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.

Severe Cardiopulmonary Disease in a Parturient With Noonan Syndrome.

Noonan syndrome is a relatively common genetic disorder and the second most common cause of congenital heart disease after trisomy 21. The spectrum of cardiac anomalies in Noonan syndrome typically involves pulmonary valve stenosis occasionally in conjunction with hypertrophic cardiomyopathy. Mitral valve involvement is a rare finding in Noonan syndrome and is most commonly associated with either mitral valve prolapse or abnormal valvular insertion causing left ventricular outflow tract obstruction. Patients with Noonan syndrome typically have preserved fertility and, given the success of cardiac surgery and medical management of heart failure in this population, are beginning to present more commonly as parturients in adulthood. Maternal physiologic changes during pregnancy introduce an added complexity to hemodynamic management and anesthetic considerations during labor and delivery. In this article, we present a case of a patient with Noonan syndrome with severe mitral stenosis, pulmonary valve insufficiency, and severe restrictive and obstructive pulmonary disease who presented preterm for delivery due to increased dyspnea at rest. Here we review the pathophysiology behind Noonan syndrome and peripartum management strategies in a patient with severe combined cardiac and pulmonary disease.

Enhanced MAPK1 Function Causes a Neurodevelopmental Disorder within the RASopathy Clinical Spectrum.

Signal transduction through the RAF-MEK-ERK pathway, the first described mitogen-associated protein kinase (MAPK) cascade, mediates multiple cellular processes and participates in early and late developmental programs. Aberrant signaling through this cascade contributes to oncogenesis and underlies the RASopathies, a family of cancer-prone disorders. Here, we report that de novo missense variants in MAPK1, encoding the mitogen-activated protein kinase 1 (i.e., extracellular signal-regulated protein kinase 2, ERK2), cause a neurodevelopmental disease within the RASopathy phenotypic spectrum, reminiscent of Noonan syndrome in some subjects. Pathogenic variants promote increased phosphorylation of the kinase, which enhances translocation to the nucleus and boosts MAPK signaling in vitro and in vivo. Two variant classes are identified, one of which directly disrupts binding to MKP3, a dual-specificity protein phosphatase negatively regulating ERK function. Importantly, signal dysregulation driven by pathogenic MAPK1 variants is stimulus reliant and retains dependence on MEK activity. Our data support a model in which the identified pathogenic variants operate with counteracting effects on MAPK1 function by differentially impacting the ability of the kinase to interact with regulators and substrates, which likely explains the minor role of these variants as driver events contributing to oncogenesis. After nearly 20 years from the discovery of the first gene implicated in Noonan syndrome, PTPN11, the last tier of the MAPK cascade joins the group of genes mutated in RASopathies.

Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas / Noonan syndrome: genetic and clinical update and treatment options

El síndrome de Noonan (SN) es una enfermedad de origen genético relativamente frecuente cuyas manifestaciones fundamentales son la talla baja, la cardiopatía congénita y un fenotipo facial característico. La causa del síndrome de Noonan y de otras enfermedades clínicamente solapadas como el síndrome de Noonan con lentiginosis múltiple (anteriormente llamado síndrome LEOPARD), el cardiofaciocutáneo o el síndrome de Costello, son mutaciones en genes que codifican para proteínas de la vía de señalización de las RAS-MAPKinasas. Debido a este sustrato común este grupo de enfermedades son denominadas colectivamente «rasopatías». A pesar de los avances genéticos de las últimas décadas, cerca de 20% de pacientes no tienen causa genética identificada, y el diagnóstico sigue siendo clínico. El síndrome de Noonan se caracteriza por una alta heterogeneidad clínica y genética, con afectación variable, y cambiante con la edad, de múltiples órganos y sistemas. Debido a esta variabilidad es fundamental que los médicos involucrados en su cuidado estén familiarizados con sus manifestaciones y conozcan las recomendaciones de seguimiento, incluido el seguimiento del crecimiento y desarrollo. Hasta la fecha los escasos datos de crecimiento con GH a talla adulta dan resultados de ganancia de talla moderados, semejantes a los obtenidos en el síndrome de Turner. La hiperactivación de la vía RAS-MAPK como base común de esta familia de enfermedades brinda una oportunidad única para el desarrollo de tratamientos dirigidos a la etiología de estos trastornos

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies». Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches

[Noonan syndrome: genetic and clinical update and treatment options]. / Síndrome de Noonan: actualización genética, clínica y de opciones terapéuticas.

Noonan syndrome (NS) is a relatively common genetic condition characterised by short stature, congenital heart defects, and distinctive facial features. NS and other clinically overlapping conditions such as NS with multiple lentigines (formerly called LEOPARD syndrome), cardiofaciocutaneous syndrome, or Costello syndrome, are caused by mutations in genes encoding proteins of the RAS-MAPKinases pathway. Because of this shared mechanism, these conditions have been collectively termed «RASopathies¼. Despite the recent advances in molecular genetics, nearly 20% of patients still lack a genetic cause, and diagnosis is still made mainly on clinical grounds. NS is a clinically and genetically heterogeneous condition, with variable expressivity and a changing phenotype with age, and affects multiple organs and systems. Therefore, it is essential that physicians involved in the care of these patients are familiarised with their manifestations and the management recommendations, including management of growth and development. Data on growth hormone treatment efficacy are sparse, and show a modest response in height gains, similar to that observed in Turner syndrome. The role of RAS/MAPK hyper-activation in the pathophysiology of this group of disorders offers a unique opportunity for the development of targeted approaches.

Cardiac manifestations and gene mutations of patients with RASopathies in Taiwan.

RASopathies are developmental diseases caused by mutations in rat sarcoma-mitogen-activated protein kinase pathway genes. These disorders, such as Noonan syndrome (NS) and NS-related disorders (NSRD), including cardio-facio-cutaneous (CFC) syndrome, Costello syndrome (CS), and NS with multiple lentigines (NSML; also known as LEOPARD syndrome), have a similar systemic phenotype. A wide spectrum of congenital heart disease and hypertrophic cardiomyopathy (HCMP) can exhibit major associated characteristics. A retrospective study was conducted at the Mackay Memorial Hospital, National Taiwan University Hospital, Buddhist Tzu-Chi General Hospital, Chang-Gung Memorial Hospital, Taichung Veterans General Hospital, and Chung Shan Medical University Hospital from January 2007 to December 2018. We reviewed the clinical records of 76 patients with a confirmed molecular diagnosis of RASopathies, including NS, CS, CFC syndrome, and NSML. We evaluated the demographic data and medical records with clinical phenotypes of cardiac structural anomalies using cross-sectional and color Doppler echocardiography, electrocardiographic findings, and follow-up data. A total of 47 (61.8%) patients had cardiac abnormalities. The prevalence of cardiac lesions according to each syndrome was 62.7, 50.0, 60.0, and 66.7% in patients with NS, CFC syndrome, CS, and NSML, respectively. An atrial septal defect was usually combined with other cardiac abnormalities, such as pulmonary stenosis (PS), HCMP, ventricular septal defect, or patent ductus arteriosus. Patients with NS most commonly showed PS. In patients with NSRD and cardiac abnormalities, HCMP (29.4%) was the most commonly observed cardiac lesion. PTPN11 was also the most frequently detected mutation in patients with NS and NSRD. Cardiac abnormalities were the most common symptoms observed in patients with RASopathies at the time of their first hospital visit. Performing precise analyses of genotype-cardiac phenotype correlations in a larger cohort will help us accurately diagnose RASopathy as soon as possible.

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.

Genotype-phenotype correlation analysis in Japanese patients with Noonan syndrome.

Noonan syndrome (NS) is a heterogeneous disorder with multiple congenital malformations. Recent advances in molecular and genetic approaches have identified a number of responsible genes for NS, most of which are components of the RAS/MAPK signaling pathway, and genotype-phenotype correlation analyses have been extensively performed; however, analysis of Japanese NS patients is limited. Here, we evaluated clinical characteristics in genetically diagnosed NS patients and their relationships to genotypes. A total of 48 clinically diagnosed NS were included, and responsible mutations were identified in 39 patients (81.3%) with PTPN11 mutations being the most prevalent followed by SOS1 mutations. Cardiac anomalies including pulmonary stenosis and hypertrophic cardiomyopathy were most prevalent (87.2%), and the prevalence of hypertrophic cardiomyopathy was greater in patients without PTPN11 mutations than in those with PTPN11 mutations. Short stature was the second-most prevalent (69.2%) characteristic, and present height SD score was significantly associated with height SD score at 1 year old. Patients with SOS1 mutations had greater present height SD score and better growth during infancy. These findings suggest the presence of a genotype-phenotype correlation in Japanese patients with NS, which enables us to use genetic information to predict the clinical course and may allow for genotype-based medical interventions.

Increasing evidence of hereditary lymphedema caused by CELSR1 loss-of-function variants.

A whole exome sequencing approach was recently used to detect a CELSR1 truncating variant associated with lymphedema in a large pedigree. Since this first report, no other similar associations have been reported in the literature. Here, we present the genetic results of 95 probands tested using a next generation sequencing panel that covered all known lymphedema-associated genes, including CELSR1. Five out of 95 probands (5.3%) were found to carry novel loss-of-function variants in CELSR1. Family segregation studies were possible in four out of five probands and showed possible sex-specific differences: CELSR1 variants showed almost complete penetrance in females and were associated with early-onset lymphedema, whereas in males they showed incomplete penetrance and were associated with late onset of the condition. Since the percentage of lymphedema patients carrying CELSR1 variants is not negligible, we do not hesitate to recommend including this gene in routine genetic testing.

Impact of Growth Hormone Therapy on Adult Height in Patients with PTPN11 Mutations Related to Noonan Syndrome.

OBJECTIVES: The aim of this study was to evaluate the response to recombinant human growth hormone (rhGH) treatment in patients with Noonan syndrome (NS). MATERIALS AND METHODS: Forty-two patients (35 PTPN11+) were treated with rhGH, and 17 were followed-up until adult height. The outcomes were changes in growth velocity (GV) and height standard deviation scores (SDS) for normal (height-CDC SDS) and Noonan standards (height-NS SDS). RESULTS: The pretreatment chronological age was 10.3 ± 3.5 years. Height-CDC SDS and height-NS SDS were -3.1 ± 0.7 and -0.5 ± 0.6, respectively. PTPN11+ patients had a better growth response than PTPN11- patients. GV SDS increased from -1.2 ± 1.8 to 3.1 ± 2.8 after the first year of therapy in PTPN11+ patients, and from -1.9 ± 2.6 to -0.1 ± 2.6 in PTPN11- patients. The gain in height-CDC SDS during the first year was higher in PTPN11+ than PTPN11- (0.6 ± 0.4 vs. 0.1 ± 0.2, p = 0.008). Similarly, the gain was observed in height-NS SDS (0.6 ± 0.3 vs. 0.2 ± 0.2, respectively, p < 0.001). Among the patients that reached adult height (n = 17), AH-CDC SDS and AH-NS SDS were -2.1 ± 0.7 and 0.7 ± 0.8, respectively. The total increase in height SDS was 1.3 ± 0.7 and 1.5 ± 0.6 for normal and NS standards, respectively. CONCLUSIONS: This study supports the advantage of rhGH therapy on adult height in PTPN11+ patients. In comparison, PTPN11- patients showed a poor response to rhGH. However, this PTPN11- group was small, preventing an adequate comparison among different genotypes and no guarantee of response to therapy in genes besides PTPN11.

Treatment with Growth Hormone in Noonan Syndrome Observed during 25 Years of KIGS: Near Adult Height and Outcome Prediction.

BACKGROUND/AIMS: There is little information how rhGH treatment affects height in NS. This study aims to analyze data from the NS patients assembled in KIGS over 25 years. PATIENTS/METHODS: Of 613 (389 m/224 f) NS patients documented, 476 (302 m/174 f) were treated for 1 year, 237 (160 m/77 f) of which served to develop a 1st year height velocity (HV) prediction algorithm. One-hundred and forty (74 m/66 f) had reached near adult height (NAH). Factors affecting NAH on rhGH were determined. RESULTS: At the start of rhGH, the NAH groups were (median, m, f) 11.0 and 10.3 years, with a height SDS of -3.2 and -3.8 SDS (Prader), respectively. The total gain after 6.3 and 5.6 years on rhGH (0.27 and 0.30 mg/kg/week) was 1.2 and 1.3 SDS. Age at the start of rhGH (negative), height at the start of rhGH, rhGH dose, number of rhGH injections/wk and birth weight (all positive) explained 36% of the variability of 1st year HV. Height at the start of rhGH, 1st year growth on rhGH, birth weight, and gender explained 74% of the variability of NAH. Causes for rhGH treatment discontinuation and adverse events were also analyzed. CONCLUSION: rhGH treatment increases NAH in NS. Prediction algorithms may optimize treatment in the future.

A severe clinical phenotype of Noonan syndrome with neonatal hypertrophic cardiomyopathy in the second case worldwide with RAF1 S259Y neomutation.

Noonan syndrome and related disorders are a group of clinically and genetically heterogeneous conditions caused by mutations in genes of the RAS/MAPK pathway. Noonan syndrome causes multiple congenital anomalies, which are frequently accompanied by hypertrophic cardiomyopathy (HCM). We report here a Tunisian patient with a severe phenotype of Noonan syndrome including neonatal HCM, facial dysmorphism, severe failure to thrive, cutaneous abnormalities, pectus excavatum and severe stunted growth, who died in her eighth month of life. Using whole exome sequencing, we identified a de novo mutation in exon 7 of the RAF1 gene: c.776C > A (p.Ser259Tyr). This mutation affects a highly conserved serine residue, a main mediator of Raf-1 inhibition via phosphorylation. To our knowledge the c.776C > A mutation has been previously reported in only one case with prenatally diagnosed Noonan syndrome. Our study further supports the striking correlation of RAF1 mutations with HCM and highlights the clinical severity of Noonan syndrome associated with a RAF1 p.Ser259Tyr mutation.

Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.

Noonan syndrome (NS) is characterised by distinctive facial features, heart defects, variable degrees of intellectual disability and other phenotypic manifestations. Although the mode of inheritance is typically dominant, recent studies indicate LZTR1 may be associated with both dominant and recessive forms. Seeking to describe the phenotypic characteristics of LZTR1-associated NS, we searched for likely pathogenic variants using two approaches. First, scrutiny of exomes from 9624 patients recruited by the Deciphering Developmental Disorders (DDDs) study uncovered six dominantly-acting mutations (p.R97L; p.Y136C; p.Y136H, p.N145I, p.S244C; p.G248R) of which five arose de novo, and three patients with compound-heterozygous variants (p.R210*/p.V579M; p.R210*/p.D531N; c.1149+1G>T/p.R688C). One patient also had biallelic loss-of-function mutations in NEB, consistent with a composite phenotype. After removing this complex case, analysis of human phenotype ontology terms indicated significant phenotypic similarities (P = 0.0005), supporting a causal role for LZTR1. Second, targeted sequencing of eight unsolved NS-like cases identified biallelic LZTR1 variants in three further subjects (p.W469*/p.Y749C, p.W437*/c.-38T>A and p.A461D/p.I462T). Our study strengthens the association of LZTR1 with NS, with de novo mutations clustering around the KT1-4 domains. Although LZTR1 variants explain ~0.1% of cases across the DDD cohort, the gene is a relatively common cause of unsolved NS cases where recessive inheritance is suspected.

M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration.

Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell-cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-RasS27N variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells exhibiting increased junction turnover and reduced E-cadherin/p120-catenin binding and migrating as a faster but less cohesive group. Consistent with these results, Noonan-associated C-Raf mutants that bypass the need for M-Ras/Shoc2 signaling exhibited a similar GOF phenotype when expressed in Shoc2-depleted MCF10A cells. Finally, expression of the Noonan-associated Myr-Shoc2 or C-Raf mutants, but not their WT counterparts, induced gastrulation defects indicative of aberrant cell migration in zebrafish embryos, further demonstrating the function of the M-Ras/Shoc2/ERK cascade signaling axis in the dynamic control of coordinated cell movement.

Hypercalcemia of Malignancy in a Patient with Hypoparathyroidism: A Complicated but Treatable Condition.

Hypercalcemia in hypoparathyroidism has rarely been described. A 55 year-old male patient with primary hypoparathyroidism, left eye melanoma, and Noonan's syndrome, was referred to the endocrinology clinics due to hypoparathyroidism. Laboratories showed serum calcium of 7.8 mg/d, and phosphate 4.8 mg/dl, while using calcium carbonate 1200 mg and vitamin D3 600 IU daily. Calcitriol 0.25 mcg daily was started and calcium carbonate discontinued. Abdominopelvic CT scan and thoracolumbar MRI, showed metastasis to liver, pancreas, and osteolytic lesions in spine, humerus, and ribs. Liver biopsy confirmed metastatic melanoma. Eight weeks later, serum calcium increased to 12 mg/dl. PTH, vitamin D 1,25-OH and PTHrP levels were within the lower range of normal compatible with hypercalcemia of malignancy, secondary to osteolytic disease. Zoledronic acid was added to treat hypercalcemia and bone pain. Our case demonstrates a successful treatment and monitoring of hypocalcemia after administration of bisphosphonate in a patient with hypoparathyroidism.

Early Outcomes of Cardiac Surgery in Patients with Noonan Syndrome.

There is a paucity of cardiac surgery outcomes data for patients with Noonan syndrome (NS). Our objective was to evaluate early results in these patients. Between January 1999 and December 2015, 29 patients (18 males, 62%) with NS underwent cardiac surgery at our institution. Mean age was 23 ± 17.9 years; 12 (41%) were under 18 years of age. Fourteen patients (48%) had prior sternotomies. The primary operations for the main diagnosis were pulmonary valve/conduit replacement/repair (n = 14, 48%), septal myectomy for obstructive hypertrophic cardiomyopathy (n = 7, 24%), aortic valve replacement/repair (n = 4, 14%), atrial septal defect (ASD) repair (n = 2, 7%), and cardiac transplantation (n = 2, 7%). Concomitant procedures were performed in 24 patients (83%), most commonly right ventricular outflow tract reconstruction (n = 13, 45%), mitral valve repair/replacement (n = 7, 24%), and ASD repair (n = 6, 21%). Mean bypass and cross-clamp times were 88.8 ± 51 minutes and 54.7 ± 67 minutes, respectively. There was 1 early death (3%). Postoperative morbidity occurred in 18 patients (62%), most commonly arrhythmias (n = 14, 48%) or respiratory insufficiency/pneumonia (n = 6, 21%). There were 2 early reoperations and 4 early readmissions. Univariate factors associated with morbidity included male gender (P = 0.03) and longer cross-clamp time (P = 0.02). Median length of hospital stay was 6 days (interquartile range 5-10.5 days). Patients with NS frequently have multiple cardiac lesions requiring a broad spectrum of operations. Early mortality is low despite procedure complexity. Although early postoperative morbidity is common, patients overall do well with reasonable hospital lengths of stay. Additional studies are needed to evaluate long-term outcomes and quality of life.

PTPN11 Gain-of-Function Mutations Affect the Developing Human Brain, Memory, and Attention.

The Ras-MAPK pathway has an established role in neural development and synaptic signaling. Mutations in this pathway are associated with a collection of neurodevelopmental syndromes, Rasopathies; among these, Noonan syndrome (NS) is the most common (1:2000). Prior research has focused on identifying genetic mutations and cellular mechanisms of the disorder, however, effects of NS on the human brain remain unknown. Here, imaging and cognitive data were collected from 12 children with PTPN11-related NS, ages 4.0-11.0 years (8.98 ± 2.33) and 12 age- and sex-matched typically developing controls (8.79 ± 2.17). We observe reduced gray matter volume in bilateral corpus striatum (Cohen's d = -1.0:-1.3), reduced surface area in temporal regions (d = -1.8:-2.2), increased cortical thickness in frontal regions (d = 1.2-1.3), and reduced cortical thickness in limbic regions (d = -1.6), including limbic structures integral to the circuitry of the hippocampus. Further, we find high levels of inattention, hyperactivity, and memory deficits in children with NS. Taken together, these results identify effects of NS on specific brain regions associated with ADHD and learning in children. While our research lays the groundwork for elucidating the neural and behavioral mechanisms of NS, it also adds an essential tier to understanding the Ras-MAPK pathway's role in human brain development.

Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions.

PURPOSE: To compare the pattern of gene-specific involvement and the spectrum of variants observed in prenatal and postnatal (mean ± SD, 8.9 ± 9.4 years) cohorts tested for Noonan syndrome and related conditions. METHODS: Outcomes of sequencing panel testing were compared between prenatal (n = 845) and postnatal (n = 409) cohorts. RESULTS: PTPN11 and SOS1 harbored the majority of observed variants in both prenatal and postnatal cohorts, and BRAF, HRAS, KRAS, MAP2K1, MAP2K2, RAF1, and SHOC2 had similarities in their pattern of involvement in both cohorts. PTPN11 was the largest contributor of pathogenic variants and had the lowest frequency of variants of uncertain significance (VUS). SOS1 had the highest VUS frequency in both cohorts. The overall VUS frequency was twice as high in prenatal specimens (58.1 vs. 29.3%). PTPN11 and SOS1 had a 1.5-fold higher VUS frequency in the prenatal cohort (10.7 vs. 7.4% and 95 vs. 61.1%, respectively). The diagnostic yield was 3.7% for prenatal samples, with a higher yield of 12.3% in fetuses with cystic hygroma as a sole finding, and 21.3% for postnatal. CONCLUSION: Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably.