Low maternal serum alpha-fetoprotein levels and congenital diaphragmatic defects

We report on 2 cases of fetal congenital diaphragmatic defects with normal chromosomes among 105 patients referred for evaluation for low maternal serum alpha-fetoprotein (MSAFP) levels. The mechanism for this striking association is not clear. The association of low MSAFP levels and congenital diaphragmatic defects may have importance for MSAFP screening programs.     

Low material serum alpha-fetoprotein levels and congenital diaphragmatic defects

We report on 2 cases of fetal congenital diaphragmatic defects with normal chromosomes among 105 patients referred for evaluation for low maternal serum alpha-fetoprotein (MSAFP) levels. The mechanism for this striking association is not clear. The association of low MSAFP levels and congenital diaphragmatic defects may have importance for MSAFP screening programs.     

Combination of elevated maternal serum alpha-fetoprotein (MSAFP) and low estriol is highly predictive of anencephaly

Increased levels of second trimester maternal serum alpha-fetoprotein (MSAFP) have long been established as a marker for neural tube defects (NTDs). In addition, decreased levels of maternal estriol in the third trimester have been reported in pregnancies with anencephalic fetuses. The purpose of this study was to evaluate whether early second trimester unconjugated serum estriol (uE3) is an independent predictor of NTDs. The study included 57,031 patients who underwent maternal serum screening with MSAFP at 14–22 weeks gestation. Of these, 23,415 also had uE3 measurements. There were 63 cases of NTD, an overall incidence of 1.1 per 1,000. Elevated MSAFP (≥2.5 MOM) was detected in 1,346 patients, 48 of which had NTDs. Decreased uE3 (≤0.5) was detected in 1,437 patients, 17 of which had NTDs. The incidence of NTDs was significantly higher in patients with low uE3, compared to patients with normal/high uE3 (1.15% vs. 0.09%, P < 001). Finally, 51 patients had both increased MSAFP and decreased uE3; 16 of these had NTDs, 14 of which were anencephalics. In conclusion, both elevated MSAFP and low maternal serum estriol are predictive of NTD but have a low sensitivity. The combination of abnormally elevated MSAFP and low estriol is highly predictive of NTD in particular anencephaly. Am. J. Med. Genet. 75:297–299, 1998. © 1998 Wiley-Liss, Inc.     

Mosaic trisomy 16 ascertained through amniocentesis: Evaluation of 11 new cases

Trisomy 16, once thought to result uniformly in early pregnancy loss, has been detected in chorionic villus samples (CVS) from on-going pregnancies and was initially ascribed to a second, nonviable pregnancy. Prenatally detected trisomy 16 in CVS and its resolution to disomy has led to the re-examination of the viability of trisomy 16. This study evaluates 11 cases of mosaic trisomy 16 detected through second trimester amniocentesis. In 9 of the 11 cases, amniocenteses were performed in women under the age of 35 because of abnormal levels of maternal serum alpha-fetoprotein (MSAFP) or maternal serum human chorionic gonadotropin (MShCG). The other two amniocenteses were performed for advanced maternal age. Five of the 11 pregnancies resulted in liveborn infants, and six pregnancies were electively terminated. The liveborn infants all had some combination of intrauterine growth retardation (IUGR), congenital heart defects (CHD), or minor anomalies. Two of them died neonatally because of complications of severe congenital heart defects. The three surviving children have variable growth retardation, developmental delay, congenital anomalies, and/or minor anomalies. In the terminated pregnancies, the four fetuses evaluated by ultrasound or autopsy demonstrated various congenital anomalies and/or IUGR. Cytogenetic and fluorescent in situ hybridization studies identified true mosaicism in 5 of 10 cases examined, although the abnormal cell line was never seen in more than 1% of cultured lymphocytes. Placental mosaicism was seen in all placentas examined and was associated with IUGR in four of seven cases. Maternal uniparental disomy was identified in three cases. Mosaic trisomy 16 detected through amniocentesis is not a benign finding but associated with a high risk of abnormal outcome, most commonly IUGR, CHD, developmental delay, and minor anomalies. The various outcomes may reflect the diversity of mechanisms involved in the resolution of this abnormality. As 80% of these patients were ascertained because of the presence of abnormal levels of MSAFP or MShCG, the increased use of maternal serum screening should bring more such cases to clinical attention. Am. J. Med. Genet. 80:473–480, 1998. © 1998 Wiley-Liss, Inc.     

4046例染色体检查结果与先天性心脏病关系的回顾性分析

目的探讨染色体异常与先天性心脏病（先心病）的关系。方法回顾性分析复旦大学附属儿科医院1990年1月至2006年12月所进行染色体检查的患儿中染色体异常的核型种类,并统计先心病患儿染色体的核型特点。结果共检测4046例患儿的染色体,染色体异常660例（16．3％）,其中常染色体异常以唐氏综合征最常见（458例,69．4％）;性染色体异常以特纳综合征最常见（105例,15．9％）。接受染色体检查的患儿中先心病391例,其中染色体异常者185／391例（47．3％）,157／185例核型表现为唐氏综合征,4／185例核型表现为特纳综合征。先心病中圆锥动脉干畸形105例,其染色体核型异常发生率较低,仅为16／105例（15．2％）（P〈0．05）。染色体核型正常的先心病患儿中,圆锥动脉于畸形和非圆锥动脉干畸形分别有95和111例。结论染色体核型异常与先心病之间存在密切的相互联系。染色体核型异常易合并先心病;某些先心病患儿的染色体核型异常发生率明显升高。但圆锥动脉干畸形与常见染色体异常间无密切联系。因此,对于染色体异常患儿应常规进行心脏检查,以及早发现先心病。另外,尽管某些先心病患儿的普通染色体核型检查未发现异常,但有必要寻找更合适的检测技术提高染色体异常的检出率。     

Congenital heart defects in Sotos sequence

Of 10 patients with typical Sotos sequence, 5 had various congenital heart defects. They included 2 patients with secundum atrial septal defect, and one patient each with patent ductus arteriosus with mitral valve regurgitation, tricuspid atresia plus pulmonary atresia, and ventricular septal defect. Increases of head circumference and weight gain were less accelerated in the patients with congenital heart defects than in those without heart defects, while growth in length was comparable between the 2 groups. In view of these findings, it is suggested that the rate of congenital heart defects in patients with Sotos sequence is much higher than that reported in the literature.     

Uterine artery Doppler velocimetry in the prediction of adverse obstetric outcomes in unexplained MSAFP elevations

Unexplained maternal serum-fetoprotein (MSAFP) elevation has been known to be associated with adverse obstetric outcomes, however it is not sufficiently useful as a screening test. This study was undertaken to determine whether uterine artery Doppler velocimetry could define a subset of patients with an elevated MSAFP level in whom complications of pregnancy might develop. The subjects included 179 women between 26 and 28 weeks' gestation with MSAFP > or = 2.5 multiples of the median, in whom either the presence of an early diastolic notch or a resistance index 0.6 was considered as an abnormal Doppler velocimetry finding. Those subjects who displayed abnormal Doppler velocimetry findings showed an increased incidence of preeclampsia, preterm birth, IUGR, and IUFD compared to those subjects with only elevated MSAFP (p < 0.05). No differences were observed in the incidence of LBW. Positive predictive values of adverse obstetric outcomes were significantly higher in the group having both elevated MSAFP and abnormal Doppler velocimetry compared to the group with only elevated MSAFP (p < 0.05). Uterine artery Doppler velocimetry in the second trimester can improve the value of unexplained MSAFP elevation in the prediction of adverse obstetric outcomes.     

5.78 Mb terminal deletion of chromosome 15q in a girl, evaluation of NR2F2 as candidate gene for congenital heart defects

All patients with terminal deletion of chromosome 15q have been reported to show intrauterine growth retardation, postnatal growth retardation, abnormal facial appearance and developmental delay. Haploinsufficiency of IGF1R was considered to be responsible for these symptoms. However, it is difficult to explain other symptoms seen in some of the patients, such as congenital heart defects by the absence of IGF1R alone. Here, we reported a patient with congenital heart defects and a 5.78 Mb terminal deletion of chromosome 15q detected by array-CGH. Among the patients reported to share congenital heart defects and terminal deletion of chromosome 15q, our patient had the smallest deletion. Evaluating the deletion map, NR2F2 was considered a candidate gene contributing to congenital heart defects in patients with terminal deletion of chromosome 15q.     

Maternal serum alpha-fetoprotein screening and fetal chromosome anomalies: is lowering maternal age for amniocentesis preferable?

We have compared the cytogenetic abnormalities diagnosed prenatally in 1,098 patients referred for amniocentesis because of low maternal serum alpha-fetoprotein (MSAFP) to those of 445 patients whose indication was elevated MSAFP and those of 361 patients who had amniocentesis for "maternal anxiety." Autosomal trisomies, sex chromosome aberrations, and various structural rearrangements were detected in all 3 groups and actually exceeded the age-related incidence estimates. The frequency of chromosome anomalies in cases studied because of "maternal anxiety" with no prior screening was similar to that in the group referred for low MSAFP (1.38 and 1.27%, respectively). A relatively higher frequency (2.02%) was detected in the group whose indication was elevated MSAFP. Maternal serum screening is designed primarily to recalculate risk figures for Down syndrome, but not for other major chromosome abnormalities. The concept of prenatal screening for chromosome aberrations must therefore be reevaluated. We think that efforts should be directed at making amniocenteses more accessible to patients who request it. "Lowering" maternal age limits to 30 would encompass a greater proportion of pregnancies at risk and would be a step toward more effective prenatal diagnosis for chromosome abnormalities.     

Maternal serum α-fetoprotein screening and fetal chromosome anomalies: Is lowering maternal age for amniocentesis preferable?

We have compared the cytogenetic abnormalities diagnosed prenatally in 1,098 patients referred for amniocentesis because of low maternal serum α-fetoprotein (MSAFP) to those of 445 patients whose indication was elevated MSAFP and those of 361 patients who had amniocentesis for “maternal anxiety.” Autosomal trisomies, sex chromosome aberrations, and various structural rearrangements were detected in all 3 groups and actually exceeded the age-related incidence estimates. The frequency of chromosome anomalies in cases studied because of “maternal anxiety” with no prior screening was similar to that in the group referred for low MSAFP (1.38 and 1.27%, respectively). A relatively higher frequency (2.02%) was detected in the group whose indication was elevated MSAFP. Maternal serum screening is designed primarily to recalculate risk figures for Down syndrome, but not for other major chromosome abnormalities. The concept of prenatal screening for chromosome aberrations must therefore be reevaluated. We think that efforts should be directed at making amniocenteses more accessible to patients who request it. “Lowering” maternal age limits to 30 would encompass a greater proportion of pregnancies at risk and would be a step toward more effective prenatal diagnosis for chromosome abnormalities.     

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.     

Genetic study of congenital heart defects in Northern Ireland (1974-1978).

Congenital heart defects are a major congenital abnormality and are assuming increasing importance. A study was undertaken to estimate the incidence of congenital heart defects in Northern Ireland over a five year period (1974-1978), to determine the age at diagnosis and to assess the risk of recurrence in sibs. An incidence rate of 7.3 per 1000 total births was found. This reduced to 3.1 per 1000 total births if only invasive methods of diagnosis (catheter studies, surgery, or necropsy) were considered. The overall risk of recurrence for sibs (excluding index patients with chromosomal abnormalities and syndromes) was 3.1%. In addition, excluding families with an affected parent and child gave a recurrence risk of 2.6%. By 6 weeks of age 63% of index patients had been diagnosed and this figure had risen to 88% by 1 year. This has important implications for studies which include only congenital heart defects diagnosed in the first year of life. Of 388 patients with a congenital heart defect confirmed by invasive criteria, 96 (24.7%) were found to have an extracardiac abnormality (ECA). Excluding those with epilepsy or mental handicap as the sole ECA left 91 (23.5%) with an ECA. This highlights the importance of looking for other abnormalities in a child with a congenital heart defect. The 388 index patients had 952 sibs of whom 72 (7.6%) had an ECA. Excluding those with minor abnormalities (inguinal hernias, undescended testes) as the sole ECA left 62 (6.5%) with a major ECA. In addition, excluding those with epilepsy or mental handicap as the sole ECA left 51 (5.4%) with a major ECA. Since parents are often reassured after the birth of a child with a congenital heart defect that their risk of having a child with a noncardiac abnormality is no greater than the general population this finding has important implications for genetic counselling.     

Neonatal progeroid syndrome: more than one disease?

We report on an infant with the neonatal progeroid syndrome whose clinical course and autopsy findings indicate that this may be a heterogeneous phenotype. The infant had intrauterine growth retardation, absence of subcutaneous fat, and a wizened, aged face, all apparently characteristic of the condition, but also had congenital heart defects and urinary reflux not reported in previous cases. An elevated maternal serum alpha fetoprotein was noted at 16 weeks of gestation and late-onset growth retardation appeared after 31 weeks. Autopsy findings showed normal cerebral myelination, in contrast to findings of sudanophilic leukodystrophy in the one patient with the syndrome previously examined at autopsy. These findings suggest that the neonatal progeroid syndrome may be a phenotype and have more than one cause.     

Prenatal diagnosis policy without routine amniocentesis in pregnancies with a positive family history for neural tube defects

The recurrence risk for neural tube defects in pregnancies of women with a family history of neural tube defects greatly exceeds the general population risk. In these high risk pregnancies, we used a prenatal diagnostic method differing from that usually employed, relying mainly on the results of maternal serum alpha-fetoprotein (MSAFP) and ultrasound examination, without routine amniocentesis. During the 6 years reviewed in this study, this method was applied in 539 pregnancies. Of a total of 20 neural tube defects, 19 were detected using this combination of MSAFP, ultrasound, and selective amniocentesis, and the authors estimate that about 8-10 spontaneous abortions were avoided because only 28 amniocenteses were carried out instead of 539. The risk of recurrence was found to be lower than that experienced earlier.     

26例胎儿先天性心脏畸形的产前诊断及临床分析

目的了解胎儿先天性心脏畸形的类型,分析胎儿先天性心脏畸形合并心外畸形及染色体异常的发生率。方法回顾性分析产前超声发现胎儿先天性心脏畸形,且经过产前染色体检查及产后病理解剖证实的26例病例。结果发现10种类型的胎儿先天性心脏畸形,其中室间隔缺损的发生率最高,达57.2%,有4例单纯一种心脏畸形（15.4%）,11例多发心脏畸形（42.3%）,15例合并心外畸形（52.7%）,12例合并染色体异常（46.2%）。结论胎儿期发现的先天性心脏畸形的类型一般较为严重,发生多种心脏畸形的机率较高,合并心外畸形和染色体异常的发生率也较高。     

The impact of MSAFP screening on genetic services, 1984-1986

The impact of maternal serum alpha-fetoprotein (MSAFP) screening on genetic centers was investigated by a questionnaire mailed to 220 genetic centers in the United States. Eighty-four (38%) of centers responded to the questionnaire; of these (34%) were adequate for analysis. About 33% of the programs performed their own MSAFP testing. Approximately 70% of centers used 2.5 times the median (MoM) as a cutoff for MSAFP elevations and approximately 75% of centers used a sliding cutoff for low MSAFP based on both maternal age and the multiple of the median. Between 1984 and 1986, the total number of women screened by the reporting centers increased by about 4.7 fold. The percentage of women seen in their centers for prenatal counseling due to high or low MSAFP levels increased from 1.3% in 1984 to 13.1% in 1986. The percentage of prenatal diagnoses utilizing amniocentesis for high or low MSAFP increased from 3% in 1984 to 10% in 1986. During this period, 76 cases of Down syndrome were detected based on low MSAFP; this represents 1.7% of amniocenteses for low MSAFP. These data demonstrate a significant increase in the number of women seen for prenatal counseling and amniocentesis at the reporting genetic centers and is likely to represent a similar trend at all genetic centers. The impact of high MSAFP screening for neural tube defects and low MSAFP screening for Down syndrome is likely to increase over the coming years and genetic programs should prepare for the increasing utilization of services necessary to handle women with high and low MSAFP levels.     

The impact of MSAFP screening on genetic services, 1984–1986

The impact of maternal serum alpha-fetoprotein (MSAFP) screening on genetic centers was investigated by a questionnaire mailed to 220 genetic centers in the United States. Eighty-four (38%) of centers responded to the questionnaire; of these (34%) were adequate for analysis. About 33% of the programs performed their own MSAFP testing. Approximately 70% of centers used 2.5 times the median (MoM) as a cutoff for MSAFP elevations and approximately 75% of centers used a sliding cutoff for low MSAFP based on both maternal age and the multiple of the median. Between 1984 and 1986, the total number of women screened by the reporting centers increased by about 4.7 fold. The percentage of women seen in their centers for prenatal counseling due to high or low MSAFP levels increased from 1.3% in 1984 to 13.1% in 1986. The percentage of prenatal diagnoses utilizing amniocentesis for high or low MSAFP increased from 3% in 1984 to 10% in 1986. During this period, 76 cases of Down syndrome were detected based on low MSAFP; this represents 1.7% of amniocenteses for low MSAFP. These data demonstrate a significant increase in the number of women seen for prenatal counseling and amniocentesis at the reporting genetic centers and is likely to represent a similar trend at all genetic centers. The impact of high MSAFP screeing for neural tube defects and low MSAFP screening for Down syndrome is likely to increase over the coming years and genetic programs should prepare for the increasing utilization of services necessary to handle women with high and low MSAFP levels.     

Cardiac abnormalities in the Rubinstein-Taybi syndrome

In order to evaluate the incidence of cardiac anomalies, type of cardiac defects, and their impact in the Rubinstein-Taybi syndrome (RTS), a questionnaire study was done. Fortyfive of 138 patients in the study (32.6%) had a known cardiac abnormality; 27 patients had single defects including atrial septal defect (ASD), ventricular septal defect (VSD), patent ductus arteriosus (PDA), coarctation of the aorta, pulmonic stenosis, or bicuspid aortic valve. Eight of these individuals had spontaneous resolution of their problems, while 8 required surgery. Sixteen patients had complex congenital heart defects or two or more abnormalities. Two patients had spontaneous resolution, while 7 required surgery. Surgery is planned in 5 additional patients. Five patients had conduction abnormalities. Individuals with congenital heart defects did not have a higher incidence of other birth defects. The significant incidence and potential severity of cardiac anomalies in our patients suggest that a cardiac evaluation should be strongly considered in patients with RTS. © 1995 Wiley-Liss, Inc.     

Web neck anomaly and its association with congenital heart disease

To investigate the relationship between congenital heart disease and jugular lymphatic obstruction as manifested in web neck anomaly, we used the Iowa Birth Defects Registry to determine the incidence of congenital heart defects (CHD) in infants with and without web neck. Sixty percent of infants with web neck had CHD, with a high incidence of flowrelated defects such as hypoplastic left heart, coarctation, and secundum atrial septal defect. Sixty-eight percent of infants with web neck had a genetic syndrome (37% Down syndrome, 13% Ullrich-Turner syndrome, and 5% Noonan syndrome), and 24% had dysmorphic features consistent with lymphatic obstruction sequence. When infants with Down, Ullrich-Turner, and Noonan syndrome and web neck were compared to infants with the same syndrome but without web neck, those with web neck were significantly more likely to have flow-related heart defects. Infants with Ullrich-Turner syndrome and web neck had an 11-fold higher incidence of coarctation, compared to those with a normal neck. Our data suggests web neck is associated with both flow and nonflow-related heart defects. This association implies a pathogenetic relationship and appears to be independent of causal factors. The finding of web neck or nuchal cystic hygroma on a prenatal ultrasound or newborn examination should prompt a search for CHD. © Wiley-Liss, Inc.