{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T07:01:22Z","timestamp":1792047682650,"version":"4.4.0"},"reference-count":38,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T00:00:00Z","timestamp":1748995200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Noonan syndrome (NS) is a relatively common RASopathy that can be associated with a variety of phenotypic and genotypic variations and potential long-term health consequences. Its most described prenatal ultrasound features in the first trimester are thickened nuchal translucency (NT) and dilated jugular sacs; while heart defects, polyhydramnios and facial dysmorphisms are its known manifestations in the second and third trimesters. Methods: We present two cases of NS with the prenatal ultrasound diagnosis of external hydrocephalus (EH) in the second trimester. Results: Case 1 had a normal first trimester scan and showed mild polyhydramnios, an echogenic intracardiac focus (EIF) in the left ventricle and pyelectasis in the second trimester in association with the EH. The whole exome sequencing (WES) confirmed a pathogenic variant in the SOS1 gene. Case 2 showed increased NT, agenesis of the ductus venosus (DV), single umbilical artery (SUA), an EIF in the right ventricle and an abnormal prefrontal space ratio (PSFR). By the 19th gestational week, EH appeared. The ambient and quadrigeminal cisterns were also slightly widened. The WES revealed a PTPN11 gene variant. Conclusions: The most reported sonographic features of NS are either non-specific or difficult to integrate into routine screening, requiring substantial experience. In our two cases, we detected EH in the second trimester, which is rarely described as a prenatal ultrasound diagnosis. To our current knowledge, this is the first case reported of EH in NS caused by an SOS1 gene variant and these are the first cases reported with the prenatal sonographic diagnosis of EH in NS.<\/jats:p>","DOI":"10.3390\/jcm14113973","type":"journal-article","created":{"date-parts":[[2025,6,4]],"date-time":"2025-06-04T11:14:12Z","timestamp":1749035652000},"page":"3973","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Second Trimester Ultrasound Diagnosis of External Hydrocephalus in Two Fetuses with Noonan Syndrome\u2014Case Report Series"],"prefix":"10.3390","volume":"14","author":[{"given":"Tibor","family":"Elekes","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aniko","family":"Ladanyi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Pap","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janos","family":"Szabo","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5351-9015","authenticated-orcid":false,"given":"Anett","family":"Illes","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine and Oncology, Semmelweis University, H-1082 Budapest, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-4105-7089","authenticated-orcid":false,"given":"Nora","family":"Gullai","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szabolcs","family":"Varbiro","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,6,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1002\/ajmg.1320210312","article-title":"Noonan Syndrome: A Review","volume":"21","author":"Mendez","year":"1985","journal-title":"Am. J. Med. Genet."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1001\/archpedi.1974.02110200050007","article-title":"The Ullrich-Noonan Syndrome (Turner Phenotype)","volume":"127","author":"Nora","year":"1974","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2382","DOI":"10.1002\/ajmg.a.61365","article-title":"Trisomy 13 and 18\u2014Prevalence and Mortality\u2014A Multi-registry Population Based Analysis","volume":"179","author":"Goel","year":"2019","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_4","first-page":"468","article-title":"Associated Noncardiac Malformations in Children with Congenital Heart Disease","volume":"63","author":"Noonan","year":"1963","journal-title":"Midwest. Soc. Pediat Res."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Baldo, F., Fachin, A., Da Re, B., Rubinato, E., Bobbo, M., and Barbi, E. (2022). New Insights on Noonan Syndrome\u2019s Clinical Phenotype: A Single Center Retrospective Study. BMC Pediatr., 22.","DOI":"10.1186\/s12887-022-03804-2"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1555","DOI":"10.1086\/340847","article-title":"PTPN11 Mutations in Noonan Syndrome: Molecular Spectrum, Genotype-Phenotype Correlation, and Phenotypic Heterogeneity","volume":"70","author":"Tartaglia","year":"2002","journal-title":"Am. J. Hum. Genet."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"418","DOI":"10.1002\/pd.4797","article-title":"Retrospective Study of Prenatal Ultrasound Findings in Newborns with a Noonan Spectrum Disorder: Prenatal Diagnosis of Noonan Spectrum Disorders","volume":"36","author":"Hakami","year":"2016","journal-title":"Prenat. Diagn."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"703","DOI":"10.1016\/S0022-3476(99)70088-0","article-title":"Congenital Heart Diseases in Children with Noonan Syndrome: An Expanded Cardiac Spectrum with High Prevalence of Atrioventricular Canal","volume":"135","author":"Marino","year":"1999","journal-title":"J. Pediatr."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"833","DOI":"10.1002\/pd.2782","article-title":"Targeted Ultrasound Examination and DNA Testing for Noonan Syndrome, in Fetuses with Increased Nuchal Translucency and Normal Karyotype","volume":"31","author":"Bakker","year":"2011","journal-title":"Prenat. Diagn."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"548","DOI":"10.1177\/000992289403300907","article-title":"Noonan Syndrome: An Update and Review for the Primary Pediatrician","volume":"33","author":"Noonan","year":"1994","journal-title":"Clin. Pediatr."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"936","DOI":"10.1038\/ejhg.2012.285","article-title":"Prenatal Diagnostic Testing of the Noonan Syndrome Genes in Fetuses with Abnormal Ultrasound Findings","volume":"21","author":"Croonen","year":"2013","journal-title":"Eur. J. Hum. Genet."},{"key":"ref_12","first-page":"195","article-title":"Prenatal Diagnosis of Noonan Syndrome in Fetuses with Increased Nuchal Translucency and a Normal Karyotype","volume":"84","year":"2019","journal-title":"Ceska Gynekol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1002\/pd.1189","article-title":"Prenatal DNA Diagnosis of Noonan Syndrome in a Fetus with Massive Hygroma Colli, Pleural Effusion and Ascites","volume":"25","author":"Steckel","year":"2005","journal-title":"Prenat. Diagn."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"2329","DOI":"10.1016\/j.gim.2022.08.002","article-title":"Using Deep Learning and Electronic Health Records to Detect Noonan Syndrome in Pediatric Patients","volume":"24","author":"Yang","year":"2022","journal-title":"Genet. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1007\/s10143-011-0327-4","article-title":"Benign External Hydrocephalus: A Review, with Emphasis on Management","volume":"34","author":"Zahl","year":"2011","journal-title":"Neurosurg. Rev."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"693","DOI":"10.1002\/uog.7660","article-title":"Depth of Brain Fissures in Normal Fetuses by Prenatal Ultrasound between 19 and 30 Weeks of Gestation","volume":"36","author":"Alonso","year":"2010","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1002\/(SICI)1096-8628(20000529)92:3<159::AID-AJMG1>3.0.CO;2-2","article-title":"Noonan Syndrome: A Cryptic Condition in Early Gestation","volume":"92","author":"Achiron","year":"2000","journal-title":"Am. J. Med. Genet."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"La Verde, M., Marrapodi, M.M., Capristo, C., Conte, A., Molitierno, R., Morlando, M., Fordellone, M., De Franciscis, P., Campitiello, M.R., and Torella, M. (2024). Racial and Ethnic Disparities in Non-Invasive Prenatal Testing Adherence: A Retrospective Cohort Study. Minerva Obstet. Gynecol., Online ahead of print.","DOI":"10.23736\/S2724-606X.24.05530-1"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1046\/j.1469-0705.1998.12020112.x","article-title":"Influence of Ethnic Origin on Nuchal Translucency Screening for Down\u2019s Syndrome","volume":"12","author":"Thilaganathan","year":"1998","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Dubois, M.-L., Winters, P.D., Rodrigue, M.-A., and Gekas, J. (2023). Patient Attitudes and Preferences about Expanded Noninvasive Prenatal Testing. Front. Genet., 14.","DOI":"10.3389\/fgene.2023.976051"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Tangshewinsirikul, C., Wattanasirichaigoon, D., Tim-Aroon, T., Promsonthi, P., Katanyuwong, P., Diawtipsukon, S., Chansriniyom, N., and Tongsong, T. (2024). Prenatal Sonographic Features of Noonan Syndrome: Case Series and Literature Review. J. Clin. Med., 13.","DOI":"10.3390\/jcm13195735"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1136\/adc.67.2.178","article-title":"A Clinical Study of Noonan Syndrome","volume":"67","author":"Sharland","year":"1992","journal-title":"Arch. Dis. Child."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"094","DOI":"10.1055\/s-0043-1772757","article-title":"A Rare Neurological Presentation of Noonan Syndrome and Its Management\u2014A Case Report","volume":"19","author":"Mahajan","year":"2024","journal-title":"Asian J. Neurosurg."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1016\/j.wneu.2019.02.054","article-title":"Diverticular Enlargement of Foramen of Luschka and Hydrocephalus in Child with Noonan Syndrome","volume":"125","author":"Spennato","year":"2019","journal-title":"World Neurosurg."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1136\/jnnp.59.3.338-a","article-title":"Noonan\u2019s Syndrome with Hydrocephalus, Hindbrain Herniation, and Upper Cervical Intracord Cyst","volume":"59","author":"Heye","year":"1995","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"104626","DOI":"10.1016\/j.ejmg.2022.104626","article-title":"Detailed Prenatal and Postnatal MRI Findings and Clinical Analysis of RAF1 in Noonan Syndrome","volume":"65","author":"Helenius","year":"2022","journal-title":"Eur. J. Med. Genet."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1111\/ahg.12436","article-title":"External Hydrocephalus as a Prenatal Feature of Noonan Syndrome","volume":"85","author":"Mastromoro","year":"2021","journal-title":"Ann. Hum. Genet."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"863","DOI":"10.4103\/0028-3886.383859","article-title":"Prenatal External Hydrocephalus in Snijders Blok\u2013Campeau Syndrome","volume":"71","author":"Varughese","year":"2023","journal-title":"Neurol. India"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1007\/PL00013727","article-title":"Ventriculomegaly and Pericerebral CSF Collection in the Fetus: Early Stage of Benign External Hydrocephalus?","volume":"17","author":"Girard","year":"2001","journal-title":"Childs Nerv. Syst."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1002\/uog.16584","article-title":"P10.04: External Hydrocephalus: A New Entity in Prenatal Diagnosis","volume":"48","author":"Baron","year":"2016","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1146","DOI":"10.3174\/ajnr.A5611","article-title":"Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies","volume":"39","author":"Cizmeci","year":"2018","journal-title":"Am. J. Neuroradiol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1007\/s13760-015-0526-9","article-title":"Severe Developmental Delay and Complete Agenesis of Corpus Callosum in a Noonan Syndrome Patient with SOS1 Mutation","volume":"116","author":"Samanta","year":"2016","journal-title":"Acta Neurol. Belg."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1111\/cge.13047","article-title":"Multiple Spinal Nerve Enlargement and SOS1 Mutation: Further Evidence of Overlap between Neurofibromatosis Type 1 and Noonan Phenotype","volume":"93","author":"Santoro","year":"2018","journal-title":"Clin. Genet."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1038\/s41398-023-02504-4","article-title":"Novel Effects of Ras-MAPK Pathogenic Variants on the Developing Human Brain and Their Link to Gene Expression and Inhibition Abilities","volume":"13","author":"Rai","year":"2023","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2915","DOI":"10.1093\/cercor\/bhy158","article-title":"PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention","volume":"29","author":"Johnson","year":"2019","journal-title":"Cereb. Cortex"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1002\/uog.23616","article-title":"ISUOG Practice Guidelines (Updated): Sonographic Examination of the Fetal Central Nervous System. Part 2: Performance of Targeted Neurosonography","volume":"57","author":"Paladini","year":"2021","journal-title":"Ultrasound Obstet. Gynecol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2420","DOI":"10.1002\/ajmg.a.36098","article-title":"Expanding the SHOC2 Mutation Associated Phenotype of Noonan Syndrome with Loose Anagen Hair: Structural Brain Anomalies and Myelofibrosis","volume":"161","author":"Gripp","year":"2013","journal-title":"Am. J. Med. Genet. A."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"NP13","DOI":"10.1177\/0883073813492384","article-title":"Unique Cerebrovascular Anomalies in Noonan Syndrome with RAF1 Mutation","volume":"29","author":"Zarate","year":"2014","journal-title":"J. Child. Neurol."}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3973\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:46:43Z","timestamp":1760032003000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/14\/11\/3973"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,6,4]]},"references-count":38,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2025,6]]}},"alternative-id":["jcm14113973"],"URL":"https:\/\/doi.org\/10.3390\/jcm14113973","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,6,4]]}}}