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congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.RESULTS: We present a TOKAS antenatal cohort, describing 11 new cases in 6 French families.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.</p

The ANTENATAL multicentre study to predict postnatal renal outcome in fetuses with posterior urethral valves: objectives and design

Abstract Background Posterior urethral valves (PUV) account for 17% of paediatric end-stage renal disease. A major issue in the management of PUV is prenatal prediction of postnatal renal function. Fetal ultrasound and fetal urine biochemistry are currently employed for this prediction, but clearly lack precision. We previously developed a fetal urine peptide signature that predicted in utero with high precision postnatal renal function in fetuses with PUV. We describe here the objectives and design of the prospective international multicentre ANTENATAL (multicentre validation of a fetal urine peptidome-based classifier to predict postnatal renal function in posterior urethral valves) study, set up to validate this fetal urine peptide signature. Methods Participants will be PUV pregnancies enrolled from 2017 to 2021 and followed up until 2023 in >30 European centres endorsed and supported by European reference networks for rare urological disorders (ERN eUROGEN) and rare kidney diseases (ERN ERKNet). The endpoint will be renal/patient survival at 2 years postnatally. Assuming α = 0.05, 1–β = 0.8 and a mean prevalence of severe renal outcome in PUV individuals of 0.35, 400 patients need to be enrolled to validate the previously reported sensitivity and specificity of the peptide signature. Results In this largest multicentre study of antenatally detected PUV, we anticipate bringing a novel tool to the clinic. Based on urinary peptides and potentially amended in the future with additional omics traits, this tool will be able to precisely quantify postnatal renal survival in PUV pregnancies. The main limitation of the employed approach is the need for specialized equipment. Conclusions Accurate risk assessment in the prenatal period should strongly improve the management of fetuses with PUV

Elucidating in utero fetal demise time to reassemble the pieces of the puzzle?

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Diagnosis of fetal urinary tract malformations: prenatal management and postnatal outcome.

International audienceOBJECTIVE: To evaluate prenatal management and to define the criteria of gravity for accurate assessment of the renal and overall prognosis of fetuses presenting malformations of the urinary tract. METHODS: We carried out a retrospective study of 127 cases of urinary tract malformation. We carried out descriptive statistical and univariate analyses as a function of severity criteria and the outcome of pregnancy. RESULTS: One-third of fetuses presented associated extrarenal malformations and 10% of the karyotypes were abnormal. There were more abortions in case of decrease in amniotic fluid volume (p < 0.001), extent of renal damage (p < 0.05), presence of associated extrarenal malformations (p < 0.05), early diagnosis of the malformation (p < 0.001) and presence of chromosomal syndrome (p = 0.01). In our study, there was an excellent correlation between prenatal data and pathological findings for the fetus following abortions for medical reasons or obtained during the surveillance of live-born children. Fetal biochemistry made very little contribution. CONCLUSION: In cases of urinary tract malformation, this work confirms the need for regular and frequent ultrasound scans, checking for the echographic factors indicative of gravity and for adapted karyotyping. It also demonstrates that pluridisciplinary management is necessary for the prenatal evaluation of renal and overall fetal prognosis

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.

International audienceWe 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

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

International audienceThe 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

International audienceObjectives 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

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

International audienceObjectives: 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