg syndrome, one Walker-Warburg syndrome, 2 chromosomal disorders, 2 caudal regression, one amniotic band disruption sequence, one associated with omphalocele, one with diaphragmatic hernia, and 4 with multiple congenital anomalies. CONCLUSION:There is a high rate of underlying genetic syndromic and/or chromosomal causes of NTDs in the Saudi Arabian population due to the high consanguinity rate. Identification of such association can lead to more accurate provisions of genetic counseling to the family including preimplantation genetic diagnosis or early termination of pregnancies associated with lethal conditions.
Project description:Neural tube defects (NTDs) constitute a major health burden (0.5-2/1000 pregnancies worldwide), and remain a preventable cause of still birth, neonatal, and infant death, or significant lifelong handicaps. The malformations result from failure of the neural folds to fuse in the midline, and form the neural tube between the third and the fourth week of embryonic development. This review article discusses their classification, clinical features, and genetics. Most NTDs are sporadic and both genetic, and non-genetic environmental factors are involved in its etiology. Consanguinity was suggested to contribute to the high incidence of NTDs in several countries, including Saudi Arabia. Syndromes, often associated with chromosomal anomalies, account for <10% of all NTDs; but a higher proportion (20%) has been documented in Saudi Arabia. Genetic predisposition constitutes the major underlying risk factor, with a strong implication of genes that regulate folate one-carbon metabolism and planar cell polarity.
Project description:Oesophageal atresia and/or tracheo-oesophageal fistula are relatively common malformations occurring in approximately 1 in 3500 births. In around half of the cases (syndromic oesophageal atresia), there are associated anomalies, with cardiac malformations being the most common. In the remainder (non-syndromic cases), oesophageal atresia/tracheo-oesophageal fistula occur in isolation. Data from twin and family studies suggest that genetic factors do not play a major role, and yet there are well-defined instances of this malformation where genetic factors clearly are important. This is highlighted by the recent identification of no fewer than three separate genes with a role in the aetiology of oesophageal atresia: those for Feingold syndrome (N-MYC), anophthalmia-oesophageal-genital (AEG) syndrome (SOX2), and CHARGE syndrome (CHD7). Additional support for genetic factors in this malformation comes from chromosomal studies and mouse models. This paper reviews current knowledge of the genetics and epidemiology of the different oesophageal atresia/tracheo-oesophageal fistula syndromes and associations.
Project description:Dental anomalies are common congenital malformations that can occur either as isolated findings or as part of a syndrome. This review focuses on genetic causes of abnormal tooth development and the implications of these abnormalities for clinical care. As an introduction, we describe general insights into the genetics of tooth development obtained from mouse and zebrafish models. This is followed by a discussion of isolated as well as syndromic tooth agenesis, including Van der Woude syndrome (VWS), ectodermal dysplasias (EDs), oral-facial-digital (OFD) syndrome type I, Rieger syndrome, holoprosencephaly, and tooth anomalies associated with cleft lip and palate. Next, we review delayed formation and eruption of teeth, as well as abnormalities in tooth size, shape, and form. Finally, isolated and syndromic causes of supernumerary teeth are considered, including cleidocranial dysplasia and Gardner syndrome.
Project description:The aim of this study was to define different characteristics of infants with esophageal atresia and correlations with neonatal level of care, morbidity and mortality occurring during hospital stay.Charts of all newborns with esophageal atresia (EA) admitted to our University NICU between January 2003 and November 2016 were reviewed and subdivided in four groups related to different clinical presentations; EA as an isolated form (A), with a concomitant single malformation (B), as VACTERL association (C), and in the context of a syndrome or an entity of multiple congenital anomalies (D).We recruited 67 infants with EA (with or without tracheoesophageal fistula), distributed in groups as follows: A 31.3%, B 16.4%, C 26.8% and D 25.3%. Type of atresia was not statistically different among different groups. Mortality was higher in groups C and D, especially if associated with congenital heart defects. In survivors, we found different auxological evolution and prognostic profiles considering duration in days of invasive mechanical ventilation and total parenteral nutrition, as well as length of stay and corrected gestational age at discharge.In the context of genetic and syndromic entities, subjects with VACTERL association showed a lower mortality rate although a higher and more complex level of intensive care was noted in comparison to infants without VACTERL genetic and syndromic entities.
Project description:The prevalence of neural tube defects worldwide is 1?-?2 per 1000 neonates. Neural tube defects result from a disturbance of neurulation in the 3rd or 4th week of development and thus represent the earliest manifestation of organ malformation. Neural tube defects (NTD) are classified into cranial dysraphism leading to anencephaly or meningoencephalocele and spinal dysraphism with or without meningomyelocele. In isolated form they have multifactorial causes, and the empirical risk of recurrence in Central Europe is 2%. As associated malformations they tend to occur sporadically, and in monogenic syndromes they follow Mendelian inheritance patterns with a high risk of recurrence.Autopsies were performed on 68 fetuses following a prenatal diagnosis of NTD and induced abortion.The incidence of NTDs in our autopsied fetuses was 8% and 11% in fetuses with malformations. The percentage of fetuses with anencephaly, encephalocele or spina bifida was 24, 18, and 60%*, respectively. Analysis of the sex distribution showed a female preponderance in cranial dysraphisms but the sex distribution of spina bifida cases was equal. The extent and localization of NTDs varied, with lumbosacral cases clearly predominating. The proportion of isolated, associated and syndromic neural tube defects was 56, 23.5 and 20.6% respectively. In the majority of syndromes, the neural tube defect represented a not previously observed syndromic feature.The high proportion of NTDs with monogenic background underlines the importance of a syndrome oriented fetal pathology. At the very least it requires a thourough photographic and radiographic documentation of the fetal phenotype to enable the genetic counsellor to identify a syndromic disorder. This is necessary to determine the risk of recurrence, arrange confirming mutation analyses and offer targeted prenatal diagnosis in subsequent pregnancies.
Project description:Background Congenital heart diseases (CHDs) are abnormalities that present in the heart since birth and are one of the leading causes of infant mortality in the world. CHDs are more common among children with dysmorphic syndromes. The current study aims to estimate the prevalence of many CHDs in different dysmorphic syndromes. Methods This was a retrospective chart review study conducted on all dysmorphic syndrome patients who attended genetic clinics at King Khalid National Guard Hospital in King Abdulaziz Medical City (KAMC), Jeddah, Saudi Arabia from 2005 to 2016. Dysmorphic pediatric patients less than 14 years old who had genetic testing to confirm their diagnosis were included in the study. Patients who did not have any previous echocardiography were excluded. Results A total of 212 individuals (47% males and 53% females) were included. Eighty-five percent of Down syndrome patients had CHDs, and the most common CHD was an atrial septal defect (ASD) (51%). In patients with Turner syndrome, 45% of them had CHDs, and bicuspid aortic valve (BAV) (40%) was the most common defect. In DiGeorge syndrome, 81% of patients had CHDs, and ventricular septal defect (VSD) (41%) was the most common. In Williams syndrome, 83% of patients had CHDs. All patients with Noonan, Edwards, CHARGE (coloboma, heart defects, atresia choanae (also known as choanal atresia), growth retardation, genital abnormalities, and ear abnormalities), and Rubinstein-Taybi syndromes were found to have CHDs. In Patau syndrome and Joubert syndrome, 50% of patients in each had CHDs. Patients with Prader Willi syndrome had normal findings in the echocardiogram. Conclusion The highest prevalence of CHDs was found in Down syndrome. This study has a significant impact on the future of managing and directing the resources to improve the quality of life for syndromic patients. Further studies are needed to confirm these findings and to increase the local data in the field of CHDs in Saudi Arabia among syndromic patients.
Project description:To estimate the prevalences of the main groups of congenital anomalies and to assess their trend over time.Population-based study of prevalences.The Basque Country, Spain.All births and all congenital anomalies diagnosed prenatally, at birth or during the first year of age, in all hospitals of the country, from 1999 to 2008.Total diagnosed prevalences and prevalences at birth of all chromosomal and non-chromosomal anomalies, Down's syndrome, anomalies of the nervous system, urinary, limbs, digestive system and congenital heart defects.Mean age (SD) of women at childbirth and the proportion of them over 35 years of age shifted from 32.1 (4.5) years, with 18.3% in 1999-2001, to 32.3 (4.7) years, with 23.9% in 2006-2008. Between 1999 and 2008, 991 cases of chromosomal anomalies and 3090 of non-chromosomal anomalies were diagnosed, which yields, respectively, total prevalences of 5.2‰ and of 16.2‰. Among chromosomal anomalies, Down's syndrome is the most frequent (2.9‰). With marginal statistical significance, the results point at an increasing trend in total diagnosed chromosomal anomalies, but a decreasing one in prevalences at birth. Among non-chromosomal congenital anomalies, congenital heart defects are the most frequent (5.2‰) one. Rates of all non-chromosomal, urinary and limb anomalies grew during the study period, whereas those of congenital heart defects and anomalies of the digestive system did not change significantly.In the Basque Country, rates of chromosomal anomalies are higher than the overall estimated prevalence in European countries, and continue to increase slightly, which may be related to the rise in maternal age. Rates of non-chromosomal anomalies are within the European frequent range of values, and the increases observed need to be checked in the following years.
Project description:EEC syndrome is an autosomal dominant disorder with the cardinal signs of ectrodactyly, ectodermal dysplasia, and orofacial clefts. EEC syndrome has been linked to chromosome 3q27 and heterozygous p63 mutations were detected in unrelated EEC families. In addition, homozygous p63 null mice exhibit craniofacial abnormalities, limb truncations, and absence of epidermal appendages, such as hair follicles and tooth primordia. In this study, we screened 39 syndromic patients, including four with EEC syndrome, five with syndromes closely related to EEC syndrome, and 30 with other syndromic orofacial clefts and/or limb anomalies. We identified heterozygous p63 mutations in three unrelated cases of EEC syndrome, two Iowa white families and one sporadic case in a Filipino boy. One family is atypical for EEC and has features consistent with Hay-Wells syndrome. In this family, the mutation ablates a splice acceptor site and, in the other two, mutations produce amino acid substitutions, R280C and R304Q, which alter conserved DNA binding sites. Germline mosaicism was detected in the founder of the mutation in one case. These three cases show significant interfamilial and intrafamilial variability in expressivity. We also screened p63 in 62 patients with non-syndromic orofacial clefts, identifying an intronic single nucleotide polymorphism but finding no evidence of mutations that would explain even a subset of non-syndromic orofacial clefts. This study supports a common role for p63 in classical EEC syndrome, both familial and sporadic, but not in other related or non-syndromic forms of orofacial clefts.
Project description:Recombinant chromosome 8 syndrome is caused by duplication of 8q and deletion of 8p. A fetus with anomalies was misdiagnosed with this syndrome based on an amniocyte karyotype. Postnatal chromosomal microarray and other studies identified a de novo derivative chromosome 8. For fetal anomalies, detailed genetic studies may be required.
Project description:Syndromic primary immunodeficiencies are rare genetic disorders that affect both the immune system and other organ systems. More often, the immune defect is not the major clinical problem and is sometimes only recognized after a diagnosis has been made based on extra-immunological abnormalities. Here, we report two sibling pairs with syndromic primary immunodeficiencies that exceptionally presented with a phenotype resembling early-onset common variable immunodeficiency, while extra-immunological characteristics were not apparent at that time. Additional features not typically associated with common variable immunodeficiency were diagnosed only later, including skeletal and organ anomalies and mild facial dysmorphism. Whole exome sequencing revealed KMT2A-associated Wiedemann-Steiner syndrome in one sibling pair and their mother. In the other sibling pair, targeted testing of the known disease gene for Roifman syndrome (RNU4ATAC) provided a definite diagnosis. With this study, we underline the importance of an early-stage and thorough genetic assessment in paediatric patients with a common variable immunodeficiency phenotype, to establish a conclusive diagnosis and guide patient management. In addition, this study extends the mutational and immunophenotypical spectrum of Wiedemann-Steiner and Roifman syndromes and highlights potential directions for future pathophysiological research.