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.     

Elevated MSAFP levels and congenital heart defects: Lack of an association

This study was undertaken to evaluate the relationship between elevated maternal serum alpha fetoprotein (MSAFP) lavels and congenital heart defects. Thirty-two infants with isolated major congenital heart defects and whose mothers had had MSAFP screening were identified. In only one case was the MSAFP greater than 2.3 multiples of the median. A review of our experience with women with elevated MSAFP levels did not document a higher rate of congenital heart malformations than would be expected based on estimated frequencies in the general population. © 1994 Wiley-Liss, Inc.     

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.     

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.     

Using log-linear models to test for associations among congenital malformations

Log-linear models can be used to test for pairwise associations and higher order interactions among anatomically distinct birth defects or congenital malformations. A log-linear model, including terms for every possible pairwise association among seven severe and easily detectable congenital malformations, was examined using data on 16,217 infants registered in the Metropolitan Atlanta Congenital Defects Program between 1968 and 1986. The resulting model showed clear patterns of strong association between some congenital malformations and not others, and the presence of 3-way interaction terms where the association between two malformations depended on the presence of a third. Examining a more parsimonious log-linear model showed overlapping patterns of pairwise association involving anal-rectal atresia and omphalocele, anal-rectal atresia and limb deficiency, and anal-rectal atresia and tracheaesophageal fistula. A second common pattern involved a triangular cluster with a hierarchical relationship among the three malformations (where there was a strong association between the first and second malformations and between the first and third malformations, but the association between the second and third was only seen in the absence of the first). Three such overlapping triangular clusters were identified from these data: neural tube defects, oral clefts, and omphalocele; neural tube defects, oral clefts, and limb deficiency; and limb deficiency, diaphragmatic hernia, and neural tube defects.(ABSTRACT TRUNCATED AT 250 WORDS)     

Diaphragmatic defects and limb deficiencies - taking sides

Diaphragmatic defects and limb deficiencies usually occur as independent anomalies, as a polytopic field defect (in which ipsilateral anomalies might be expected) or as wider pattern of defects, potentially involving disturbance of laterality or the midline (in which bilateral or contralateral defects would occur). Data on cases from previous studies and/or the literature were used to determine whether there is an association between the sides involved in the defects. The 88 adequately described cases identified included 20 with de Lange syndrome, seven with Poland anomaly, four with trisomy 18, 52 with other patterns of multiple malformations and five with diaphragmatic and limb defects alone. Evaluation of the position of the limb (left, right, bilateral) and the diaphragmatic defects (left, right, bilateral) did not show significant association in patterns of sidedness (P = 0.48). In 56% of cases, the limb deficiencies were bilateral. Among the 32 unilateral cases, 19 (59%) were ipsilateral (15 left; 4 right) and 13(41%) were contralateral (P = 0.38). Eleven of the 13 contralateral cases had left sided diaphragmatic defects and right sided limb deficiency; four had de Lange syndrome and nine had other patterns of multiple anomalies. Only cases with Poland anomaly or otherwise isolated defects showed a trend towards ipsilateral defects. Most cases with multiple congenital anomalies, had limbs defects on both the right and left (57%) or both sides of the diaphragm were affected (an additional 10%), indicating a widespread dysmorphogenetic process rather than a more restricted field defect. In other cases, defects were bilateral or, if unilateral, reflected the propensities for diaphragmatic defects to more often involve the left side, and limb defects, the right.     

Etiologic complexities of diaphragmatic defects: right diaphragmatic hernia, pulmonary hypoplasia/agenesis, and hydrocephalus in sibs.

Here we review the complexities of diaphragmatic defects and describe sibs with small, right diaphragmatic defects with pulmonary hypoplasia/agenesis and hydrocephalus. Despite a poor initial prognosis, the propositus has progressed remarkably well. Antenatal sonographic study detected hydrocephalus but not the diaphragmatic defect in the sib of the propositus. Because diaphragmatic defects are most commonly found in association with other anomalies and may occur in association with chromosome anomalies careful workup of all affected infants is crucial for accurate genetic counseling.     

Morgagni hernia with Down syndrome: a rare association -- case report and review of literature

Morgagni hernia is a rare diaphragmatic hernia accounting for only 2% of the congenital diaphragmatic defects. A case of Morgagni hernia was diagnosed radiologically in a 12-months-old male with Down syndrome, with recurrent respiratory distress and chest deformity. The 2-dimensional echocardiography was normal. The diagnosis of Morgagni hernia was confirmed by barium studies. The patient underwent a corrective surgery at 18 months of age following which his symptoms subsided. Literature review revealed only 18 cases of Morgagni hernia with Down syndrome reported till date, with age of presentation varying from neonatal age group to 12 years of age. The mode of presentations varied from asymptomatic detection to severe respiratory distress. The possible mechanism of association and its clinical implication has been discussed. The case emphasises a need for diaphragmatic hernia to be looked for as a possible cause of respiratory distress in Down syndrome.     

Etiologic complexities of diaphragmatic defects: Right diaphragmatic hernia,pulmonary hypoplasia/agenesis,and hydrocephalus in sibs

Here we review the complexities of diaphragmatic defects and describe sibs with small, right diaphragmatic defects with pulmonary hypoplasia/agenesis and hydrocephalus. Despite a poor initial prognosis, the propositus has progressed remarkably well. Antenatal sonographic study detected hydrocephalus but not the diaphragmatic defect in the sib of the propositus. Because diaphragmatic defects are most commonly found in association with other anomalies and may occur in association with chromosome anomalies careful workup of all affected infants is crucial for accurate genetic counseling.     

A family study of congenital diaphragmatic defects

The occurrence of specific and nonspecific congenital anomalies was determined in first degree relatives of index patients with congenital diaphragmatic defects who were born in Hungary between 1970 and 1979 and were ascertained through a population-based registry. The cases were grouped into Bochdalek types (N = 156), other types (N = 26), unclassified types (N = 55), and multiple congenital anomalies (MCA) cases including those with congenital diaphragmatic defects (N = 96). The sib occurrence in the Bochdalek type was 0.9% (taking into consideration also the unclassified cases or the total material, it was 0.5% or 0.4%, respectively). Specific familial clusters were not found in other types. Neural tube defects were detected in 1.8% of sibs in the total material and 2.4% in MCA cases.     

Low MSAFP levels and Williams syndrome

Williams syndrome (WS) is associated with a deletion of the elastin gene in over 90% of cases. We report maternal serum alpha feto-protein (MSAFP) levels in 5 women whose fetuses were later diagnosed as having WS. MSAFP levels ranged from 0.5–0.8 multiples of the median (MOM). Although further confirmation is necessary, it appears that MSAFP levels are lower than the median in WS. This apparent association has implications for counselling women following maternal serum screening. Am. J. Med. Genet. 72:448–450, 1997. © 1997 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.     

Diaphragmatic muscle reconstruction with an aligned electrospun poly(ε-caprolactone)/collagen hybrid scaffold

Large diaphragmatic muscle defects in congenital diaphragmatic hernia (CDH) are reconstructed by prosthetic materials or autologous grafts, which are associated with high complications and reherniation. In this study we examined the feasibility of using aligned electrospun poly(ε-caprolactone) (PCL)/collagen hybrid scaffolds for diaphragmatic muscle reconstruction. The hybrid scaffolds were implanted into a central left hemi-diaphragmatic defect (approximately 70% of the diaphragmatic tissue on the left side) in rats. Radiographic and magnetic resonance imaging (MRI) analyses showed no evidence of herniation or retraction up to 6 months after implantation. Histological and immunohistochemical evaluations revealed ingrowth of muscle tissue into the scaffolds. The mechanical properties of the retrieved diaphragmatic scaffolds were similar to those of normal diaphragm at the designated time points. Our results show that the aligned electrospun hybrid scaffolds allowed muscle cell migration and tissue formation. The aligned scaffolds may provide implantable functional muscle tissues for patients with diaphragmatic muscle defects.     

Giant Meckel's diverticulum associated with a congenital diaphragmatic hernia

Giant Meckel's diverticulum is a very rare lesion and its association with a congenital diaphragmatic hernia has not been reported previously. We report a case of newborn with a giant Meckel's diverticulum and congenital diaphragmatic hernia. A large round atypical air-filled bowel segment was found by chest radiography preoperatively, and a giant Meckel's diverticulum was located within the left hemithorax during surgery.     

Cardiovascular malformations in Fryns syndrome: is there a pathogenic role for neural crest cells?

We performed a comprehensive literature and case report review to characterize the cardiovascular malformations (CVMs) associated with Fryns syndrome (OMIM #229850), a multiple congenital anomaly/mental retardation syndrome consisting of diaphragmatic defects, significant pulmonary hypoplasia, distinctive facial appearance, distal digital hypoplasia, and numerous other external and internal anomalies. A total of 112 patients meeting diagnostic guidelines for Fryns syndrome were identified, of whom 82 met narrowly defined criteria (Group I) and 30 met broader diagnostic criteria (Group II). Twelve patients reported as having Fryns syndrome with atypical features (Group III) were also analyzed. A CVM was reported in 51% (42 of 82) of Group I patients, most commonly an atrial or ventricular septal defect (VSD) (23 of 42, 55%). Conotruncal and aortic arch CVMs were common (11 of 42, 26%), but not significantly so compared to the general population of infants to age 1 year [Ferencz et al., 1997]. Recognizing that minor septal defects associated with congenital diaphragmatic hernia (CDH) may occur in response to altered hemodynamics (instead of being a bonafide CVM), we excluded four patients reported as having hemodynamically insignificant VSDs. Following these exclusions, conotruncal CVMs were found more commonly than in the general population (11 of 38, 29%, P < or = 0.025). In Group II, 9 of 30 (30%) had a CVM with no predominant type among the small number of cases reviewed. Among the atypical Fryns syndrome patients in Group III, half (6 of 12, 50%) had a CVM; most (4 of 6, 67%) were conotruncal, in particular, type B interrupted aortic arch (3 of 4). Patients with Fryns syndrome have a high rate of CVMs, warranting thorough cardiac evaluation including echocardiogram (fetal and/or postnatal) in all patients, similar to the evaluation for other patients with diaphragmatic hernia. The possible association between conotruncal CVMs and Fryns syndrome may provide additional support for an etiologic role of genes related to neural crest cell development in the pathogenesis of Fryns syndrome and hence, congenital diaphragmatic hernia.     

Pentalogy of Cantrell and ectopia cordis, a familial developmental field complex.

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.     

Pentalogy of Cantrell and ectopia cordis,a familial developmental field complex

The association of sternal fusion defects with various cardiac, diaphragmatic, and anterior body wall defects represents a developmental field complex that includes the Pentalogy of Cantrell and ectopia cordis. No familial cases have been reported previously. We present 3 consecutively born brothers with extensive diaphragmatic defects, 2 who had the Pentalogy of Cantrell. One of the 2 also had ectopia cordis.     

影响先天性膈疝患儿生存率的危险因素分析

目的探讨影响先天性膈疝（CDH）患儿生存率的危险因素。方法青岛市第八人民医院产科1995年10月至2010年09月15年间分娩临床资料完整的CDH患儿11例,回顾性分析出生胎龄、母体分娩方式、诊断时机、患儿染色体核型、膈疝发生的部位、合并的其他结构畸形、是否有肝突出、纵膈移位等因素。结果 11例CDH中单纯CDH 6例,染色体核型异常CDH 3例,伴相关结构畸形者4例（其中2例同时伴染色体核型异常）。左侧膈疝8例,右侧膈疝3例。产前诊断1例,其余均产后诊断或死亡后尸检诊断。患儿的总体病死率为81.8%。其中围产儿死亡率72.7%（8/11）,新生儿晚期死亡率9.1%（1/11）,幸存率18.2%（2/11）。结论 CDH患儿病死率很高。右侧膈疝、肝突出、纵膈移位等可能是单纯性CDH预后不良的危险因素。CDH合并相关结构畸形和染色体核型异常者预后不良。加强产前诊断中高危因素的评估有望提高CDH幸存率。