Maternal corticosteroid use and risk of selected congenital anomalies

Evidence for the teratogenicity of corticosteroids in humans is limited and has resulted in inconsistent recommendations regarding their use during early pregnancy. We examined the association between women's corticosteroid use during the periconceptional period (1 month before to 3 months after conception) and delivering infants with selected congenital anomalies. Data were derived from a population-based case-control study that included cases of orafacial clefts (n = 662), conotruncal heart defects (n = 207), neural tube defects (n = 265), and limb reduction defects (n = 165). Information on medication use was collected via maternal telephone interviews. Corticosteroid use was associated with an increased risk for isolated cleft lip with or without cleft palate (odds ratio 4.3, 95% confidence interval 1.1–17.2) and isolated cleft palate (odds ratio 5.3, 95% confidence interval 1.1–26.5). Increased risks were not observed for the other anomaly groups studied. These data in conjunction with other epidemiologic data suggest a possible causal association between cleft lip and palate and corticosteroid use. Am. J. Med. Genet. 86:242–244, 1999. © 1999 Wiley-Liss, Inc.     

Case-control study of cleft lip or palate after maternal use of topical corticosteroids during pregnancy

A case-control survey of 48 children with nonsyndromic cleft lip or palate showed a significant increase in prevalence of maternal use of topical corticosteroid preparations in the first trimester of pregnancy, compared to 58 controls born in the same hospital; the odds ratio was 13.154, 95% confidence interval 1.67-586, P = 0.0049 on Fisher's exact two-tail test. The results were statistically significant although the wide confidence interval reflected the small sample size. Although older epidemiological studies have not detected any association between systemic corticosteroid treatment and the combined incidence of all congenital malformations, experimental studies over several decades have shown that maternal corticosteroid exposure in several species of animals is specifically associated with oral clefts. This association has been confirmed by more specific case-control surveys where the cases were children with cleft lip or palate and the exposure was maternal systemic corticosteroid treatment in the first trimester. Only one previous survey also analyzed topical corticosteroids, and it demonstrated an increased odds ratio for cleft lip or palate. A national survey of children with cleft palate will be necessary to evaluate the results of this pilot study.     

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts.

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C-->T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 -7.86, P = 0. 02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81-3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16-3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71-74, 1999. Published 1999 Wiley-Liss, Inc.     

Methylenetetrahydrofolate reductase thermolabile variant and oral clefts

Folic acid can prevent neural tube defects; in some cases the mechanism is probably a correction of a metabolic defect caused by thermolabile methylenetetrahydrofolate reductase (MTHFR) found in increased frequency in cases. It is less clear whether folic acid can prevent oral clefts, in part because it is not known whether thermolabile MTHFR is more common in those with oral clefts. This study examined the prevalence of the mutation (677 C→T) that causes thermolabile MTHFR in subjects with oral clefts from a national Irish support group, and an anonymous control group randomly selected from a neonatal screening program covering all births in Ireland. Eighty-three of 848 control subjects were homozygous (TT) thermolabile MTHFR (9.8%). This defect was almost three times as common in the 27 subjects (25.9%) with isolated cleft palate (odds ratio 3.23, 95% confidence interval 1.32 –7.86, P = 0.02) and somewhat more common in the 66 subjects with cleft lip with or without cleft palate (15.2%, odds ratio 1.65, 95% confidence interval 0.81–3.35, P = 0.20). When the two groups with different etiologies were combined, the overall odds ratio was 2.06 (95% confidence interval 1.16–3.66, P = 0.02). In the Irish population homozygosity for the common folate-related polymorphism associated with thermolabile MTHFR is significantly more frequent in those with isolated cleft palate, and could be etiologically important. Am. J. Med. Genet. 86:71–74, 1999. Published 1999 Wiley-Liss, Inc.     

Influencing clinical practice regarding the use of antiepileptic medications during pregnancy: Modeling the potential impact on the prevalences of spina bifida and cleft palate in the United States

Selected antiepileptic drugs (AEDs) increase the risk of birth defects. To assess the impact of influencing AED prescribing practices on spina bifida and cleft palate we searched the literature for estimates of the association between valproic acid or carbamazepine use during pregnancy and these defects and summarized the associations using meta-analyses. We estimated distributions of the prevalence of valproic acid and carbamazepine use among women of childbearing age based on analyses of four data sets. We estimated the attributable fractions and the number of children born with each defect that could be prevented annually in the United States if valproic acid and carbamazepine were not used during pregnancy. The summary odds ratio estimate for the association between valproic acid and spina bifida was 11.9 (95% uncertainty interval (UI): 4.0–21.2); for valproic acid and cleft palate 5.8 (95% UI: 3.3–9.5); for carbamazepine and spina bifida 3.6 (95% UI: 1.3–7.8); and for carbamazepine and cleft palate 2.4 (95% UI: 1.1–4.5) in the United States. Approximately 40 infants (95% UI: 10–100) with spina bifida and 35 infants (95% UI: 10–70) with cleft palate could be born without these defects each year if valproic acid were not used during pregnancy; 5 infants (95% UI: 0–15) with spina bifida and 5 infants (95% UI: 0–15) with cleft palate could be born without these defects each year if carbamazepine were not used during pregnancy. This modeling approach could be extended to other medications to estimate the impact of translating pharmacoepidemiologic data to evidence-based prenatal care practice. Published 2011 Wiley-Liss, Inc.     

Use of folic acid supplements and risk of cleft lip and palate in infants: a population-based cohort study

Background

Orofacial clefts occur when the lips or the roof of the mouth do not fuse properly during the early weeks of pregnancy. There is strong evidence that periconceptional use of folic acid can prevent neural tube defects but its effect on oral clefts has generated debate.

Aim

To identify factors associated with suboptimal periconceptional use of folic acid and its potential effect on oral clefts.

Design and setting

The population-based infant cohort of the national Growing Up in Ireland study, which consists of 11 134 9-month-old infants.

Method

Data collection comprised questionnaires conducted by interviewers with parents in parents’ homes. Characteristics of mothers who did or did not take folic acid before and during pregnancy, as well as the effect of folic acid use on the prevalence of cleft lip and palate were recorded.

Results

The prevalence of cleft lip and palate was 1.98 (95% confidence interval [CI] = 1.31 to 2.99) per 1000 9-month-olds. The odds ratio for cleft lip was 4.36-fold higher (95% CI = 1.55 to 12.30, P = 0.005) for infants of mothers who did not take folic acid during the first 3 months of pregnancy, when compared with those who did have a folate intake during the first trimester. Folic acid use was suboptimal in 36.3% (95% CI = 35.4 to 37.2) of the sample.

Conclusion

These findings support the hypothesis that taking folic acid may partially prevent cleft lip and palate. They are particularly relevant for GPs, because they are usually the first port of call for women before and during early pregnancy.     

HLA Phenotype Frequencies in Individuals with Cleft Lip and/or Cleft Palate

The HLA types of 133 patients with cleft lip and/or cleft palate were determined. Caucasian patients with isolated cleft palate showed a possible association with HLA. Ten of 11 male patients had HLA--A2 as compared to one out of eight female patients (P less than 0.005). Caucasian males with cleft lip and cleft palate had a slight increased frequency of HLA--Aw24 (P = 0.07) and Mexican-American males with cleft lip and/or cleft palate showed an increase of antigen HLA-A28 (P = 0.07), though neither were statistically significant. Females with cleft lip and/or cleft palate from either racial group had no differences from the controls. The serum from 90 mothers of patients with cleft lip and/or cleft palate were reacted against their child's lymphocytes. Of these crossmatch tests, 12% were found to be positive. These preliminary results suggest that male patients with isolated cleft palate are worthy of further studies with respect of HLA associations.     

C677T variant form at the MTHFR gene and CL/P: a risk factor for mothers?

Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C-->T mutation (C677T), converting an alanine to a valine residue in 5,10-methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR's involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30-5.57) and 2.51 (1.00-6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo's genotype.     

C677T variant form at the MTHFR gene and CL/P: A risk factor for mothers?

Maternal folic acid supplementation in early pregnancy has been suggested to play a role in the prevention of nonsyndromic orofacial cleft, i.e., cleft lip with or without cleft palate (CL/P). Moreover, some authors demonstrated association of the C→T mutation (C677T), converting an alanine to a valine residue in 5,10‐methylenetetrahydrofolate reductase (MTHFR) gene, with other congenital anomalies such as neural tube defects (NTDs). Because of MTHFR’s involvement in the metabolism of folate, we investigated 64 CL/P patients and their parents for C677T MTHFR mutation. No linkage disequilibrium was found using the transmission disequilibrium test (TDT). However, a significantly higher mutation frequency was detected in mothers of CL/P patients compared to controls. The odds ratios calculated for mothers having CT or TT genotype, compared to the normal CC genotype, were 2.75 (95% confidence interval 1.30–5.57) and 2.51 (1.00–6.14), respectively. These results support the involvement of the folate pathway in the etiology of CL/P, and indicate an effect of the maternal genotype, rather than influence of the embryo’s genotype. © 2001 Wiley‐Liss, Inc.     

Cleft lip and palate incidence among the live births in the Republic of Korea

We present an epidemiologic study of cleft lip and palate in the Republic of Korea from January 1, 1993 through December 31, 1993. In 1993, the number of total live births was 715,817. And from 1993 through 1995, a total of 1,293 new patients with cleft lip and palate who were born in 1993 were identified. The incidence of cleft lip and palate was 1.81 per 1000, that is, 1 per 554 live births. The cleft lip: cleft lip and palate: cleft palate alone ratio was 1.13:1:1.19. The male: female ratio was 2.1:1 in the cleft lip group, and 2.5:1 in the cleft lip and palate group. We could detect a male predominance in both groups. In contrast, the ratio was 0.95:1 in the cleft palate group. The left: right: bilateral ratio was 1.9:1:0.23 in cleft lip group, and the ratio was 2.2:1:1.1 in the cleft lip and palate group. This is the first nation-wide study to provide detailed data on the incidence of cleft lip and palate in the live births in the Republic of Korea.     

Associated anomalies among infants with oral clefts at birth and during a 1-year follow-up

Reports of birth defects rates may focus on defects observed in the newborn period or include defects diagnosed at older ages. However, little information is available on the rates of additional anomalies detected after birth or on the ages at which such anomalies are diagnosed. The aims of this work were to describe the initial diagnoses of oral clefts, isolated or associated with other defects, in newborn infants ascertained in hospitals of the ECLAMC network, and diagnostic changes that occurred due to detection of additional defects during a 1-year follow-up period. Seven hundred ten liveborn infants with cleft lip only (CLO), cleft lip with cleft palate (CLP), or cleft palate (CP) were ascertained between 2003 and 2005. Prevalence estimates of isolated and associated (ASO) clefts, diagnoses in infants with associated clefts, and the percentage of isolated clefts that were reclassified as associated were established. Birth prevalence estimates (per 1,000) were as follows: Total: 1.7; CLP: 0.94 (ASO = 23.5%); CP: 0.46 (ASO = 42.3%); CLO: 0.28 (ASO = 7.6%). Initial diagnoses in infants with associated clefts included 38 infants with chromosomal abnormalities, 33 with non-chromosomal syndromes, 16 with malformation sequences, and 98 with multiple anomalies of unknown etiology. Seven percent of newborns initially classified as isolated were later reclassified as associated. Ten infants without associated defects or clinically suspected syndromes were diagnosed as syndromic only through laboratory findings or family history, illustrating the difference between the terms associated versus isolated, which refers to presence or absence of associated anomalies, and syndromic versus non-syndromic, which refers to etiology.     

Inverse association between severe nausea and vomiting in pregnancy and some congenital abnormalities

The objective of the study was to investigate the possible association between nausea and vomiting in early pregnancy and congenital abnormalities. The prevalence of medically-recorded severe nausea and vomiting in early pregnancy in cases with congenital abnormalities and their available matched population controls without any defect was compared in the population-based large data set of the Hungarian Case-Control Surveillance System of congenital abnormalities, 1980-1996. Of 22,843 cases with as 25 different congenital abnormality groups, 1,713 (7.5%) cases had mothers with medically recorded and treated severe nausea and vomiting during pregnancy. Of 38,151 matched population controls, 3,777 (9.9%) had mothers with severe nausea and vomiting (adjusted prevalence odds ratio (POR) with 95% CI: 0.74, 0.68-0.79). Five congenital abnormality groups: cleft lip with or without cleft palate (0.50, 0.37-0.70), posterior cleft palate (0.53, 0.32-0.89), renal a/dysgenesis (0.23, 0.06-0.96), obstructive defects of urinary tract (0.32, 0.18-0.58), and cardiovascular malformations (0.68, 0.57-0.81) had mothers with a lower prevalence of severe nausea and vomiting in pregnancy (adjusted PORs with 95% CI included in parentheses). Of 25 congenital abnormality groups, 22 had POR lower than 1. Thus in this study the mothers of cases with congenital abnormalities were 26% less likely to have had severe nausea and vomiting in early pregnancy than the mothers of population controls without congenital abnormalities.     

Distribution of human papillomavirus genotypes in invasive squamous carcinoma of the vulva

Many studies have established a critical role for human papillomavirus (HPV) in the development of anogenital squamous neoplasia. In this report, we show the distribution of 37 high- and low-risk HPV types in 116 cases of invasive squamous vulvar carcinoma. Sections from paraffin-embedded tissue blocks were dissected as necessary to select areas of invasive carcinoma. Clinical and pathologic variables were analyzed using t-tests, univariate odds ratios and logistic regression analysis. Seventy percent of cases were HPV-positive, with an average patient age of 65 years (n=81). HPV-negative cases (n=35) had a higher average age (70 years), but these populations were not statistically different (t=1.65, P=0.10). HPV16 was most common (n=65). Other HPV types were less frequent (HPV33, n=12; HPV45, n=4; HPV52 and 6, each n=3; HPV18, 53 and 62, each n=2). Additional HPV types were identified only once. Multiple infections typically included HPV16 (12/14 cases). Tumors showing low-risk HPV (11 cases) and low-risk HPV only (three cases) were uncommon. Regional node metastasis was documented in 29 of 116 tumors, and 8/9 HPV-positive nodes contained HPV types identical to the primary tumor. Of tumor types, warty carcinoma was most strongly associated with high-risk HPV (odds ratio 4.34, 95% confidence interval 1.32-18.45), particularly high-risk HPVs other than type 16 (odds ratio 9.04, 95% confidence interval 1.60-54.00). Tumors associated with any HPV type (odds ratio 0.40, 95% confidence interval 0.14-1.17), any high-risk type (odds ratio 0.36, 95% confidence interval 0.12-1.08), or type 16 alone (odds ratio 0.34, 95% confidence interval 0.11-1.12) were less likely to metastasize than HPV-negative tumors. Correcting for possible confounding variables, such as patient age and tumor histology, linear logistic regression analysis confirmed this association (high-risk HPV odds ratio 0.28, 95% confidence interval 0.09-0.89).     

Epidemiologic analysis of histologic cervical inflammation: relationship to human papillomavirus infections

Infections with carcinogenic human papillomaviruses, the causal agents of cervical intraepithelial neoplasia and cancer, as well as infections with noncarcinogenic human papillomaviruses, are common but typically resolve spontaneously. Effective cell-mediated immune responses are critical for human papillomavirus clearance; however, data relating cervical inflammation to the outcome of human papillomavirus infection are lacking. To investigate this topic, we performed a masked parallel review of inflammation in the stroma and epithelium of cervical biopsies (n = 564) collected from a retrospectively defined subcohort of women systematically followed up in the Atypical Squamous Cells of Undetermined Significance/Low-Grade Squamous Intraepithelial Lesion Triage Study. Women in our analysis had undergone colposcopically directed enrollment biopsies diagnosed as negative or cervical intraepithelial neoplasia 1 and had corresponding human papillomavirus polymerase chain reaction test results of negative (n = 250), positive for a single carcinogenic (n = 237), or noncarcinogenic (n = 81) type. Inflammation in cervical stroma varied with cofactors for human papillomavirus progression: current smokers showed less inflammation (odds ratio, 0.55; 95% confidence interval, 0.31-0.97), whereas current oral contraceptive users had increased inflammation (odds ratio, 1.7; 95% confidence interval, 0.92-3.0) as did those with a self-reported 2-year history of a sexually transmitted disease (odds ratio, 1.9; 95% confidence interval, 1.0-3.5). Biopsies of women with carcinogenic human papillomaviruses had greater inflammation within the epithelium (odds ratio, 1.6; 95% confidence interval, 1.1-2.3) compared with human papillomavirus-negative women. Associations with human papillomavirus type-specific persistence or progression to histologic cervical intraepithelial neoplasia 3 were diminished among women with moderate or marked inflammation in stroma (odds ratio, 0.49; 95% confidence interval, 0.25-0.99) or within epithelium (odds ratio, 0.51; 95% confidence interval, 0.26-0.97). These data suggest that cervical inflammation varies with human papillomavirus cofactors, type of human papillomavirus infection, and risk of persistence and progression. Additional studies are needed to confirm and extend these findings.     

蛋氨酸合酶基因A275 6G位点多态性与非综合征型唇腭裂的关联性研究

目的 研究蛋氨酸合酶基因(methionine synthase,MS)A2756G位点多态性与非综合征型唇腭裂(nonsyndromic cleft lip with or without cleft palate,NSCL/P)的关联性.方法 采用PCR-限制性片段长度多态性技术检测97个NSCL/P病例组核心家庭和104个对照家庭的MS基因A2756G位点的多态性;用人群关联研究分析、病例组核心家庭的传递不平衡检测(transmission disequilibrium test,TDT)、单体型的相对危险度分析(haplotype-based haplotype relative risk,HHRR)、家庭为基础的关联研究(family-based association tests,FBAT)等统计分析.结果 子代、父亲、母亲病例组和对照组之间基因型和等位基因的分布差异均无统计学意义(P>0.05);本研究中在子代和母亲组中未检出GG基因型,AG基因型相对于AA基因型的比值比OR和95%CI分别为子代1.78(0.74～4.34)、父亲0.80(0.36～1.79)、母亲1.26(0.54～2.93),G相对于A基因的OR和95%CI分别为子代1.70(0.78～3.73)、父亲0.88(0.49～1.75)、母亲1.23(0.59～2.60),携带有突变基因G并不能增加患NSCL/P的危险.病例组核心家庭分析,TDT分析χ2=0.034,P>0.05;HHRR分析χ2=0.03,P>0.05;FBAT分析Z=0.186,P>0.05.结论 结果未显示出MS基因A2756G位点多态性和NSCL/P发生的相关性,还待进一步研究.     

Contribution of MSX1 variants to the risk of non-syndromic cleft lip and palate in a Malay population

Oral clefts are clinically and genetically heterogeneous disorders that are influenced by both genetic and environmental factors. The present family-based association study investigated the role of the MSX1 and TGFB3 genes in the etiology of non-syndromic oral cleft in a Malay population. No transmission distortion was found in the transmission disequilibrium analysis for either MSX1-CA or TGFB3-CA intragenic markers, whereas TGFB3-CA exhibited a trend to excess maternal transmission. In sequencing the MSX1 coding regions in 124 patients with oral cleft, five variants were found, including three known variants (A34G, G110G and P147Q) and two novel variants (M37L and G267A). The P147Q and M37L variants were not observed in 200 control chromosomes, whereas G267A was found in one control sample, indicating a very rare polymorphic variant. Furthermore, the G110G variant displayed a significant association between patients with non-syndromic cleft lip, with or without cleft palate, and normal controls (P=0.001, odds ratio=2.241, 95% confidence interval, 1.357-3.700). Therefore, these genetic variants may contribute, along with other genetic and environmental factors, to this condition.     

Clinical epidemiologic study of holoprosencephaly in South America

ECLAMC: Latin American Study of Congenital Malformations examined 4,157,224 births (1967-2000), detecting 370 newborns with suspected holoprosencephaly (HPE): 182 (49.2%) had only craniofacial defects; 99 (26.8%) had defects in other systems; (15.1%) had chromosomal anomalies; 5 (1.4%) had recognized syndromes; and 28 (7.6%) had isolated median cleft lip. The latter group was excluded from subsequent analyses because of epidemiological differences from the other groups. The birth prevalence rate (BPR) of isolated HPE was homogeneous among the 11 sampled countries, increasing from 0.5/10,000 births to 1/10,000 births between 1967 and 2000, suggesting improved ascertainment, mainly after 1996. Microtia, cleft lip/palate, and microstomia were preferentially associated with HPE, but cleft palate only was not. Maternal diabetes was more prevalent in HPE than in controls when adding the isolated and associated groups (OR: 3.5; 95% CI: 0.9-16.2). Maternal flu was more prevalent in isolated HPE (OR: 3.6; 0.9-16.6) and in isolated plus associated HPE (OR: 2.8; 1.0-7.9) than in controls. A second series of better documented HPE cases, 179 in number (2.2/10,000), ascertained from 827,968 births occurring from 2000 to 2003, was used for phenotypic definition of cerebral and facial anomalies. In 83 of 174 HPE cases with specified cerebral defects, 40% were alobar, 43% were semilobar, and 17% were lobar. All cases of cyclopia, ethmocephaly, and cebocephaly were of the alobar or semilobar types. Female excess occurred in the total sample, but not within the subgroups themselves because of their small sample sizes. Neither alobar HPE nor cyclopia was associated with female predilection. Among the 174 HPE cases, 39% had neither oral clefting nor a severe dysmorphic face. Of facial phenotypes, 26% had cyclopia, ethmocephaly, or cebocephaly; 25% had premaxillary agenesis; and 10% had cleft lip and palate or cleft palate only. Cyclopia was not associated with oral clefts; 6 of 8 cases of ethmocephaly had cleft palate; 6 of 20 cases of cebocephaly had oral clefts; 4 of 20 cases had premaxillary agenesis; and 2 of 20 cases had cleft palate.     

Velo-cardio-facial syndrome and DiGeorge sequence with meningomyelocele and deletions of the 22q11 region

Approximately 5% of children with neural tube defects (NTDs) have a congenital heart defect and/or cleft lip and palate. The cause of isolated meningomyelocele, congenital heart defects, or cleft lip and palate has been largely thought to be multifactorial. However, chromosomal, teratogenic, and single gene causes of combinations of NTDs with congenital heart defects and/or cleft lip and palate have been reported. We report on 3 patients with meningomyelocele, congenital heart defects, and 22q11 deletions. Two of the children had the clinical diagnosis of velo-cardio-facial syndrome (VCFS); both also have bifid uvula. The third child had DiGeorge sequence (DGS). The association of NTDs with 22q11 deletions has not been reported previously. An accurate diagnosis of the 22q11 deletions is critical as this micro-deletion and its associated clinical problems is transmitted as an autosomal dominant trait due to the inheritance of the deletion-bearing chromosome. We recommend that all children with NTDs and congenital heart defects, with or without cleft palate, have cytogenetic and molecular studies performed to detect 22q11 deletions. © 1994 Wiley-Liss, Inc.     

X-chromosome inactivation patterns in monozygotic twins and sib pairs discordant for nonsyndromic cleft lip and/or palate

Nonsyndromic clefts of the lip and/or palate are common birth defects with a strong genetic component. Based on unequal gender ratios for clefting phenotypes, evidence for linkage to the X chromosome and the occurrence of several X-linked clefting syndromes, we investigated the role of skewed X chromosome inactivation (XCI) in orofacial clefts. Our samples consisted of female monozygotic (MZ) twins (n = 8) and sister pairs (n = 152) discordant for nonsyndromic clefting. We measured the XCI pattern in peripheral blood lymphocyte DNA using a methylation based androgen receptor gene assay. Skewing of XCI was defined as the deviation in inactivation pattern from a 50:50 ratio. Our analysis revealed no significant difference in the degree of skewing between twin pairs (P = 0.3). However, borderline significant differences were observed in the sister pairs (P = 0.02), with the cleft lip with cleft palate group showing the most significant result (P = 0.01). We did not find evidence for involvement of skewed XCI in the discordance for clefting in our sample of female MZ twins. However, results from the paired sister study suggest the potential contribution of skewed XCI to orofacial clefting, particularly cleft lip and palate.     

柳州地区非综合征型唇腭裂环境危险因素1：1病例对照研究

目的探讨柳州地区非综合征型唇腭裂发生的环境危险因素,分析各因素的危险程度。方法采用1：1配对病例对照研究的方法,对广西柳州地区非综合征型唇腭裂患儿进行了环境影响因素的流行病学调查,采用配对资料χ2检验和单因素及多因素条件logistic回归分析筛选出与非综合征型唇腭裂易感性有关的环境因素,使用SPSS13.0进行统计分析。结果共调查非综合征型唇腭裂儿童与正常健康对照儿童178对。非综合征型唇腭裂患儿中单纯唇裂53例,唇裂合并腭裂79例,单纯腭裂46例。多因素分析提示居住在农村（OR=2.35）、母亲孕前6个月或孕早期接触宠物（OR=4.46）、母亲孕前6个月或孕早期被动吸烟（OR=2.20）、先兆流产（OR=20.8）、母亲慢性病史（OR=31.84）、母亲出生缺陷家族史（OR=11.14）、父亲职业有害物理因素接触史（OR=4.62）是非综合征型唇腭裂发生的危险因素,而母亲孕前6个月至孕早期补充叶酸（OR=0.30）、父亲文化程度高（OR=0.14）是非综合征型唇腭裂发生的保护因素。结论影响非综合征型唇腭裂发生的危险因素众多,根据研究结果采取有针对性的健康促进措施,提高孕前保健意识,对降低出生缺陷的发生率将起到积极作用。