REVIEW ARTICLE Year : 2023  |  Volume : 31  |  Issue : 1  |  Page : 13-16

Prenatal diagnosis of euploid increased nuchal translucency on fetal ultrasound (II): RASopathy disorders – Prenatal ultrasound findings and genotype–phenotype correlations

Chih-Ping Chen
Department of Obstetrics and Gynecology, MacKay Memorial Hospital, Taipei; Department of Medical Research, MacKay Memorial Hospital, Taipei; School of Chinese Medicine, College of Chinese Medicine, China Medical University, Taichung; Institute of Clinical and Community Health Nursing, National Yang Ming Chiao Tung University, Taipei; Department of Obstetrics and Gynecology, School of Medicine, National Yang Ming Chiao Tung University, Taipei; Department of Medical Laboratory Science and Biotechnology, College of Medical and Health Science, Asia University, Taichung, Taiwan

Date of Submission09-Aug-2022Date of Acceptance11-Aug-2022Date of Web Publication09-Nov-2022

Correspondence Address:
Prof. Chih-Ping Chen
Department of Obstetrics and Gynecology, MacKay Memorial Hospital, No. 92, Section 2, Chung-Shan North Road, Taipei 10449
Taiwan

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jmu.jmu_79_22

Prenatal diagnosis of euploid increased nuchal translucency (NT) remains a challenge to obstetricians and genetic counselors, although increased euploid NT at prenatal diagnosis can be associated with a favorable outcome. Prenatal diagnosis of euploid increased NT should include a differential diagnosis of pathogenetic copy number variants and RASopathy disorders (RDs) including Noonan syndrome. Therefore, chromosomal microarray analysis, whole-exome sequencing, RASopathy-disorder testing, and protein-tyrosine phosphatase nonreceptor type 11 gene testing may be necessary under such a circumstance. In this report, a comprehensive review of RDs with its prenatal ultrasound findings and genotype-phenotype correlations is presented.

Keywords: Increased nuchal translucency, Noonan syndrome, prenatal diagnosis, RASopathy disorder, ultrasound

How to cite this article:
Chen CP. Prenatal diagnosis of euploid increased nuchal translucency on fetal ultrasound (II): RASopathy disorders – Prenatal ultrasound findings and genotype–phenotype correlations. J Med Ultrasound 2023;31:13-6
How to cite this URL:
Chen CP. Prenatal diagnosis of euploid increased nuchal translucency on fetal ultrasound (II): RASopathy disorders – Prenatal ultrasound findings and genotype–phenotype correlations. J Med Ultrasound [serial online] 2023 [cited 2023 Mar 23];31:13-6. Available from: http://www.jmuonline.org/text.asp?2023/31/1/13/360634   Introduction 

Prenatal diagnosis of euploid increased nuchal translucency (NT) remains a challenge to obstetricians and genetic counselors, although euploid increased NT at prenatal diagnosis can be associated with a favorable outcome. Prenatal diagnosis of euploid increased NT should include a differential diagnosis of pathogenetic copy number variants, Noonan syndrome (NS), and/or RASopathy disorders (RDs). Therefore, chromosomal microarray analysis (CMA), whole-exome sequencing (WES), RD testing, and protein-tyrosine phosphatase nonreceptor type 11 (PTPN11) gene testing may be necessary under such a circumstance.

  RASopathy 

RASopathy is used for a clinically defined group of disorders caused by germline pathogenic variants in components of the RAS protein/mitogen-activated protein kinase (RAS/MAPK) pathway.[1],[2],[3] The RAS/MAPK pathway is a signal transduction cascade associated with cellular processes such as proliferation, survival, differentiation, and metabolism, and is composed of the RAS proteins, RAS guanine nucleotide exchange factors (GEFs), RAS GTPase-activating proteins, RAS effector proteins and their targets, and other pathway modulators.[4] The common mutations of RASopathy-associated genes include the genes of (1) HRAS, NRAS, MRAS, RRAS, and RIT1 for RAS isoforms; (2) BRAF, RAF1 (CRAF), MAP2K1 (MEK1), and MAP2K2 (MEK2) for kinases; (3) SOS1 and SOS2 for GEFs; (4) CBL and LZTR1 for ubiquitination machinery; (5) SHOC2 for scaffolds; and (6) PPP1CB and PTPN11 for phosphatases.[4] The reported RDs include NS, neurofibromatosis type 1 (NF1), cardiofaciocutaneous syndrome (CFC), NS with multiple lentigines, Costello syndrome (CS), Legius syndrome (LS), central conducting lymphatic anomaly syndrome, SYNGAP1 syndrome, and capillary malformation-arteriovenous malformation syndrome with overlapping features of short stature, facial dysmorphism, congenital heart defect (CHD), and lymphatic dysfunction.[1],[2],[3],[4]

  Genetic Counseling of Euploid Increased Nuchal Translucency 

Genetic counseling of increased NT in the presence of normal chromosomes remains a challenge to obstetricians and genetic counselors.[5],[6],[7],[8] Souka et al.[5] in a review concluded that the adverse perinatal outcome of the fetuses with euploid increased NT dose not statistically increase until the NT measurement ≥ 3.5 mm. They also concluded that if the fetus survives until midgestation without ultrasound abnormalities at 20–22 weeks of gestation, the risk of an adverse perinatal outcome and postnatal developmental delay is not statistically increased. Bilardo et al.[6] in a review concluded that in the fetuses with euploid increased NT, the adverse outcome is proportional to the degree of NT enlargement, and the majority of the babies with normal detailed ultrasound examination and echocardiography will have an uneventful outcome with no increased risk for developmental delay when compared to the general population. Alamillo et al.[7] in a review of euploid increased NT concluded that NS is the only molecular genetic condition that has a clear association with the finding of increased NT in the first trimester, and further prenatal testing is recommended. Bakker et al.[8] in a review of euploid increased NT concluded that CMA and mutational analysis for NS are recommended in the fetuses with euploid increased NT as well as a detailed sonographic investigation of the fetal heart and dysmorphic features, and the chance of a favorable fetal outcome is high if the above examinations are normal.

  Increased Nuchal Translucency, Cystic Hygroma, Pleural Effusion, Hydrops Fetalis, Polyhydramnios, Congenital Heart Defect, and Renal Anomaly on Prenatal Ultrasound and Genotype-Phenotype Correlations 

NS has been reported to be the most common single-gene disorder associated with increased NT. Pergament et al.[9] reported an incidence of 6.7% (8/120) for NS in the fetuses with euploid increased NT in the first trimester. Lee et al.[10] reported an incidence of 9% (12/134) for NS with PTPN11 mutations in the fetus with cystic hygroma, increased NT and/or hydrops fetalis, and in the fetuses with cystic hygroma, 16% had PTPN11 mutations, whereas in the fetuses with increased NT, only 2% had PTPN11 mutations. Ali et al.[11] reported an incidence of 10.3% (4/39) for NS in the fetuses with euploid increased NT. Sinajon et al.[12] applied microarray and RD testing in 226 fetuses with increased NT and found that 51.3% (116/226) had aneuploidy, and 48.7% (110/226) had normal karyotypes, of which microarray detected abnormalities in 8.2% (9/110) of the cases, and RD testing detected pathogenic variants in 2.9% (3/103) of the cases. Mellis et al.[13] in a systematic review and meta-analysis to determine the diagnostic yield of WES, found a diagnostic yield of 2% (95% confidence interval [CI] 0%–5%, P = 0.04) for isolated increased NT. Wald et al.[14] in a review of prenatal screening for serious CHD using NT suggested that prenatal screening for serious CHD using NT measurement is likely to be effective. Clur et al.[15] found major CHD in 4.9% (34/693) fetuses with euploid increased NT (median: 5.2 mm, 2.5–9.6 mm) including conotruncal defects, branchial arch derivative defects, and left and right obstructive lesions and shunts. Houweling et al.[16] detected gene mutations in three euploid fetuses. One fetus had a KRAS gene mutation and was associated with increased NT, pleural effusion, and dilated renal pelvis. Another fetus had a PTPN11 gene mutation and was associated with increased NT. The third fetus had a PTPN11 gene mutation and was associated with increased NT, pericardial effusion, and complete atrioventricular septal defect.

In a study of prenatal features of NS in 47 patients with molecular diagnosis of NS, Baldassarre et al.[17] found that 41% of the cases had increased NT, 38% had polyhydramnios, and 21% had fetal ultrasound anomalies. Bakker et al.[18] used targeted ultrasound examination and DNA testing for NS and detected three cases of NS (two with PTPN11 mutations and one with RAF1 mutation) associated with euploid increased NT. They suggested that DNA testing for NS is indicated in fetuses with euploid increased NT if there are persistent nuchal fold or cystic hygroma and at least one of the following findings of hydrops fetalis, pleural effusion, cardiac anomalies, polyhydramnios, or specific facial abnormalities. Croonen et al.[19] in a study of prenatal diagnostic testing of the NS genes in 75 euploid fetuses with increased NT distended jugular lymphatic sacs (JLS), pleural effusion, ascites, hydrops fetalis, cystic hygroma, polyhydramnios, and cardiac anomalies, found that 17.3% (13/75) had mutated NS genes including PTPN11 (n = 9), RAF1 (n = 3), and KRAS (n = 1). They also found mutated NS genes including PTPN11 (n = 2) and RAF1, BRAF, and MAP2K1 (each n = 1) in five cases among 60 other euploid fetuses with sonographic abnormalities such as increased NT, cardiac anomaly, hydrops fetalis, cystic hygroma, distended JLS, hydrothorax, and/or polyhydramnios.

Hakami et al.[20] in a retrospective study of prenatal ultrasound findings in 46 newborns with Noonan spectrum disorder (NSD) found that 67.4% (31/46) had only one ultrasound abnormality ranging from CHD (n = 12) (26.1%), cystic hygroma (n = 9) (19.6%), increased NT (n = 4) (8.7%), polyhydramnios (n = 2) (4.3%), pleural effusion (n = 2) (4.3%), hydrops (n = 2) (4.3%) to CHD and cystic hygroma (n = 5) (10.9%), and two more above ultrasound abnormalities (n = 10) (21.8%), and suggested that prenatal molecular testing for NSD should be considered even in the presence of a single associated abnormal ultrasound finding. Pierpont and Digilio[21] in a review of cardiovascular disease in NS found that the most common forms of cardiac defects include pulmonary stenosis, hypertrophic cardiomyopathy (HCM), and atrial septal defect, of which HCM is associated with an increased risk of mortality and morbidity. PTPN11, KRAS, RAF1, SOS1, and SHOC2 are associated with a higher incidence of CHD, whereas RIT1, BRAF, and SOS2 are associated with HCM.

In a study of 424 euploid fetuses with prenatal ultrasound findings of increased NT and/or cystic hygroma, distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects, and renal anomalies, Stuurman et al.[22] found that 9.4% (40/424) had RASopathies including mutations of the genes of PTPN11 (n = 27) (6.4%), RAF1 (n = 5) (1.2%), RIT1 (n = 3) (0.7%), SOS1 (n = 1) (0.2%), HRAS (n = 1) (0.2%), MAP2K2 (n = 1) (0.2%), BRAF (n = 1) (0.2%), and SHOC2 (n = 1) (0.2%). Stuurman et al.[22] suggested that RD testing including A2ML1, BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1 is recommended when three is an isolated increased NT ≥5.0 mm or when there is an isolated increased NT of ≥3.5 mm with one of the following ultrasonographic findings of a distended JLS, hydrops fetalis, polyhydramnios, pleural effusion, ascites, cardiac defects, and renal anomalies.

In a study of 76 patients with RASopathies including NS (n = 59), CS (n = 9), CFC syndrome (n = 6), and NSML (n = 6), Lee et al.[23] found that 61.8% (47/76) had cardiac abnormalities including atrial septal defects, pulmonary stenosis, HCM, ventricular septal defect, and patent ductus arteriosus. The mutated genes in 59 cases of NS with CHD included PTPN11 (n = 41), RIT1 (n = 4), KRAS (n = 3), NF1 (n = 3), SOS1 (n = 2), BRAF (n = 2), RAF1 (n = 2), MAP2K2 (n = 1), and SPRED1 (n = 1). The mutated genes in five cases of CS with CHD included HRAS (n = 4) and RAF1 (n = 1). The mutated genes in six cases of CFC with CHD included BRAF (n = 3), SHOC2 (n = 2), and RAF1 (n = 1). The mutated gene in six cases of NSML with CHD was PTPN11 (n = 6).

Sparks et al.[24] in a study of 127 fetuses with unexplained nonimmune hydrops fetalis by WES found that 29% (37/127) had diagnostic genetic variants including RASopathy (n = 11), inborn error metabolism (n = 4), musculoskeletal disorders (n = 4), lymphatic disorders (n = 3), neurodevelopmental disorders (n = 3), cardiovascular disorders (n = 3), hematological disorders (n = 3), immunological disorders (n = 2), renal disorders (n = 1), ciliopathy (n = 1), overgrowth disorders (n = 1), and CHARGE syndrome (n = 1). RASopathy accounted for 30% (11/37) of the abnormalities. Mangels et al.[25] in a study of 63 cases of polyhydramnios found that 33 cases had a single-gene disorder including 15 cases with RASopathy. Scott et al.[26] suggested that when any sonographic finding suggesting lymphatic dysplasia and/or CHD, RD testing should be considered following normal CMA. By use of RD testing including the tested genes of BRAF, HRAS, KRAS, MAP2K1, MAP2K2, NRAS, PTPN11, RAF1, RIT1, SHOC2, and SOS1, Scott et al.[26] performed a systematic analysis of 325 CMA-negative fetuses with RASopathy prenatal ultrasound feathers of increased NT, cystic hygroma, hydrops fetalis, effusions, CHD, polyhydramnios, and/or renal anomalies and found that 14% (50/352) had RASopathies including mutations in the genes of PTPN11 (30%, 15/50), RIT1 (16%, 8/50), RAF1 (14%, 7/50), HRAS (12%, 6/50), and LZTR1 (8%, 4/50) and others such as BRAF, KRAS, NRAS, SHOC2, SOS1, and SOS2. Scott et al.[26] reported the genotype–phenotype correlations between prenatal sonographic findings and the involved genes. In their study, PTPN11, SOS1, and KRAS variants showed a milder phenotype, and about 50% of the variants of PTPN11, SOS1, and KRAS showed no significant prenatal sonographic abnormalities. However, most LZTR1 and HRAS variants showed a significant prenatal phenotype, and more than half of the RAF1 variants had hydrops, effusions, and CHD of HCM.

In summary, in this review article, a comprehensive review of RD and its prenatal ultrasound findings and genotype-phenotype correlations is presented, and the information provided is useful for ultrasonographers as well as genetic counselors.

Financial support and sponsorship

This work was supported by research grants MOST-110-2314-B-195-005 from the Ministry of Science and Technology, Taiwan, and MMH-E-111-04 from MacKay Memorial Hospital, Taipei, Taiwan.

Conflicts of interest

Prof. Chih-Ping Chen, an Editorial-in-Chief at Journal of Medical Ultrasound, had no role in the peer review process of or decision to publish this article.

 

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