Etiology and Treatment of Growth Delay in Noonan Syndrome

Rodrı́guez, Fernando; Gaete, Ximena; Cassorla, Fernando

doi:10.3389/fendo.2021.691240

Cited by 17 publications

(10 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…While there is ample evidence that GH treatment leads to accelerated growth in NS, irrespective of the presence of GH deficiency, the long-term benefit on adult height is still unclear. 21 More generally, early diagnosis of NS should lead to evaluation of the coagulation system to avoid bleeding complications during surgery, and an early genetic diagnosis would help distinguish NS from other RASopathy conditions with a separate risk profile, and avoid unnecessary examinations (eg, imaging, metabolic assessments). It can be speculated that, in future, a prospective observational study of the natural history of the syndrome in patients diagnosed young would help to clarify the natural history of facets of the syndrome, such as heart disease, and the severity of the bleeding disorders.…”

Section: Introductionmentioning

confidence: 99%

Noonan syndrome: improving recognition and diagnosis

et al. 2022

View full text Add to dashboard Cite

Noonan syndrome (NS) is a mostly dominantly inherited disorder affecting 1:1000 to 1:2500 live births. The phenotype varies in severity and can involve multiple organ systems over a patient’s lifetime. Diagnosis is based on a combination of features, including typical facial features, short stature, skeletal abnormalities, presence of cardiac defects, mild developmental delay, cryptorchidism, lymphatic dysplasia and a family history of NS. The phenotype varies from oligosymptomatic adults without significant medical issues to severely affected neonates with life-threatening heart disease. Early, accurate diagnosis is important for individualised management and to optimise developmental and long-term outcomes, but mildly affected patients often go undiagnosed for both healthcare provider (HCP)-related and patient-related reasons. Lack of awareness of NS among HCPs means that some do not recognise the condition, particularly in mildly affected patients and families. Some families do not want to receive a diagnosis that medicalises a condition that may account for family traits (eg, distinctive facial features and short stature), particularly when a child’s physical and cognitive development may be satisfactory. As for any condition with lifelong effects on multiple organ systems, a multidisciplinary approach provides the best care. It is proposed that increasing awareness of NS among non-specialist HCPs and other professionals could help direct a parent/carer to seek specialist advice and increase the number of NS diagnoses, with the potential to optimise lifelong patient outcomes. Non-specialists do not need to become experts in either diagnosis or treatment; however, early recognition of NS and referral to an appropriate specialist is important.

show abstract

Section: Introductionmentioning

confidence: 99%

Noonan syndrome: improving recognition and diagnosis

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Longitudinal growth and somatic maturation are mainly regulated by IGF1 binding to IGF1R and the subsequent IGF1R activation of main intracellular signaling pathways in target tissues [29,35,36,37]. To determine sex differences in putative IGF1 signaling pathway dysregulation in response to Pappa2 de ciency, we analyzed key intracellular pathways, including PI3K, AKT, AMPKα, ERK1/2, mTOR and GSK3β, among others, in the hypothalamus-pituitary-liver axis of Pappa2 ko/ko male and female mice.…”

Section: Discussionmentioning

confidence: 99%

Sex-based differences in IGF1 signaling pathways in response to PAPP-A2 deficiency

Navarro

López-Gambero

Fernández‐Arjona

et al. 2023

Preprint

View full text Add to dashboard Cite

Background. Patients with pregnancy-associated plasma protein-A2 (PAPP-A2) mutations have progressive postnatal growth retardation and high circulating levels of IGF1 bound in ternary complexes. The present study aims to assess whether Pappa2 deficiency is associated with sex-specific differences in the main components of IGF1 ternary complexes and IGF1 signaling pathways in response to low IGF1 bioavailability. Methods. Plasma, hypothalamus, pituitary gland and liver were analyzed in constitutive Pappa2ko/ko mice of both sexes that have reduced skeletal growth and impaired bone composition. Results. The reduction in body and femur length of Pappa2ko/ko mice was associated with increases in total IGF1 and IGFBP5 concentrations in plasma of females, Igfbp5 mRNA levels in the hypothalamus of males, and Igf1, Igfbp3 and Igfals mRNA levels in the liver of females, suggesting sex- and tissue-specific effects of Pappa2 deficiency on IGF ternary/binary complexes. Pappa2 deficiency was also accompanied by increased pituitary GH concentrations in both sexes. Sex-specific dysregulation of IGF1 signaling pathways was found in Pappa2ko/ko mice with higher phosphorylated forms of AKT, mTOR, GSK3β and ERK1/2 in the female hypothalamus, GSK3β in the male pituitary gland, and PI3K and AMPKα in the female liver, suggesting sex-based alterations in regulators of cell proliferation/growth and protein/glucose metabolism. Conclusions. These data suggest that sex-specific differences in IGF ternary complexes and IGF1 signaling pathways are associated with Pappa2 deficiency, pointing to molecular mechanisms that may participate in the physiopathology of postnatal growth retardation in a sex-dependent manner.

show abstract

“…MAPK activation is important in regulating the proliferation of pituitary somatotrophs and, therefore, proper GH secretion (46). The partial GH insensitivity in RASopathies has also been postulated, implying that the response to rGH in MAP2K1 deficiency-related CFCS may not be entirely satisfactory (42,43,47). In the presented patient, the GH secretion was just below the cut-off value and was accompanied by a very low IGF-1 and IGF-binding protein 3 (IGFBP-3) that might suggest a coexisting GH insensitivity.…”

Section: Discussionmentioning

confidence: 99%

Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature

et al. 2022

View full text Add to dashboard Cite

Cardio-facio-cutaneous syndrome (CFCS) belongs to the group of RASopathies, clinical disorders defined by disruptions in the RAS/MAPK signaling pathway. It is caused by heterozygous gain-of-function germline mutations in genes encoding protein kinases: BRAF, MAP2K1 (MEK1), MAP2K2 (MEK2), and in the GTPase-encoding gene KRAS. CFCS is characterized by craniofacial dysmorphic features, congenital heart defects, severe malnutrition, proportionate short stature, anomalies within the structure of skin and hair, and psychomotor disability. The pathophysiology of growth impairment is multifactorial with feeding difficulties, growth hormone deficiency, and insensitivity. Immunodeficiency has not been hitherto reported as an integral part of CFCS yet an increased activation of the RAS/MAPK signaling pathway may contribute to explaining the causal relationship between RASopathy and the dysfunctions within the B and T lymph cell compartments resulting in a deficiency in T cell costimulation and B cell maturation with impaired class switch recombination, somatic hypermutation, and high-affinity antibody production. We report on a boy born prematurely at 32 WGA, with the perinatal period complicated by pneumonia, respiratory distress syndrome, and valvular pulmonary stenosis. The boy suffered from recurrent pneumonia, obstructive bronchitis, sepsis, urinary tract infection, and recurrent fevers. He presented with severe hypotrophy, psychomotor disability, short stature, craniofacial dysmorphism, dental hypoplasia, sparse hair, and cryptorchidism. Whole genome sequencing showed a novel heterozygous pathogenic germline missense variant: c.364A > G; p.Asn122Asp in the MAP2K1 gene, supporting the diagnosis of CFCS. The immunological workup revealed hypogammaglobulinemia, IgG subclass, and specific antibody deficiency accompanied by decreased numbers of T helper cells and naive and memory B cells. Replacement immunoglobulin therapy with timely antibiotic prophylaxis were instituted. At the age of six years, growth hormone deficiency was diagnosed and the rGH therapy was started. The ever-increasing progress in genetic studies contributes to establishing the definitive CFCS diagnosis and sheds the light on the interrelated genotype-phenotype heterogeneity of RASopathies. Herein, we add new phenotypic features of predominating humoral immunodeficiency to the symptomatology of CFCS with a novel mutation in MAP2K1. While CFCS is a multifaceted disease, increased pediatricians’ awareness is needed to prevent the delay in diagnostics and therapeutic interventions.

show abstract

Etiology and Treatment of Growth Delay in Noonan Syndrome

Cited by 17 publications

References 70 publications

Noonan syndrome: improving recognition and diagnosis

Noonan syndrome: improving recognition and diagnosis

Sex-based differences in IGF1 signaling pathways in response to PAPP-A2 deficiency

Case report: The cardio-facio-cutaneous syndrome due to a novel germline mutation in MAP2K1: A multifaceted disease with immunodeficiency and short stature

Contact Info

Product

Resources

About