A three generation family study of cleft lip with or without cleft palate.

A family study of cleft lip, with or without cleft palate, was based on those treated by operation at The Hospital for Sick Children, London, between 1920 and 1939 in order to give information on the proportion affected of children and grandchildren. The probands were those who had survived, were successfully traced, and found to have had at least one child. Care was taken to exclude patients who were traced through a child, whether normal or affected, and not through the usual tracing procedure. Patients with recognised syndromes were also excluded. Because the series was based on patients who had survived and reproduced it was biased in favour of those with milder degrees of the malformation, and against those with any severe associated malformation. The proportion affected of children of probands was 3.15% (+/- 0.56), of sibs 2.79% (+/- 0.52), and of parents 1.18% (+/- 0.37), respectively. The lower proportion of parents affected is attributed to reduced reproductive fitness of patients born two generations ago. The proportion affected of nephews and nieces, aunts and uncles, and grandchildren was 0.47% (+/- 0.18), 0.59% (+/- 0.13), and 0.8% (+/- 0.6) respectively. The proportion affected of first cousins was 0.27% (+/- 0.08). The birth frequency of cleft lip (+/- cleft palate) is estimated to be about 0.1% in England. There were two first cousin and one second cousin marriages among the marriages of the parents. There was no increase of cleft palate among the relatives of the probands. The proportion of sibs affected increased with increasing severity of the malformation in the proband, where the proband was female, and where the proband had an affected parent or already had one affected sib. It was not, however, increased where a more remote relative was affected. The proportion of children affected was not increased when the proband had an affected parent or sib, but few families provided information. The most economical hypothesis to explain the findings is the multifactorial threshold model. The birth frequency of the malformation and the family patterns found make it improbable that one single mutant gene makes a major contribution to the liability to develop the condition.     

New study on the relationship between oral clefts and fetal loss

The sibships of 741 non-syndromic individuals with cleft lip with or without cleft palate (CL +/- P), those of 115 subjects with isolated cleft palate (CP), plus 2 series of controls of the same size were studied in a variety of ways. The 2 most significant findings were a) a higher fetal loss in the sibships of probands of the most frequently affected sex (CL +/- P: male; CP: female) and b) increased fetal mortality in the sibships with sporadic cases of CL +/- P when compared to that found in sibships with more than one affected. In general the results do not support the hypothesis of a causal relationship between fetal death and non-syndromic CL +/- P or CP.     

Etiological subgroups in non-syndromic isolated cleft palate. A genetic-epidemiological study of 52 Danish birth cohorts

Isolated cleft palate (CP) is considered to be a heterogeneous trait with an important genetic contribution to the etiology. Multifactorial-threshold models of non-syndromic CP inheritance assume a female predominance. The present study of 52 Danish birth cohorts, using several ascertainment sources, identified 2301 CP cases. It was found that, although females tended to be more severely affected than males, the overall sex ratio was close to one. For the latter half of the study period (1962-87), which probably had the best ascertainment, the sex ratio for non-syndromic CP was 0.95 (95% C.I. 0.85-1.07). Marked difference in sex ratios for non-syndromic overt CP including the hard palate (CPH) and non-syndromic overt CP of the soft palate only (CPS) (0.69 vs 1.00, p<1.00, p<0.05) suggested that these two conditions may be etiologically distinct, a hypothesis which is embryologically plausible. In agreement with this hypothesis, Danish family data from surgically treated CP cases showed a strong tendency to segregate only one of the CP subtypes within families. Future studies are recommended to test the existence of a possible etiological difference between CPH and CPS.     

Sex ratios of affected and transmitting members of multiple case families with neural tube defects.

In order to study the genetic aspects of the relation between neural tube defects and sex, we selected families with at least two closely related affected members. The sex ratios of both affected and normal transmitting persons were determined in these multiple case families. Our results indicate that there is a relation between the position of the lesion in the spine and sex. Furthermore, the affected persons in one family show significant concordance for sex as shown by the analysis of families with just two affected members. To our surprise, the group of normal transmitters appears to consist of significantly more females than males. This is in contrast to similar families with non-syndromic cleft lip +/- palate, where males predominate both among affected persons and normal transmitters. Finally, affected females most often inherited the predisposition to a neural tube defect from their mother. The possible role of inherited factors is discussed.     

腭裂患儿120例电反应测听法脑干听力阈值分析

目的：分析腭裂患儿脑干听力阈值特征。方法：使用电反应测听法检测120例腭裂患儿听力阈值，采用分组对照研究，进行Χ^2检验。结果：①240耳中141耳听力阈值异常，听力障碍发生率为58．8％；②Ⅱ°与Ⅲ°腭裂患儿听力障碍发生率有极显著性差异，P〈0．005；腭裂程度与听力障碍程度之间无相关性，P〉0．75；③3岁前后比较，听力障碍发生率差异极显著，P〈0．005，3—6岁与〉6岁比较无显著差异，P〉0．05。结论：①58．8％腭裂患儿存在不同程度听力障碍；②腭裂程度越重听力障碍发生率越高，但与听力障碍程度无相关性；③患病年龄越小听力障碍发生率越高，3岁前后有极显著性差异。     

全外显子组测序技术检测一家系非综合征型唇腭裂基因突变

目的通过全外显子组测序技术,检测非综合征型唇腭裂家系致病基因新型突变。为该家系产前诊断以及遗传咨询提供可靠的遗传学依据。方法经知情同意,对死胎接生术后的胎儿进行检测。分析整理孕妇家系资料并绘制系谱图,采用高通量测序技术(NGS)对引产胎儿进行全外显子组测序,找到死产胎儿的高度可疑致病突变位点,并用Sanger测序的方法对家系成员一一验证。结果该家系中共5人,1名患者为非综合征型轻微唇裂,已实施手术修复。2名已故患者,由家系成员自述均为孕20w左右,B超提示严重唇腭裂,行死胎接生术,引产胎儿外观均符合唇腭裂表型。采用高通量测序技术(NGS)对引产胎儿行全外显子组测序,检测到先证者CDON c.323G>C(p.Ser108Thr)的错义突变;Sanger测序证实该家系中现存1人携带CDON c.323G>C(p.Ser108Thr)错义突变,为非综合征型轻微唇裂,已实施手术修复。该位点变异导致第108号氨基酸由Ser变为Thr(p.Ser108Thr),该变异可能导致蛋白功能受到影响,经家系验证该位点突变源自胎儿姥姥。生物信息学分析预测这种新型突变会引发蛋白功能异常。结论研究筛选出先证者及家系成员CDON基因的新型突变,该家系中携带CDON c.323G>C突变的成员临床表型差异较大,CDON基因符合常染色体显性遗传方式,结合常染色体显性遗传的外显率不同以及该家系的检测结果,认为CDON c.323G>C突变有可能是本家系致病的分子基础。     

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。     

Facial clefting in an Arab town in Israel

To study the prevalence of cleft palate and cleft lip with or without cleft palate in an Israeli Arab town, questionnaires were sent to the parents of 1375 pupils in grades 1 and 2 in all seven primary schools in the town of Taibe, and 1281 responded. The information requested included data about siblings and members of the parental generation to give a total of 16 174, and the presence of consanguinity and history of exposure to medication, radiation, smoking or alcohol during pregnancy. There were four affected individuals among the index cases, of whom two had cleft palate only and two cleft lip with cleft palate, giving prevalence rates for each of these of 1.56/1000. Adding to these the number of affected siblings gave a total of 10 affected individuals; two with cleft palate only (0.39/1000) and eight with cleft lip with or without cleft palate (1.56/1000). Among the parental generation, of 16 reported affected individuals, two had cleft palate only (0.18/1000) and 14 cleft lip with or without cleft palate (1.26/1000). The overall prevalence rate for all 26 affected individuals was 1.6/1000; four of these had cleft palate only (0.24/1000) and 22 had cleft lip with or without cleft palate (1.36/1000). There were no cases whose mothers had been exposed to medication, radiation, smoking or alcohol during pregnancy. The effect of consanguinity was not significant (P < 0.92). This study shows that the prevalence of facial clefting in an Israeli Arab community is consistent with that in the general population worldwide.     

TP63 mutation and clefting modifier genes in an EEC syndrome family

Autosomal dominant EEC syndrome consists of ectrodactyly, ectodermal dysplasia, and cleft lip with or without cleft palate (CL/P). We investigated an EEC kindred with 10 affected persons in three generations in order to map the causative mutation in this family and to map modifier genes that contribute to the expression of facial clefting in the phenotype. DNA from 15 family members was genotyped for 388 genome screen markers. Analysis revealed maximal linkage between EEC and chromosome 3q27, which contains a known EEC gene - tumor protein 63 (TP63). Sequencing showed a CGT-->TGT missense mutation (R280C) in exon 7, previously reported to cause EEC in four families, and ectrodactyly alone (split hand-foot malformation) in one sporadic case and one large kindred. Analysis of the clefting phenotype in this EEC family demonstrated maximal linkage to two regions on chromosomes 4q and 14, which multiple studies have implicated in non-syndromic CL/P. In conclusion, this study demonstrates that the mutation of TP63 is the major (Mendelian) EEC gene in this kindred and suggests that additional minor modifying genes which predispose to non-syndromic CL/P could also contribute to the expression of the clefting component of the syndrome in this family.     

非综合征型单侧完全性唇腭裂患者牙弓形态学特点

目的 通过对上颌牙弓进行测量,了解非综合征型单侧完全性唇腭裂患者上颌牙弓的形态学特点,为临床评价牙弓发育、咬关系提供参考,为临床咬诱导治疗提供依据.方法 使用丹麦3Shape公司牙科模型扫描仪及应用软件,对32副非综合征型单侧完全性唇腭裂患者上颌牙弓的模型(分非裂侧和裂侧)进行扫描和数据测量,内容包括牙弓各段的宽度、长度、非裂侧和裂侧牙弓周长.使用SPSS14.0统计软件对裂侧和非裂侧牙弓测量值进行配对t检验.结果 双尖牙区,裂侧与非裂侧的宽度差异有统计学意义(第1双尖牙区t=5.19,P<0.01;第2双尖牙区t=3.24,P<0.05).第1恒磨牙区,裂侧与非裂侧的宽度差异无统计学意义(t=0.48,P>0.05).患者非裂侧比裂侧牙弓实际周长长约4.2mm,差异有统计学意义(t=4.61,P<0.01).结论 对于非综合征型单侧完全性唇腭裂患者,上颌牙弓在裂隙侧宽度明显发育不足,牙弓周长明显小于非裂侧.     

Fetal mortality in sibships with one or more affected members with oral clefts

We investigated the fetal mortality in 903 sibships with at least one member having cleft lip with or without cleft palate [CL(P)] and 213 with at least one individual affected with cleft palate (CP) derived from three different data sources in México. The frequency of fetal wastage (abortion and/or stillbirth) was not increased in sibships where the propositi had cleft lip and palate (CLP) as compared with cleft lip (CL) nor in those where index cases had a bilateral lesion as compared to a unilateral one, nor when the index cases with CL(P) were female rather than males, nor when the index case was a female with bilateral lesion as compared to males with a unilateral one. Similarly fetal mortality was not increased in sibships in which the propositus had CP compared to those in which the index case was a female. These findings are contrary to some reports that claim to support a two-threshold model according to which individuals reaching the first one would be born with an oral cleft, and those reaching the second would be aborted. Our results, together with others, suggest the possibility that liability to oral clefts is independent of liability to fetal wastage.     

一个非综合征型唇腭裂家系的致病基因鉴定

目的对一个非综合征型唇腭裂家系进行分子遗传学研究,探寻其致病原因。方法对该家系成员进行详细的体格检查和既往史调查,排除综合征型唇腭裂。对该家系1例患儿的基因组DNA进行全外显子组测序及生物信息学分析。筛查到候选致病基因突变位点后,采用Sanger测序对该家系成员及100名健康对照个体进行共分离分析和人群验证分析。结果全外显子组测序及疾病共分离分析显示,该家系患者IRF6基因第4外显子存在c.253A>G(p.Cys85Arg)变异,且该突变未在健康对照个体中检出,文献尚未见报道。结论IRF6基因第4外显子c.253A>G错义变异是导致该家系发病的原因。     

Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate

Mitchell LE, Risch N. Correlates of genetic risk for non-syndromic cleft lip with or without cleft palate. Clin Genet 1993: 43: 255–260. © Munksgaard, 1993 Multivariate analysis was used to determine which characteristics: sex of the proband, sibling sex, severity of the proband's defect or family history, are the best predictors of recurrence risk among siblings of individuals with non-syndromic cleft lip with or without cleft palate (CL \pm P). Sibling recurrence risks are not significantly related to the sex of the proband. Severity of the proband's defect, classified by the extent of the lip defect (unilateral versus bilateral), was found to be a significant predictor of sibling recurrence, whereas involvement of the palate in the proband's defect was not. A positive family history of clefting (i.e. at least one affected first-degree relative in addition to the proband) and the sex of the sibling were also found to be significant predictors of sibling recurrence. The associations between sibling risk and family history, and sibling risk and bilaterality of the proband's defect appear to be mildly confounded. After adjusting for the effects of family history, the risk to siblings of probands with bilateral lip defects is twice the risk to siblings of probands with unilateral defects (O.R. = 2.00; 95% C.I. 1.25-3.19). A positive family history of clefting increases the risk to siblings by greater than 4-fold (O.R. =4.49; 95% C.I. 2.74-7.35), after adjusting for the extent of the proband's lip defect. These results provide a rational strategy for identifying subsets of the ‘at risk’ population which have markedly different recurrence risks. This information is important for genetic counseling, since it allows for more precise estimation of sibling recurrence risks in individual cases. Furthermore, our findings indicate that the power to detect linkage between a genetic marker or a candidate gene and CL \pm P will increase if the study population is ascertained through individuals with bilcteral clefts of the lip, rather than through individuals with either unilateral or bilateral CL \pm P.     

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.     

A novel mutation in the PHF8 gene is associated with X-linked mental retardation with cleft lip/cleft palate

Recently, two truncating mutations in the PHF8 (plant homeodomain finger protein 8) gene have been found to cause X-linked mental retardation associated with cleft lip/cleft palate (CL/P). One of the truncating mutations was found in the original family with Siderius-Hamel CL/P syndrome where only two of the three affected individuals had mental retardation (MR) with CL/P and one individual had mild MR. The second mutation was present in a family with four affected men, three of whom had MR and CL/P, while the fourth individual had mild MR without clefting. Here, we report a novel nonsense mutation (p.K177X) in a male patient who has MR associated with CL/P. The mutation results in a truncated PHF8 protein lacking the Jumonji-like C terminus domain and five nuclear localization signals. Our finding further supports the hypothesis that the PHF8 protein may play an important role in cognitive function and midline formation.     

Microdeletion 20p12.3 involving BMP2 contributes to syndromic forms of cleft palate

Orofacial clefts of the lip and/or palate comprise one of the most common craniofacial birth defects in humans. Though a majority of cleft lip and/or cleft palate (CL/P) occurs as isolated congenital anomalies, there exist a large number of Mendelian disorders in which orofacial clefting is part of the clinical phenotype. Here we report on two individuals and one multi-generational family with microdeletions at 20p12.3 that include the bone morphogenetic protein 2 (BMP2) gene. In two propositi the deletion was almost identical at ～600 kb in size, and BMP2 was the only gene deleted; the third case had a ～5.5-Mb deletion (20p13p12.2) that encompassed at least 20 genes including BMP2. Clinical features were significant for cleft palate and facial dysmorphism in all three patients, including Pierre-Robin sequence in two. Microdeletion 20p13p12 involving BMP2 is rare and has been implicated in Wolff-Parkinson-White (WPW) syndrome with neurocognitive deficits and with Alagille syndrome when the deletion includes the neighboring JAG1 gene in addition to BMP2. Despite a significant role for the BMPs in orofacial development, heterozygous loss of BMP2 has not been previously reported in patients with syndromic clefting defects. Because BMP2 was the sole deleted gene in Patients 1 and 2 and one of the genes deleted in Patient 3, all of whom had clinical features in common, we suggest that haploinsufficiency for BMP2 is a crucial event that predisposes to cleft palate and additional anomalies. Lack of significant phenotypic components in family members of Patient 1 suggests variable expressivity for the phenotype.     

Microdeletions at chromosome bands 1q32-q41 as a cause of Van der Woude syndrome.

Van der Woude syndrome (VWS) is an autosomal dominant disorder comprising cleft lip and/or cleft palate and lip pits. We reported previously a family whose underlying mutation is a 500-800 kb deletion localized to chromosome bands 1q32-q41 [Sander et al., 1994: Hum Mol Genet 3:576-578]. Along with cleft lip/palate and lip pits, affected relatives exhibit developmental delays, suggesting that the function of a gene nearby may also be disrupted. To further localize the VWS gene we searched for other deletions that cause VWS. An allele loss assay was performed using a novel highly polymorphic marker, D1S3753. From a panel of 37 unrelated individuals, we detected an allele loss in one family, indicating the presence of a deletion. In this family, the phenotype in three generations of affected individuals was confined to the cardinal signs of VWS. Surprisingly, mapping of the new deletion showed that it extended 0.2-1 Mb beyond the proximal breakpoint for the deletion described previously. No deletions were detected in seven cases of popliteal pterygia syndrome, 76 cases of mixed syndromic forms of cleft lip and palate, and 178 cases of nonsyndromic cleft lip and palate. These observations suggest that genetic searches for microdeletions should be routine in screening patients for causes of VWS and may facilitate the positional cloning efforts of the VWS gene and of a nearby gene or genes that may be involved in brain development.     

Consanguinity and occurrence of cleft lip/palate: a hospital-based registry study in Riyadh

This paper focuses on the influence of consanguinity on the occurrence of orofacial clefts. All patients with orofacial clefts registered at King Faisal Specialist Hospital and Research Center, Riyadh since June 1999 until December 2009 were included in this study. Patients were classified in two distinct groups: cleft lip with or without cleft palate (CL?±?P) and isolated cleft palate (CP). Chi-squared test was used to test independence of variables. Intracluster correlation coefficient was estimated to assess the degree of concordance between siblings. Among 1,171 total patients, CL?±?P was found to be more common (64.0%). Males were more likely to be affected with CL?±?P (M:F?=?1.5:1) and females were more likely to be affected with CP (M:F?=?0.9:1; P?相似文献   

武汉地区167例先天性唇腭裂临床分析

目的探讨先天性唇腭裂的临床流行病学特征,了解先天性唇腭裂的发病情况,为先天性唇腭裂的深入研究提供数据。方法对我院2008年1月至2013年6月在我院引产及分娩的先天性唇腭裂畸形儿病例进行回顾性分析,并进行统计学处理。结果单纯唇裂、唇裂合并腭裂性别、单双侧比较差异有统计学意义。唇腭裂左右侧比较无统计学意义。唇腭裂城乡分布无统计学意义。唇腭裂家族发病亲缘关系、三种类型比较,差异均无统计学意义。唇腭裂伴发畸形性别比较无统计学意义。结论唇裂合并腭裂最常见。唇腭裂各类型中除单纯腭裂外男性多于女性,单侧多于双侧。唇腭裂家族发病情况与亲缘关系的远近无关。唇腭裂伴发畸形无性别差异。