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congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.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.

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.

TCF2/HNF-1beta mutations: 3 cases of fetal severe pancreatic agenesis or hypoplasia and multicystic renal dysplasia.

OBJECTIVE: The aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. METHODOLOGY: We describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CASES: Case 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. CONCLUSION: TCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered.