Cancer incidence and surveillance strategies in individuals with RASopathies.

RASopathies are a set of clinical syndromes that have molecular and clinical overlap. Genetically, these syndromes are defined by germline pathogenic variants in RAS/MAPK pathway genes resulting in activation of this pathway. Clinically, their common molecular signature leads to comparable phenotypes, including cardiac anomalies, neurologic disorders and notably, elevated cancer risk. Cancer risk in individuals with RASopathies has been estimated from retrospective reviews and cohort studies. For example, in Costello syndrome, cancer incidence is significantly elevated over the general population, largely due to solid tumors. In some forms of Noonan syndrome, cancer risk is also elevated over the general population and is enriched for hematologic malignancies. Thus, cancer surveillance guidelines have been developed to monitor for the occurrence of such cancers in individuals with some RASopathies. These include abdominal ultrasound and urinalyses for individuals with Costello syndrome, while complete blood counts and splenic examination are recommended in Noonan syndrome. Improved cancer risk estimates and refinement of surveillance recommendations will improve the care of individuals with RASopathies.

Lymphatic anomalies during lifetime in patients with Noonan syndrome: Retrospective cohort study.

Noonan syndrome (NS) has been associated with an increased risk of lymphatic anomalies, with an estimated prevalence of 20%. The prevalence of lymphatic anomalies seems to differ between pathogenic variants. Therefore, this study aims to describe the clinical presentation, prevalence and genotype-phenotype correlations of lymphatic anomalies during life in patients with NS. This retrospective cohort study included patients (n = 115) who were clinically and genetically diagnosed with NS and visited the Noonan expertise Center of the Radboud University Medical Center between January 2015 and March 2021. Data on lymphatic anomalies during lifetime were obtained from medical records. Lymphatic anomalies most often presented as an increased nuchal translucency, chylothorax and/or lymphedema. Prenatal lymphatic anomalies increased the risk of lymphatic anomalies during infancy (OR 4.9, 95% CI 1.7-14.6). The lifetime prevalence of lymphatic anomalies was 37%. Genotype-phenotype correlations showed an especially high prevalence of lymphatic anomalies during infancy and childhood in patients with a pathogenic SOS2 variant (p = 0.03 and p < 0.01, respectively). This study shows that patients with NS have a high predisposition for developing lymphatic anomalies during life. Especially patients with prenatal lymphatic anomalies have an increased risk of lymphatic anomalies during infancy. Genotype-phenotype correlations were found in pathogenic variants in SOS2.

Molecular and clinical profile of patients referred as Noonan or Noonan-like syndrome in Greece: a cohort of 86 patients.

Noonan syndrome (NS) is an autosomal dominant disorder characterized by clinical and genetic heterogeneity. It belongs to a wider group of pathologies, known as Rasopathies, due to the implication of genes encoding components of the Ras/MAPK signalling pathway. Recording the genetic alterations across populations helps assessing specific features to specific genes which is essential for better disease's recognition, prognosis and monitoring. Herein, we report the clinical and molecular data of a Greek cohort comprising of 86 NS or NS-like patients admitted at a single tertiary Centre in Athens, Greece. The analysis was performed using Sanger and next-generation sequencing, comprising 14 different genes. The mutational rates of the confirmed NS-associated genes in the Greek NS population are as follows: PTPN11 32.5%; RIT1 5.8%; SOS1 4.7%; BRAF 1.2%; CBL 1.2%; KRAS 1.2%; MAP2K1 1.2%; RAF1 1.2%; SHOC2 1.2%, corresponding to 50% of positivity in total NS population. The genotype-phenotype analysis showed statistically significant differences in craniofacial dysmorphisms (p = 0.005) and pulmonary valve stenosis (PS) (p < 0.001) frequencies between patients harbouring a pathogenic variant and patients without pathogenic variant in any of the tested genes. Patients with at least a pathogenic variant had 6.71 times greater odds to develop PS compared to pathogenic variant-negative patients (OR = 6.71, 95%; CI = (2.61, 17.27)). PTPN11 positive patients showed higher frequency of epicanthal folds (p = 0.004), ptosis (p = 0.001) and coarseness (p = 0.001) and lower frequency of neurological findings (p = 0.006), compared to patients carrying pathogenic variants in other genes. CONCLUSION: Craniofacial dysmorphism and PS prevail among pathogenic variant positive compared to pathogenic variant negative NS and NS-like patients while neurological defects are less common in PTPN11-affected NS patients compared to patients harbouring pathogenic variants in other genes. The significant prevalence of the Ras/MAPK pathogenic variants (17.4%), other than PTPN11, in Greek NS patients, highlights the necessity of a wider spectrum of molecular diagnosis. WHAT IS KNOWN: • Noonan syndrome (NS) has been associated with pathogenic variants in molecules-components of the Ras/MAPK pathway. • Clinical and genetic description of NS patients worldwide helps establishing personalized monitoring. WHAT IS NEW: • NS and NS-like mutational rate in Greece reaches 50% with pathogenic variants identified mostly in PTPN11 (32.5%), RIT1 (6%) and SOS1 (4.7%) genes. • The risk for pulmonary stenosis increases 6.71-fold in NS patients with a pathogenic variant compared to patients without genetic alterations.

Prevalence of Genetic Diagnoses in a Cohort With Valvar Pulmonary Stenosis.

BACKGROUND: Valvar pulmonary stenosis (vPS) accounts for 8% to 12% of congenital heart disease cases. Multiple genetic syndromes are associated with vPS, most commonly Noonan syndrome, but the cause is unknown in most cases. We analyzed genomic data from a large cohort with vPS to determine the prevalence of genetic diagnosis. METHODS: The Pediatric Cardiac Genomics Consortium database was queried to identify probands with vPS without complex congenital heart disease or aneuploidy and with existing whole exome or genome sequencing. A custom analysis workflow was used to identify likely pathogenic or pathogenic variants in disease-associated genes. Demographic and phenotypic characteristics were compared between groups with and without molecular diagnoses. RESULTS: Data from 119 probands (105 trios) were included. A molecular diagnosis was identified in 22 (18%); 17 (14%) had Noonan syndrome or a related disorder. Extracardiac and neurodevelopmental comorbidities were seen in 67/119 (56%) of probands. Molecular diagnosis was more common in those with extracardiac and neurodevelopmental phenotypes than those without (18/67 versus 4/52, P=0.0086). CONCLUSIONS: Clinicians should have high suspicion for a genetic diagnosis in individuals with vPS, particularly if additional phenotypes are present. Our results suggest that clinicians should consider offering sequencing of at least the known congenital heart disease and RASopathy genes to all individuals with vPS, regardless of whether that individual has extracardiac or neurodevelopmental phenotypes present.

Noonan syndrome and pregnancy outcomes.

BACKGROUND: Noonan syndrome is a genetic disorder with high prevalence of congenital heart defects, such as pulmonary stenosis, atrial septal defect and hypertrophic cardiomyopathy. Scarce data exists regarding the safety of pregnancy in patients with Noonan syndrome, particularly in the context of maternal cardiac disease. STUDY DESIGN: We performed a retrospective chart review of patients at Yale-New Haven Hospital from 2012 to 2020 with diagnoses of Noonan syndrome and pregnancy. We analysed medical records for pregnancy details and cardiac health, including echocardiograms to quantify maternal cardiac dysfunction through measurements of pulmonary valve peak gradient, structural heart defects and interventricular septal thickness. RESULTS: We identified five women with Noonan syndrome (10 pregnancies). Three of five patients had pulmonary valve stenosis at the time of pregnancy, two of which had undergone cardiac procedures. 50% of pregnancies (5/10) resulted in pre-term birth. 80% (8/10) of all deliveries were converted to caesarean section after a trial of labour. One pregnancy resulted in intra-uterine fetal demise while nine pregnancies resulted in the birth of a living infant. 60% (6/10) of livebirths required care in the neonatal intensive care unit. One infant passed away at 5 weeks of age. CONCLUSIONS: The majority of mothers had pre-existing, though mild, heart disease. We found high rates of prematurity, conversion to caesarean section, and elevated level of care. No maternal complications resulted in long-term morbidity. Our study suggests that women with Noonan syndrome and low-risk cardiac lesions can become pregnant and deliver a healthy infant with counselling and risk evaluation.

Therapy-related Myeloid Neoplasms in Children: A Single-institute Study.

Therapy-related myeloid neoplasm (t-MN) in the pediatric population is not well characterized. We studied 12 pediatric patients diagnosed with t-MN in our institution since 2006. The median age at the t-MN diagnoses was 14.8 years (range, 9 to 20 y). The primary malignancies included 9 solid tumors and 3 hematopoietic malignancies. Rhabdomyosarcoma (n=4) was the most common primary malignancy. Five of the 9 patients with solid tumors and all 3 patients with hematopoietic malignancies had primary neoplasms involving bone marrow. The median latency period was 5.2 years (range, 1.8 to 13.8 y). Thrombocytopenia was present in all patients at the t-MN diagnoses. Complete or partial monosomy of chromosome 5 or 7 were the 2 most common cytogenetic abnormalities. A quarter of patients demonstrated a genetic predisposition to t-MN: 1 with Li-Fraumeni syndrome with a germline TP53 R248Q mutation, 1 with Noonan syndrome with a somatic mutation (PTPN11 S502T), and 1 with a constitutive chromosomal translocation [t(X;9)(p22;q34)] and a germline TP53 L130V mutation. Outcomes remain poor. Two patients survived 3 and 5.1 years after hematopoietic stem cell transplantation.

Joint involvement in Noonan syndrome. A retrospective paediatric descriptive study.

OBJECTIVES: Noonan syndrome is a rare genetic disorder characterized mainly by congenital heart disease, occasional intellectual disability, and varied orthopaedic, rheumatological and haematologic anomalies. Despite potentially serious functional consequences, joint involvement has been rarely studied in the literature. Our objective was to perform a retrospective study evaluating the prevalence and characteristics of joint involvement in Noonan syndrome. METHODS: We recorded articular symptoms, including their type and frequency, in patients with Noonan syndrome followed up in French hospitals. Patients were included if the diagnosis was confirmed before the age of 20 based on the van der Burgt criteria or genetic analysis. Data are presented as frequencies or medians (ranges), and patient groups were compared using chi-square or Fisher tests. RESULTS: Seventy-one patients were included from 4 centres. The average age was 12.5 years (range: 2-36). Musculoskeletal pain was found in 18 patients (25%) and joint stiffness in 10 (14%) located in the wrists, elbows, ankles, knees and hips, which was usually bilateral. Only one destructive form was described (multiple villonodular synovitis and a giant cell lesion of the jaw). There were no cases of systemic lupus erythaematosus (SLE) or other autoimmune arthritis. Raynaud's phenomenon was observed in 3 patients. Only 50% of joint complaints led to additional exploration. SOS1 mutations (P<0.05) and treatment with growth hormone (GH) (P<0.05) were the only factors significantly related to musculoskeletal pain. Patients treated with GH did not have more SOS1 mutations. Patients experiencing pain were not more likely to experience stiffness, joint hypermobility, or coagulation abnormalities. CONCLUSION: Joint manifestations were frequent in Noonan syndrome, predominant in large joints, and rarely explored. Multiple villonodular synovitis is characteristic but rare. Auto-immune disorders were not described in this cohort. A more multidisciplinary approach could be recommended for the early detection of possibly disabling rheumatologic manifestations.

Expanding the clinical phenotype of RASopathies in 38 Turkish patients, including the rare LZTR1, RAF1, RIT1 variants, and large deletion in NF1.

RASopathies are a group of disorders caused by pathogenic variants in the genes encoding Ras/mitogen-activated protein kinase pathway and share overlapping clinical and molecular features. This study is aimed to describe the clinical and molecular features of 38 patients with RASopathies. Sanger or targeted next-generation sequencing of related genes and multiplex ligation-dependent-probe amplification analysis for NF1 were performed. The pathogenic variant detection rate was 94.4%. While PTPN11 was responsible for 50% of 18 patients with Noonan syndrome (NS), SOS1, LZTR1, RIT1, and RAF1 were responsible for the remaining 27.8%, 11.1%, 5.5%, and 5.5%, respectively. Three variants in LZTR1 were novel, of which two were identified in the compound heterozygous state in a patient with intellectual disability and hypertrophic cardiomyopathy, whereas the third variant was found in the heterozygous state in a patient with pulmonary stenosis and normal intelligence. We described pyloric stenosis, knee dislocation, and cleft palate in patients with SOS1, RIT1, and RAF1 variants, respectively, that was not previously reported. We detected a PTPN11 variant in three patients from same family with NS with multiple lentigines. BRAF and MAP2K2 variants were found in eight patients with Cardiofaciocutaneous syndrome. Two variants in HRAS were detected in two Costello syndrome patients, one with a mild and the other with a severe phenotype. While large NF1 deletions were identified in four Neurofibromatosis-NS patients with intellectual disability, intelligence was normal in one patient with missense variant. In conclusion, this study provided three novel variants in LZTR1 and expanded the clinical phenotype of rare RASopathies.

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.

RASopathies: A significant cause of polyhydramnios?

OBJECTIVE: The aim of the study is to determine the prevalence of RASopathies in a polyhydramnios cohort selected by postnatal medical genetics evaluation. METHODS: In this retrospective study, we reviewed 622 pregnancies with polyhydramnios seen at Lucile Packard Children's Hospital between 2008 and 2017. The findings from 131 cases evaluated by Medical Genetics were included in our final analysis. Genetic testing information was extracted to determine the rate of chromosomal or single gene conditions focusing on the RASopathies. Additional variables collected were: maternal characteristics, ultrasound findings, and the severity and timing of diagnosis of polyhydramnios. RESULTS: Postnatal genetic testing or clinical examination identified a genetic disorder in 63 (48.1%) cases, more than half (n = 33) of which had a single gene condition. Postnatal testing revealed an underlying RASopathy in 15 (11.5%) cases. An underlying RASopathy was significantly associated with the severity and timing of polyhydramnios (p < 0.05). CONCLUSION: Focusing on a selected cohort postnatally evaluated by Medical Genetics, our study identified a chromosomal or genetic disorder in almost half of pregnancies complicated by polyhydramnios. Specifically, an underlying RASopathy was found in 11.5% of cases with 13/15 of these cases having additional ultrasound findings.

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.

Síndrome de Noonan e insuficiencia aórtica severa en un paciente adulto / Noonan Syndrome and Severe Aortic Regurgitation in an Adult Patient

Introducción: El síndrome de Noonan es una enfermedad congénita con una incidencia de 1:1000-2500 recién nacidos vivos. Se encuentra subdiagnosticada en nuestro medio debido a la variabilidad clínica, lo cual no permite un adecuado control y seguimiento para detectar complicaciones consecuentes a los defectos cardiovasculares congénitos. En Perú no existen reportes de casos sobre el síndrome de Noonan y sus complicaciones. Objetivo: Discutir la importancia del examen clínico para su adecuado diagnóstico a partir de las características del síndrome de Noonan en un adulto. Caso clínico: Presentamos el caso de un varón de 33 años con síndrome de Noonan, endocarditis infecciosa e insuficiencia aórtica severa. Conclusiones: Se resalta la importancia del examen físico y el uso de criterios diagnósticos para realizar el diagnóstico del síndrome de Noonan(AU)

Introduction: Noonan syndrome is a congenital disease with an incidence of 1: 1000-2500 live newborns. Due to its clinical variability, it is underdiagnosed in our setting, which does not allow adequate control and follow-up to detect complications resulting from congenital cardiovascular defects. In Peru, there are no case reports on Noonan syndrome and its complications. Objective: To discuss the importance of clinical examination for adequate diagnosis of Noonan syndrome, based on the characteristics of the disease in an adult. Clinical case: We present the case of a 33-year-old male patient with Noonan syndrome, infective endocarditis, and severe aortic regurgitation. Conclusions: The importance of physical examination and the use of diagnostic criteria to diagnose Noonan syndrome are highlighted(AU)

Noonan Syndrome in Thai Children.

This study describes clinical features of Noonan syndrome and gene mutations, including PTPN11, SOS1, and BRAF in the Thai population.Widely spaced eyes were the most common finding from the digital facial analysis technology used in this study.

The Genetic Epidemiology of Pediatric Pulmonary Arterial Hypertension.

OBJECTIVE: To describe the prevalence of pulmonary arterial hypertension (PAH)-associated gene mutations, and other genetic characteristics in a national cohort of children with PAH from the Dutch National registry and to explore genotype-phenotype associations and outcomes. STUDY DESIGN: Children (n = 70) diagnosed with idiopathic PAH, heritable PAH, PAH associated with congenital heart disease with coincidental shunt (PAH-congenital heart disease group 3), PAH after closure of a cardiac shunt (PAH-congenital heart disease group 4), or PAH associated with other noncardiac conditions were enrolled. Targeted next-generation sequencing was performed on PAH-associated genes (BMPR2, ACVRL1, EIF2AK4, CAV1, ENG, KCNK3, SMAD9, and TBX4). Also, children were tested for specific genetic disorders in case of clinical suspicion. Additionally, children were tested for copy number variations. RESULTS: Nineteen children (27%) had a PAH-associated gene mutation/variant: BMPR2 n = 7, TBX4 n = 8, ACVRL1 n = 1, KCNK3 n = 1, and EIF2AK4 n = 2. Twelve children (17%) had a genetic disorder with an established association with PAH (including trisomy 21 and cobalamin C deficiency). In another 16 children (23%), genetic disorders without an established association with PAH were identified (including Noonan syndrome, Beals syndrome, and various copy number variations). Survival rates differed between groups and was most favorable in TBX4 variant carriers. CONCLUSIONS: Children with PAH show a high prevalence of genetic disorders, not restricted to established PAH-associated genes. Genetic architecture could play a role in risk-stratified care management in pediatric PAH.

Young children with Noonan syndrome: evaluation of feeding problems.

Noonan syndrome (NS) is a common genetic syndrome with a high variety in phenotype. Even though genetic testing is possible, NS is still a clinical diagnosis. Feeding problems are often present in infancy. We investigated the feeding status of 108 patients with clinically and genetically confirmed NS. Only patients with a documented feeding status before the age of 6 were included. A distinction was made between patients with early onset feeding problems (< 1 year) and children with late onset feeding problems (> 1 year). Seventy-one of 108 patients had feeding problems, of which 40 patients required tube feeding. Children with a genetic mutation other than PTPN11 and SOS1 had significantly more feeding problems in the first year. Fifty-two of all 108 patients experienced early onset feeding problems, of which 33 required tube feeding. A strong decrease in prevalence of feeding problems was found after the first year of life. Fifteen children developed feeding problems later in life, of which 7 required tube feeding.Conclusion: Feeding problems occur frequently in children with NS, especially in children with NS based on genetic mutations other than PTPN11 and SOS1. Feeding problems develop most often in infancy and decrease with age. What is Known: • Young children with Noonan syndrome may have transient feeding problems. • Most of them will need tube feeding. What is New: • This is the first study of feeding problems in patients with clinically and genetically proven Noonan syndrome. • Feeding problems most often develop in infancy and resolve between the age of 1 and 2.

Molecular and clinical studies in 107 Noonan syndrome affected individuals with PTPN11 mutations.

BACKGROUND: Noonan syndrome (NS), an autosomal dominant developmental genetic disorder, is caused by germline mutations in genes associated with the RAS / mitogen-activated protein kinase (MAPK) pathway. In several studies PTPN11 is one of the genes with a significant number of pathogenic variants in NS-affected patients. Therefore, clinically diagnosed NS individuals are initially tested for pathogenic variants in PTPN11 gene to confirm the relationship before studying genotype-phenotype correlation. METHODS: Individuals (363) with clinically diagnosed NS from four hospitals in South India were recruited and the exons of PTPN11 gene were sequenced. RESULTS: Thirty-two previously described pathogenic variants in eight different exons in PTPN11 gene were detected in 107 patients, of whom 10 were familial cases. Exons 3, 8 and 13 had the highest number of pathogenic variants. The most commonly identified pathogenic variants in this series were in exon 8 (c.922A > G, c.923A > G), observed in 22 of the affected. Congenital cardiac anomalies were present in 84% of the mutation-positive cohort, the majority being defects in the right side of the heart. The most common facial features were downward-slanting palpebral fissures, hypertelorism and low-set posteriorly rotated ears. Other clinical features included short stature (40%), pectus excavatum (54%) and, in males, unilateral or bilateral cryptorchidism (44%). CONCLUSION: The clinical features and mutational spectrum observed in our cohort are similar to those reported in other large studies done worldwide. This is the largest case series of NS-affected individuals with PTPN11 mutations described till date from India.

Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome.

INTRODUCTION: Few data exist on long-term growth hormone (GH) treatment in patients with Noonan syndrome (NS). OBJECTIVE: To evaluate the effectiveness and safety of GH treatment in NS in clinical practice. METHODS: Height gain, near-adult height (NAH), and safety were assessed in 2 complementary non-interventional studies: NordiNet® IOS and ANSWER. The safety analysis included 412 patients, and the effectiveness analysis included 84 GH-treated patients (male, n = 67) with ≥4 years' height standard deviation score (HSDS) data. HSDS was determined using national reference (NR) and NS-specific (NSS) data. RESULTS: The mean (SD) baseline age was 8.38 (3.57) years; HSDS, -2.76 (1.03); GH dose, 41.6 (11.1) µg/kg/day. The mean (SD) HSDS increase from baseline (ΔHSDS) was 0.49 (0.37) (first year), 0.79 (0.58) (second year), and 1.01 (0.60) (third year) (NR). The mean (SD) HSDS at year 3 was -1.66 (1.00) (NR; 1.06 [1.12] [NSS]). Twenty-four patients achieved NAH. The mean (SD) NAH SDS (NR) was -1.51 (0.60) (154.90 [3.21] cm) in females and -1.79 (1.09) (165.61 [7.19] cm) in males; 70.8% (17/24) had NAH SDS ≥ -2. Adverse drug reactions and GH-unrelated serious adverse events (n = 34) were reported in 22/412 (5.3%) patients. Four neoplasms and 3 cases of scoliosis were reported; no cardiovascular adverse events occurred. CONCLUSIONS: GH-treated children with NS achieved substantial height gain during the first 3 years of follow-up. Overall, 24 patients achieved NAH, with 70.8% having NAH SDS ≥ -2. There was no evidence to support a higher prevalence of neoplasm, or cardiac or other comorbidities.

Providing more evidence on LZTR1 variants in Noonan syndrome patients.

Noonan syndrome (NS, OMIM 163950) is a common autosomal dominant RASopathy caused mainly by gain-of-function germline pathogenic variants in genes involved in the RAS/MAPK signaling pathway. LZTR1 gene has been associated with both dominant and recessive NS. Here, we present seven patients with NS and variants in the LZTR1 gene from seven unrelated families, 14 individuals in total. The detection rAte of LZTR1 variants in our NS cohort was 4% similar to RAF1 and KRAS genes, indicating that variants in this gene might be frequent among our population. Three different variants were detected, c.742G>A (p.Gly248Arg), c.360C>A (p.His120Gln), and c.2245T>C (p.Tyr749His). The pathogenic variant c.742G>A (p.Gly248Arg) was found in five/seven patients. In our cohort 50% of patients presented heart defects and neurodevelopment delay or learning disabilities, short stature was present in 21% of them and one patient had acute lymphoblastic leukemia. This study broadens the spectrum of variants in the LZTR1 gene and provides increased knowledge of the clinical phenotypes observed in Argentinean NS patients.

Turner syndrome in diverse populations.

Turner syndrome (TS) is a common multiple congenital anomaly syndrome resulting from complete or partial absence of the second X chromosome. In this study, we explore the phenotype of TS in diverse populations using clinical examination and facial analysis technology. Clinical data from 78 individuals and images from 108 individuals with TS from 19 different countries were analyzed. Individuals were grouped into categories of African descent (African), Asian, Latin American, Caucasian (European descent), and Middle Eastern. The most common phenotype features across all population groups were short stature (86%), cubitus valgus (76%), and low posterior hairline 70%. Two facial analysis technology experiments were conducted: TS versus general population and TS versus Noonan syndrome. Across all ethnicities, facial analysis was accurate in diagnosing TS from frontal facial images as measured by the area under the curve (AUC). An AUC of 0.903 (p < .001) was found for TS versus general population controls and 0.925 (p < .001) for TS versus individuals with Noonan syndrome. In summary, we present consistent clinical findings from global populations with TS and additionally demonstrate that facial analysis technology can accurately distinguish TS from the general population and Noonan syndrome.

Pain in individuals with RASopathies: Prevalence and clinical characterization in a sample of 80 affected patients.

Pain in individuals with RASopathies is a neglected topic in literature. In this article, we assessed prevalence and profile of pain in a sample of 80 individuals affected by RASopathies. The study sample included individuals with Noonan syndrome (N = 42), Costello syndrome (N = 17), and cardio-facio-cutaneous syndrome (N = 21). A set of standardized questionnaires and scales were administered (VAS/numeric scale, r-FLACC, Wang-Baker scale, NPSI, BPI, NCCPC-R) to detect and characterize acute and chronic pain and to study the influence of pain on quality of life (PEDs-QL, SF-36) and sleeping patterns (SDSC); revision of past medical history and multisystemic evaluation was provided. Available clinical data were correlated to the presence of pain. High prevalence of acute (44%) and chronic (61%) pain was documented in the examined sample. Due to age and intellectual disability, acute pain was localized in 18/35 individuals and chronic pain in 33/49. Muscle-skeletal and abdominal pain was more frequently reported. The intensity of acute and chronic pain interfered with daily activities in 1/3 of the sample. Pain negatively impacted on QoL and sleeping patterns. This work documents that pain is highly prevalent in RASopathies. Future studies including subjective and objective measures of pain are required to discriminate a somatosensory abnormality from an abnormal elaboration of painful stimuli at a central level.