Extending the clinical spectrum of X-linked Tonne-Kalscheuer syndrome (TOKAS): new insights from the fetal perspective.

INTRODUCTION: Tonne-Kalscheuer syndrome (TOKAS) is a recessive X-linked multiple congenital anomaly disorder caused by RLIM variations. Of the 41 patients reported, only 7 antenatal cases were described. METHOD: After the antenatal diagnosis of TOKAS by exome analysis in a family followed for over 35 years because of multiple congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases. RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families. We report a high frequency of diaphragmatic hernia (9 of 11), differences in sex development (10 of 11) and various visceral malformations. We report some recurrent dysmorphic features, but also pontocerebellar hypoplasia, pre-auricular skin tags and olfactory bulb abnormalities previously unreported in the literature. Although no clear genotype-phenotype correlation has yet emerged, we show that a recurrent p.(Arg611Cys) variant accounts for 66% of fetal TOKAS cases. We also report two new likely pathogenic variants in RLIM, outside of the two previously known mutational hotspots. CONCLUSION: Overall, we present the first fetal cohort of TOKAS, describe the clinical features that made it a recognisable syndrome at fetopathological examination, and extend the phenotypical spectrum and the known genotype of this rare disorder.

Prenatal phenotype of 22q11 micro-duplications: A systematic review and report on 12 new cases.

The 22q11 region is prone to generating recurring Copy Number Variations (CNVs) as a result of the large numbers of Low Copy Repeats (LCRs). Typical duplications encompass the LCR-A-to-D region but atypical duplications of various sizes have also been reported. These duplications are responsible for highly variable phenotypes with incomplete penetrance and expressivity, which is challenging for adequate genetic counselling, especially in the prenatal period. To better delineate prenatal phenotypes associated with these CNVs, we report here a clinical and molecular description of twelve cases (9 foetuses and 3 deceased new-borns babies) carrying recurrent 22q11 duplications (diagnosed via aCGH), along with a review of the existing literature. 22q11 duplications were inherited from an apparently healthy parent in almost 60% of the cases. Other CNVs were diagnosed for 8% of the cases. Increased nuchal translucency and cardiac anomalies (CHD) were the most prominent phenotypes observed, along with mild renal and skeletal anomalies. Duplications encompassing the LCR-C-to-D region (and the CRKL gene) seemed more likely to generate CHDs and renal malformations. Cleft lip/palate were observed in foetuses with duplications encompassing the LCR-A-to-B region or the SPECC1L gene, as previously suggested. However, genotype-phenotype correlations remain difficult to ascertain. Second-hit point variants, epigenetic or environmental variations could play a role in the phenotypic variability of 22q11 duplications, but remain a challenge for assessment in the short period of pregnancy.

Predicting the risk of respiratory distress in newborns with congenital pulmonary malformations.

OBJECTIVES: Most children with prenatally diagnosed congenital pulmonary malformations (CPMs) are asymptomatic at birth. We aimed to develop a parsimonious prognostic model for predicting the risk of neonatal respiratory distress (NRD) in preterm and term infants with CPM, based on the prenatal attributes of the malformation. METHODS: MALFPULM is a prospective population-based nationally representative cohort including 436 pregnant women. The main predictive variable was the CPM volume ratio (CVR) measured at diagnosis (CVR first) and the highest CVR measured (CVR max). Separate models were estimated for preterm and term infants and were validated by bootstrapping. RESULTS: In total, 67 of the 383 neonates studied (17%) had NRD. For infants born at term (>37 weeks, n=351), the most parsimonious model included CVR max as the only predictive variable (receiver operating characteristic (ROC) curve area: 0.70±0.04, negative predictive value: 0.91). The probability of NRD increased linearly with increasing CVR max and remained below 10% for CVR max <0.4. In preterm infants (n=32), both CVR max and gestational age were important predictors of the risk of NRD (ROC: 0.85±0.07). Models based on CVR first had a similar predictive ability. CONCLUSIONS: Predictive models based exclusively on CVR measurements had a high negative predictive value in infants born at term. Our study results could contribute to the individualised general risk assessment to guide decisions about the need for newborns with prenatally diagnosed CPM to be delivered at specialised centres.

Multicolor-FISH Characterization of a Prenatal Mosaicism for a Chromosomal Rearrangement Undetected by Molecular Cytogenetics.

Fetal mosaicism for chromosomal rearrangements remains a challenge to diagnose, even in the era of whole-genome sequencing. We present here a case of fetal mosaicism for a chromosomal rearrangement explored in amniocytes and fetal muscle, consisting of a major cell population (95%) with partial monosomy 4q and a minor population (5%) with additional material replacing the 4qter deleted segment. Molecular techniques (MLPA, array-CGH) failed to assess the origin of this material. Only multicolor-FISH identified the additional segment on chromosome 4 as derived from chromosome 17. Due to the poor prognosis, the couple chose to terminate the pregnancy. Because of low-level mosaicism, chromosomal microarray analysis (CMA), now considered as first-tier prenatal genetic analysis, did not allow the identification of the minor cell line. In case of large CNVs (>5 Mb) detected by CMA, karyotyping may be considered to elucidate the mechanism of the underlying rearrangement and eliminate mosaicism.

Antenatal Management of Bronchopulmonary Sequestration by Intrafetal Vascular Laser Ablation under Ultrasound Control: Narrative Review of the Literature and Report of Three Cases.

OBJECTIVE: The objective of this study is to assess the effectiveness and safety of intrafetal vascular laser ablation (VLA) for fetuses with bronchopulmonary sequestration (BPS) with hydrops. METHODS: First, we present 3 cases of fetuses with BPS and hydrops treated by VLA. Second, we aimed to conduct a narrative review to identify all reported cases of fetuses with BPS treated by intrafetal VLA. RESULTS: The review of the literature identified 41 fetuses treated by VLA for BPS with hydrops. The median gestational age of the VLA was 27+0 weeks' gestation [25+0-31+0] with an associated procedure at the same time in 43% of the cases (pleuroamniotic shunt, thoracentesis, and amniodrainage). A second procedure was required in 25% of cases for residual flow in the feeding vessel. No stillbirth or neonatal death was reported. The complications reported were a fetal thoracic hematoma complicated by fetal anemia and 4 preterm deliveries with a rate of 9%. CONCLUSION: VLA of the feeding vessel can be an effective treatment but is not without complications. In cases demonstrating cardiac output failure, intrafetal VLA should be considered as a treatment for BPS.

Performance of diagnostic ultrasound to identify causes of hydramnios.

INTRODUCTION: We aimed to assess the diagnostic yield of ultrasonography in the identification of the etiology of hydramnios, and the added value of MRI or amniocentesis. METHODS: We conducted a single-center retrospective study including pregnancies with confirmed hydramnios (defined as deepest pocket ≥8 cm) between January 2013 and May 2017. Twin pregnancies, secondary hydramnios discovered after the diagnosis of a causal pathology, and pregnancies of unknown outcome were excluded. All pregnancies underwent a targeted scan, and selected cases underwent MRI or amniocentesis. RESULTS: A total of 158 patients with confirmed hydramnios were included. Hydramnios was associated with a fetal pathology in 37 cases (23.4%), with diabetes in 39 (24.6%), isolated macrosomia in 16 (10.1%), and considered idiopathic in 66 (41.7%). Ultrasonography established a diagnosis of the underlying pathology in 73% of cases. Amniocentesis was done in 31 cases (20%) and it allowed diagnosis of chromosome anomalies, esophageal atresia, myotonic dystrophy congenital type, Prader-Willi syndrome, and Bartter syndrome. MRI was done in 15 cases (10%) and it allowed one additional diagnosis of esophageal atresia. The diagnostic yields of MRI and amniocentesis were 91.7% and 95.2%, respectively. There were five false positive diagnoses at ultrasonography, and one false positive diagnosis at MRI. CONCLUSION: Hydramnios can be associated with a wide variety of underlying pathologies. Diagnostic ultrasound can attain a diagnosis in the majority of cases. Amniocentesis offers a valuable complementary assessment.

Is laterality of congenital diaphragmatic hernia a reliable prognostic factor? French national cohort study.

OBJECTIVES: The objective of this study was to assess whether the laterality of congenital diaphragmatic hernia (CDH) was a prognostic factor for neonatal survival. METHODS: This was a cohort study using the French national database of the Reference Center for Diaphragmatic Hernias. The principal endpoint was survival after hospitalization in intensive care. We made a comparative study between right CDH and left CDH by univariate and multivariate analysis. Terminations and stillbirths were excluded from analyses of neonatal outcomes. RESULTS: A total of 506 CDH were included with 67 (13%) right CDH and 439 left CDH (87%). Rate of survival was 49% for right CDH and 74% for left CDH (P < .01). Multivariate analysis showed two factors significantly associated with mortality: thoracic herniation of liver (OR 2.27; IC 95% [1.07-4.76]; P = .03) and lung-to-head-ratio over under expected (OR 2.99; IC 95% [1.41-6.36]; P < .01). Side of CDH was not significantly associated with mortality (OR 1.87; IC 95% [0.61-5.51], P = .26). CONCLUSION: Rate of right CDH mortality is more important than left CDH. Nevertheless after adjusting for lung-to-head-ratio and thoracic herniation of liver, right CDH does not have a higher risk of mortality than left CDH.

Prenatal therapy with pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission of toxoplasmosis: a multicenter, randomized trial.

BACKGROUND: The efficacy of prophylaxis to prevent prenatal toxoplasmosis transmission is controversial, without any previous randomized clinical trial. In France, spiramycin is usually prescribed for maternal seroconversions. A more potent pyrimethamine + sulfadiazine regimen is used to treat congenital toxoplasmosis and is offered in some countries as prophylaxis. OBJECTIVE: We sought to compare the efficacy and tolerance of pyrimethamine + sulfadiazine vs spiramycin to reduce placental transmission. STUDY DESIGN: This was a randomized, open-label trial in 36 French centers, comparing pyrimethamine (50 mg qd) + sulfadiazine (1 g tid) with folinic acid vs spiramycin (1 g tid) following toxoplasmosis seroconversion. RESULTS: In all, 143 women were randomized from November 2010 through January 2014. An amniocentesis was later performed in 131 cases, with a positive Toxoplasma gondii polymerase chain reaction in 7/67 (10.4%) in the pyrimethamine + sulfadiazine group vs 13/64 (20.3%) in the spiramycin group. Cerebral ultrasound anomalies appeared in 0/73 fetuses in the pyrimethamine + sulfadiazine group, vs 6/70 in the spiramycin group (P = .01). Two of these pregnancies were terminated. Transmission rates, excluding 18 children with undefined status, were 12/65 in the pyrimethamine + sulfadiazine group (18.5%), vs 18/60 in the spiramycin group (30%, P = .147), equivalent to an odds ratio of 0.53 (95% confidence interval, 0.23-1.22) and which after adjustment tended to be stronger (P = .03 for interaction) when treatment started within 3 weeks of seroconversion (95% confidence interval, 0.00-1.63). Two women had severe rashes, both with pyrimethamine + sulfadiazine. CONCLUSION: There was a trend toward lower transmission with pyrimethamine + sulfadiazine, but it did not reach statistical significance, possibly for lack of statistical power because enrollment was discontinued. There were also no fetal cerebral toxoplasmosis lesions in the pyrimethamine + sulfadiazine group. These promising results encourage further research on chemoprophylaxis to prevent congenital toxoplasmosis.

Terminal 6.9 Mb deletion of chromosome 15q, associated with a structurally abnormal X chromosome in a patient with congenital diaphragmatic hernia and heart defect.

We report the case of a female patient exhibiting multiple congenital malformations including diaphragmatic hernia and heart defect. Cytogenetic studies (including karyotype, FISH and array-CGH) showed a de novo terminal deletion (6.9 Mb) on chromosome 15 in association with a recombinant X chromosome bearing a 9-Mb Xp duplication and a 46-Mb Xq deletion distal to XIST. The recombinant X chromosome was caused by a maternal inv(X)(p22.31q22.3). The X chromosome inactivation pattern was skewed in the patient suggesting a possible inactivation of the recombinant X chromosome. Considering these results, the phenotype was linked to the de novo terminal 15q deletion. These results strengthen the assumption that array-CGH should be applied to each fetus/newborn with multiple congenital malformations.

Congenital diaphragmatic hernia: prenatal diagnosis permits immediate intensive care with high survival rate in isolated cases. A population-based study.

OBJECTIVES: To estimate the prognosis of prenatally diagnosed isolated congenital diaphragmatic hernia (PDICDH) treated with 'immediate planned care' (IPC) between 1999 and 2003 in Eastern Brittany. METHODS: The prognosis of PDICDH was compared with the prognosis of the other live-born CDH, either prenatally undiagnosed or not having had IPC. IPC consisted in prenatal lung maturation with corticosteroids, elective caesarean section at 37 weeks, immediate intubation, surfactant, high- frequency ventilation or oscillation, nitric oxide, intravenous prostacyclin, anaesthesia and haemodynamic support. Surgical repair was performed in the NICU 34 h after birth. RESULTS: The incidence of CDH was 0.8 per thousand with a prenatal diagnosis rate of 27/30 (90%), leading to a termination of pregnancy in nine cases. Ten CDH were associated with other malformations. IPC in PDICDH was performed in 12 cases. The survival rate of PDICDH with IPC was 11/12 versus 1/9 in CDH with no IPC or no prenatal diagnosis (p < 0.01). Logistic regression analysis showed that IPC was determinant for survival (p < 0.01). CONCLUSION: Prenatal diagnosis of isolated CDH treated with immediate planned care is associated with a high survival rate. This suggests that prenatal diagnosis associated with specifically adapted postnatal procedure may improve the prognosis of isolated CDH.

Perinatal management and outcome of prenatally diagnosed congenital diaphragmatic hernia: a 1995-2000 series in Rennes University Hospital.

OBJECTIVES: To assess the prognosis of prenatally diagnosed congenital diaphragmatic hernia (CDH) during the years 1995-2000 in order to improve prenatal counselling. METHODS: Retrospective study of all 31 cases of women with prenatally diagnosed CDH. RESULTS: Nine pregnancies (29%) were terminated and two fetuses (6%) were stillborn. Ten fetuses (32%) had associated anomalies (four Fryns' syndrome) and four (13%) had underlying chromosomal anomalies. Twenty pregnancies were continued. Seven babies died before surgery either immediately in the delivery room (five between 1 and 45 min), or during the 'stabilisation period' (two babies, 7 and 21 h). Three babies presented with trisomy 18, Fryns' syndrome or transposition of the great arteries with microdeletion 22q11. Thirteen babies had the defect repaired (median 18 h, range 4-72 h) and 12 survived. Mechanical ventilation was required for a median of 12 days. One survivor has cerebral palsy. CONCLUSION: Of 31 prenatally diagnosed CDH cases 38% are alive, of 20 ongoing pregnancies 60% are alive, and of 13 babies who underwent surgery 92% are alive. No baby with associated malformations survived. These numbers need to be known by each member of the counselling team in order to give parents adequate information to make their decision.