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

J Med Genet

. 2024 Jun 7:jmg-2024-109854.

 doi: 10.1136/jmg-2024-109854. Online ahead of print.

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

Silvestre Cuinat 1Chloé Quélin 2 3Claire Effray 2Christèle Dubourg 4 5Gwenaelle Le Bouar 6Anne-Sophie Cabaret-Dufour 6Philippe Loget 3Maia Proisy 7Fanny Sauvestre 8Mélie Sarreau 8Sophie Martin-Berenguer 8 9Claire Beneteau 10Sophie Naudion 10Vincent Michaud 10 11Benoit Arveiler 10 11Aurélien Trimouille 10 11Pierre Macé 12Sabine Sigaudy 13Olga Glazunova 13Julia Torrents 14Laure Raymond 15Marie-Hélène Saint-Frison 16Tania Attié-Bitach 17 18Mathilde Lefebvre 19Yline Capri 20Nicolas Bourgon 21 22Christel Thauvin-Robinet 22 23 24Frédéric Tran Mau-Them 22 23Ange-Line Bruel 22 23Antonio Vitobello 22 23Anne-Sophie Denommé-Pichon 22 23Laurence Faivre 22 24Anne-Claire Brehin 25 26Alice Goldenberg 26 27Sophie Patrier-Sallebert 28Alexandre Perani 29Benjamin Dauriat 29Sylvie Bourthoumieu 29 30Catherine Yardin 29 30Valentine Marquet 29Marion Barnique 29Maryse Fiorenza-Gasq 9Isabelle Marey 31Danielle Tournadre 32Raïa Doumit 33Frédérique Nugues 33Tahsin Stefan Barakat 34 35 36Francisco Bustos 37 38Sylvie Jaillard 39 40Erika Launay 39Laurent Pasquier 2 5 41Sylvie Odent 2 5 41

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congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.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

Keywords: Exome Sequencing; Genetic Diseases, Inborn; Genetic Diseases, X-Linked; Genetics; Genomics.

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