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BACKGROUND Noonan syndrome is a clinically diagnosed genetic disorder frequently associated with congenital and structural cardiac abnormalities such as valvular dysplasia and cardiomyopathy, which may predispose patients to infective endocarditis. Delayed recognition, particularly in underserved populations, can lead to advanced cardiac complications and complex presentations. CASE REPORT A 29-year-old woman from a rural area with no previous medical history presented with severe respiratory distress, weight loss, and newly detected cardiac murmurs. Physical examination revealed dysmorphic features suggestive of Noonan syndrome, including low-set ears, hypertelorism, short stature, and broad thorax, leading to a clinical diagnosis. Echocardiography demonstrated severe mitral regurgitation with mobile vegetations, a pedunculated mass in the right ventricular outflow tract, left atrial enlargement, reduced right ventricular systolic function (Tricuspid Annular Plane Systolic Excursion, 14 mm), and mild pericardial effusion. Blood cultures remained negative after prolonged incubation, consistent with blood culture-negative infective endocarditis. Concomitant hyperthyroidism contributed to heart failure decompensation. A multidisciplinary team initiated empirical antibiotics, heart failure therapy, thyroid control, and supportive care. The patient improved clinically and was discharged with a plan for elective valve surgery after infection control. CONCLUSIONS This case highlights infective endocarditis as a serious complication in late-diagnosed Noonan syndrome due to underlying structural cardiac abnormalities. Early recognition of Noonan syndrome and multidisciplinary management are essential to improve outcomes and ensure timely referral for definitive cardiac intervention.

Both RIT1 and RIT2 are members of the RAS superfamily of small GTPases, which regulate various cellular processes. RIT1 is widely expressed, whereas RIT2 is primarily found in neuronal tissues. Dysregulation of these proteins has been associated with several human diseases, including Noonan syndrome, cancer, Parkinson's disease, autism, and schizophrenia. Although RIT1 and RIT2 are often compared to classical RAS proteins, they exhibit distinct regulatory and biochemical properties. Here, we demonstrate that RIT1 differs from classical RAS in GTPase cycling. Unlike classical RAS proteins, RIT1 did not respond to SOS1-mediated nucleotide exchange or p120GAP-stimulated GTP hydrolysis under cell-free conditions. These results imply that RIT1 may depend on regulatory mechanisms that differ from those of classical RAS proteins. However, the relevant physiological regulators remain unknown. Disease-associated RIT1 mutations cluster around the P-loop and Switch II regions. In this transient overexpression screening system, however, these mutations had only a modest effect on the canonical MAPK, PI3K/AKT, and JNK signaling pathways in HEK293T overexpression experiments. This suggests the existence of additional context-specific effectors and regulatory factors. We demonstrate that RIT1 and RIT2 interact with membrane lipids via a basic C-terminal extension. The KRLK-containing region contributes to the binding of phosphatidylserine and phosphoinositides. Charge-reversal mutations disrupt lipid interactions and liposome binding, supporting the functional importance of this region. In a reconstituted liposome system, galectin-3 and LZTR1, but not galectin-1, reduced the interaction of GDP-loaded RIT1 and RIT2 with liposomes. These results suggest that accessory proteins may influence RIT membrane interactions. However, their cellular relevance requires further validation. Together, our findings provide biochemical insights into RIT GTPase regulation and its interactions with membrane lipids under cell-free conditions.

BACKGROUND: Giant Axonal Neuropathy (GAN) is a rare autosomal recessive neurodegenerative disorder caused by biallelic pathogenic variants in the GAN gene, which encodes gigaxonin. The disease typically begins in childhood and is characterized by muscle weakness, gait disturbances, peripheral neuropathy, and distinctive kinky hair. CASE DESCRIPTION: We report the clinical, radiological, and molecular findings of a 7-year-old Mexican girl from Jalisco, Mexico, born to consanguineous parents, who presented with global developmental delay and absence of independent ambulation by age of seven. Additional features included kinky hair, broad forehead, blepharoptosis, depressed nasal bridge with a bulbous tip, high-arched palate, micrognathia, and generalized joint hyperlaxity. Given the phenotypic overlap with Noonan syndrome, PTPN11 Sanger sequencing was initially performed, followed by a RASopathy gene panel; both analyses yielded negative results. RESULTS: Whole-exome sequencing identified a homozygous splice-site variant in GAN c.851 + 1 G>A, which was confirmed by Sanger sequencing. Both parents were heterozygous carriers, consistent with parental consanguinity. According to ACMG/AMP guidelines (PVS1, PM2, PM3), the variant was classified as pathogenic. Additional studies, including brain magnetic resonance imaging, revealed peridentate hyperintensities compatible with gliosis or hypomyelination. CONCLUSION: The integration of clinical features, neuroimaging findings, and molecular analysis confirmed the diagnosis of giant axonal neuropathy type 1. This case underscores the clinical relevance of whole-exome sequencing in patients with overlapping syndromic features. Notably, the GAN c.851 + 1 G>A variant has previously been reported in at least five homozygous patients of Mexican ancestry, supporting a possible founder effect in this population.

Pulmonary hypertension (PH) may complicate a broad range of genetic syndromes beyond the established spectrum of heritable pulmonary arterial hypertension. Although these conditions are individually rare, together they represent an emerging field at the crossroads of developmental biology, vascular medicine, and precision genomics. In many cases, PH may be the presenting feature or may remain unrecognized because it occurs within complex multisystem disorders involving congenital heart disease, developmental lung abnormalities, parenchymal lung disease, vascular malformations, or extra-pulmonary manifestations. Recent advances in human genetics have expanded the spectrum of genes and syndromes associated with PH, including disorders involving altered lung and vascular development, dysregulated hypoxia signaling, smooth muscle dysfunction, chromosomal abnormalities, and syndromic vasculopathies.In this review, we summarize the main genetic syndromes associated with PH and discuss their underlying mechanisms, clinical phenotypes, diagnostic clues, and therapeutic implications. We paid particular attention to conditions that illustrate the marked heterogeneity of syndromic PH such as FLNA-related disorders, neurofibromatosis type 1, Noonan syndrome, Down syndrome, Alagille syndrome, Cantú syndrome, Chuvash polycythaemia, cobalamin C deficiency, multisystemic smooth muscle dysfunction syndrome, alveolar capillary dysplasia with misalignment of pulmonary veins, and Moya Moya syndrome.

BACKGROUND: Dysregulation of the RAS-mitogen-activated protein kinase signalling pathway underlies RASopathies, a family of neurodevelopmental disorders associated with variable cancer predisposition. However, the prevalence and spectrum of solid tumours and the contribution of specific variants to tumour susceptibility remain poorly defined. METHODS: We assessed solid tumour prevalence and spectrum in the largest single-centre cohort of individuals with RASopathies (n=138), excluding neurofibromatosis type 1 and integrated these findings with a systematic literature review to evaluate tumour distribution and genotype-phenotype correlations. RESULTS: In our cohort, at least one solid tumour was identified in 10.8% of individuals with Noonan syndrome (NS), 47.8% with Costello syndrome (CS) and 7.3% with cardiofaciocutaneous syndrome (CFCS). Malignant tumours occurred in 5.4%, 30.4% and 2.4%, respectively. CS showed the highest tumour burden, frequently with multiple primary tumours, predominantly of the bladder. In NS, low-grade central nervous system (CNS) tumours were most common, particularly among individuals carrying PTPN11 variants. Tumour onset occurred with a median age of 19, 14 and 13 years in NS, CS and CFCS, respectively. Literature data analysis identified candidate variants in HRAS, PTPN11 and SOS1 genes associated with increased risk for solid tumours, which differed from mutational hotspots reported in childhood leukaemia or sporadic cancers. CONCLUSION: Solid tumour risk in RASopathies is syndrome-dependent and genotype-dependent, with CS showing a high burden of bladder tumours and NS mainly associated with CNS tumours. These findings may support tailored surveillance strategies.