Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway. (10th March 2022)

• Record Type: Journal Article
• Authors: Bourgon, N.; Carmignac, V.; Sorlin, A.; Duffourd, Y.; Philippe, C.; Thauvin‐Robinet, C.; Guibaud, L.; Faivre, L.; Vabres, P.; Kuentz, P.
• Other Names: Tisserand Emilie investigator.; Chevarin Martin investigator.; Delanne Julian investigator.; Jouan Thibaud investigator.; Pöe Charlotte investigator.; Abel Carine investigator.; Allory Patrick investigator.; Amram Daniel investigator.; Attie‐Bitach Tania investigator.; Aziza Jacqueline investigator.; Benevent Jean‐Baptiste investigator.; Bidat Laurent investigator.; Bessières Bettina investigator.; Boussion Françoise investigator.; Cabaret‐Dufour Anne‐Sophie investigator.; Chanoz‐Poulard Geneviève investigator.; Chassaing Nicolas investigator.; Ciorna‐Monferrato Viorica investigator.; Cordier Anne‐Gaëlle investigator.; Cordier Marie‐Pierre investigator.; Cuillier Fabrice investigator.; Doray Berenice investigator.; Encha‐Razavi Ferechte investigator.; Eszto Marie‐Laure investigator.; Bianco Catherine Fallet investigator.; Fernandez Carla investigator.; Ferry Mathilde investigator.; Fichez Axel investigator.; Vequeau Valérie Goua investigator.; Grevent David investigator.; Guichet Agnès investigator.; Laurent Nicole investigator.; Le Gac Marie‐Pascale investigator.; Lefebvre Mathilde investigator.; Letard Pascaline investigator.; Loget Philippe investigator.; Loisel Didier investigator.; Martinovich Jelena investigator.; Masutti Jean‐Paul investigator.; Millischer Anne‐Elodie investigator.; Musizzano Yuri investigator.; Nord Jean‐François investigator.; Perez Marie‐Josée investigator.; Prieur Fabienne investigator.; Proisy Maia investigator.; Quelin Chloé investigator.; Roth Philippe investigator.; Rousseau Thierry investigator.; Salomon Laurent investigator.; Sonigo Pascale investigator.; Spaggiari Emmanuel investigator.; Stempfle Noëlle investigator.; Stirnemann Julien investigator.; Tanteau Julia investigator.; Triau Stéphane investigator.; Vasiljevic Alexandre investigator.; Ville Yves investigator.; Zidane‐Marinnes Merzouka investigator.; Kaltenbach Sophie investigator.; Rivière Jean‐Baptiste investigator.;
• Is Part Of: Ultrasound in obstetrics & gynecology. Volume 59:Number 4(2022)
• Page Start: 532
• Page End: 542
• Publication Date: 2022-03-10
• Subjects: cultured amniocytes -- genetic counseling -- localized overgrowth disorder -- PI3K‐AKT‐mTOR -- postzygotic -- prenatal diagnosis; Ultrasonics in obstetrics -- Periodicals; Generative organs, Female -- Diseases -- Diagnosis -- Periodicals; Diagnosis, Ultrasonic -- Periodicals; Genital Diseases, Female -- ultrasonography -- Periodicals; Ultrasonography, Prenatal -- Periodicals; 618.047543
• DOI: 10.1002/uog.23715
• Languages: English
• ISSNs: 0960-7692

Abstract

ABSTRACT: Objectives: To describe clinical and molecular findings in a French multicenter cohort of fetuses with prenatal diagnosis of congenital abnormality and suspicion of a localized overgrowth disorder (LOD) suggestive of genetic variants in the PI3K‐AKT‐mTOR signaling pathway. Methods: We analyzed retrospectively data obtained between 1 January 2013 and 1 May 2020 from fetuses with brain and/or limb overgrowth referred for molecular diagnosis of PI3K‐AKT‐mTOR pathway genes by next‐generation sequencing (NGS) using pathological tissue obtained by fetal autopsy. We also assessed the diagnostic yield of amniotic fluid. Results: During the study period, 21 subjects with LOD suspected of being secondary to a genetic variant of the PI3K‐AKT‐mTOR pathway were referred for analysis. Of these, 17 fetuses had brain overgrowth, including six with isolated megalencephaly (MEG) and 11 with hemimegalencephaly (HMEG). Of the six with MEG, germline variants were identified in four cases, in either PIK3R2, AKT3 or MTOR, and a postzygotic PIK3R2 variant was found in the other two cases. Of the 11 with HMEG, a postzygotic PIK3CA variant was found in three fetuses with extracerebral features of PIK3CA ‐related overgrowth spectrum, and in seven fetuses with isolated HMEG. No pathogenic variant was identified in the 11 th case with HMEG. Four fetuses with limb overgrowth also had one or more lymphatic malformations (LM) and harbored a postzygotic PIK3CA variant. NGS on cultured amniocytes performed in 10 cases, of which nine had been found positive on analysis of pathological fetal tissue, showed variants in four, in either PIK3CA, PIK3R2 or AKT3 . Conclusions: Isolated MEG or HMEG may lead to identification of genetic variants in the PI3K‐AKT‐mTOR signaling pathway. Cases of limb overgrowth and LM or isolated HMEG are likely associated with PIK3CA variants. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.