Obstetrical and neonatal outcomes of cardio‐facio‐cutaneous syndrome: Prenatal consequences of Ras/MAPK dysregulation

• Published in: American journal of medical genetics. Part A Vol. 191; no. 2; pp. 323 - 331
• Main Authors: Jelin, Angie C., Mahle, Amanda, Tran, Susan H., Sparks, Teresa N., Rauen, Katherine A.
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01.02.2023; Wiley Subscription Services, Inc
• Subjects: Birth weight; cardio‐facio‐cutaneous syndrome; Cesarean section; Diabetes mellitus; Ectodermal Dysplasia - diagnosis; Ectodermal Dysplasia - genetics; Ectodermal Dysplasia - pathology; Facies; Female; Fetal Macrosomia; Gestational age; Heart; Heart Defects, Congenital - diagnosis; Heart Defects, Congenital - genetics; Heart Defects, Congenital - pathology; Humans; Macrocephaly; MAP kinase; Medical records; Megalencephaly; Neonates; Phenotypes; Polyhydramnios; Pre-eclampsia; Pregnancy; Pregnancy complications; prenatal; Proto-Oncogene Proteins B-raf - genetics; Ras/MAPK; RASopathy; Retrospective Studies; signal transduction pathway; Ultrasonic imaging; Ultrasound; Vagina; RASopathy; cardio-facio-cutaneous syndrome; prenatal; Ras/MAPK; signal transduction pathway
• ISSN: 1552-4825; 1552-4833
• DOI: 10.1002/ajmg.a.63020

We systematically delineated the prenatal phenotype, and obstetrical and neonatal outcomes of the RASopathy cardio‐facio‐cutaneous (CFC) syndrome. A comprehensive, retrospective medical history survey was distributed to parents of children with confirmed CFC in collaboration with CFC International, Inc. Data were collected on CFC gene variant, maternal characteristics, pregnancy course, delivery, and neonatal outcomes with the support of medical records. We identified 43 individuals with pathogenic variants in BRAF (81%), MEK1 (14%), or MEK2 (5%) genes. The median age was 8.5 years. Hyperemesis gravidarum, gestational diabetes, gestational hypertension, and preeclampsia occurred in 5/43 (12%), 4/43 (9%), 3/43 (7%), and 3/43 (7%) of pregnancies, respectively. Second and third trimester ultrasound abnormalities included polyhydramnios, macrocephaly, macrosomia, and renal and cardiac abnormalities. Delivery occurred via spontaneous vaginal, operative vaginal, or cesarean delivery in 15/42 (36%), 7/42 (16%), and 20/42 (48%), respectively. Median gestational age at delivery was 37 weeks and median birth weight was 3501 grams. Germline pathogenic vaiants had mutiple congenital consequences including polyhydramnios, renal and cardiac abnormalities, macrosomia, and macrocephaly on second and third trimester ultrasound. Elevated rates of operative delivery and neonatal complications were also noted. Understanding and defining a prenatal phenotype may improve prenatal prognostic counseling and outcomes.