Cell-Free DNA Screening Positive for Monosomy X: Clinical Evaluation and Management of Suspected Maternal or Fetal Turner Syndrome

Tazim Dowlut-McElroy, Pediatric and Adolescent Gynecology, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD. Department of Surgery, Children's National Hospital, Washington D.C. Electronic address: tazim.dowlut-mcelroy@nih.gov.
Shanlee Davis, eXtraOrdinarY Kids Turner Syndrome Clinic, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO.
Susan Howell, eXtraOrdinarY Kids Turner Syndrome Clinic, Children's Hospital Colorado, Aurora, CO; Department of Pediatrics, University of Colorado Anschutz School of Medicine, Aurora, CO.
Iris Gutmark-Little, Division of Endocrinology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Vaneeta Bamba, Division of Endocrinology, Children's Hospital of Philadelphia, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Siddharth Prakash, Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX.
Sheetal Patel, Division of Pediatric Cardiology, Ann & Robert H Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL.
Doris Fadoju, Division of Pediatric Endocrinology, Emory University School of Medicine/Children's Healthcare of Atlanta, Atlanta, GA.
Nandini Vijayakanthi, Division of Pediatric Endocrinology, Emory University School of Medicine/Children's Healthcare of Atlanta, Atlanta, GA.
Mary Haag, Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, Aurora, CO.
Ms Deborrah Hennerich, Colorado Genetics Laboratory, Department of Pathology, University of Colorado School of Medicine, Aurora, CO.
Lorraine Dugoff, Divisions of Reproductive Genetics and Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA.
Roopa Kanakatti Shankar, Division of Endocrinology, Children's National Hospital, The George Washington University School of Medicine, Washington D.C.

Document Type

Journal Article

Publication Date

7-13-2022

Journal

American journal of obstetrics and gynecology

DOI

10.1016/j.ajog.2022.07.004

Keywords

NIPT; Turner syndrome; cell-free DNA; cfDNA; monosomy X; non-invasive prenatal testing; sex-chromosome anomalies

Abstract

Initially provided as an alternate to evaluation of serum analytes and nuchal translucency for the evaluation of pregnancies at high-risk of Trisomy 21, cell-free DNA (cfDNA) screening for fetal aneuploidy, also referred to as non-invasive prenatal screening (NIPS), can now also screen for fetal sex chromosome anomalies (SCAs) such as monosomy X as early as 9 to 10 weeks of gestation. Early identification of Turner syndrome, a SCA resulting from the complete or partial absence of the second X chromosome, allows for medical interventions such as optimizing obstetrical outcomes, hormone replacement therapy, fertility protection and support as well improved neurocognitive outcomes. However, cfDNA screening for SCAs and monosomy X in particular is associated with high false positive rates and low positive predictive value. A cfDNA result positive for monosomy X may represent fetal TS, maternal TS, or confined placental mosaicism. A positive screen for monosomy X with discordant results of diagnostic fetal karyotype presents unique interpretation and management challenges due to potential implications for previously unrecognized maternal Turner syndrome (TS). . The current international consensus clinical practice guidelines for the care of individuals with TS throughout the lifespan do not specifically address management of individuals with a cfDNA screen positive for monosomy X. The objective of this manuscript is to provide context and expert-driven recommendations for maternal and/or fetal evaluation and management when cfDNA screening is positive for monosomy X. We highlight unique challenges of cfDNA screening that is incidentally positive for monosomy X, present recommendations for determining if the result is a true positive and discuss when diagnosis of TS is applicable to the fetus or the mother. While we defer the subsequent management of confirmed TS to the clinical practice guidelines, we highlight unique considerations for these individuals initially identified through cfDNA screening.

Department

Pediatrics

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