Predicting the risk of cystic fibrosis with abnormal ultrasound signs of fetal bowel: Results of a French molecular collaborative study based on 641 prospective cases

Abstract

Hyperechogenic fetal bowel is prenatally detected by ultrasound during the second trimester of pregnancy in 0.1-1.8% of fetuses. It has been described as a normal variant but has often been associated with severe diseases, notably cystic fibrosis (CF). The aim of our study was to determine the risk of CF in a prospective study of 641 fetuses with ultrasonographically abnormal fetal bowel and the residual risk when only one mutation is detected in the fetus. Fetal cells and/or parental blood cells were screened for CFTR mutations. Two screening steps were used, the first covering the mutations most frequently observed in French CF patients (mutation detection rate of 70-90%) and, when a CF mutation was detected, a DGGE-sequencing strategy. We observed a 3.1% risk of CF when a digestive tract anomaly was prenatally observed at routine ultrasound examination. The risk was higher when hyperechogenicity was associated with bowel dilatation (5/29; 17%) or with the absence of gall bladder (2/8; 25%). The residual risk of CF was 11% when only one CF mutation was detected by the first screening step, thereby justifying in-depth screening. Mutations associated with severe CF (DeltaF508 mutation) were more frequently observed in these ultrasonographically and prenatally detected CF cases. However, the frequency of heterozygous cases was that observed in the normal population, which demonstrates that heterozygous carriers of CF mutations are not at increased risk for hyperechogenic bowel. In conclusion, fetal bowel anomalies indicate a risk of severe cystic fibrosis and justify careful CFTR molecular analysis.

Amniotic Fluid Digestive Enzyme Analysis Is Useful for Identifying CFTR Gene Mutations of Unclear Significance

“…Our database consisted of 43 fetuses carrying 2 CFTR mutations or variants, from whom AF was sampled at 16 - tine ultrasound scanning (8 ). Informed consent for AF sampling and biochemical and genetic testing was obtained from all patients.…”

“…Previous studies have revealed a 3%-5% prevalence of CF in fetuses with hyperechogenic fetal bowel, leading to 10%-13% residual risk of CF when 1 CFTR mutation is detected (8,15 ). An abnormal AF-DE pattern would increase the risk of fetal CF, leading to a complete CFTR gene screening.…”

Best practice guidelines for molecular genetic diagnosis of cystic fibrosis and CFTR-related disorders – updated European recommendations

“…54 Significant anomalies were grade III hyperechogenicity (ie, where the ultrasound echogenicity of the fetal abdomen was equal to the surrounding bone tissue) and loop dilatation.…”

Notable contribution of large CFTR gene rearrangements to the diagnosis of cystic fibrosis in fetuses with bowel anomalies

“…7 It is noteworthy that 3/5 CF fetuses carrying a deletion had associated digestive signs, all 3 with gallbladder anomalies. Few studies have been published about the association between CF and fetal gallbladder anomalies, 7,26,27 thus calling for larger studies to assess better the frequency of CF in fetuses with such anomalies.…”

“…1,2 It can be benign and transient, or an indicator of varied fetal pathologies including cystic fibrosis (CF) (MIM 219700), which has been reported in 2.5-10.0% of cases. [2][3][4][5][6][7] CF is the most common severe autosomal recessive disorder in the Caucasian population with an overall incidence of approximately 1 in 3500 live births. [8][9][10] Although patients' life expectancy has greatly improved over past decades, CF remains a severe disease, allowing prenatal diagnosis when both parents are known carriers for CF mutations or when abnormal ultrasound signs are detected during pregnancy.…”