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RASopathies comprise a group of congenital malformation syndromes with predominant neuro-cardio-facial-cutaneous involvement resulting from pathogenic variants in RAS/mitogen-activated protein kinase (MAPK) signaling pathway genes. In this study 33 patients are presented with their clinical and molecular findings as an RASopathy cohort including a family with an AMMECR1-related disorder. The diagnostic distribution of the cohort included Noonan syndrome (n = 18), neurofibromatosis type 1 (n = 8), and single cases of cardiofaciocutaneous syndrome, Costello syndrome, neurofibromatosis-Noonan syndrome, NF1 microdeletion syndrome, Noonan syndrome-like disorder with loose anagen hair, Noonan syndrome with multiple lentigines and AMMECR1-related midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis (MIM# 300990). The most prevalent clinical manifestations were dermatological findings (90.9%), skeletal features (84.4%), cardiovascular involvement (75.8%), and typical craniofacial dysmorphism suggestive of RASopathy (72.7%). Variants were most frequently identified in PTPN11 and NF1, followed by single cases involving the BRAF, HRAS, LZTR1, RAF1, RIT1, SHOC2, and SOS1. Notably, one patient harbored a variant in AMMECR1, which is not involved in the RAS/MAPK pathway. Overall, this study delineates the clinical and molecular landscape of a cohort from Türkiye and underscores that the AMMECR1-related phenotype represents a distinct entity that closely mimics Noonan syndrome.

BACKGROUND: RASopathies are disorders caused by variants in a gene in the RAS-mitogen-activated protein kinase (RAS-MAPK) pathway that have an association with cardiovascular anomalies, most commonly pulmonary stenosis and hypertrophic cardiomyopathy. There are some reported cases of coronary artery aneurysms (CAAs) in patients with RASopathies, but there is limited understanding of CAAs in this population, particularly in younger patients and in those with varying genotypes. CASE SUMMARY: We describe 3 pediatric cases of patients with RASopathy developing CAA or ectasia: a 3-year-old with CBL-related RASopathy with giant CAAs, one of which required surgical intervention with a coronary artery bypass graft; an 8-year-old with PTPN11-related Noonan syndrome with giant CAAs; and an 11-year-old with a clinical diagnosis of Noonan syndrome with coronary ectasia. DISCUSSION: CAAs may be related to underlying RASopathies. Further exploration of the association and pathophysiology of CAAs in RASopathy is needed to guide screening, prevention, and management.

BACKGROUND: Genetic mutations causing dysregulation of the RAS/mitogen-activated protein kinase pathway contribute to hypertrophic cardiomyopathy (HCM). Genotype-phenotype associations in this population remain poorly understood. This study aimed to evaluate the impact of RASopathy subtype on cardiovascular outcomes. METHODS: We included 24 patients diagnosed with RAS signaling pathway mutations and HCM (RAS-HCM) before age 18. Data on sociodemographic, prenatal, clinical, genetic, and echocardiographic parameters were retrospectively collected from medical records spanning 2004-2024. Death, heart failure (HF), transplant (Ts), and use of implantable cardioverter defibrillator (ICD) were also evaluated. RESULTS: Median age at HCM diagnosis was 0.42 years (IQR 7.1); median follow-up was 8.5 years. Patients were classified into Noonan syndrome (62.5%) and other RASopathies (37.5%). Pathogenic mutations were identified in PTPN11 (38%), RAF1 and BRAF (17% each), and SOS1 and RIT1 (13% each). Patients with Noonan syndrome underwent significantly more therapeutic strategies (p = 0.026). Increased end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) were linked to the development of HF (p = 0.006, p = 0.007; respectively), while increased IVSd was associated with higher mortality (p = 0.013). CONCLUSIONS: Echocardiographic parameters (IVSd and LVPWd), and RASopathy subtype may serve as prognostic indicators in pediatric RAS-HCM patients. Further studies are warranted to elucidate the underlying molecular mechanisms. IMPACT: Demonstrates that RASopathy subtype may influence hypertrophic cardiomyopathy (HCM) progression and clinical outcomes in pediatric patients. Identifies end-diastolic interventricular septal thickness (IVSd) and left ventricular posterior wall thickness (LVPWd) as critical echocardiographic predictors of heart failure and cardiac mortality from early stages. Supports early genetic testing and echocardiographic monitoring to guide personalized care in pediatric RASopathies.

Noonan syndrome (NS) is a rare autosomal dominant disorder characterized by distinctive craniofacial features, congenital heart disease, bleeding disorders, and variable cognitive impairment. Oral manifestations may include malocclusion, delayed tooth eruption, enamel defects, and dental anomalies. This report describes the multidisciplinary management of a 34-year-old man with NS presenting with dental trauma, unaesthetic anterior teeth, and functional concerns. Management involved surgical extractions, endodontic treatment, and prosthetic rehabilitation, coordinated with cardiology and hematology teams to minimize systemic risks. Individualized treatment planning, behavioral adaptations, and tailored hemostatic strategies facilitated safe dental rehabilitation. This case highlights the importance of interprofessional collaboration and risk-adapted dental care in patients with complex systemic conditions.

BACKGROUND: Nonimmune factors are the most common cause of fetal hydrops, which are characterized by the accumulation of pathological fluid due to various causes. The etiology of this disease is complex, with a relatively high mortality rate, and the prognosis largely depends on the underlying cause. Notably, fetal hydrops attributable to genetic causes, such as chromosomal abnormalities or gene mutations, are typically associated with a poor prognosis. CASE PRESENTATION: A fetus diagnosed with severe nonimmune fetal hydrops at 27 weeks of gestation presented with multiple abnormalities on prenatal ultrasound, including progressively thickened nuchal translucency (NT) and nuchal fold (NF), cystic hygroma, pleural effusion, and renal pelvis duplication. Amniotic fluid cytogenetic analysis revealed a normal karyotype. Integrated chromosomal microarray analysis (CMA) and trio-based whole-exome sequencing (Trio-WES) revealed a pathogenic 2.82 Mb duplication at chromosome 22q11.21, designated as arr[GRCh37] 22q11.21(18984188-21804597)x3, associated with 22q11.2 duplication syndrome, which was inherited from the father. Additionally, a heterozygous missense variant in the LZTR1 gene NM_006767.3: c.848G > A (p.Arg283Gln) was detected and classified as pathogenic, associated with Noonan syndrome type 10, maternally inherited. After comprehensive counseling and careful consideration, the parents elected to terminate the pregnancy. CONCLUSION: This study revealed that fetuses carrying both a pathogenic copy number variant of duplication in the 22q11.2 region and a heterozygous pathogenic missense variant of the LZTR1 gene (c.848G > A) simultaneously constitute the main genetic basis for its multisystem abnormalities and severe hydrops. This study highlights the role of multiple genetic superimposition effects in the formation of complex fetal phenotypes and emphasizes that in genetic counseling and prenatal diagnosis, a combined strategy of CMA and Trio-WES should be adopted to improve the detection rate of complex genetic diseases and the accuracy of recurrence risk assessment.