Noonan syndrome: genetic and clinical update and treatment options

Carcavilla, Atilano; Suarez-Ortega, Larisa; Sánchez, Amparo Rodríguez; González‐Casado, Isabel; Ramón-Krauel, Marta; Labarta, José Ignacio; González, Sofı́a Quinteiro; Galán, Isolina Riaño; López-Siguero, Juan Pedro

doi:10.1016/j.anpede.2020.04.009

Cited by 16 publications

(37 citation statements)

References 36 publications

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“…1 The prevalence of cardiovascular involvement is estimated to be between 70% and 90%. [1][2][3] Pulmonary valve stenosis (PS) is the most common cardiac lesion in NS affecting approximately 57%-65% of patients. 1,4 The majority of cases with NS and PS are mild (60%).…”

Section: Introductionmentioning

confidence: 99%

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Supravalvular pulmonary stenosis: A risk factor for reintervention in Noonan syndrome with pulmonary valve stenosis

Abumehdi

Mehta

Afifi

et al. 2022

Cathet Cardio Intervent

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Objectives: To assess the short-and long-term outcomes of balloon pulmonary valvuloplasty (BPV) in children with Noonan syndrome (NS).Background: Pulmonary stenosis (PS) is the most common congenital heart lesion in NS. BPV is the accepted first line treatment in PS. However, BPV in NS patients has been reported to be less effective, without specific factors for the need for reintervention being identified.Methods: Retrospective case-note review of all patients with NS who underwent BPV between 1985 and 2020. Patients were divided into 2 groups: those with supravalvular pulmonary stenosis (SPS) in addition to valvar PS, and those with isolated valvar PS.Results: A cohort of 54 patients with NS underwent BPV at a median of 275 (interquartile range [IQR]: 108-575) days of age. SPS was present in 32 (59%) patients whereas 22 had (41) isolated PS. The preprocedural invasive gradient was 47 (IQR: 35-69) mmHg, and 44 (IQR: 35-48) mmHg in those with SPS and those without respectively (p = 0.88). Reintervention was required in 22 patients (41%): 17 (77%) with SPS and 5 (23%) without (p = 0.017). Fourteen patients (11 with SPS) required surgical reintervention and 8 (6 with SPS) required further BPV. There was no significant difference in the age at initial BPV, pre-and postprocedural gradients and interval until reintervention between groups.Conclusion: This is the largest reported cohort of patients with NS undergoing BPV.Although BPV is often successful, the reintervention rates are high. SPS was a risk factor for reintervention.

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Section: Introductionmentioning

confidence: 99%

“…Noonan syndrome (NS) is a relatively common autosomal dominant condition affecting 1 in every 1000–2500 live births 1 . The prevalence of cardiovascular involvement is estimated to be between 70% and 90% 1–3 . Pulmonary valve stenosis (PS) is the most common cardiac lesion in NS affecting approximately 57%–65% of patients 1,4 .…”

Section: Introductionmentioning

confidence: 99%

Supravalvular pulmonary stenosis: A risk factor for reintervention in Noonan syndrome with pulmonary valve stenosis

Abumehdi

Mehta

Afifi

et al. 2022

Cathet Cardio Intervent

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“…Among these, NS with multiple lentigines (NSML, previously known as LEOPARD syndrome; OMIM 151100), Mazzanti syndrome (also known as NS-like disorder with loose anagen hair) (NS-LAH; OMIM 607721 and 617506), Legius syndrome (LGSS; OMIM 611431), and a phenotype originally denominated neurofibromatosis-NS (OMIM 601321), a condition representing a distinct form of neurofibromatosis 1 (NF1, OMIM 162200) are the most closely related conditions. There are also significant clinical overlaps with cardiofaciocutaneous syndrome (CFCS; OMIM 115150), and Costello syndrome (CS; OMIM 218040) (8)(9)(10), and other recently recognized diseases (11,12). Unsurprisingly, the molecular mechanisms underlying the pathogenesis of these disorders are closely related.…”

Section: Introductionmentioning

confidence: 99%

Inside the Noonan “universe”: Literature review on growth, GH/IGF axis and rhGH treatment: Facts and concerns

Stagi

Ferrari

et al. 2022

Front. Endocrinol.

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Noonan syndrome (NS) is a disorder characterized by a typical facial gestalt, congenital heart defects, variable cognitive deficits, skeletal defects, and short stature. NS is caused by germline pathogenic variants in genes coding proteins with a role in the RAS/mitogen-activated protein kinase signaling pathway, and it is typically associated with substantial genetic and clinical complexity and variability. Short stature is a cardinal feature in NS, with evidence indicating that growth hormone (GH) deficiency, partial GH insensitivity, and altered response to insulin-like growth factor I (IGF-1) are contributing events for growth failure in these patients. Decreased IGF-I, together with low/normal responses to GH pharmacological provocation tests, indicating a variable presence of GH deficiency/resistance, in particular in subjects with pathogenic PTPN11 variants, are frequently reported. Nonetheless, short- and long-term studies have demonstrated a consistent and significant increase in height velocity (HV) in NS children and adolescents treated with recombinant human GH (rhGH). While the overall experience with rhGH treatment in NS patients with short stature is reassuring, it is difficult to systematically compare published data due to heterogeneous protocols, potential enrolment bias, the small size of cohorts in many studies, different cohort selection criteria and varying durations of therapy. Furthermore, in most studies, the genetic information is lacking. NS is associated with a higher risk of benign and malignant proliferative disorders and hypertrophic cardiomyopathy, and rhGH treatment may further increase risk in these patients, especially as dosages vary widely. Herein we provide an updated review of aspects related to growth, altered function of the GH/IGF axis and cell response to GH/IGF stimulation, rhGH treatment and its possible adverse events. Given the clinical variability and genetic heterogeneity of NS, treatment with rhGH should be personalized and a conservative approach with judicious surveillance is recommended. Depending on the genotype, an individualized follow-up and close monitoring during rhGH treatments, also focusing on screening for neoplasms, should be considered.

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“…Mutations most commonly occur in the PTPN11 gene, accounting for approximately 50-60% of mutations identified in NS patients (2,6). However, in around 20-30% of cases, the underlying mutation has not yet been identified (6,7), although this proportion can depend upon the stringency of the criteria for clinical diagnosis (2).…”

Section: Introductionmentioning

confidence: 99%

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status

Jorge

Edouard

Maghnie

et al. 2022

Endocrine Connections

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Introduction: Mutations in PTPN11 are associated with Noonan syndrome (NS). Although the effectiveness of growth hormone therapy (GHT) in treating short stature due to NS has been previously demonstrated, the effect of PTPN11 mutation status on the long-term outcomes of GHT remains to be elucidated. Methods: This analysis included pooled data from the observational American Norditropin Studies: Web-Enabled Research Program (NCT01009905) and the randomized, double-blind GHLIQUID-4020 clinical trial (NCT01927861). Pediatric patients with clinically diagnosed NS and confirmed PTPN11 mutation status were eligible for inclusion. The effectiveness analysis included patients who were GHT-naïve and pre-pubertal at GHT start. Growth outcomes and safety were assessed over 4 years of GHT (Norditropin®, Novo Nordisk A/S). Results: A total of 69 patients were included in the effectiveness analysis (71% PTPN11 positive). The proportion of females was 32.7% and 30.0% in PTPN11-positive and negative patients, respectively, and mean age at GHT start was 6.4 years in both groups. Using general population reference data, after 4 years of GHT, the mean (standard deviation [SD]) height SD score (HSDS) was −1.9 (1.1) and −1.7 (0.8) for PTPN11-positive and PTPN11-negative patients, respectively, with no statistical difference observed between groups. The mean (SD) change in HSDS at 4 years was +1.3 (0.8) in PTPN11-positive patients and +1.5 (0.7) in PTPN11-negative patients (no significant differences between groups). Safety findings were consistent with previous analyses. Conclusions: GHT resulted in improved growth outcomes over 4 years in GHT-naïve, pre-pubertal NS patients, irrespective of PTPN11 mutation status.

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Noonan syndrome: genetic and clinical update and treatment options

Cited by 16 publications

References 36 publications

Supravalvular pulmonary stenosis: A risk factor for reintervention in Noonan syndrome with pulmonary valve stenosis

Supravalvular pulmonary stenosis: A risk factor for reintervention in Noonan syndrome with pulmonary valve stenosis

Inside the Noonan “universe”: Literature review on growth, GH/IGF axis and rhGH treatment: Facts and concerns

Outcomes in growth hormone-treated Noonan syndrome children: impact of PTPN11 mutation status

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