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1.
Ann Ist Super Sanita ; 59(4): 295-303, 2023.
Article in English | MEDLINE | ID: mdl-38088397

ABSTRACT

BACKGROUND: Holoprosencephaly is a rare (1/16,000 livebirths) and severe brain malformation occurring during early embryogenesis. The malformation originates from absent or incomplete forebrain division and is associated with altered embryonic patterning. OBJECTIVES: A narrative review to identify and assess the evidence on non-genetic risk factors. RESULTS: Genes involved include sonic hedgehog, Zinc finger protein, SIX homeobox 3. Pregestational diabetes, with periconceptional hyperglycaemia, is the main non-genetic risk factor; increased oxidative stress in neuroectoderm, in particular neural crest cells, appears as the main mechanism. Several widespread pollutants, including inorganic arsenic, PFAS and PCBs, may increase the risk of pregestational diabetes by altering metabolic factors, including lipids and insulin. A scenario "widespread exposures-rare outcomes in susceptible subjects" suggests that exposure to dietary pollutants may increase the risk of pregestational diabetes, hence of holoprosencephaly in susceptible embryos. CONCLUSIONS: This complex pathway is plausible and worth being investigated; moreover, it highlights the importance of assessing risk factors, and the associated uncertainties, in order to support primary prevention strategies for multifactorial malformations.


Subject(s)
Diabetes Mellitus , Holoprosencephaly , Humans , Diabetes Mellitus/epidemiology , Diabetes Mellitus/etiology , Hedgehog Proteins/genetics , Hedgehog Proteins/metabolism , Holoprosencephaly/epidemiology , Holoprosencephaly/etiology , Food Contamination
4.
Environ Health ; 19(1): 65, 2020 06 08.
Article in English | MEDLINE | ID: mdl-32513280

ABSTRACT

BACKGROUND: Pesticide exposure during susceptible windows and at certain doses are linked to numerous birth defects. Early experimental evidence suggests an association between active ingredients in pesticides and holoprosencephaly (HPE), the most common malformation of the forebrain in humans (1 in 250 embryos). No human studies to date have examined the association. This study investigated pesticides during multiple windows of exposure and fetal risk for HPE. It is hypothesized that pre-conception and early pregnancy, the time of brain development in utero, are the most critical windows of exposure. METHODS: A questionnaire was developed for this retrospective case-control study to estimate household, occupational, and environmental pesticide exposures. Four windows of exposure were considered: preconception, early, mid and late pregnancy. Cases were identified through the National Human Genome Research Institute's ongoing clinical studies of HPE. Similarly, controls were identified as children with Williams-Beuren syndrome, a genetic syndrome also characterized by congenital malformations, but etiologically unrelated to HPE. We assessed for differences in odds of exposures to pesticides between cases and controls. RESULTS: Findings from 91 cases and 56 controls showed an increased risk for HPE with reports of maternal exposure during pregnancy to select pesticides including personal insect repellants (adjusted odds ratio (aOR) 2.89, confidence interval (CI): 0.96-9.50) and insecticides and acaricides for pets (aOR 3.84, CI:1.04-16.32). Exposure to household pest control products during the preconception period or during pregnancy was associated with increased risk for HPE (aOR 2.60, OR: 0.84-8.68). No associations were found for occupational exposures to pesticides during pregnancy (aOR: 1.15, CI: 0.11-11.42), although exposure rates were low. Higher likelihood for HPE was also observed with residency next to an agricultural field (aOR 3.24, CI: 0.94-12.31). CONCLUSIONS: Observational findings are consistent with experimental evidence and suggest that exposure to personal, household, and agricultural pesticides during pregnancy may increase risk for HPE. Further investigations of gene by environment interactions are warranted.


Subject(s)
Environmental Exposure/adverse effects , Holoprosencephaly/epidemiology , Pesticides/adverse effects , Prenatal Exposure Delayed Effects/epidemiology , Adolescent , Adult , Case-Control Studies , Female , Holoprosencephaly/chemically induced , Humans , Male , Maternal Exposure/adverse effects , Occupational Exposure/adverse effects , Pregnancy/drug effects , Prenatal Exposure Delayed Effects/chemically induced , Retrospective Studies , Risk Factors , United States/epidemiology , Young Adult
5.
Prenat Diagn ; 40(5): 565-576, 2020 04.
Article in English | MEDLINE | ID: mdl-31955448

ABSTRACT

OBJECTIVE: The objective of this study is to evaluate the prenatal diagnosis, postnatal characteristics, and the spectrum of associated findings in fetuses with holoprosencephaly (HPE). METHODS: Fetal neurosonograms, postnatal assessment, and chromosomal analysis were performed in a cohort of 25 fetuses with HPE. RESULTS: The prevalence of HPE in high-risk pregnancies was 4.4:10 000. The alobar subtype was the most frequently encountered, with 17 cases (68%). Interestingly, among them, four cases (16%) presented with the rare agnathia-otocephaly complex. Chromosomal abnormalities were detected in 11 cases (44%), the most frequent being trisomy 13 in seven cases (five alobar, one semilobar, and one lobar HPE), followed by trisomy 18 in two cases with semilobar HPE. One case of alobar HPE had 45, XX, t(18;22) (q10;q10), -18p karyotyping, and one case of semilobar HPE was associated with triploidy. Facial malformations in HPE spectrum ranged from cyclopia, proboscis, and arrhinia that were associated with the alobar subtype to hypotelorism and median cleft that were frequent among the semilobar and lobar subtypes. Associated neural tube defects were identified in 12% of cases. CONCLUSION: Our study illustrates the clinical and genetic heterogeneity of HPE and describes different chromosomal abnormalities associated with HPE.


Subject(s)
Chromosome Disorders/epidemiology , Craniofacial Abnormalities/epidemiology , Hernia, Umbilical/epidemiology , Holoprosencephaly/epidemiology , Neural Tube Defects/epidemiology , Abortion, Induced , Adolescent , Adult , Chromosome Disorders/diagnostic imaging , Chromosomes, Human, Pair 18 , Chromosomes, Human, Pair 22 , Consanguinity , Craniofacial Abnormalities/diagnostic imaging , Egypt/epidemiology , Encephalocele/diagnostic imaging , Encephalocele/epidemiology , Female , Fetal Death , Hernia, Umbilical/diagnostic imaging , Holoprosencephaly/diagnostic imaging , Humans , Male , Neural Tube Defects/diagnostic imaging , Pregnancy , Pregnancy in Diabetics/epidemiology , Prevalence , Translocation, Genetic , Triploidy , Trisomy 13 Syndrome/diagnosis , Trisomy 13 Syndrome/epidemiology , Trisomy 18 Syndrome/diagnosis , Trisomy 18 Syndrome/epidemiology , Ultrasonography, Prenatal , Young Adult
6.
Pediatr Int ; 62(5): 593-599, 2020 May.
Article in English | MEDLINE | ID: mdl-31886593

ABSTRACT

BACKGROUND: Holoprosencephaly (HPE) is a congenital malformation with an estimated prevalence of 0.10-6.06 per 10 000 births but with no nationwide data specific to Japan. METHODS: This nationwide retrospective questionnaire survey was conducted from 2011 to 2013. All 467 training hospitals for perinatal and neonatal care certified by the Japan Society of Perinatal and Neonatal Medicine were contacted. The birth prevalence rate (BPR) was assessed from the primary survey and clinical characteristics from the secondary survey. RESULTS: We received valid responses from 253 hospitals in the primary survey (54.6%). Of 390 342 live births, 60 were diagnosed with HPE (23 males and 37 females), resulting in an actual BPR of 1.54 per 10 000 live births. The point estimate for HPE cases was 100 (95% confidence interval [CI]: 80.7-120), and the estimated BPR of HPE was calculated to be 0.32 per 10 000 live births (95% CI: 0.26-0.38) based on 3 117 853 live births according to Japanese national statistics during the study period. In the secondary survey, we obtained data for 49 cases (19 males and 30 females). Of these, 20 were alobar (40.8%), 20 were semilobar (40.8%), five were lobar (10.4%), and four were of unknown type. Genetic examination was performed in 37 of the 49 HPE patients and revealed that chromosomes 13, 18, and 7 were affected in eight, six, and four patients, respectively. CONCLUSIONS: This is the most extensive survey on holoprosencephaly to date in Japan. The estimated BPR was consistent with that reported in previous research.


Subject(s)
Holoprosencephaly/epidemiology , Female , Genetic Testing , Holoprosencephaly/genetics , Humans , Infant, Newborn , Japan/epidemiology , Live Birth/epidemiology , Male , Prevalence , Retrospective Studies , Surveys and Questionnaires
7.
Am J Obstet Gynecol ; 222(2): 176.e1-176.e11, 2020 02.
Article in English | MEDLINE | ID: mdl-31454511

ABSTRACT

BACKGROUND: Diabetes is associated with an increased risk for many birth defects and is likely to have an increasing impact on birth defect prevalence because of the rise in diabetes in the United States in recent decades. One of the first analyses in which specific birth defects were assessed for their relationship with both pregestational and gestational diabetes used data from the initial 6 years of the National Birth Defects Prevention Study. That analysis reported strong associations for pregestational diabetes with several birth defects, but few exposures among some of the less common birth defects led to unstable estimates with wide confidence intervals. Since that analysis, the study continued to collect data for another 8 years, including information on approximately 19,000 additional cases and 6900 additional controls. OBJECTIVE: Our objective was to use data from the National Birth Defects Prevention Study, the largest population-based birth defects case-control study in the United States, to provide updated and more precise estimates of the association between diabetes and birth defects, including some defects not previously assessed. STUDY DESIGN: We analyzed data on deliveries from October 1997 through December 2011. Mothers of case and control infants were interviewed about their health conditions and exposures during pregnancy, including diagnosis of pregestational (type 1 or type 2) diabetes before the index pregnancy or gestational diabetes during the index pregnancy. Using logistic regression, we separately assessed the association between pregestational and gestational diabetes with specific categories of structural birth defects for which there were at least 3 exposed case infants. For birth defect categories for which there were at least 5 exposed case infants, we calculated odds ratios adjusted for maternal body mass index, age, education, race/ethnicity, and study site; for defect categories with 3 or 4 exposed cases, we calculated crude odds ratios. RESULTS: Pregestational diabetes was reported by 0.6% of mothers of control infants (71 of 11,447) and 2.5% of mothers of case infants (775 of 31,007). Gestational diabetes during the index pregnancy was reported by 4.7% of mothers of control infants (536 of 11,447) and 5.3% of mothers of case infants (1,653 of 31,007). Pregestational diabetes was associated with strong, statistically significant odds ratios (range, 2.5-80.2) for 46 of 50 birth defects considered. The largest odds ratio was observed for sacral agenesis (adjusted odds ratio, 80.2; 95% confidence interval, 46.1-139.3). A greater than 10-fold increased risk was also observed for holoprosencephaly (adjusted odds ratio, 13.1; 95% confidence interval, 7.0-24.5), longitudinal limb deficiency (adjusted odds ratio, 10.1; 95% confidence interval, 6.2-16.5), heterotaxy (adjusted odds ratio, 12.3; 95% confidence interval, 7.3-20.5), truncus arteriosus (adjusted odds ratio, 14.9; 95% confidence interval, 7.6-29.3), atrioventricular septal defect (adjusted odds ratio, 10.5; 95% confidence interval, 6.2-17.9), and single ventricle complex (adjusted odds ratio, 14.7; 95% confidence interval, 8.9-24.3). For gestational diabetes, statistically significant odds ratios were fewer (12 of 56) and of smaller magnitude (range, 1.3- 2.1; 0.5 for gastroschisis). CONCLUSION: Pregestational diabetes is associated with a markedly increased risk for many specific births defects. Because glycemic control before pregnancy is associated with a reduced risk for birth defects, ongoing quality care for persons with diabetes is an important opportunity for prevention.


Subject(s)
Congenital Abnormalities/epidemiology , Diabetes, Gestational/epidemiology , Pregnancy in Diabetics/epidemiology , Abnormalities, Multiple/epidemiology , Adult , Case-Control Studies , Female , Gastroschisis/epidemiology , Heart Defects, Congenital/epidemiology , Holoprosencephaly/epidemiology , Humans , Limb Deformities, Congenital/epidemiology , Meningocele/epidemiology , Nervous System Malformations/epidemiology , Pregnancy , Sacrococcygeal Region/abnormalities , United States/epidemiology , Young Adult
8.
PLoS One ; 14(6): e0217835, 2019.
Article in English | MEDLINE | ID: mdl-31170204

ABSTRACT

OBJECTIVE: To describe the epidemiology of holoprosencephaly (HPE) in China with special reference to prevalence and associated anomalies. METHODS: Data were abstracted from the Chinese Birth Defects Monitoring Network for the period 2007-2014. Birth prevalence of HPE were assessed by birth year, fetal/infant sex, maternal age, and maternal residential area. Poisson regressions were used to calculate the crude and adjusted prevalence ratios (PR) and their 95% confidence intervals, and linear chi-square test was used to explore time trend for the prevalence of HPE. RESULTS: A total of 1222 HPE cases were identified in 13,284,142 births, yielding an overall prevalence of 0.92 per 10,000 births. The annual prevalence of HPE presented an upward trend (P<0.001), from 0.54 per 10,000 births in 2007 to 1.21 per 10,000 births in 2014. Higher prevalence was found in older maternal-age groups (30-34 years, adjusted PR: 1.19, 95% CI: 1.02-1.40; ≥35 years, adjusted PR: 1.53, 95% CI: 1.26-1.86) in comparison with the maternal-age group of 25 to 29 years. Higher prevalence was also found in infants born to mothers resided in urban areas (adjusted PR: 1.23, 95% CI: 1.08-1.39) and female infants (adjusted PR: 1.30, 95% CI: 1.15-1.47). CONCLUSIONS: HPE is an important perinatal health issue because of its poor prognosis. This is the first study depicting a picture of epidemiological characteristics of HPE in China, which can provide useful references for future studies.


Subject(s)
Holoprosencephaly/epidemiology , Population Surveillance , Adult , China/epidemiology , Female , Humans , Infant, Newborn , Male , Retrospective Studies , Young Adult
10.
Am J Med Genet C Semin Med Genet ; 178(2): 151-164, 2018 06.
Article in English | MEDLINE | ID: mdl-29761639

ABSTRACT

Holoprosencephaly (HPE) is a major structural birth defect of the brain that occurs in approximately 1 in 10,000 live births. Although some genetic causes of HPE are known, a substantial proportion of cases have an unknown etiology. Due to the low birth prevalence and rarity of exposure to many potential risk factors for HPE, few epidemiologic studies have had sufficient sample size to examine risk factors. A 2010 review of the literature identified several risk factors that had been consistently identified as occurring more frequently among cases of HPE, including maternal diabetes, twinning, and a predominance of females, while also identifying a number of potential risk factors that had been less widely studied. In this article, we summarize a systematic literature review conducted to update the evidence for nongenetic risk factors for HPE.


Subject(s)
Holoprosencephaly/epidemiology , Holoprosencephaly/etiology , Diabetes Mellitus , Female , Humans , Pregnancy , Risk Factors , Twins
11.
Rev Med Chil ; 143(7): 874-9, 2015 Jul.
Article in Spanish | MEDLINE | ID: mdl-26361024

ABSTRACT

BACKGROUND: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. AIM: To estimate holoprosencephaly prevalence at birth. PATIENTS AND METHODS: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. RESULTS: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. CONCLUSIONS: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).


Subject(s)
Holoprosencephaly/epidemiology , Adolescent , Adult , Chile/epidemiology , Cleft Lip/epidemiology , Cleft Lip/etiology , Cleft Palate/epidemiology , Cleft Palate/etiology , Female , Holoprosencephaly/classification , Holoprosencephaly/complications , Humans , Live Birth , Male , Maternal Age , Prevalence , Sex Factors , Stillbirth , Young Adult
12.
Rev. méd. Chile ; 143(7): 874-879, jul. 2015. tab
Article in Spanish | LILACS | ID: lil-757912

ABSTRACT

Background: Holoprosencephaly is a structural anomaly of the brain that consists in a defect of the prosencephalon development that leads to face and neurological defects of variable intensity. Aim: To estimate holoprosencephaly prevalence at birth. Patients and Methods: All cases of holoprosencephaly, born alive or stillbirths, registered in the 15 Chilean Hospitals of the Latin American Collaborative Study of Congenital Malformations (ECLAMC) between 1972 and 2012, were studied. Craniofacial and other anomalies found in newborns affected by holoprosencephaly are described. Results: Fifty five cases of holoprosencephaly (58% males) were found among the 798.222 registered births (rendering a prevalence at birth of 0.69 per 10.000 newborns). The most common cranial defect was medial cleft lip with cleft palate (27.3%), bilateral cleft lip (11%) or both (38.2%), cyclopia (14%), single nostril (10.9%) and proboscis (9.1%). Eleven percent cases had a trisomy 13. A slight increase in prevalence over time was observed. Conclusions: Holoprosencephaly has a low frequency in Chile and is associated to trisomy 13. The increase in prevalence could be explained by a better prenatal diagnosis (ultrasonography).


Subject(s)
Adolescent , Adult , Female , Humans , Male , Young Adult , Holoprosencephaly/epidemiology , Chile/epidemiology , Cleft Lip/epidemiology , Cleft Lip/etiology , Cleft Palate/epidemiology , Cleft Palate/etiology , Holoprosencephaly/classification , Holoprosencephaly/complications , Live Birth , Maternal Age , Prevalence , Sex Factors , Stillbirth
13.
Radiographics ; 35(1): 275-90, 2015.
Article in English | MEDLINE | ID: mdl-25590404

ABSTRACT

Structural malformations of the brain are an important cause of childhood mortality and morbidity, with the latter having long-term financial and psychosocial implications for the affected child and family. Holoprosencephaly (HPE) is a severe brain malformation characterized by abnormal cleavage of the prosencephalon in the 5th gestational week. Aprosencephaly and atelencephaly occur earlier because of failure in the formation of the prosencephalon and telencephalon, respectively. The HPE holoprosencephaly spectrum classically includes alobar, semilobar, and lobar forms, although there are no clear-cut defining features. The middle interhemispheric variant (MIH), also known as syntelencephaly, is classified as a variant of HPE holoprosencephaly with midline interhemispheric fusion. Other conditions sometimes included in the spectrum of HPE holoprosencephaly include septo-optic dysplasia (SOD); "minimal" HPE holoprosencephaly , which is associated with subtle craniofacial malformations and mild developmental delay; and microform HPE holoprosencephaly , which by definition excludes brain involvement. The focus of this article will be on the spectrum of findings visible in fetal manifestation of the HPE holoprosencephaly spectrum. Brain embryology; the imaging characteristics, epidemiology, and embryology of HPE; and the more common associated anomalies, particularly those of the face ("the face predicts the brain") are reviewed. Recognition of these anomalies is important for accurate parental counseling, since the prognosis is poor but not invariably lethal; children with the milder forms may live well into their teens with severe developmental delays, endocrine dysfunction, and disrupted homeostasis. Available data on outcome in surviving children are summarized. Illustrative fetal ultrasonographic and magnetic resonance images are presented with clinical, autopsy, and postnatal imaging correlation.


Subject(s)
Holoprosencephaly/diagnosis , Prenatal Diagnosis/methods , Female , Holoprosencephaly/epidemiology , Holoprosencephaly/etiology , Humans , Pregnancy , Prognosis , Risk Factors
14.
Prenat Diagn ; 33(13): 1233-7, 2013 Dec.
Article in English | MEDLINE | ID: mdl-24018978

ABSTRACT

OBJECTIVE: The aim of this study was to determine whether choroid plexus morphology ('butterfly' sign) and biparietal diameter (BPD) are effective sonographic screening tools for holoprosencephaly (HPE) in the first trimester. METHODS: An axial view of the fetal head was obtained routinely to determine the presence of the 'butterfly' sign in pregnancies presenting for sonographic screening at 11-13 weeks of gestation. The same view was also used to obtain BPD measurements. The definitive diagnosis of HPE was established by the sonographic demonstration of an anterior cerebral monoventricular cavity and thalamic fusion. RESULTS: During a 9-year study period, 11 068 live fetuses were screened. There were 11 cases of HPE (prevalence 1/1006); all of them were detected by demonstration of an absent 'butterfly' sign with no false-positive cases. The BPD was less than the 5th percentile in 40% of the cases. CONCLUSIONS: The 'butterfly' sign appears to be a highly sensitive marker for HPE in the first trimester. On the other hand, BPD measurements had a lower sensitivity, implying that microcephaly is not a prominent first-trimester feature in these cases. Incorporation of the 'butterfly' sign into the first trimester anatomy scan is simple and can facilitate the identification of the vast majority of fetuses with HPE in the first trimester.


Subject(s)
Choroid Plexus/anatomy & histology , Choroid Plexus/diagnostic imaging , Holoprosencephaly/diagnostic imaging , Parietal Lobe/anatomy & histology , Parietal Lobe/diagnostic imaging , Pregnancy Trimester, First , Ultrasonography, Prenatal , Adolescent , Adult , Body Weights and Measures , Chile/epidemiology , Choroid Plexus/abnormalities , Female , Head/diagnostic imaging , Holoprosencephaly/epidemiology , Humans , Middle Aged , Parietal Lobe/abnormalities , Pregnancy , Prevalence , Ultrasonography, Prenatal/statistics & numerical data , Young Adult
15.
Reprod Toxicol ; 41: 80-5, 2013 Nov.
Article in English | MEDLINE | ID: mdl-23791929

ABSTRACT

Holoprosencephaly, a major congenital malformation of the brain, consists in a complete or partial failure of the prosencephalon to divide into separate hemispheres. Alobar holoprosencephaly with cyclopia was analyzed on the basis of autopsy reports performed for hospitals admitting patients from the Lublin Region in Eastern Poland in the period of 20 years (1981-2000). The malformation was found in seven newborns - five girls, one boy and one child with sex not established due to agenesia of the genital organs, all autopsied in the years 1990-1999. According to clinical data, none of the mothers (age 24-39 years) was exposed to any prescribed or over-the-counter (OTC) drugs during pregnancy, but one was exposed to paints in early pregnancy. The proboscis was present in four of seven cases. Six of seven children displayed additional congenital malformations. In two cases intrapancreatic accessory spleen suggesting trisomy 13 was found. Alobar holoprosencephaly with cyclopia is a rare lethal congenital anomaly frequently accompanied by other malformations and characterized by large variations in incidence.


Subject(s)
Holoprosencephaly/epidemiology , Academic Medical Centers , Autopsy , Female , Humans , Incidence , Infant, Newborn , Male , Poland/epidemiology
16.
Genet Couns ; 23(3): 341-6, 2012.
Article in English | MEDLINE | ID: mdl-23072180

ABSTRACT

Holoprosencephaly is frequently accompanied by midline facial abnormalities such as hypotelorism, cyclopia, etmocephaly and cebocephaly. Cebocephaly is a very rare congenital anomaly combining with semilobar holoprosencephaly. Chromosomal analysis shows normal karyotyping. Lissencephaly and holoprosencephaly are rare associations, that have not been reported yet with cebocephaly. Herein we present the first case of cebocephaly with severe semilobar holoprosencephaly and lissencephaly.


Subject(s)
Abnormalities, Multiple/diagnosis , Craniofacial Abnormalities/diagnosis , Holoprosencephaly/diagnosis , Lissencephaly/diagnosis , Abnormalities, Multiple/epidemiology , Abnormalities, Multiple/genetics , Comorbidity , Craniofacial Abnormalities/epidemiology , Craniofacial Abnormalities/genetics , Female , Holoprosencephaly/epidemiology , Holoprosencephaly/genetics , Humans , Infant, Newborn , Lissencephaly/epidemiology , Lissencephaly/genetics , Severity of Illness Index
17.
Am J Med Genet A ; 158A(4): 751-8, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22419615

ABSTRACT

Holoprosencephaly (HPE) is one of the most common developmental field defects, occurring in 1 in 250 conceptuses and in 1 in 10,000-20,000 live births. Nearly half of patients with HPE have a recognized syndrome or a single gene defect. However, little is known about the risk factors for the remainder with "nonsyndromic" HPE. In our case-control study, we examine factors associated with nonsyndromic HPE. We identified 47 patients with HPE from the genetics clinic database with an equal number of controls matched for gender and birthdate. Of the 47 patients, 23 were identified as nonsyndromic. No statistically significant differences were noted between the mean maternal and paternal ages of patients and controls. Factors associated with nonsyndromic HPE were: having an Aboriginal mother (unadjusted odds ratio [OR] 3.5, 95% confidence interval [CI] 1.1-11.1), an Aboriginal father (OR 12.8, 95% CI 3.0-55.1), at least one Aboriginal parent (OR 5.0, 95% CI 1.6-16.0), or two Aboriginal parents (OR 8.8, 95% CI 2.0-37.8), the presence of a family history of a midline facial defect (OR 8.2, 95% CI 1.5-45.2), and being of low socioeconomic status (OR 3.0, 95% CI 1.0-9.1). Having an Aboriginal background remained statistically significant after adjusting for low socioeconomic status. Other associations evaluated--history of prior spontaneous abortion, stillbirth, neonatal death, prepregnancy diabetes, infections during pregnancy, alcohol exposure, smoking, and substance abuse--were not significantly associated with nonsyndromic HPE. The use of periconceptional folic acid or vitamins was not associated with a lower risk of nonsyndromic HPE.


Subject(s)
Brain/abnormalities , Chromosome Aberrations/embryology , Holoprosencephaly/epidemiology , Abnormalities, Multiple/genetics , Case-Control Studies , Female , Holoprosencephaly/etiology , Holoprosencephaly/genetics , Humans , Male , Manitoba/epidemiology , Risk Factors
18.
Clin Genet ; 81(1): 70-5, 2012 Jan.
Article in English | MEDLINE | ID: mdl-21204792

ABSTRACT

Mutations in the human GLI2 gene were first reported in association with defective anterior pituitary formation, panhypopituitarism, and forebrain anomalies represented by typical holoprosencephaly (HPE) and holoprosencephaly-like (HPE-L) phenotypes and postaxial polydactyly. Subsequently, anophthalmia plus orbital anomalies, heminasal aplasia, branchial arch anomalies and polydactyly have also been incorporated into the general phenotype. Here we described six Brazilian patients with phenotypic manifestations that range from isolated cleft lip/palate with polydactyly, branchial arch anomalies to semi-lobar holoprosencephaly. Novel sequence variants were found in the GLI2 gene in patients with marked involvement of the temporomandibular joint (TMJ), a new clinical finding observed with mutations of this gene. Clinical, molecular and genetic aspects are discussed.


Subject(s)
Genetic Association Studies , Kruppel-Like Transcription Factors/genetics , Mutation , Nuclear Proteins/genetics , Polydactyly/genetics , 3' Untranslated Regions , Adult , Branchial Region/abnormalities , Brazil/epidemiology , Child, Preschool , Cleft Lip/epidemiology , Cleft Lip/genetics , Craniofacial Abnormalities/genetics , DNA Mutational Analysis , Female , Genome, Human , Genomic Structural Variation , Holoprosencephaly/epidemiology , Holoprosencephaly/genetics , Humans , Infant , Male , Phenotype , Polydactyly/epidemiology , Temporomandibular Joint/abnormalities , Zinc Finger Protein Gli2
20.
Am J Med Genet C Semin Med Genet ; 157C(4): 344-57, 2011 Nov 15.
Article in English | MEDLINE | ID: mdl-22006661

ABSTRACT

Cyclopia is characterized by the presence of a single eye, with varying degrees of doubling of the intrinsic ocular structures, located in the middle of the face. It is the severest facial expression of the holoprosencephaly (HPE) spectrum. This study describes the prevalence, associated malformations, and maternal characteristics among cases with cyclopia. Data originated in 20 Clearinghouse (ICBDSR) affiliated birth defect surveillance systems, reported according to a single pre-established protocol. A total of 257 infants with cyclopia were identified. Overall prevalence was 1 in 100,000 births (95%CI: 0.89-1.14), with only one program being out of range. Across sites, there was no correlation between cyclopia prevalence and number of births (r = 0.08; P = 0.75) or proportion of elective termination of pregnancy (r = -0.01; P = 0.97). The higher prevalence of cyclopia among older mothers (older than 34) was not statistically significant. The majority of cases were liveborn (122/200; 61%) and females predominated (male/total: 42%). A substantial proportion of cyclopias (31%) were caused by chromosomal anomalies, mainly trisomy 13. Another 31% of the cases of cyclopias were associated with defects not typically related to HPE, with more hydrocephalus, heterotaxia defects, neural tube defects, and preaxial reduction defects than the chromosomal group, suggesting the presence of ciliopathies or other unrecognized syndromes. Cyclopia is a very rare defect without much variability in prevalence by geographic location. The heterogeneous etiology with a high prevalence of chromosomal abnormalities, and female predominance in HPE, were confirmed, but no effect of increased maternal age or association with twinning was observed.


Subject(s)
Congenital Abnormalities/epidemiology , Eye Abnormalities/epidemiology , International Cooperation , Population Surveillance/methods , Adult , Americas/epidemiology , Australia/epidemiology , Biomedical Research/trends , China/epidemiology , Chromosome Disorders/genetics , Chromosomes, Human, Pair 13/genetics , Congenital Abnormalities/genetics , Congenital Abnormalities/pathology , Epidemiologic Studies , Europe/epidemiology , Eye Abnormalities/genetics , Eye Abnormalities/pathology , Female , Holoprosencephaly/epidemiology , Holoprosencephaly/genetics , Holoprosencephaly/pathology , Humans , Infant, Newborn , Male , Pregnancy , Prevalence , Registries , Trisomy/genetics , Trisomy 13 Syndrome
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