J Med Genet

. 2024 Jun 7:jmg-2024-109854.

 doi: 10.1136/jmg-2024-109854. Online ahead of print. https://pubmed.ncbi.nlm.nih.gov/38849204/

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

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

Affiliations expand

• PMID: 38849204
• DOI: 10.1136/jmg-2024-109854

Free article

Abstract

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congenital anomalies in five male fetuses, a call for collaboration was made, resulting in a cohort of 11 previously unpublished cases.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

© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.