142例胎儿唇腭裂的超声诊断与遗传因素分析

目的探讨胎儿唇腭裂的影像学特征与遗传基础。方法142例病例均接受产前超声系统检查,经过两级医生检查及会诊做出最终诊断。同时收集活产胎儿的胎儿脐带或引产胎儿的大腿肌肉组织,进行全基因组测序(whole genome sequening,WGS),以发现染色体数目异常和拷贝数异常(copy number variations,CNVs)。结果142例孕妇年龄分布为21~41岁,孕周为12~35周。142例胎儿中,男性94例,女性48例,男女比例为1∶0.51。根据唇腭裂的类型,单纯唇裂有84/142例(59.15%),唇裂合并其他系统畸形情况有31/142例(21.83%)。单纯唇腭裂有14/142例(9.86%),唇腭裂合并其他系统畸形情况有13/142例(9.15%)。9.2%(13/142)的胎儿有染色体数目异常,8.4%(12/142)的胎儿检出了致病性CNV。结论对CNVs的检测可以增加胎儿腭裂的遗传检测诊断率,在临床中应重视检测致病性CNVs。     

Alpha-tocopherol levels in mothers of children with cleft lip or with cleft lip and palate

OBJECTIVES: Environmental factors may play equally critical role as genes in facial embryogenesis. It was suggested that cleft palate occurring in association with cleft lip may result from environmental factors that affect development of both the lip and the palate. Cleft lip forms from the third through seventh week of embryonic development. During these period fetal nutrition is histotrophic, pressure of oxygen is low, genes for antioxidant enzymes are supressed and alpha-tocopherol play an essential role in the fetal tissues antioxidant capacity. Cleft palate forms from the fifth through twelfth weeks of gestation, when hemonutrition and antioxidant enzymes are developing, and hypothetical deficiency of tocopherol is not so crucial. AIM: The goal of the study was to investigate concentrations of alpha-tocopherol in women who gave birth to a child with cleft lip and mothers of children with cleft lip and palate. MATERIAL AND METHODS: Blood samples from 31 healthy mothers of children with isolated cleft lip (CL) and 29 healthy mothers of children with isolated cleft lip and palate (CLP) were collected. Fasting plasma alpha-tocopherol concentrations were measured by the high performance liquid chromatography. Kolmologorov-Smirnov test with Lilefors correction and k-means cluster analysis were applied to determine differences between the groups of women. RESULTS: We found that alpha-tocopherol concentrations were lower in CL compared to CLP, but the difference did not achieve level of statistical significantly (medians: 15.8 micromol/L vs. 20.0 micromol/L; p = 0.066). There were identified three clusters of alpha-tocopherol concentrations: 14.0 micromol/L (19CL+8CLP), 19.6 micromol/L (8CL+13CLP), and 21.1 micromol/L (4CL+8CLP). The distribution of results to the clusters was dependent on type of the orofacial cleft (chi squared = 6.95 with 2 degrees of freedom, p = 0,031). CONCLUSIONS: Analysis for environmental risk factors should be performed separately for cleft lip and cleft lip and palate because these two conditions appear to be etiologically distinct. The role of a higher periconceptional intake of alpha-tocopherol in reduction of risk of giving birth to a child with cleft lip requires further research.     

Prenatal diagnosis of craniofacial malformations with ultrasonography

Although the utility of ultrasound in the prenatal diagnosis of many congenital anomalies is well established, its accuracy in detecting craniofacial malformations has not been examined in a large series. Sonographic examinations of 223 patients at risk for fetuses with craniofacial malformations were performed between 18 and 40 weeks. The risk factors included a familial history of craniofacial malformations, extrafacial anomalies diagnosed on ultrasound, fetal chromosomal aberrations, and maternal drug intake. Sonographic diagnosis was possible in 151 (67.7%) patients on the first scan and in 47 (21.1%) patients on the second scan and was not possible in 25 patients (11.2%). Of the 198 cases diagnosed antenatally, craniofacial malformation was detected in 14 and confirmed postnatally. No false positive diagnoses were made. A negative diagnosis of craniofacial malformation was made in 184 cases with two false negative results (1.0%). Anomalies diagnosed sonographically included anophthalmia, anterior cleft lip and/or palate, hypotelorism, hypertelorism, and micrognathia. The results of this study demonstrate that ultrasound is an accurate and reliable tool for the prenatal diagnosis of craniofacial malformations.     

Sonographic evaluation of fetal clefts of the lip, alveolus and palate

Clefts of the lip, alveolus and palate are among the most common congenital malformations. Due to their frequent combination with other structural anomalies, chromosomal defects and genetic syndromes, the prenatal diagnosis of clefts plays an important role. Furthermore, the prenatal detection of clefts enhances the parents' psychological preparation and enables the planning of postnatal management. This article reviews the occurrence, appearance and pathophysiology of these malformations as well as the different sonographic techniques used to diagnose clefts and their extent. Previously reported 2D- and 3D-techniques as well as our own recent diagnostic approach focussing on the diagnosis of isolated cleft palate are described.     

胎儿期唇裂的诊断和治疗

文章概述了胎儿期唇腭裂的发生、相关因素、诊断和治疗。介绍了胎儿唇腭裂与染色体异常发生率的关系。随着产前诊断技术(超声、MR I等)的提高,越来越多的胎儿唇腭裂得到诊断。胎儿镜等技术促进了胎儿宫内治疗的发展,唇腭裂的宫内治疗亦是一个趋势,但目前大量的研究仍然是局限在动物模型。     

Prenatal diagnosis of cleft palate by 3D ultrasound

A case of a fetus seen at 33.2 weeks of gestation who was diagnosed with cleft lip in the third quarter by routine ultrasound. Describes the sequential steps that led to a multidisciplinary support the diagnosis of cleft palate by three-dimensional image reconstruction, which were originally obtained to demonstrate the fetal face surface. Birth confirmed the prenatal findings and established the diagnosis of cleft lip and cleft hard and soft palate. It has been reported that the diagnosis of facial clefts can be done with relative ease prenatally, but the detection rate of facial clefts in routine tests is only 20%. Until recently the diagnosis of cleft palate is not considered possible, however in recent years advances in three-dimensional technology has made possible the development of techniques for the assessment of the palate and various authors have reported promising results of ingenious applications that make think that in the near future will approach the palate a fact. We discuss the advantages and disadvantages of these methods are relatively new and highlights how valuable this information is for parents of the affected creature.     

Evaluation of prenatal diagnosis of associated congenital heart diseases by fetal ultrasonographic examination in Europe

Ultrasound scans in the mid trimester of pregnancy are now a routine part of antenatal care in most European countries. With the assistance of Registries of Congenital Anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of congenital heart defects (CHD) by routine ultrasonographic examination of the fetus. All congenital malformations suspected prenatally and all congenital malformations, including chromosome anomalies, confirmed at birth were identified from the Congenital Malformation Registers, including 20 registers from the following European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries follow the same methodology. The study period was 1996-1998, 709 030 births were covered, and 8126 cases with congenital malformations were registered. If more than one cardiac malformation was present the case was coded as complex cardiac malformation. CHD were subdivided into 'isolated' when only a cardiac malformation was present and 'associated' when at least one other major extra cardiac malformation was present. The associated CHD were subdivided into chromosomal, syndromic non-chromosomal and multiple. The study comprised 761 associated CHD including 282 cases with multiple malformations, 375 cases with chromosomal anomalies and 104 cases with non-chromosomal syndromes. The proportion of prenatal diagnosis of associated CHD varied in relation to the ultrasound screening policies from 17.9% in countries without routine screening (The Netherlands and Denmark) to 46.0% in countries with only one routine fetal scan and 55.6% in countries with two or three routine fetal scans. The prenatal detection rate of chromosomal anomalies was 40.3% (151/375 cases). This rate for recognized syndromes and multiply malformed with CHD was 51.9% (54/104 cases) and 48.6% (137/282 cases), respectively; 150/229 Down syndrome (65.8%) were livebirths. Concerning the syndromic cases, the detection rate of deletion 22q11, situs anomalies and VATER association was 44.4%, 64.7% and 46.6%, respectively. In conclusion, the present study shows large regional variations in the prenatal detection rate of CHD with the highest rates in European regions with three screening scans. Prenatal diagnosis of CHD is significantly higher if associated malformations are present. Cardiac defects affecting the size of the ventricles have the highest detection rate. Mean gestational age at discovery was 20-24 weeks for the majority of associated cardiac defects.     

Chromosomal defects and associated malformations in fetal cleft lip with or without cleft palate

OBJECTIVE: To describe the incidence, associated features including chromosomal defects in fetuses, with cleft lip and/or palate and assess the need for karyotyping. METHODS: Retrospective study of 62 cases of prenatally diagnosed facial cleft lip and/or palate in a tertiary fetal medicine unit between January 1991 and December 1999. Chromosome analysis was performed in all fetuses with associated ultrasound findings and in 14 (39%) fetuses with isolated facial clefts. RESULTS: Associated abnormalities were detected in 26 (42%) of the 62 fetuses of which 22 (35%) fetuses had multiple other abnormalities. Central nervous system abnormalities and limb malformations were the most common. Three fetuses had genetic syndromes confirmed after birth. All fetuses with isolated clefts were chromosomally normal, whereas 15 of the 26 with additional abnormalities (58 or 24% of the total group) had chromosomal defects (eight cases of trisomy 13, five of trisomy 18, one unbalanced translocation between chromosomes 7 and 8, and one deletion 4p-). All 22 women who chose not to undergo fetal karyotype analysis delivered phenotypically normal infants. There were five midline clefts; each of them was associated with additional sonographic findings and four were associated with holoprosencephaly. CONCLUSION: Isolated facial clefting is not associated with an increased risk for chromosomal defect. Amniocentesis is recommended when facial cleft is found in association with additional ultrasonographic abnormalities as it is unnecessary for isolated clefts.     

Prenatal imaging of facial clefts by magnetic resonance imaging with emphasis on the posterior palate

OBJECTIVE: To evaluate the role of Magnetic Resonance Imaging (MRI) in the prenatal diagnosis of facial clefts. MATERIALS AND METHODS: Six fetuses with a sonographic diagnosis of cleft lip and palate underwent MRI at a median age of 30 weeks (range 28-32). The defect was bilateral in two cases. RESULTS: Fetal MRI confirmed the presence of a cleft involving at least the anterior palate in all cases. Distinction between unilateral and bilateral clefts could be made in all cases and was always confirmed after birth. Sagittal views of the fetal face were found to be particularly useful in identifying the degree of extension of the cleft into the palate. The diagnosis was confirmed after birth. CONCLUSION: Our results suggest that MRI may be ancillary to ultrasound in prenatal investigation of a fetus with cleft lip, allowing a better staging of the lesion by demonstrating the degree of involvement of the palate.     

唇腭裂患儿中先天性心脏病的发生率及其特点

目的探讨唇腭裂患儿中先天性心脏病(简称先心病)的发生率及其特点。 方法广州市儿童医院口腔科2004-01—2005-05共收治567例拟行唇腭裂修复术的患儿，将患儿分成单纯唇裂组、单纯腭裂组及唇裂合并腭裂组3组，对3组患儿均行彩色多普勒超声心动图检查，对检查结果进行统计学分析。 结果567例唇腭裂患儿中共检出先天性心脏病37例，总发生率为653%，主要的先心病为：房间隔缺损(ASD)、动脉导管未闭(PDA)、室间隔缺损(VSD)；其中单纯唇裂组和单纯腭裂组患儿先心病发生率分别为508%、1056%，唇裂合并腭裂组患儿先心病发生率为521%。运用Pearson卡方检验进行统计学分析，3组患儿的先心病发生率差异无显著性。 结论先心病在唇腭裂患儿中发生率较高，彩色多普勒超声心动图检查能清楚准确地诊断各类型的先天性心脏病，可用于唇腭裂修复术前的常规检查。     

Prenatal diagnosis of six major cardiac malformations in Europe--a population based study

AIM: To present data on prenatal diagnosis of six major cardiac malformations in low-risk European populations. METHODS: Data from 12 Eurocat registries on congenital malformations. All registries have multiple sources of information and use the same methods of data collection and coding. The six cardiac malformations included were hypoplastic left heart, tricuspid atresia, single ventricle, Tetralogy of Fallot, transposition of great arteries and common A-V-canal. RESULTS: There were significant differences in the proportion of cases diagnosed prenatally, with the highest detection rate in France (91% for single ventricle in Paris) and the lowest detection rate in countries without prenatal ultrasound screening (no cases diagnosed prenatally in the Danish registry area). Prenatal detection rate was significantly higher for the three malformations affecting the size of the ventricles (hypoplastic left heart, tricuspid atresia, single ventricle) compared to the other three malformations (46% versus 24%, p<0.001). Time of diagnosis was late, with only one third diagnosed before 24 weeks of gestation. The risk of fetal death seems to be low. CONCLUSION: There are significant regional differences in prenatal detection rate of major cardiac malformations in Europe.     

上海市10年出生缺陷监测情况分析

目的 了解近10年来上海市出生缺陷的发生、消长趋势及存在的问题,为采取相应的干预措施提供依据。方法 采用回顾性调查方法,以无脑儿、脑积水、脊柱裂、脑膨出、腹裂和联体双胎6种致死率高、伤残性大且孕中期大多可通过B超发现的主要形态畸形及其他畸形,进行专题回顾性个案调查。结果 上海市近10年出生缺陷发生率为8.42‰,前3位依次为先心病、多指和唇腭裂。与全国相比除先心病、21-三体、尿道下裂、唇裂、腭裂和小耳的发生率高于全国水平外,其余都较低。在198例21-三体中,产妇35岁以上者占34.34％;主要形态畸形的产前确诊率为60.64％,平均确诊时间在孕30周以上。所有出生缺陷儿的围产期死亡率为23.27％。结论 上海市出生缺陷发生率低于全国水平,但产前诊断的覆盖率和质量还需提高。     

产前诊断唇腭裂308例回顾性研究

目的:探讨胎儿唇腭裂与染色体异常的关系,为该疾病的临床咨询及预后评估提供依据。方法:回顾性分析我院2008年1月至2016年12月所有超声诊断为唇裂/腭裂/唇腭裂的308例孕妇的产前诊断情况,比较不同类型唇腭裂的超声表型特征及染色体异常的发生率。结果:(1)超声诊断结果显示,在308例唇腭裂胎儿中非综合征型唇腭裂258例(83.77%),综合征型唇腭裂50例(16.23%),其中单纯唇裂40例(12.99%),唇裂合并腭裂266例(86.36%),单纯腭裂2例(0.65%)。(2)同意进行产前诊断137例(44.48%),染色体异常共22例(16.06%),其中23例综合征型唇腭裂中发现染色体异常共12例(52.17%),分别为13-三体8例(66.67%),18-三体2例(16.67%),三倍体2例(16.67%);而在114例非综合征型唇腭裂中发现染色体异常10例(8.77%),分别为18-三体1例,21-三体1例,标记染色体1例,发现基因微缺失微重复等遗传综合征4例(B超检查均无任何软指标及除唇腭裂外的其他结构异常),臂间倒位等染色体多态性3例。染色体基因芯片分析(CMA)检测的染色体异常检出率为16.16%(16/99),染色体核型分析异常检出率为15.79%(6/38)。(3)随访到204例患者,186例患者选择引产,18例患者出生后进行手术干预治疗。结论:唇腭裂胎儿染色体异常发生率较高,建议对所有类型唇腭裂均进行产前诊断;CMA检测可以发现除非整倍体外的拷贝数变异,建议对唇腭裂胎儿优选基因芯片进行产前诊断。     

Prenatal diagnostic rates and postnatal outcomes of fetal orofacial clefts in a Taiwanese population

Objective

To report the incidence, prenatal diagnostic rate, and postnatal outcomes of fetal orofacial cleft at a tertiary referral center in Taiwan.

Methods

The demographic data, maternal and fetal characteristics, and postnatal outcomes for fetuses with cleft lip and/or cleft palate (CL/P) born between January 1998 and December 2008 at Chang Gung Memorial Hospital, Taipei, were reviewed retrospectively, and diagnostic rates were evaluated according to cleft type.

Results

Among 26 499 deliveries, 84 were affected with CL/P. The mean maternal age and gestational age at detection of CL/P were 30.37 years (range 21-41 years) and 24.7 weeks (range 18-33 weeks), respectively. Thirty-one fetuses had associated structural anomalies, 5 of which involved chromosomal aberrations. CL/P was diagnosed prenatally for 74 (88%) fetuses. After consultations, 17 pregnancies (20%) were aborted. The postnatal survival rate was 95.5% (64/67 infants). The type of cleft had a significant influence on correct prenatal diagnosis (P < 0.001).

Conclusion

For fetuses diagnosed prenatally with an orofacial cleft, access to an experienced craniofacial team, well-planned delivery, and pediatric intensive care led to favorable postnatal outcomes after lethal malformations were excluded through detailed sonographic and chromosomal evaluations.     

Prenatal detection of facial clefts

OBJECTIVES: To determine (1) the antenatal detection rate for isolated cleft lip and/or cleft palate during the routine anomaly scan; (2) the correlation between prenatal diagnosis and postnatal findings, and (3) the association of apparently isolated cleft lip and/or cleft palate with other anomalies, in particular chromosomal abnormalities. METHOD: A population-based retrospective analysis of all cases of isolated cleft lip and/or cleft during an 8-year period in an academic teaching hospital in the UK. RESULTS: Thirty-nine cases of isolated cleft lip and/or cleft palate were identified among deliveries at the hospital. Twenty-eight cases had a routine anomaly scan. Fourteen cases were detected prenatally (sensitivity 50%). None of the isolated cleft palates was detected, while 14 of 20 cases of cleft lip (70%) were detected. One of the isolated cases of cleft lip was associated with trisomy 21, while 3 of the isolated cleft palate cases were associated with the Pierre Robin syndrome. In all cases, an antenatal diagnosis of cleft was confirmed following delivery or post-mortem examination (specificity 100%). CONCLUSIONS: Ultrasound is a useful tool in screening for cleft lip with or without cleft palate, but not for cleft palate alone. Even with an isolated cleft lip, there is an increased risk of chromosomal abnormality. The role of prenatal education and support is extremely important in the preparation of prospective parents and can help alleviate the shock which occurs when there is an unexpected cleft at birth.     

Catel-Manzke syndrome without cleft palate: a case report

We report a boy who presented with mild facial dysmorphism, pectus excavatum, bilateral brachydactyly and ulnar deviation of both index fingers. Radiological examination of the hands showed abnormal proximal phalanges of the second digits. This case differs from the classical Catel-Manzke syndrome in having isolated hand malformations without any other malformations such as cleft palate or cardiac abnormalities.     

Prenatal sonographic diagnosis of Malpuech syndrome

Malpuech syndrome (MS) is a rare autosomal recessive syndrome featuring pre- and post-natal growth deficiency, mental retardation, facial dysmorphism, cleft lip and palate (typically midline or bilateral), caudal appendage, renal malformations and male genital abnormalities. A prenatal diagnosis of MS was made in this fetus based on the family history and a combination of conventional and 3D prenatal ultrasound findings. The family were consanguineous with an affected first child. Prenatal ultrasound in the second pregnancy demonstrated bilateral cleft lip and palate in association with intrauterine growth retardation on serial prenatal ultrasound scans. Dysmorphic facial features and a small penis consistent with the diagnosis were confirmed on 3D scanning. Post-natal examination of the neonate confirmed the diagnosis of MS. To the best of our knowledge, this is the first prenatal diagnosis of this syndrome.     

Evaluation of the prenatal diagnosis of limb reduction deficiencies. EUROSCAN Study Group

Ultrasound scans in the mid-trimester of pregnancy are now a routine part of antenatal care in most European countries. Using data from registries of congenital anomalies a study was undertaken in Europe. The objective of the study was to evaluate prenatal detection of limb reduction deficiencies (LRD) by routine ultrasonographic examination of the fetus. All LRDs suspected prenatally and all LRDs (including chromosome anomalies) confirmed at birth were identified from 20 Congenital Malformation Registers from the following 12 European countries: Austria, Croatia, Denmark, France, Germany, Italy, Lithuania, Spain, Switzerland, The Netherlands, UK and Ukrainia. These registries are following the same methodology. During the study period (1996-98) there were 709,030 births, and 7,758 cases with congenital malformations including LRDs. If more than one LRD was present the case was coded as complex LRD; 250 cases of LRDs with 63 (25.2%) termination of pregnancies were identified including 138 cases with isolated LRD, 112 with associated malformations, 16 with chromosomal anomalies and 38 non chromosomal recognized syndromes. The prenatal detection rate of isolated LRD was 24.6% (34 out of 138 cases) compared with 49.1% for associated malformations (55 out of 112; p<0.01). The prenatal detection of isolated terminal transverse LRD was 22.7% (22 out of 97), 50% (3 out of 6) for proximal intercalary LRD, 8.3% (1 out of 12) for longitudinal LRD and 0 for split hand/foot; for multipli-malformed children with LRD those percentages were 46.1% (30 out of 65), 66.6% (6 out of 9), 57.1% (8 out of 14) and 0 (0 out of 2), respectively. The prenatal detection rate of LRDs varied in relation with the ultrasound screening policies from 20.0% to 64.0% in countries with at least one routine fetal scan.     

Male gender significantly increases risk of oxidative stress related congenital anomalies in the non-diabetic population

Objective.?Oxidative stress (OS) is an important mechanism of teratogenesis. Recent work suggests increased OS in males. We evaluated whether male gender increased the risk of cyanotic congenital heart defects (CCHD) whose development is linked to OS and other common congenital anomalies (CA) in non-diabetic pregnancies.

Methods.?CDC-National Center for Health Statistics data for 19 states in 2006 were reviewed. CCHD, anencephaly, spina bifida, congenial diaphragmatic hernia (CDH), omphalocele, gastroschisis, limb defects, cleft lip with or without cleft palate (CL/P) and isolated cleft palate were evaluated. Adjusted odds ratio (OR) (95% CI) were calculated for CA in males with females as the reference group.

Results.?Of 1,194, 581, cases analyzed after exclusions, 3037 (0.25%) had major CA. Males had elevated adjusted OR (95% CI) for CCHD: 1.198 (1.027, 1.397), CDH: 1.487 (1.078, 2.051), and CL/P: 1.431 (1.24, 1.651). There was a significant interaction between cigarette use and (male) fetal gender and also with maternal age in the CL/P group.

Conclusions.?In non-diabetic pregnancies, male gender appears to be an independent risk factor for some types of CA believed to be associated with OS. Cigarette smoking, a well recognized source of OS only increased the risk of CL/P in males.     

Cigarette smoking as an etiologic factor in cleft lip and palate.

A case-control study has been made on smoking habits in women who, during 1975, gave birth to infants with closure defects of the central nervous system (ASB) or with cleft lip or cleft palate (CLP). For each case, two control subjects with nonmalformed infants were selected and matched for delivery unit, time of delivery, maternal age, and maternal parity. Smoking habits were routinely included in hospital records at first visit to a maternity health clinic during pregnancy. Data were studied for 66 cases of CLP, 66 cases of ASB, and 261 control subjects. Significantly more women who had infants with CLP smoked than did control women, but women with ASB infants showed a normal smoking pattern. Drug use did not explain the findings. It is suggested that maternal smoking is one of many factors of importance in the etiology of cleft lip and cleft palate in humans.