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1.
Am J Med Genet A ; 2019 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-31436871

RESUMO

Esophageal atresia (EA) with or without tracheoesophageal fistula (TEF) is a foregut defect that is a major component of the VATER/VACTERL association. The specific diagnostic criteria for the VATER/VACTERL association phenotype have changed over time. The current definition is presence of at least three of the following: Vertebral defects, Anal atresia, Cardiac defects, TE fistula, or Renal and Limb anomalies in the absence of a specific genetic diagnosis. Using the Texas Birth Defect Registry, 1,175 cases of EA+/-TEF (174 EA; 1,001 EA + TEF) were evaluated against strict definitions of VATER/VACTERL. Nine (5.2%) cases of EA alone and 164 (16.3%) cases of EA + TEF met criteria for a diagnosis of VATER; and 20 (11.5%) and 223 (22.2%), respectively, met criteria for VACTERL. Trisomy 21, Trisomy 18, 22q11 deletion, and CHARGE were the most common syndromic diagnoses. About 88.5% (154) cases of EA and 77.8% (778) cases of EA + TEF were likely not to meet the criteria for VACTERL. EA+/-TEF is more likely to be an isolated defect or part of a multiple malformation syndrome in a pattern other than VACTERL, than be part of the defined association. This study reinforces the need to consider broader evaluation for alternate diagnoses in the presence of these defects.

2.
Genet Med ; 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31263215

RESUMO

PURPOSE: Haploinsufficiency of DYRK1A causes a recognizable clinical syndrome. The goal of this paper is to investigate congenital anomalies of the kidney and urinary tract (CAKUT) and genital defects (GD) in patients with DYRK1A variants. METHODS: A large database of clinical exome sequencing (ES) was queried for de novo DYRK1A variants and CAKUT/GD phenotypes were characterized. Xenopus laevis (frog) was chosen as a model organism to assess Dyrk1a's role in renal development. RESULTS: Phenotypic details and variants of 19 patients were compiled after an initial observation that one patient with a de novo pathogenic variant in DYRK1A had GD. CAKUT/GD data were available from 15 patients, 11 of whom presented with CAKUT/GD. Studies in Xenopus embryos demonstrated that knockdown of Dyrk1a, which is expressed in forming nephrons, disrupts the development of segments of embryonic nephrons, which ultimately give rise to the entire genitourinary (GU) tract. These defects could be rescued by coinjecting wild-type human DYRK1A RNA, but not with DYRK1AR205* or DYRK1AL245R RNA. CONCLUSION: Evidence supports routine GU screening of all individuals with de novo DYRK1A pathogenic variants to ensure optimized clinical management. Collectively, the reported clinical data and loss-of-function studies in Xenopus substantiate a novel role for DYRK1A in GU development.

3.
Birth Defects Res ; 2019 Jul 16.
Artigo em Inglês | MEDLINE | ID: mdl-31313535

RESUMO

BACKGROUND: Few studies have systematically evaluated birth defect co-occurrence patterns, perhaps, in part, due to the lack of software designed to implement large-scale, complex analytic methods. METHODS: We created an R-based platform, "co-occurring defect analysis" (CODA), designed to implement analyses of birth defect co-occurrence patterns in birth defect registries. CODA uses an established algorithm for calculating the observed-to-expected ratio of a given birth defect combination, accounting for the known tendency of birth defects to co-occur nonspecifically. To demonstrate CODA's feasibility, we evaluated the computational time needed to assess 2- to 5-way combinations of major birth defects in the Texas Birth Defects Registry (TBDR) (1999-2014). We report on two examples of pairwise patterns, defects co-occurring with trisomy 21 or with non-syndromic spina bifida, to demonstrate proof-of-concept. RESULTS: We evaluated combinations of 175 major birth defects among 206,784 infants in the TBDR. CODA performed efficiently in the data set, analyzing 1.5 million 5-way combinations in 18 hr. As anticipated, we identified large observed-to-expected ratios for the birth defects that co-occur with trisomy 21 or spina bifida. CONCLUSIONS: CODA is available for application to birth defect data sets and can be used to better understand co-occurrence patterns. Co-occurrence patterns elucidated by using CODA may be helpful for identifying new birth defect associations and may provide etiological insights regarding potentially shared pathogenic mechanisms. CODA may also have wider applications, such as assessing patterns of additional types of co-occurrence patterns in other large data sets (e.g., medical records).

4.
JAMA Oncol ; 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31219523

RESUMO

Importance: Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. Objectives: To identify specific birth defect-childhood cancer (BD-CC) associations and characterize cancer risk in children by increasing number of nonchromosomal birth defects. Design, Setting, and Participants: This multistate, population-based registry linkage study pooled statewide data on births, birth defects, and cancer from Texas, Arkansas, Michigan, and North Carolina on 10 181 074 children born from January 1, 1992, to December 31, 2013. Children were followed up to 18 years of age for a diagnosis of cancer. Data were retrieved between September 26, 2016, and September 21, 2017, and data analysis was performed from September 2, 2017, to March 21, 2019. Exposures: Birth defects diagnoses (chromosomal anomalies and nonchromosomal birth defects) recorded by statewide, population-based birth defects registries. Main Outcomes and Measures: Cancer diagnosis before age 18 years, as recorded in state cancer registries. Cox regression models were used to generate hazard ratios (HRs) and 95% CIs to evaluate BD-CC associations and the association between number of nonchromosomal defects and cancer risk. Results: Compared with children without any birth defects (n = 10 181 074), children with chromosomal anomalies (n = 539 567) were 11.6 (95% CI, 10.4-12.9) times more likely to be diagnosed with cancer, whereas children with nonchromosomal birth defects (n = 2123) were 2.5 (95% CI, 2.4-2.6) times more likely to be diagnosed with cancer before 18 years of age. An increasing number of nonchromosomal birth defects was associated with a corresponding increase in the risk of cancer. Children with 4 or more major birth defects were 5.9 (95% CI, 5.4-6.5) times more likely to be diagnosed with cancer compared with those without a birth defect. In the analysis of 72 specific BD-CC patterns, 40 HRs were statistically significant (adjusted P < .05) after accounting for multiple comparisons. Cancers most frequently associated with nonchromosomal defects were hepatoblastoma and neuroblastoma. Conclusions and Relevance: Several significant and novel associations were observed between specific birth defects and cancers. Among children with nonchromosomal birth defects, the number of major birth defects diagnosed was significantly and directly associated with cancer risk. These findings could inform clinical treatment for children with birth defects and may elucidate mechanisms that lead to these complex outcomes.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31145939

RESUMO

BACKGROUND: The Observational Study of the Use and Safety of Xolair (omalizumab) during Pregnancy (EXPECT) pregnancy registry was a prospective observational study established in 2006 to evaluate perinatal outcomes in pregnant women exposed to omalizumab and their infants. OBJECTIVE: This analysis compares EXPECT outcomes with those from a disease-matched population of pregnant women not treated with omalizumab. Data from a substudy of platelet counts among newborns are also presented. METHODS: The EXPECT study enrolled 250 women with asthma exposed to omalizumab during pregnancy. The disease-matched external comparator cohort of women with moderate-to-severe asthma (n = 1153), termed the Quebec External Comparator Cohort (QECC), was created by using data from health care databases in Quebec, Canada. Outcome estimates were age adjusted based on the maternal age distribution of the EXPECT study. RESULTS: Among singleton infants in the EXPECT study, the prevalence of major congenital anomalies was 8.1%, which was similar to the 8.9% seen in the QECC. In the EXPECT study 99.1% of pregnancies resulted in live births, which was similar to 99.3% in the QECC. Premature birth was identified in 15.0% of EXPECT infants and 11.3% in the QECC. Small for gestational age was identified in 9.7% of EXPECT infants and 15.8% in the QECC. CONCLUSION: There was no evidence of an increased risk of major congenital anomalies among pregnant women exposed to omalizumab compared with a disease-matched unexposed cohort. Given the observational nature of this registry, however, an absence of increased risk with omalizumab cannot be definitively established.

6.
Am J Med Genet A ; 179(8): 1415-1419, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31119873

RESUMO

Incontinentia Pigmenti (IP; MIM 308300) is an X-linked dominant genodermatosis caused by pathogenic variant in IKBKG. The phenotype in adults is poorly described compared to that in children. Questionnaire survey of 99 affected women showed an age at diagnosis from newborn to 41 years, with 53 diagnosed by 6 months of age and 30 as adults. Stage I, II, and III lesions persisted in 16%, 17%, and 71%, respectively, of those who had ever had them. IP is allelic to two forms of ectodermal dysplasia. Many survey respondents reported hypohidrosis and/or heat intolerance and most had Stage IV findings. This suggests that "Stage IV" may be congenitally dysplastic skin that becomes more noticeable with maturity. Fifty-one had dentures or implants with 26 having more invasive jaw or dental surgery. Half had wiry or uncombable hair. Seventy-three reported abnormal nails with 27 having long-term problems. Cataracts and retinal detachment were the reported causes of vision loss. Four had microphthalmia. Respondents without genetic confirmation of IP volunteered information suggesting more involved phenotype or possibly misassigned diagnosis. Ascertainment bias likely accounts for the low prevalence of neurocognitive problems in the respondents.

7.
Birth Defects Res ; 111(13): 872-887, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31124321

RESUMO

BACKGROUND: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs). METHODS: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria. RESULTS: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs. CONCLUSION: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.

8.
Birth Defects Res ; 111(10): 598-612, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31021057

RESUMO

BACKGROUND: Acculturation has been examined with respect to various pregnancy adverse outcomes, including birth defects. Given the mixed and limited findings on the association between nativity and birth defects, we sought to further explore parental nativity and years lived in the U.S. across a range of defects. METHODS: Data from the National Birth Defects Prevention Study were used for this analysis. Infants with one of 46 major isolated birth defects (30 noncardiac/16 cardiac conditions) and infants without birth defects (controls) born during 1997-2011 were included. We examined parental nativity (foreign-born mothers, fathers, and both parents combined compared to a referent of both U.S.-born parents) and the number of years lived in the U.S. (≤5/6+ years). Descriptive statistics and logistic regression analyses were performed to estimate crude/adjusted odds ratios and 95% confidence intervals. RESULTS: Compared to U.S.-born mothers, foreign-born mothers tended to be older (25+ years), of Hispanic or Other race/ethnicity and were less likely to have reported drinking, smoking, illicit drug use, or having taken folic acid. In the adjusted analysis, seven findings among both parents reporting a foreign-birth were significant, including an increased association with spina bifida, anotia/microtia, and diaphragmatic hernia (aORs range: 1.3-1.7), and a reduced association with craniosynostosis and gastroschisis (aORs = 0.7). A generally protective effect was observed among foreign-born subjects living in the U.S. ≤5 years. CONCLUSIONS: We found that nativity was associated with some selected isolated defects, although the direction of effect varied by phenotype and by a number of years residing in the U.S.

9.
Int J Pediatr Otorhinolaryngol ; 122: 18-26, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30928866

RESUMO

OBJECTIVE: Anotia and microtia are congenital malformations of the external ear with few known risk factors. We conducted a comprehensive assessment of a wide range of potential risk factors using data from the National Birth Defects Prevention Study (NBDPS), a population-based case-control study of non-chromosomal structural birth defects in the United States. METHODS: Mothers of 699 infants with anotia or microtia (cases) and 11,797 non-malformed infants (controls) delivered between 1997 and 2011 were interviewed to obtain information about sociodemographic, health behavioral, and clinical characteristics. Adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated with logistic regression. RESULTS: Infants with anotia/microtia were more likely to be male (aOR, 1.29; 95% CI, 1.10-1.50) and from a multifetal pregnancy (aOR, 1.68; 95% CI, 1.16-2.42). Cases were also more likely to have parents of Hispanic ethnicity (maternal aOR, 3.19; 95% CI, 2.61-3.91; paternal aOR, 2.11; 95% CI, 1.54-2.88), and parents born outside the United States (maternal aOR, 1.29; 95% CI, 1.06-1.57; paternal aOR, 1.92; 95% CI, 1.53-2.41). Maternal health conditions associated with increased odds of anotia/microtia included obesity (aOR, 1.31; 95% CI, 1.06-1.61) and pre-pregnancy diabetes (type I aOR, 9.89; 95% CI, 5.46-17.92; type II aOR, 4.70; 95% CI, 2.56-8.63). Reduced odds were observed for black mothers (aOR, 0.57; 95% CI, 0.38-0.85) and mothers reporting daily intake of folic acid-containing supplements (aOR, 0.59; 95% CI, 0.46-0.76). CONCLUSION: We identified several risk factors for anotia/microtia, some which have been previously reported (e.g., diabetes) and others which we investigate for perhaps the first time (e.g., binge drinking) that warrant further investigation. Our findings point to some potentially modifiable risk factors and provide further leads toward understanding the etiology of anotia/microtia.


Assuntos
Microtia Congênita/epidemiologia , Diabetes Mellitus/epidemiologia , Adulto , Afro-Americanos/estatística & dados numéricos , Estudos de Casos e Controles , Microtia Congênita/etnologia , Suplementos Nutricionais , Orelha Externa/anormalidades , Pai/estatística & dados numéricos , Feminino , Ácido Fólico/uso terapêutico , Comportamentos Relacionados com a Saúde , Hispano-Americanos/estatística & dados numéricos , Humanos , Recém-Nascido , Masculino , Mães/estatística & dados numéricos , Obesidade/epidemiologia , Gravidez , Gravidez Múltipla , Fatores de Proteção , Fatores de Risco , Fatores Sexuais , Estados Unidos/epidemiologia
10.
Birth Defects Res ; 111(10): 584-590, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30864280

RESUMO

OBJECTIVE: Assess temporal trends in congenital microcephaly. METHODS: We used Texas inpatient discharge diagnoses between 2000 and 2015, restricting to newborns. Between 2000 and 2003, the maximum number of fields for recording diagnostic codes was eight, and between 2004 and 2015 it was 24. Microcephaly was classified into four subgroups based on co-occurring diagnoses: A (Known Causes), B (Other Birth Defects), C (Preterm Birth or Fetal Growth Restriction) and D (Isolated Cases). RESULTS: We identified 2,301 cases of microcephaly or 4.0 cases per 10,000 live births. There was an increase in the prevalence of microcephaly in 2012-2015 compared with 2000-2003, odds ratio = 1.85 (95% CI 1.64-2.10) Significant temporal increases in microcephaly were observed within each of the four microcephaly subgroups and significant temporal increases were also observed for eight other neonatal diagnoses during the same time period. When we restricted our analysis to cases with microcephaly identified using only the eight diagnostic codes available throughout the entire study period, the temporal trend for microcephaly was diminished or absent. CONCLUSIONS: It remains uncertain whether the observed increases in microcephaly and other neonatal diagnoses are real or an artifact of the change in the number of fields. However, since it is unlikely that there would be a simultaneous increase in microcephaly and eight other neonatal diagnoses, it is likely that some or all of the temporal increases in neonatal diagnoses are artifactual.

11.
Am J Med Genet A ; 2018 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-30450763

RESUMO

Hennekam lymphangiectasia-lymphedema syndrome (HKLLS) is a genetically heterogeneous lymphatic dysplasia with characteristic of facial dysmorphism, neurocognitive impairments, and abnormalities of the pericardium, intestinal tract, and extremities. It is an autosomal recessive condition caused by biallelic mutations in CCBE1 (collagen- and calcium-binding epidermal growth factor domain-containing protein 1) (HKLLS1; OMIM 235510) or FAT4 (HKLLS2; OMIM 616006). CCBE1 acts via ADAMTS3 (a disintegrin and metalloprotease with thrombospondin motifs-3 protease) to enhance vascular endothelial growth factor C signaling. There is report of one family supporting mutations in ADAMTS3 as causative for the phenotype labeled as HKLLS3. Here, we report an additional case of HKLLS that appears to be associated with homozygous nonsense mutation of ADAMTS3.

12.
Am J Hum Genet ; 103(4): 602-611, 2018 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-30269814

RESUMO

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome sequencing (WES) and whole-genome sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.

13.
Eur J Hum Genet ; 26(10): 1521-1536, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29891884

RESUMO

RASA1-related disorders are vascular malformation syndromes characterized by hereditary capillary malformations (CM) with or without arteriovenous malformations (AVM), arteriovenous fistulas (AVF), or Parkes Weber syndrome. The number of cases reported is relatively small; and while the main clinical features are CMs and AVMs/AVFs, the broader phenotypic spectrum caused by variants in the RASA1 gene is still being defined. Here, we report the clinical and molecular findings in 69 unrelated cases with a RASA1 variant identified at ARUP Laboratories. Sanger sequencing and multiplex ligation-dependent probe amplification were primarily used to evaluate RASA1. Several atypical cases were evaluated using next-generation sequencing (NGS) and array-comparative genomic hybridization (aCGH). Sixty individuals had a deleterious RASA1 variant of which 29 were novel. Nine individuals had a variant of uncertain significance. Five large RASA1 deletions were detected, giving an overall deletion/duplication rate of 8.3% (5/60) among positive cases. Most (75.4%) individuals with a RASA1 variant had CMs, and 44.9% had an AVM/AVF. Clinical findings in several cases expand the RASA1 phenotype. Our data suggest that screening for large RASA1 deletions and duplications in this disorder is important and suggest that NGS multi-gene panel testing is beneficial for the molecular diagnosis of cases with complex vascular phenotypes.

14.
Arthritis Rheumatol ; 70(9): 1399-1407, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-29623679

RESUMO

OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNF agents are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc-free anti-TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP, especially those exposed during early pregnancy. METHODS: Prospective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. RESULTS: Of 1,137 prospectively reported pregnancies with maternal exposure to CZP, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies. CONCLUSION: This analysis represents the largest cohort of pregnant women exposed to an anti-TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP.

15.
Birth Defects Res ; 110(5): 395-405, 2018 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-29171191

RESUMO

BACKGROUND: There are limited population-based studies on microcephaly. We characterized the epidemiology of microcephaly in Texas during a 5-year period (2008-2012), prior to the Zika epidemic in the Western hemisphere (2015). The associations of suspected risk factors were compared across four clearly defined case groups. METHODS: Data from the Texas Birth Defects Registry were used to calculate the prevalence of congenital microcephaly and crude and adjusted prevalence ratios using Poisson regression. Twelve maternal and infant factors were assessed across case groups, which included total (explained + unexplained), explained (e.g., syndromic), unexplained, and severe unexplained microcephaly (head circumference <3rd percentile). RESULTS: The birth prevalence for total and total severe microcephaly were 14.7 and 4.8 per 10,000 livebirths, respectively. For explained and unexplained cases, significantly elevated risks were noted for mothers who were older (35+), less educated (≤12 years), diabetic (pre-pregnancy or gestational), or had a preterm delivery. Unlike explained cases, however, mothers who were non-White or smoked had an increased risk for unexplained microcephaly. Furthermore, young maternal age (<20), multiparity, and higher BMI reduced the risk for unexplained microcephaly. For severe unexplained cases, the risk profile was similar to that for all unexplained cases-with the exception of null associations noted for diabetes and birth year. CONCLUSIONS: We found that risk patterns for microcephaly varied across case groupings. Risk factors included maternal race/ethnicity, age, and smoking during pregnancy. Among severe unexplained cases, notable positive associations were seen among mothers who were non-Hispanic Black or less educated, while inverse associations were noted for obesity.


Assuntos
Bases de Dados Factuais , Microcefalia/epidemiologia , Zika virus , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Prevalência , Estudos Retrospectivos , Texas/epidemiologia , Infecção por Zika virus/epidemiologia
16.
J Dent Child (Chic) ; 84(1): 39-43, 2017 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-28387189

RESUMO

The purpose of this paper is to describe the clinical findings and management of a case involving a patient with co-occurring ring chromosome 14 syndrome and 47,XXX presenting with enamel pit defects and taurodontism. Ring chromosome 14 syndrome is an unusual condition with uncontrolled seizure disorder as its most significant finding; 47,XXX (trisomy X; triple X) is a more common condition and has characteristic physical and behavioral findings. Neither condition has been associated with enamel pit defects.


Assuntos
Esmalte Dentário/anormalidades , Cavidade Pulpar/anormalidades , Cromossomos em Anel , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/complicações , Anormalidades Dentárias/etiologia , Anestesia Geral , Criança , Cromossomos Humanos Par 14 , Cromossomos Humanos X , Cárie Dentária/diagnóstico por imagem , Cárie Dentária/reabilitação , Cárie Dentária/terapia , Esmalte Dentário/diagnóstico por imagem , Hipoplasia do Esmalte Dentário/diagnóstico por imagem , Epilepsia , Feminino , Humanos , Nova Orleans , Aberrações dos Cromossomos Sexuais , Transtornos do Cromossomo Sexual no Desenvolvimento Sexual/fisiopatologia , Trissomia/fisiopatologia , Estimulação do Nervo Vago
17.
J Craniofac Surg ; 28(2): 308, 2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28060101
18.
Birth Defects Res A Clin Mol Teratol ; 106(11): 935-939, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27511745

RESUMO

BACKGROUND: Pharmaceutical pregnancy exposure registries seek to evaluate temporal associations between drug exposures and adverse outcomes, particularly congenital anomalies. These registries record observed associations that may or may not be causally-related to the exposure. Most major congenital malformations (i.e., structural birth defects) result from abnormal development during embryogenesis. A standardized catalog of defects of concern (colloquially the "BPA Codes") is used both in public health surveillance programs and pregnancy exposure registries. There are, however, some anomalies that cause significant morbidity and mortality for which isolated second or third trimester exposures may be pathogenically significant. There currently exists no standardized list of defects for which exposure limited to the fetal period may be problematic. METHODS: The six-digit-code list was used to determine anomalies that might result from medication exposures limited to the fetal period. RESULTS: Defects with documented first trimester pathogenesis (e.g., anencephaly, heterotaxy) were eliminated from consideration, as were chromosomal and single gene disorders (e.g., trisomy 21, achondroplasia). The remaining defects include the following: (1) those that are known to or could reasonably originate or manifest after the embryonic period (e.g., porencephaly, cataracts); (2) those for which pathogenesis is unclear or variable enough that exposure at any gestational age might be considered relevant (e.g., club foot, microcephaly); and (3) those that include some component of abnormal growth (e.g., hemihyperplasia). "Unspecified" defects (e.g., "abnormality of the leg") were included by default because there is insufficient information to assume first trimester embryogenesis. CONCLUSION: The final result is a list of major and minor anomalies in 11 organ system categories that may be caused by teratogen exposure during the fetal period. Birth Defects Research (Part A) 106:935-939, 2016. © 2016 Wiley Periodicals, Inc.


Assuntos
Aberrações Cromossômicas , Anormalidades Congênitas , Exposição Ambiental/efeitos adversos , Exposição Materna/efeitos adversos , Primeiro Trimestre da Gravidez , Teratogênios/toxicidade , Anormalidades Congênitas/epidemiologia , Anormalidades Congênitas/patologia , Feminino , Humanos , Recém-Nascido , Masculino , Gravidez
19.
Eur J Obstet Gynecol Reprod Biol ; 197: 6-10, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26687320

RESUMO

OBJECTIVE: To assess the risk for ventricular septal defects and congenital heart defects following zidovudine exposure during pregnancy using data from the Antiretroviral Pregnancy Registry. STUDY DESIGN: Data on 16,304 prospectively reported pregnancies were analyzed to estimate the frequency and risk of ventricular septal defects and congenital heart defects, comparing exposure between zidovudine-containing regimens and non-zidovudine antiretroviral regimens. The numerator includes defect cases in outcomes at ≥ 20 weeks of gestational age. The denominator includes live birth outcomes. Infants with chromosomal anomalies were excluded. RESULTS: There were 15,451 live birth outcomes; 13,073 were prenatally exposed to zidovudine-containing regimens and 2378 to non-zidovudine containing regimens. There were 36 ventricular septal defect cases: 31 exposed to prenatal zidovudine and 5 unexposed. Nine of the zidovudine-exposed cases had earliest exposure in the first trimester; 22 had second/third trimester exposure. Of the 5 ventricular septal defect cases not exposed to zidovudine, 2 had earliest exposure to non-zidovudine antiretroviral regimens in the first trimester, and 3 had exposure in the second/third trimester. The prevalence of ventricular septal defect was 0.24% (95% confidence interval: 0.16, 0.34) for infants exposed to zidovudine-containing regimens and 0.21% (95% confidence interval: 0.07, 0.49) for non-zidovudine regimens. The relative risk comparing the 2 was 1.13 (95% confidence interval: 0.44, 2.90). There were a total of 90 congenital heart defect cases; 78 were exposed prenatally to zidovudine-containing regimens, and 12 were unexposed. Twenty-six of the zidovudine-exposed cases had earliest exposure in the first trimester and 52 had second/third trimester exposure. Six congenital heart defect cases with non-zidovudine antiretroviral regimens had earliest exposure in the first trimester and 6 had exposure in the second/third trimester. The prevalence of congenital heart defects was 0.60% (95% confidence interval: 0.47, 0.74) for infants exposed to zidovudine-containing regimens and 0.50% (95% confidence interval: 0.26, 0.88) for non-zidovudine regimens. The relative risk comparing the 2 was 1.18 (95% confidence interval: 0.64, 2.17). CONCLUSIONS: The prevalence and risk of ventricular septal defects and congenital heart defects among infants exposed to zidovudine-containing regimens is not significantly different from the prevalence and risk in infants exposed to non-zidovudine containing regimens. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01137981.


Assuntos
Fármacos Anti-HIV/uso terapêutico , Terapia Antirretroviral de Alta Atividade/métodos , Infecções por HIV/tratamento farmacológico , Comunicação Interventricular/epidemiologia , Nascimento Vivo , Complicações Infecciosas na Gravidez/tratamento farmacológico , Sistema de Registros , Zidovudina/uso terapêutico , Adolescente , Adulto , Argentina/epidemiologia , Brasil/epidemiologia , Estudos de Casos e Controles , Feminino , França/epidemiologia , Idade Gestacional , Cardiopatias Congênitas/epidemiologia , Humanos , Pessoa de Meia-Idade , Gravidez , Segundo Trimestre da Gravidez , Efeitos Tardios da Exposição Pré-Natal , Prevalência , Estudos Prospectivos , Fatores de Risco , África do Sul/epidemiologia , Uganda/epidemiologia , Reino Unido/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem
20.
Hum Mutat ; 37(2): 148-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26507355

RESUMO

Mandibulofacial dysostosis with microcephaly (MFDM) is a multiple malformation syndrome comprising microcephaly, craniofacial anomalies, hearing loss, dysmorphic features, and, in some cases, esophageal atresia. Haploinsufficiency of a spliceosomal GTPase, U5-116 kDa/EFTUD2, is responsible. Here, we review the molecular basis of MFDM in the 69 individuals described to date, and report mutations in 38 new individuals, bringing the total number of reported individuals to 107 individuals from 94 kindreds. Pathogenic EFTUD2 variants comprise 76 distinct mutations and seven microdeletions. Among point mutations, missense substitutions are infrequent (14 out of 76; 18%) relative to stop-gain (29 out of 76; 38%), and splicing (33 out of 76; 43%) mutations. Where known, mutation origin was de novo in 48 out of 64 individuals (75%), dominantly inherited in 12 out of 64 (19%), and due to proven germline mosaicism in four out of 64 (6%). Highly penetrant clinical features include, microcephaly, first and second arch craniofacial malformations, and hearing loss; esophageal atresia is present in an estimated ∼27%. Microcephaly is virtually universal in childhood, with some adults exhibiting late "catch-up" growth and normocephaly at maturity. Occasionally reported anomalies, include vestibular and ossicular malformations, reduced mouth opening, atrophy of cerebral white matter, structural brain malformations, and epibulbar dermoid. All reported EFTUD2 mutations can be found in the EFTUD2 mutation database (http://databases.lovd.nl/shared/genes/EFTUD2).


Assuntos
Anormalidades Múltiplas/genética , Perda Auditiva/genética , Deficiência Intelectual/genética , Disostose Mandibulofacial/genética , Microcefalia/genética , Mutação , Fatores de Alongamento de Peptídeos/genética , Ribonucleoproteína Nuclear Pequena U5/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/patologia , Motivos de Aminoácidos , Bases de Dados Genéticas , Expressão Gênica , Haploinsuficiência , Perda Auditiva/diagnóstico , Perda Auditiva/patologia , Humanos , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/patologia , Disostose Mandibulofacial/diagnóstico , Disostose Mandibulofacial/patologia , Microcefalia/diagnóstico , Microcefalia/patologia , Modelos Moleculares , Dados de Sequência Molecular , Penetrância , Fenótipo , Estrutura Secundária de Proteína , Estrutura Terciária de Proteína , Processamento de RNA , Spliceossomos/genética
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