A bicarotid trunk with associated right retroesophageal subclavian artery in a child with neurofibromatosis type 1 complicated by a left hemispheric stroke.

PURPOSE: To describe the association between two aortic arch branch variants and its possible relationship with neurofibromatosis-1. METHODS: A 5-year-old female with NF-1 diagnosis presented to the emergency department at 2 months of age with irritability, vomiting and left gaze deviation. Brain MRI showed a left side acute hemispheric stroke and left internal carotid occlusion. RESULTS: CT angiography of the neck showed the right and left common carotid arteries arising from a common vascular trunk coming from the aortic arch and a right retroesophageal subclavian artery. CONCLUSION: Although the relationship between NF-1 mutation and aortic arch branch abnormalities has not been described, there is a recognized condition known as neurofibromatosis/Noonan syndrome which is an accepted variant of NF-1 with clinical features of both NF-1 and Noonan syndrome caused by dysregulation of the RAS-MAPK pathway. Aortic arch branch variations in patients with NF-1 could be explained by this association.

Hipertrofia grave del ventrículo derecho secundaria a estenosis valvular pulmonar en lactante mayor con síndrome de Noonan: reporte de caso / Severe right ventricular hypertrophy secondary to pulmonary valve stenosis in an older infant with Noonan syndrome: a case report

Introducción: El Síndrome de Noonan se caracterizada por alteraciones del crecimiento, retraso psicomotor y mental, dismorfia facial, alteraciones musculo-esqueléticas y alteraciones cardíacas hasta en el 80 % de los pacientes, miocardiopatía hipertrófica 30%, estenosis valvular pulmonar 50 % y defectos septales, estenosis de ramas pulmonares, tetralogía de Fallot o coartaciones aórticas. Caso clínico: lactante de 8 meses con hipertelorismo, ptosis palpe-bral, orejas con implantación baja, cuello corto y escoliosis. Se presenta con cianosis y disnea asociada a hipotonía muscular. Peso: score Z: -3, talla: score Z: -3, a la auscultación cardiaca: soplo meso-sistólico grado 4/6 en segundo espacio intercostal izquierdo, línea para-esternal. En el ecocardiograma se observa estenosis pulmonar valvular de grado moderado (gradiente sistólico de 52 mmHg) y dilatación del tronco arterial pulmonar. Evolución: Se efectúa cateterismo cardíaco con evidencia estenosis valvular pulmonar grave, reacción infundibular, hipertrofia del ventrículo derecho, apertura valvular en domo y conducto arterioso persistente filiforme "tipo E", estos hallazgos justificaban el desarrollo de hipertrofia cardíaca. Se realizó una valvuloplastia pulmonar con balón que mejoró las presiones cardíacas. Conclusiones: Las alteraciones cardíacas presentes en un lactante con síndrome de Noonan fueron: Hipertrofia biventricular, hipertensión pulmonar, estenosis valvular pulmonar, conducto arterioso persistente.

Introduction: Noonan syndrome is characterized by growth disorders, psychomotor and mental retardation, facial dysmorphia, musculoskeletal disorders, and cardiac disorders in up to 80% of patients, hypertrophic cardiomyopathy in 30%, pulmonary valve stenosis in 50%, septal defects, pulmonary branch stenosis, tetralogy of Fallot, and aortic coarctations. Clinical case: 8-month-old infant with hypertelorism, palpebral ptosis, low-set ears, short neck, and scoliosis. It presents with cyanosis and dyspnea associated with muscle hypotonia. Weight: Z score: -3, height: Z score: -3, on cardiac auscultation: mid-systolic murmur grade 4/6 in the second left intercostal space, parasternal line. The echocardiogram shows moderate valvular pulmonary stenosis (52 mmHg systolic gradient) and dilatation of the pulmonary arterial trunk. Evolution: Cardiac catheterization was performed with evidence of severe pulmonary valve stenosis, infundibular reaction, right ventricular hypertrophy, dome valve opening, and "type E" filiform patent ductus arteriosus. These findings justified the development of cardiac hypertrophy. Pulmonary balloon valvuloplasty was performed, which improved cardiac pressure. Conclusions: The cardiac alterations present in an infant with Noonan syndrome were biventricular hypertrophy, pulmonary hypertension, pulmonary valve stenosis, and patent ductus arteriosus.

Novel Approach to Improve the Identification of the Bleeding Phenotype in Noonan Syndrome and Related RASopathies.

OBJECTIVES: To characterize the bleeding phenotype in Noonan syndrome (NS), to test the utility of following national guidelines in detecting this phenotype, to evaluate thromboelastography (TEG) as a diagnostic tool, and to evaluate the cohort for genotype-phenotype correlations. STUDY DESIGN: Participants with a clinical diagnosis of NS or related RASopathies were enrolled in a cohort study. Study procedures included clinical bleeding assessment, coagulation testing per guidelines, and hematology consultation. TEG was completed in a subset, and genetic testing was conducted for those without a molecular diagnosis. International Society of Haemostasis and Thrombosis Bleeding Assessment Tool scores were calculated with hematology consultation. Bleeding phenotype was defined as abnormal bleeding score. RESULTS: Twenty participants were enrolled; 12 completed clinical and laboratory evaluation, and five of whom met the definition for bleeding phenotype. Four of the five participants with a bleeding phenotype had platelet aggregation defects and at least one additional coagulation defect. TEG was performed in nine participants, four with bleeding phenotype and five without, and results were normal in all cases. No genotype-phenotype correlation was found. CONCLUSION: Five of the 20 participants had a bleeding phenotype identified. Based on available data, we do not recommend incorporating TEG into clinical practice for patients with NS. Platelet aggregation defects were the most common abnormalities, which would not be detected on tier 1 testing of current guidelines; therefore, we propose a new algorithm.

Dermatological manifestations, management, and care in RASopathies.

RASopathies are rare genetic disorders caused by germline pathogenic variants in genes belonging to the RAS/MAPK pathway, which signals cell proliferation, differentiation, survival and death. The dysfunction of such signaling pathway causes syndromes with overlapping clinical manifestations. Skin and adnexal lesions are the cardinal clinical signs of RASopathies, such as cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines, formerly known as LEOPARD syndrome, Costello syndrome, neurofibromatosis (NF1), Legius syndrome, Noonan-like syndrome with loose anagen hair (NSLH) and Noonan syndrome. As NF1, one of the most common RASopathies, described in 1882, has its clinical features well delineated, we will focus on the dermatological diagnosis, management and care of non-NF1 RASopathies, which are less known and more recently described. Dermatological manifestations are important clinical diagnostic elements that can aid differential diagnosis among RASopathies. They can affect dermis and epidermis, causing pigmented lesions (melanocytic nevi, café-au-lait spots, and lentigines), hyperkeratosis (keratosis pilaris, ulerythema ophryogenes, and palmoplantar keratosis) or hyperplasia. To date there are rare known links to malignancy, but oftentimes skin lesions require close attention because they can highly affect quality of life.

Challenges in genetic diagnosis, co-occurrence of 22q11.2 deletion syndrome and Noonan syndrome.

Noonan syndrome (NS) is caused by pathogenic variants in genes involved in the RAS/MAPK pathway. On the other hand, 22q11.2 Deletion Syndrome (22q11.2DS) is caused by heterozygous microdeletion on chromosome 22q11.2. The clinical characteristics of both syndromes are expected to be relatively distinct, and, in fact, there is only one report of these syndromes occurring together, but on daily clinical practice and especially in early childhood phenotypes may overlap. In this study, we describe a patient with NS and 22q11.2DS features harboring a heterozygous 2.54 Mb deletion of chromosome 22q11.2 and a variant in LZTR1, c.1531G > A p.(Val511Met). In 1993, Wilson et al reported a patient with both 22q11.2DS and NS, proposing that probably more than one gene is deleted in the proband and that one of the deleted genes is responsible for Noonan's phenotype. In our patient, one of the deleted genes within the 22q11.2 region was the LZTR1 gene which was associated with NS in 2015. This case also highlights the importance of the long-term patients' follow-up to detect evolutionary changes that may appear in the phenotype and alerts clinicians of the co-occurrence of two syndromes that may manifest over time.

Trametinib for Refractory Chylous Effusions and Systemic Complications in Children with Noonan Syndrome.

OBJECTIVE: To evaluate the effect of the RAS-MAPK pathway inhibitor trametinib on medically refractory chylous effusions in 3 hospitalized patients with Noonan syndrome. STUDY DESIGN: Pharmacologic MEK1/2 inhibition has been used to treat conditions associated with Noonan syndrome, given that activation of RAS-MAPK pathway variants leads to downstream MEK activation. We describe our experience with 3 patients with Noonan syndrome (owing to variants in 3 distinct genes) and refractory chylous effusions treated successfully with MEK inhibition. A monitoring protocol was established to standardize medication dosing and monitoring of outcome measures. RESULTS: Subjects demonstrated improvement in lymphatic leak with additional findings of improved growth and normalization of cardiac and hematologic measurements. Trametinib was administered safely, with only moderate skin irritation in 1 subject. CONCLUSIONS: Improvements in a variety of quantifiable measurements highlight the potential utility of MEK1/2 inhibition in patients with Noonan syndrome and life-threatening lymphatic disease. Larger, prospective studies are needed to confirm efficacy and assess long-term safety.

Delayed Puberty Phenotype Observed in Noonan Syndrome Is More Pronounced in Girls than Boys.

INTRODUCTION: Pubertal delay is described as one of the clinical features in Noonan syndrome (NS) and it may be one of the factors causing short adult height in those patients. The present study aimed at characterizing pubertal development in NS and identifying pubertal delay predictors. METHODS: We analyzed 133 individuals with a molecular diagnosis of NS and clinical puberty evaluation. We characterized delayed puberty as pubertal onset after 12 years in girls and 13.5 years in boys, according to parameters of the Brazilian population. To investigate its predictors, we correlated the age at onset of puberty with several characteristics and genotype in a multilevel regression model. For comprehending pubertal development in NS, we assessed age and anthropometric measures at each Tanner stage and adult age. RESULTS: The mean age at puberty onset for girls was 11.9 ± 1.9 years and for boys, 12.5 ± 1.7 years, significantly later than the Brazilian population (p = 0.025; p < 0.001). Girls (49.1%) presented delayed puberty more frequently than boys (27.9%, p = 0.031). Body mass index standard deviation scores (SDS) and insulin growth factor 1 SDS at puberty onset significantly predicted later puberty entry. Height gain from the onset of puberty to adult height was lower in children with pubertal delay. CONCLUSION: Pubertal delay is characteristically found in children with NS, more frequently in females. The low weight of patients with NS could modulate the age of puberty, just as the increase in overweight/obesity in the general population has shown an effect on reducing the age of onset of puberty.

Síndrome de Noonan asociado a mutación del gen SOS1, reporte de caso / Noonan syndrome associated with a mutation of the SOS1 gene, case report

Introducción: El síndrome de Noonan es un trastorno genético de herencia autosómica dominante con una expresión fenotípica variable. Se encuentra dentro de las enfermedades conocidas como rasopatías, producidas por las mutaciones en los genes RAS. Los pacientes se caracterizan por dismorfismo facial, talla baja, enfermedad cardíaca congénita, alteraciones músculos esqueléticas y en algunos casos discapacidad intelectual. Caso clínico: En el presente reporte se describe el caso de un paciente masculino de un mes de edad que acude a consulta externa, presentando dismorfismo facial y estenosis pulmonar, por lo que se realiza un seguimiento multidisciplinario por sospecha de Síndrome de Noonan. A partir del cuarto mes desarrolló linfedema en la zona del deltoides. Evolución: A los 7 meses de vida se realiza secuenciación de exoma, encontrando una variante patogénica en el gen SOS1, confirmando el diagnóstico de dicho síndrome. Conclusión: Este caso documenta la presencia de síndrome de Noonan con mutación del gen SOS1 con dismorfología facial típica, estenosis de la válvula pulmonar, criptorquidia y displasia linfática con linfedema del deltoides, hallazgo no descrito en casos previos.

Introduction: Noonan syndrome is a dominant autosomal inherited ge-netic disorder with variable phenotypic expression. It is found within diseases known as rasopathies and is pro-duced by mutations in RAS genes. Patients are character-ized by facial dysmorphism, short stature, congenital heart disease, musculoskeletal disorders, and, in some cases, intellectual disability. Clinical case: This report describes the case of a one-month-old male patient who comes to the outpatient clinic, presenting with facial dysmorphism and pulmonary steno-sis, for which a multidisciplinary follow-up is carried out due to suspicion of Noonan syndrome. From the fourth month, the patient developed lymphedema in the deltoid area. Evolution: At 7 months of age, exome sequencing was per-formed, finding a pathogenic vari-ant in the SOS1 gene and confirming the diagnosis of this syndrome. Conclusion: This case documents the presence of Noonan syndrome with a mutation of the SOS1 gene with typical facial dysmorphology, pulmonary valve stenosis, cryptor-chidism and lymphatic dysplasia with deltoid.

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies.

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure.

Atypical, severe hypertrophic cardiomyopathy in a newborn presenting Noonan syndrome harboring a recurrent heterozygous MRAS variant.

Noonan syndrome (NS) is a Mendelian phenotype, member of a group of disorders sharing neurocardiofaciocutaneous involvement, known as RASopathies, caused by germline variants in genes coding for components of the RAS/MAPK signaling pathway. Recently, a novel gene of the RAS family (MRAS) was reported to be associated with NS in five children, all of them presenting, among the cardinal features of NS, the same cardiac finding, hypertrophic cardiomyopathy (HCM). We report on a 2-month-old infant boy also presenting this cardiac anomaly that evolved to a fatal outcome after a surgical myectomy. In addition, a thick walled left ventricle apical aneurysm, rarely described in NS, was also disclosed. Next-generation sequencing revealed a missense, previously reported variant in MRAS (p.Thr68Ile). This report reinforces the high frequency of HCM among individuals harboring MRAS variants, contrasting to the 20% overall prevalence of this cardiac anomaly in NS. Thus, these preliminary data suggest that variants in MRAS per se are high risk factors for the development of an early, severe HCM, mostly of them with left ventricle outflow tract obstruction, with poor prognosis. Because of the severity of the cardiac involvement, other clinical findings could not be addressed in detail. Therefore, long-term follow-up of these individuals and further descriptions are required to fully understand the complete phenotypic spectrum of NS associated with MRAS germline variants, including if these individuals present an increased risk for cancer.

Etiology and Treatment of Growth Delay in Noonan Syndrome.

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

The Prevalence of Noonan Spectrum Disorders in Pediatric Patients with Pulmonary Valve Stenosis.

OBJECTIVE: To investigate the prevalence of Noonan spectrum disorders in a pediatric population with pulmonary valve stenosis (PVS) and explore other characteristics of Noonan spectrum disorders associated with PVS. STUDY DESIGN: A retrospective medical record review was completed for patients with a diagnosis of PVS seen at the Children's Hospital Colorado Cardiology clinic between 2009 and 2019. Syndromic diagnoses, genotypes, cardiac characteristics, and extracardiac characteristics associated with Noonan spectrum disorders were recorded; statistical analysis was conducted using R. RESULTS: Syndromic diagnoses were made in 16% of 686 pediatric patients with PVS, with Noonan spectrum disorders accounting for 9% of the total diagnoses. Individuals with Noonan spectrum disorders were significantly more likely to have an atrial septal defect and/or hypertrophic cardiomyopathy than the non-Noonan spectrum disorder individuals. Supravalvar pulmonary stenosis was also correlated significantly with Noonan spectrum disorders. Extracardiac clinical features presenting with PVS that were significantly associated with Noonan spectrum disorders included feeding issues, failure to thrive, developmental delay, short stature, and ocular findings. The strongest predictors of a Noonan spectrum disorder diagnosis were cryptorchidism (70%), pectus abnormalities (66%), and ocular findings (48%). The presence of a second characteristic further increased this likelihood, with the highest probability occurring with cryptorchidism combined with ocular findings (92%). CONCLUSIONS: The 9% prevalence of Noonan spectrum disorder in patients with PVS should alert clinicians to consider Noonan spectrum disorders when encountering a pediatric patient with PVS. The presence of PVS with 1 or more Noonan spectrum disorder-related features should prompt a genetic evaluation and genetic testing for RAS pathway defects. Noonan spectrum disorders should also be included in the differential when a patient presents with supravalvar pulmonary stenosis.

Noonan syndrome with loose anagen hair with variants in the PPP1CB gene: First familial case reported.

Rasopathies are a group of phenotypically overlapping conditions that include Noonan, Noonan with multiple lentigines, Noonan with loose anagen hair, Costello, Cardio-facio-cutaneous, and Neurofibromatosis-Noonan syndromes. Noonan syndrome with loose anagen hair (NS-LAH) is clinically characterized by prominent forehead, macrocephaly, growth hormone deficiency, sparse, loose and slow-growing anagen hair, hyperpigmented skin with eczema or ichthyosis, mild psychomotor delays, hypernasal voices, and attention deficit hyperactivity disorder. Variants in SHOC2 are responsible for the majority of the cases. Gripp et al. identified four unrelated individuals with similar phenotype to NS-LAH with pathogenic variants in PPP1CB. In this study, we present one family and one patient with NS-LAH and variants in PPP1CB. The first patient belongs to a family with a likely pathogenic variant, c.545T>A (p.Met182Lys), the first family published so far with a variant in this gene. The second patient harbors a de novo pathogenic variant, c.146C>G (p.Pro49Arg). This study presents two additional patients with this rare syndrome in order to increase the clinical characterization of the syndrome and provide more evidence of the pathogenicity of the c.545T>A (p.Met182Lys) variant in PPP1CB, a gene recently associated with NS-LAH.

Noonan syndrome patients beyond the obvious phenotype: A potential unfavorable metabolic profile.

Noonan syndrome (NS) and NS related disorders (NRD) are frequent monogenic diseases. Pathogenic variants in PTPN11 are observed in approximately 50% of these NS patients. Several pleiotropic phenotypes have previously been described in this condition. This study aimed at characterizing glucose and lipid profiles in patients with NS/NRD. We assessed fasting blood glucose, insulin, cholesterol (total and fractions), and triglyceride (TG) levels in 112 prepubertal children and 73 adults. Additionally, an oral glucose tolerance test (OGTT) was performed in 40 children and 54 adults. Data were analyzed between age groups according to the presence (+) or absence (-) of PTPN11 mutation. Prepubertal patients with NS/NRD were also compared with a control group. Despite the lean phenotype of children with NS/NRD, they presented an increased frequency of low HDL-cholesterol (63% in PTPN11+, 59% in PTPN11- and 16% in control, p < .001) and high TG levels (29% in PTPN11+, 18% in PTPN11- and 2.3% in control). PTPN11+ patients had a higher median HOMA-IR (1.0, ranged from 0.3 to 3.2) in comparison with PTPN11- (0.6; 0.2 to 4.4) and controls (0.6; 0.4 to 1.4, p = .027). Impaired glucose tolerance was observed in 19% (10:54) of lean adults with NS/NRD assessed by OGTT. Moreover, women with PTPN11 mutations had lower HDL-cholesterol levels than those without. Our results suggest that children and young adult patients with NS/NRD have an unfavorable metabolic profile characterized by low HDL, a tendency of elevated TGs, and glucose metabolism impairment despite a lean phenotype.

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Highlights - The Ras (Rat Sarcoma) gene family is a group of small G proteins - Ras is regulated by growth factors and neurohormones affecting cardiomyocyte growth and hypertrophy - Ras directly affects cardiomyocyte physiological and pathological hypertrophy - Genetic alterations of Ras and its pathways result in various cardiac phenotypes? - Ras and its pathway are differentially regulated in acquired heart disease - Ras modulation is a promising therapeutic target in various cardiac conditions.

Clinical and molecular analysis of 26 individuals with Noonan syndrome in a reference institution in Colombia.

Our aim was to characterize the phenotype and genotype of individuals with Noonan syndrome in Colombia. There are published cohorts of Noonan individuals from several countries in Latin America including Brazil, Chile, and Argentina, but none from Colombia. We described 26 individuals with NS from a single large referral center in the South West of Colombia using an established database in the genetics department and hospital records search using ICD-10 codes. All patients included in this study were evaluated by a medical geneticist and have molecular confirmation of NS diagnosis. The median age at referral was 3.5 years (range, 0-39), and at molecular diagnosis was 5 years (range, 0-40). Patients mostly originated from the southwest region of Colombia (19/26, 73%). Pathogenic variants in PTPN11 are the most common cause of NS in Colombian individuals followed by SHOC2 and SOS1 variants. The prevalence of cardiomyopathy was low in this population compared to other populations. Further research is needed with a larger sample size and including different regions of Colombia to correlate our findings. This study provides new information about time to diagnosis of NS in Colombia, genotypes, and provides important information to help develop guidelines for diagnosis and management of this disease in the region.