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Vol. 16 Supplement 2

May 2019


The History of Noonan Syndrome

Bradley S. Miller, MD, PhD



Early in her career, Jacqueline Noonan, a pediatric cardiologist, recognized that a number of children with valvular pulmonary stenosis had similar facial features. Dr. Noonan reported the clinical characteristics of this condition including short stature, hypertelorism, ptosis, mild mental retardation, undescended testes, and skeletal malformations. Further characterization of Noonan Syndrome led to the development of clinical criteria for the diagnosis of the condition. Identification of the first genetic cause of Noonan Syndrome, mutation of ptpn11 was reported in 2001. Multiple subsequent genes have been identified as causes of Noonan Syndrome and the related Rasopathies.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):424-427

doi: 10.17458/per.vol16.2019.m.historynoonan


Clinical Manifestations of Noonan Syndrome and Related Disorders 

Margo Sheck Breilyn, MD, Lakshmi Mehta, MD, FACMG



Noonan syndrome represents a heterogeneous group of genetic disorders caused by mutations in genes of the RAS/MAPK pathway. Related syndromes include cardiofaciocutaneous syndrome, Noonan syndrome with multiple lentigines and Costello syndrome. The common phenotypic features of Noonan syndrome include facial dysmorphisms, short stature, congenital heart defects and genitourinary abnormalities. These and other findings as well as features of related disorders are discussed. In addition we briefly review clinical diagnosis and prenatal findings of these syndromes and genetic counseling implications.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):428-434

doi: 10.17458/

Molecular Genetics of Noonan Syndrome and RASopathies

Jun Liao, PhD, FACMG, Lakshmi Mehta, MD, FACMG



The RAS/MAPK signaling pathway plays an essential role in development and tumorigenesis by regulating cell proliferation, differentiation, apoptosis, migration, and metabolism. Therefore, it is not surprising that germline mutations in genes encoding components or regulators of this signaling pathway cause numerous human genetic conditions, including Noonan syndrome and related disorders. The term “RASopathies” has been used to describe these disorders collectively due to their common underlying RAS/MAPK pathway dysregulation and overlapping clinical features. Taken together, the RASopathies represent one of the most common groups of genetic disorders, affecting approximately 1 in 1,000 individuals. This review describes the RAS/MAPK signaling pathway, summarizes multiple molecular genetic approaches used during the last several decades to discover genes responsible for different RASopathies, and finally focuses on several major disease genes associated with Noonan syndrome and related disorders with regard to genomic locations, structure, mutations, and genotypephenotype correlations.

Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):435-446

doi: 10.17458/per.vol16.2019.lm.molecularnoonan


Pathogenesis of Growth Failure in Rasopathies

Sommayya Aftab, MBBS MRCPCH FCPS (Paediatrics), Mehul T Dattani, MD, FRCP, FRCPCH



The RASopathies are a group of developmental genetic syndromes that are caused by germline mutations in genes encoding proteins of the Ras-Mitogen-Activated Protein kinase (RAS-MAPK) pathway. RASopathies include Noonan Syndrome (NS), Neurofibromatosis Type 1 (NF1), Noonan syndrome with multiple lentigines (NSML/LEOPARD), Costello syndrome (CS), Cardio-facio-cutaneous syndrome (CFC), capillary malformation-arteriovenous malformation syndrome (CM-AVM) and Legius Syndrome. These syndromes have many overlapping features; however, the most persistent feature common to all is the postnatal growth failure. The mechanism of growth failure in Rasopathies is highly complex and there are many proposed hypotheses including partial growth hormone insensitivity, growth hormone deficiency, neurosecretory dysfunction of growth hormone secretion, delayed puberty, poor feeding and skeletal abnormalities. Amongst these causes, the most widely accepted is partial growth hormone insensitivity due to a post-receptor signaling defect. Growth hormone therapy seems to be effective in improving height velocity in these syndromes, although the long-term effects on final height remain unproven. However, it is important to consider the potential risk of tumors and cardiomyopathy before and during growth hormone therapy.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):447-458

doi: 10.17458/


Growth and Growth Hormone Treatment in Noonan Syndrome

Alicia A. Romano, MD



Short stature is a common characteristic of Noonan Syndrome (NS), a genetic condition caused by mutations affecting the RAS / mitogen-activated protein kinase (MAPK) cascade. Growth hormone (GH) has been used to normalize childhood growth and increase adult height in NS. GH is effective in increasing growth velocity, and significantly improves height SDS at adult height. Studies of GH treatment to adult height have shown height gains of 9.5-13.0 cm for males and 9.0 - 9.8 cm for females. Factors associated with improved height outcomes are earlier initiation of therapy, a greater height SDS at pubertal onset, and a longer duration of GH therapy. The safety data to date is reassuring and includes no evidence of adverse cardiac effects or increased occurrence of malignancies. Further studies will likely clarify the role of different RAS/MAPK pathway aberrations in growth and GH responsiveness. Continued surveillance is needed to assure the long term safety of GH therapy.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):459-464

doi: 10.17458/per.vol16.2019.r.growthhormonenoonan

Endocrine Complications of Noonan Syndrome beyond Short Stature

Vijay Venugopal, MD, Christopher J Romero, MD



Noonan syndrome (NS) is a diagnosis that is made clinically based on features including typical facies, congenital heart defects, short stature and developmental delay. Approximately 50% of the patients have identified mutations in the PTPN11 gene, and a smaller percentage of mutations have been reported in other genes such as SOS1, RAF1 and RIT1 Despite normal birth length, patients typically reach adult height below normal. Other than growth, endocrine complications of NS are not as commonly reported. These include possible pathology in thyroid function, pubertal development and bone metabolism. Some investigators have looked to see if genetic mutations in these patients could pose a risk for future endocrinopathies. This chapter reviews reports on endocrine dysfunction other than growth in patients with NS. The information is meant to enhance awareness in those providers who care for these patients to the possibility of other existing endocrinopathies. Most importantly, it supports and highlights the endocrinologist’s role in the care of patients with NS.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):465-470

doi: 10.17458/per.vol16.2019.vr.endocrinecomplicationsnoonan


Cardiac Manifestations of Noonan Syndrome

Ruchika Karnik, MBBS, Ira Parness, MD, Miwa Geiger, MD



Noonan syndrome (NS), a RASopathy, is commonly seen in association with cardiovascular abnormalities, with structural defects and/or cardiomyopathy present in 80-90-% of cases. Though a wide spectrum of cardiac pathology has been reported, pulmonary stenosis is the most common structural abnormality and more likely to be seen in PTPN11 mutations. Hypertrophic cardiomyopathy is the second most common and is more often associated with RAF1 mutations. Cardiac disease tends to be more progressive in infants and children with NS and therefore close cardiology follow-up is indicated. In general, the earlier the presentation, the more severe the phenotype and worse the long term prognosis. As genotype phenotype associations are being better understood, the mechanisms for development of cardiomyopathy are also becoming elucidated, raising the possibility of medical therapies targeted at the involved pathway.


Ref: Ped. Endocrinol. Rev. 2019;16(Suppl2):471-476

doi: 10.17458/per.vol16.2019.kpg.manifestationsnoonan


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