Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in <scp>PI3K‐AKT‐mTOR</scp> signaling pathway

Bourgon, Nicolas; Carmignac, Virginie; Sorlin, Arthur; Duffourd, Yannis; Philippe, Christophe; Thauvin‐Robinet, Christel; Guibaud, Laurent; Faivre, Laurence; Vabres, P.; Kuentz, Paul

doi:10.1002/uog.23715

Cited by 7 publications

(4 citation statements)

References 59 publications

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“…We found that mutations in genes leading to disruptions in proliferation of neurons and glia ( PNKP, ASPM ) 30,31 , abnormal migration of neurons ( L1CAM, TUBA1A ) 32,33 and metabolic defects ( EARS2, GCDH, PEX1 ) 27,34,35 can result in abnormal brain development. In addition, prenatal diagnosis of megacephaly led to the discovery of genetic variants in the PI3K‐AKT‐mTOR signaling pathway ( PIK3CA, PIK3R2, MTOR in Cases 32, 33 and 41, respectively), which was consistent with the findings reported by Bourgon et al 36 …”

Section: Discussionsupporting

confidence: 88%

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Zhi

Liu

Wang

et al. 2023

Ultrasound in Obstet & Gyne

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ObjectiveTo evaluate the utility of prenatal exome sequencing (pES) in fetuses with central nervous system (CNS) abnormalities.MethodsThe parents of fetuses identified with CNS abnormalities were considered as potential participants for this retrospective cohort study. After performing chromosomal microarray (CMA), fetuses with confirmed aneuploidy or causal pathogenic copy number variants (CNVs) were excluded from the pES analyses.ResultsOf the 167 pregnancies included in the study, 42 (25.1%) were identified to have pathogenic or likely pathogenic (P/LP) variants. The diagnostic rate was significantly higher in fetuses with non‐isolated CNS abnormalities than in those with single CNS abnormalities (20/56, 35.7% vs. 8/55, 14.5%, P = 0.010). Moreover, when a fetus combined with three or more brain abnormalities, the positive diagnostic rate increased to 42.9%. Among the 42 positive cases, de novo mutations were the primary factors (25/42, 59.5%), the remaining cases were inherited and carried a significant risk of recurrence. Patients with P/LP mutations in their fetuses were more likely to choose advanced pregnancy termination than those with VUS or negative pES results (83.3% vs. 41.3%, P < 0.001).ConclusionpES significantly improved the identification of genetic disorders in fetuses with CNS anomalies without chromosomal abnormalities or P/LP CNVs, regardless of whether the fetal anomalies are isolated or not, and it can significantly impact parents’ decision‐making.This article is protected by copyright. All rights reserved.

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Section: Discussionsupporting

confidence: 88%

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Zhi

Liu

Wang

et al. 2023

Ultrasound in Obstet & Gyne

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“…Notably, six articles (27%) focused primarily on fetal MRI findings, often lacking detailed prenatal ultrasound description [12,18,23,24,27,29]. One report describing a prenatal case of bilateral megalencephaly [32] and one series detailing genetic studies in postmortem samples from 11 HME cases in which no clear description between prenatal ultrasound and MRI findings were available [33] were excluded from analysis.…”

Section: Discussionmentioning

confidence: 99%

Neuroimaging Findings in Fetal Hemimegalencephaly: Case Study and Review

Sepulveda,

Schonstedt

et al. 2023

Fetal Diagn Ther

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Background: Limited information exists in the prenatal literature regarding the neuroimaging features of fetal hemimegalencephaly. Summary: This report describes ultrasound and magnetic resonance imaging (MRI) findings in a second-trimester fetus with an isolated, severe form of hemimegalencephaly. The most prominent imaging findings included unilateral enlarged cerebral hemisphere and ipsilateral ventriculomegaly causing cerebral asymmetry, midline shift, and macrocephaly. Abnormal cortical development imaging signs were also evident. A literature review encompassing 23 reports describing 36 cases, including ours, is presented. Key Messages: Characteristic ultrasound findings for the diagnosis of hemimegalencephaly are not always apparent prenatally. Asymmetric ventriculomegaly emerges as the most common but nonspecific presenting feature during routine second- or third-trimester ultrasound scans. Subsequent high-resolution prenatal neurosonography and fetal MRI facilitate definitive prenatal diagnosis, showcasting associated features primarily related to cortical migration, differentiation, and maturation. Postnatally, the prognosis is poor due to intractable seizures, hemiplegia, and progressive neurodevelopmental delay.

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“…The risk of receiving a delayed diagnosis and the difficult task of finding the right care team are only some of the first issues to arise, followed by the difficult management of symptoms and the lack of effective therapeutic options [61]. Furthermore, sporadic case reports of patients with germline variants in PIK3CA are not sufficient to obtain enough evidence to justify surveillance protocols [62,63].…”

Section: Italian Law-conclusionmentioning

confidence: 99%

Work-Up and Treatment Strategies for Individuals with PIK3CA-Related Disorders: A Consensus of Experts from the Scientific Committee of the Italian Macrodactyly and PROS Association

Gazzin,

Leoni,

Viscogliosi

et al. 2023

Genes

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PIK3CA-related disorders encompass many rare and ultra-rare conditions caused by somatic genetic variants that hyperactivate the PI3K-AKT-mTOR signaling pathway, which is essential for cell cycle control. PIK3CA-related disorders include PIK3CA-related overgrowth spectrum (PROS), PIK3CA-related vascular malformations and PIK3CA-related non-vascular lesions. Phenotypes are extremely heterogeneous and overlapping. Therefore, diagnosis and management frequently involve various health specialists. Given the rarity of these disorders and the limited number of centers offering optimal care, the Scientific Committee of the Italian Macrodactyly and PROS Association has proposed a revision of the most recent recommendations for the diagnosis, molecular testing, clinical management, follow-up, and treatment strategies. These recommendations give insight on molecular diagnosis, eligible samples, preferable sequencing, and validation methods and management of negative results. The purpose of this paper is to promote collaboration between health care centers and clinicians with a joint shared approach. Finally, we suggest the direction of present and future research studies, including new systemic target therapies, which are currently under evaluation in several clinical trials, such as specific inhibitors that can be employed to downregulate the signaling pathway.

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Clinical and molecular data in cases of prenatal localized overgrowth disorder: major implication of genetic variants in PI3K‐AKT‐mTOR signaling pathway

Cited by 7 publications

References 59 publications

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Prenatal exome sequencing analysis in fetuses with central nervous system anomalies

Neuroimaging Findings in Fetal Hemimegalencephaly: Case Study and Review

Work-Up and Treatment Strategies for Individuals with PIK3CA-Related Disorders: A Consensus of Experts from the Scientific Committee of the Italian Macrodactyly and PROS Association

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