Bi-allelic loss-of-function variants in KIF21A cause severe fetal akinesia with arthrogryposis multiplex.

BACKGROUND: Fetal akinesia (FA) results in variable clinical presentations and has been associated with more than 166 different disease loci. However, the underlying molecular cause remains unclear in many individuals. We aimed to further define the set of genes involved. METHODS: We performed in-depth clinical characterisation and exome sequencing on a cohort of 23 FA index cases sharing arthrogryposis as a common feature. RESULTS: We identified likely pathogenic or pathogenic variants in 12 different established disease genes explaining the disease phenotype in 13 index cases and report 12 novel variants. In the unsolved families, a search for recessive-type variants affecting the same gene was performed; and in five affected fetuses of two unrelated families, a homozygous loss-of-function variant in the kinesin family member 21A gene (KIF21A) was found. CONCLUSION: Our study underlines the broad locus heterogeneity of FA with well-established and atypical genotype-phenotype associations. We describe KIF21A as a new factor implicated in the pathogenesis of severe neurogenic FA sequence with arthrogryposis of multiple joints, pulmonary hypoplasia and facial dysmorphisms. This hypothesis is further corroborated by a recent report on overlapping phenotypes observed in Kif21a null piglets.

Turner syndrome-omphalocele association: Incidence, karyotype, phenotype and fetal outcome.

OBJECTIVE: Omphalocele is known to be associated with genetic anomalies like trisomy 13, 18 and Beckwith-Wiedemann syndrome, but not with Turner syndrome (TS). Our aim was to assess the incidence of omphalocele in fetuses with TS, the phenotype of this association with other anomalies, their karyotype, and the fetal outcomes. METHOD: Retrospective multicenter study of fetuses with confirmed diagnosis of TS. Data were extracted from a detailed questionnaire sent to specialists in prenatal ultrasound. RESULTS: 680 fetuses with TS were included in this analysis. Incidence of small omphalocele in fetuses diagnosed ≥12 weeks was 3.1%. Including fetuses diagnosed before 12 weeks, it was 5.1%. 97.1% (34/35) of the affected fetuses had one or more associated anomalies including increased nuchal translucency (≥3 mm) and/or cystic hygroma (94.3%), hydrops/skin edema (71.1%), and cardiac anomalies (40%). The karyotype was 45,X in all fetuses. Fetal outcomes were poor with only 1 fetus born alive. CONCLUSION: TS with 45,X karyotype but not with X chromosome variants is associated with small omphalocele. Most of these fetuses have associated anomalies and a poor prognosis. Our data suggest an association of TS with omphalocele, which is evident from the first trimester.

Assessment of the maxilla-mandible-nasion angle in normal and aneuploid foetuses in the first trimester of pregnancy.

PURPOSE: This retrospective study aims to determine whether the maxilla-mandible-nasion (MMN) angle can be reliably measured in the first trimester, to describe normal ranges, and to determine if significant changes occur in foetuses with aneuploidies. METHODS: The MMN angle was measured in stored 2D-ultrasound images of 200 normal fetal profiles between 11+0 and 13+6 weeks of gestation. Each image was analyzed by two observers at two independent time points. Bland-Altmann analysis was performed to evaluate the reliability of the measurements. Additionally, the MMN angle was measured on sonograms from 140 aneuploid foetuses. RESULTS: The mean MMN angle in normal foetuses from 11 to 14 weeks of gestation was 15.4°. Reliability of the measurement was high when repeatedly measured by the same observer (ICC = 0.92 and 0.82) and between two observers (ICC = 0.77 and 0.63). Average MMN values in foetuses with trisomy 21, 13, and Turner syndrome were significantly higher than those measured in normal foetuses. The highest differences were observed in foetuses with trisomy 13. Among those, 62% had an MMN angle above the 95th percentile and 92% above the normal mean. CONCLUSION: The MMN angle can be reliably measured in early pregnancy and is abnormal in about 60% of foetuses with trisomy 13.

Pregnancy outcome in foetuses with increased nuchal translucency - 10-years' experience in a prenatal medical practice.

This retrospective study describes pregnancy outcome for foetuses with increased nuchal translucency (NT) in relation to the degree of increase in a local specialised medical practice. Data from 7352 first trimester pregnancies examined by a single observer between 10/07 and 07/17 were screened. Three hundred and ninety-three foetuses (5.3%) that had an increased NT ≥ 95th percentile and available pregnancy outcome were identified. For this population, the frequencies of chromosomal abnormality, foetal malformation, intrauterine death (IUD) and termination of pregnancy (TOP) were determined in relation to the degree of NT thickness. Favourable pregnancy outcome decreased from 77.8% (lowest NT group, 95th percentile-3.5 mm) to 5% (highest NT ≥ 6.5 mm), whereas chromosomal abnormalities rose from 18.1% to 70%. An abnormal karyotype occurred in 39.2% of foetuses with increased NT. In euploid foetuses, cardiac defects were the most common structural abnormalities. The data largely matches with earlier studies conducted in large hospital-based settings. However, a rather high proportion of foetuses with abnormal karyotype was observed.IMPACT STATEMENTWhat is already known on this subject? Increased NT is associated with chromosomal abnormalities as well as an adverse perinatal outcome also in foetuses with a normal karyotype. The prevalence of an adverse outcome increases with NT thickness. These studies were conducted more than 10 years ago mainly in academic settings.What do the results of this study add? This study describes pregnancy outcome of a population of foetuses with increased NT that were examined in a medical practice by a single observer over a period of 10 years with state of the art ultrasound equipment. We observed a relatively large proportion of foetuses with abnormal karyotype. In euploid foetuses, increased NT was associated with a wide range of foetal malformations and genetic syndromes.What are the implications of these findings for clinical practice and/or further research? Even mildly increased NT thickness is associated with an adverse pregnancy outcome, underlining the importance of thorough ultrasound examinations. Specialised prenatal medical practices can provide state-of the art technology and provide improve parental counselling.

The diagnostic value of a detailed first trimester anomaly scan in fetuses with increased nuchal translucency thickness.

Objectives To assess the diagnostic value of an early anomaly scan in fetuses with increased nuchal translucency (NT) in the prediction of aneuploidy. Methods In this study we analyzed the data of pregnant women obtained at their first trimester screening in our unit. The detailed examination routinely includes measurement of NT and a scan for anatomical defects. For fetuses with an NT≥3.5 mm, the diagnostic power of early major sonographic findings (MSF) regarding abnormal karyotype was calculated. Results A total of 7352 first trimester examinations were screened. Two hundred and twenty-two fetuses with an NT≥3.5 mm were analyzed. The median gestational age was 12.5 weeks (range 11.0-14.6) and the median NT was 5.1 mm (range 3.5-15.3). MSF were detected in 51.8% of fetuses with increased NT. Among 115 fetuses with MSF, 91 were aneuploid, yielding a positive predictive value for aneuploidy of 79.1%. In the absence of MSF, the negative predictive value was 70.1%. The presence of MSF was significantly predictive for aneuploidy both in bivariate and multivariate regression analysis. Conclusion Our study underlines the importance of a detailed anatomical ultrasound in fetuses with increased NT, as MSF occurred frequently. However, the diagnostic value of MSF regarding aneuploidies appears to be moderate.

Measurement of inferior facial angle and prefrontal space ratio in first trimester fetuses with aneuploidies: a retrospective study.

Objective To determine whether the measurement of inferior facial angle (IFA) and prefrontal space ratio (PFSR) in two-dimensional (2D) ultrasound images in the first trimester of pregnancy is reliable and to describe these markers in normal and aneuploid fetuses. Methods IFA and PFSR were measured in stored 2D midsagittal images of 200 normal and 140 aneuploid fetal profiles between 11 + 0 and 13 + 6 weeks of gestation. Limits of agreement (LOAs) and intraclass correlation coefficients (ICCs) for inter- and intraobserver differences were calculated. Results The mean IFA in normal fetuses was 76.5° ± 6.3. Between the two measurement rounds of the same observer, the LOAs were -5.4 to 7.1 (obs. 1) and 7.4 to 8.4 (obs. 2). For IFA measurements by the same observer the ICC was 0.88 (obs. 1) and for measurements by two different observers the ICC was 0.74. The mean PFSR was 0.76 ± 0.40 and the intraobserver LOAs were -0.372 to 0.395 (obs. 1) and -0.555 to 0.667 (obs. 2). For PFSR measurements by the same observer the ICC was 0.89 (obs. 1) and for measurements by two different observers the ICC was 0.65. Among aneuploid fetuses, IFA was below the normal range in one third of the cases with trisomy 18. PFSR was below the 95% prediction limit in 16.2% of fetuses with trisomy 21% and 17.9% of fetuses with trisomy 18. Conclusion IFA can be reliably measured in 2D ultrasound images in the first trimester of pregnancy with a high interobserver agreement and may provide information about retrognathia associated with various syndromes and aneuploidies at early stages of pregnancy.

The Value of Detailed First-Trimester Ultrasound Anomaly Scan for the Detection of Chromosomal Abnormalities.

PURPOSE: To evaluate the performance of first-trimester ultrasound screening involving a detailed anomaly scan for the detection of trisomy 18, trisomy 13, triploidy, Turner syndrome and trisomy 21. METHODS: Data of pregnant women who underwent aneuploidy screening at 11-13 weeks of gestation was retrospectively analyzed. Crown-rump length (CRL), fetal nuchal translucency thickness (NT) and nasal bone (NB) anatomy, blood flow across the tricuspid valve (TV) and through the ductus venosus (DV) were assessed. Furthermore, a detailed scan for fetal anatomical anomalies (FA) was carried out. Performance of these markers was assessed by logistic regression and ROC analyses for different screening models. RESULTS: 4005 fetuses were analyzed. 3856 were euploid, 149 aneuploid (trisomy 18: 40; trisomy 13: 14; triploidy: 3; Turner syndrome: 17; trisomy 21: 75 cases). 70-100 % of the fetuses with trisomy 18 and 13, triploidy and Turner syndrome but only 34.7 % with trisomy 21 had at least one fetal defect. Considering all aneuploidies, the detection rate (DR) for screening based on MA+NT+NB+TV+DV was 90.6 % and improved to 96.0 % if an FA was added (fixed false-positive rate: 3 %). If screening was based on MA+NT+FA, the detection rate for all aneuploidies was 85.2 %. However, the DR for trisomy 18, trisomy 13, triploidy and Turner syndrome (excluding trisomy 21) was 94.6 %, indicating the high diagnostic value of an anomaly scan for these aneuploidies. CONCLUSION: Incorporation of a detailed fetal anomaly scan (FA) into first-trimester screening algorithms can improve the detection rates for trisomy 18 and 13, triploidy and Turner syndrome.

Is Fetal Hydrops in Turner Syndrome a Risk Factor for the Development of Maternal Mirror Syndrome?

Mirror syndrome is a rare and serious maternal condition associated with immune and non-immune fetal hydrops after 16 weeks of gestational age. Subjacent conditions associated with fetal hydrops may carry different risks for Mirror syndrome. Fetuses with Turner syndrome are frequently found to be hydropic on ultrasound. We designed a retrospective multicenter study to evaluate the risk for Mirror syndrome among pregnancies complicated with Turner syndrome and fetal hydrops. Data were extracted from a questionnaire sent to specialists in maternal fetal medicine in Germany. Out of 758 cases, 138 fulfilled our inclusion criteria and were included in the analysis. Of the included 138, 66 presented with persisting hydrops at or after 16 weeks. The frequency of placental hydrops/placentomegaly was rather low (8.1%). Of note, no Mirror syndrome was observed in our study cohort. We propose that the risk of this pregnancy complication varies according to the subjacent cause of fetal hydrops. In Turner syndrome, the risk for Mirror syndrome is lower than that reported in the literature. Our observations are relevant for clinical management and parental counseling.

Cell-free DNA Testing in Routine Practice: Characterisation of a Cohort with Positive Results for Trisomies, Sex Chromosome Anomalies and Microdeletions.

Introduction Cell-free DNA (cfDNA) testing is increasingly used as a screening method not only for trisomy (T) 21 but also for T18 and T13, sex chromosome anomalies (SCA) and microdeletions. Based on cases with a positive cfDNA result in our specialised prenatal practice, this study aims to characterise the usage of cfDNA testing and to estimate the positive predictive value (PPV) in routine practice in Germany. Patients and Methods In this retrospective study we analysed the data of all pregnant women with a positive cfDNA result seen between 09/2013 and 12/2019. Women were either referred due to the positive result or the test was initiated in our practice. The primary parameter of interest was the concordance of cfDNA tests with confirmatory genetic testing. Results We encountered 81 cases with a positive cfDNA test (T21: 49.4%; T18: 9.9%; T13: 8.6%; SCA: 22.2%; 22q12del: 8.6%). The PPV was 95.0% for T21, but considerably lower for T18 (55.6%) and T13 (28.6%). For SCAs it was 23.1% and no case with DiGeorge syndrome was confirmed. 63% of the patients had not received a fetal anomaly scan before cfDNA testing. In first-trimester fetuses with a cfDNA test predicting an autosomal aneuploidy, fetal anomalies were detected in 90.3% of the cases. No false positive case had an abnormal US result. Conclusions Despite the excellent specificity of cfDNA tests, the PPV for aneuploidies other than T21 is low in routine practice. In discordance with the current guidelines, cfDNA test is often used without a previous detailed anomaly scan. Our data provide valuable information to assist patient counselling and shared decision making.

Assessment of rapid fetal fibronectin in predicting preterm delivery.

OBJECTIVE: The aim of this study was to estimate the effectiveness of cervical fetal fibronectin assayed by the rapid fetal fibronectin assay in predicting preterm delivery in patients with signs or symptoms of preterm labor. METHODS: Patients with preterm labor between 24 and 34 weeks of gestation were included. At the time of speculum examination, fetal fibronectin samples were collected from the cervix. The probe was analyzed for fetal fibronectin using the rapid fetal fibronectin assay. Managing obstetricians were blinded to fetal fibronectin results. Outcome data were collected after delivery. RESULTS: One hundred seventy patients had fetal fibronectin samples and outcome data. The mean (+/- standard deviation) gestational age at delivery was 38.63 +/- 2.5 weeks among those with negative fetal fibronectin results (n = 124) and 35.71 +/- 3 weeks for those with positive results (n = 46; P < .001). The admission-to-delivery interval was 27.3 days shorter in the group with positive fetal fibronectin results (36.1 +/- 29.9 compared with 63.4 +/- 29.2; P < .001). The rapid fetal fibronectin assays were useful in predicting risk of delivery within 7, 14, or 21 days (sensitivity 81.8%, 87.5%, and 77.3%; specificity 76.7%, 79.2%, and 80.4; positive predictive value 19.6% [9/46], 30.4% [14/46], 37% [17/46]; negative predictive value 98.4% [122/124], 98.4% [122/124], and 96% [119/124], respectively). CONCLUSION: In a population of patients with signs and symptoms of preterm labor, the presence of cervical fetal fibronectin is effective in predicting risk of delivery within 7, 14, or 21 days. The negative predictive values of fetal fibronectin using the Tli systems compared well with data from previous reports using enzyme-linked immunosorbent assay-based assays. LEVEL OF EVIDENCE: III.

Suppression of IL-2 and IFN-gamma production in women with spontaneous preterm labor.

AIMS: To determine the TH-1/TH-2 cytokine pattern in peripheral blood leukocytes (PBL) in late second- and third trimester in normal pregnancies, in comparison to patients with spontaneous preterm delivery (PTD; < 37 completed weeks' gestation). METHODS: A cross-sectional retrospective study was performed in a tertiary care obstetric unit with healthy non-pregnant women (n=7); healthy pregnant women (n=25); patients (n=25) with preterm labor (defined as uterine contractions or changes in cervical length). The phenotypic analysis of TH-1/TH-2 immune deviation was examined in PBL. RESULTS: 26% PTD (n=13) were recorded. Patients delivering at term (n=37, 74%) were characterized by an upregulation of IL-2, IFN-gamma and IL-4 production during weeks 20-25, followed by a strong suppression in cytokine production, except for TGF-beta. Towards the end of pregnancy cytokine levels returned to normal as observed in non-pregnant women. In contrast, PTD showed an inverse pattern for IL-2 and IFN-gamma with marked suppression in IL-2 and IFN-gamma production between weeks 20-25, followed by a strong stimulation of these cytokines. No differences were observed in IL-4 and TGF-beta production. CONCLUSION: An inverse pattern in IL-2 and IFN-gamma production in PBLs between weeks 20-30 is seen in PTD as compared to patients delivering at term.

The value of quantitative ultrasound tissue characterization of the cervix and rapid fetal fibronectin in predicting preterm delivery.

OBJECTIVE: To evaluate clinical risk factors, cervical fetal fibronectin (fFN), cervical length, and mean gray value assessment in predicting of preterm delivery (PTD) in patients with signs and/or symptoms of preterm labor (PTL). STUDY DESIGN: One hundred and seventeen women with PTL between 24 and 34 weeks of gestation were included. Cervical swabs were tested for fFN using the rapid fFN assay. When 2-dimensional transvaginal ultrasound measurement of cervical length was completed, a region of interest (ROI) of constant size was defined in the midsection of the posterior wall, and the tissue-specific gray scale was determined. The end point were PTDs at <34 and <37 weeks of gestation. RESULTS: In univariate analysis, the three strongest predictors of spontaneous preterm birth <34 weeks were positive fFN (relative risk [RR] 8.9; 95% confidence interval [CI] 2.6-30.1), cervical length < or =2.5 cm (RR 6.9; 95% CI 1.6-29.7), and a low mean gray value of < or =5.97 (RR 7.9; 95% CI 2.3-27.2). Predictors significantly associated with spontaneous PTD at less than 37 weeks of gestation included previous PTD in multiparas (RR 3.9; 95% CI 1.6-9.5), positive fFN (RR 7.6; 95% CI 3.8-15.3), cervical length < or =2.5 cm (RR 2.6; 95% CI 1.4-5.1) and a low gray scale value of < or =6.54 (RR 4.5; 95% CI 2.3-8.9). In the final regression models used to predict spontaneous PTD <34 weeks and <37 weeks of gestation, both a positive fetal fibronectin (odds ratio [OR] 13.4; 95% CI, 2.5-72.1, P=0.003 vs. OR, 17.3; 95% CI 4.9-61.8, P<0.001) and a low gray scale value (OR 6.3 95% CI 1.3-29.4, P=0.02 vs. OR, 7.1; 95% CI 2-25.2, P=0.003) remained powerful predictors. The RRs of spontaneous PTD <37 weeks has been analyzed by a combination of these significant parameters. Low mean gray value < or =6.54 and negative fFN had a 10.3-fold (95% CI 2-74.5) increased risk of spontaneous preterm birth at <37 weeks. Combination of positive fFN and normal gray level (>6.54), had a higher increase risk of PTD (RR 18.1; 95% CI 4.4-76.7). When both factors were positive, the RR increases to 24.8 (95% CI 6.2-98.7). CONCLUSIONS: Combined use of rapid fFN and cervical gray value analysis improves the diagnostic efficiency and allows identification of women at risk for preterm delivery and in need for further prophylactic/therapeutic intervention.

Perinatal management of a preterm neonate affected by hyperprostaglandin E2 syndrome (HPS).

BACKGROUND: Neonates affected by hyperprostaglandin E(2) syndrome (HPS) present with severe polyuria. Both urinary losses as well as prostaglandin synthesis inhibitors may precipitate acute renal failure (ARF). AIM: Our goal was to maintain euvolaemia by replacement of urinary losses. PATIENT: Our patient was born prematurely with a family history typical of HPS. Urinary salt and water losses and PGE(2) excretion were determined in 2- to 4-h intervals. Salt and water were replaced accordingly. RESULTS: Within the first 48 h, urinary losses and PGE(2) increased continuously to 50 ml/kg/h and 374 ng/h/1.73 m(2), respectively. Following exposure to 0.05-0.5 mg/kg/d indomethacin, urinary output decreased steadily to 10-15/ml/kg/h. CONCLUSION: In euvolaemic preterm neonates with HPS and the need for excessive replacement of salt and water, inhibition of renal PGE(2) excretion with indomethacin effectively reduces polyuria and natriuresis without acutely compromising renal function.

Fetoscopic placement of a transurethral stent for intrauterine obstructive uropathy.

PURPOSE: Fetal urinary obstructive uropathy and consecutive oligohydramnios result in a poor outcome. Usually renal insufficiency and life threatening lung hypoplasia have developed at term. We report a case of in utero fetal cystoscopy and successful placement of a transurethral vesico-amniotic Double-J (Medical Engineering Corp., New York, New York) stent. Indications, results and the potential benefits of different techniques are discussed. MATERIAL AND METHODS: A 36-year-old woman (primipara) was evaluated at week 26 due to a male fetus with bilateral hydronephrosis, massive distended bladder and an open posterior urethra. Using local anesthesia the fetal bladder was punctured, a 2.6 mm endoscope was inserted and a wire was advanced antegrade through the penis. A 2.8Fr Double-J stent was then placed between the bladder and amniotic cavity. RESULTS: The bladder drained into the amnion, hydronephrosis disappeared and the lung developed normally. At week 37 a healthy infant was delivered who voided spontaneously. CONCLUSIONS: After careful selection of candidates for fetal intervention in obstructive uropathy direct vision fetoscopy and transurethral stent placement can be performed in patients with oligohydramnios, favorable urinary electrolytes and normal appearing kidneys.

Assessment of fetal lung development by quantitative ultrasonic tissue characterization: a methodical study.

OBJECTIVES: This study was performed to evaluate the quantitative ultrasonic tissue characterization of the normal fetal lung development by using acoustic raw data captured after preprocessing. METHODS: One hundred and sixty-two patients with completed gestational ages between 22 and 37 weeks were enrolled in this study. Longitudinal and transverse sections of the fetal thorax and upper abdomen were imaged. A region of interest of constant size was defined and the tissue-specific gray scale was determined by using an interactive software. RESULTS: A total of 162 patients met the inclusion criteria. The echogenicity of the fetal lung showed a particular changing pattern during pregnancy: the mean gray value of the fetal lung (MGV) is almost the same as the MGV of the fetal liver at 22 and 23 weeks, decreases between 22 and 31 weeks and increases between 31 and 37 weeks. The MGV of the fetal liver decreases significantly from 24 weeks to 31 weeks and increases significantly again toward 37 weeks. We stated that the MGV of the lung is smaller than the MGV of the liver during 31 weeks of gestation and the relation reverses in late gestation. At term, the MGV of the liver is greater than the MGV of the lung. The lung-to-liver ratio is <1 between 24 and 29 weeks and >1 between 30 and 35 weeks. CONCLUSION: The echogenicity of the fetal lung showed a particular changing pattern during pregnancy, which corresponds to morphologic changes of the fetal lung development.

Evaluation of quantitative ultrasound tissue characterization of the cervix and cervical length in the prediction of premature delivery for patients with spontaneous preterm labor.

OBJECTIVE: This study was to evaluate the predictive value of the uterine cervix tissue with the use of quantitative ultrasound gray level analysis for preterm delivery. STUDY DESIGN: Sixty-eight patients with preterm labor between 20 and 35 weeks of gestation were included. When two-dimensional transvaginal ultrasound measurement of cervical length was completed, a region of interest of constant size was defined in the midsection of the posterior wall, and the tissue-specific gray scale was determined. Preterm delivery of <37 weeks of gestation was sought. RESULTS: Twenty-eight patients (41.2%) were delivered preterm. The risk for preterm delivery was increased significantly in patients with cervical length of /=4 (odds ratio, 3.44; 95% CI, 1.21-9.75), and with decreased mean gray scale value (odds ratio, 12.13; 95% CI, 3.69-39.88). Parity and uterine contractions were not significant as predictors for preterm delivery, although the risk for preterm delivery increased with higher parity (odds ratio, 1.8; 95% CI, 0.68-4.79). The risk for preterm delivery remained nearly the same by uterine contractions (odds ratio, 0.92; 95% CI, 0.28-3.01). A mean scale value of

Operative fetoscopical management of intrauterine obstructive uropathia by urethral stent.

We report on an innovative therapeutic attempt in a case with obstructive uropathia in a fetus. Placement of an anterograd urethral stent was performed in the 26th gestational week. Transurethral catheterization via the fetal megacystis, the urethra and the orificium externum of the penis was feasible during fetal endoscopy (Fetendo). During serial ultrasound scans from the 27th to the 36th gestational week a normalization of the amniotic fluid volume was observed. The postpartal evaluation demonstrated that the kidney structure, values of kreatinin serum levels and renal clearance were in the normal range. The boy's development after the seventh month is completely normal. Fetendo with urethral stent application for obstructive uropathy should be performed for the carefully selected patient with oligohydramnion and normal kidney appearance.