Correlation between genetic heterogeneity and variability for response to growth hormone in Noonan syndrome

Shin, Young-Lim

doi:10.3345/kjp.2019.00220

Cited by 1 publication

(5 citation statements)

References 13 publications

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“…Up to 70% of NS subjects present with postnatal short stature ( 17 , 37 ), even though the majority has a normal birth weight and length ( 20 ); the presence of edema may result in an overestimation of weight which should be carefully evaluated ( 20 ). Some authors have reported a significantly higher frequency of NS subjects who are small for gestational age (SGA) compared with the general population (24%), particularly for length ( 24 ), and in specific genotypes ( 24 , 38 ).…”

Section: Growth and Growth Hormone-igf-1 Axis In Noonan Syndromementioning

confidence: 99%

“…As NS is a condition characterized by clinical variability and genetic heterogeneity, different mechanisms implicated with altered GH secretory dynamics or response have been reported, including GHD, neurosecretory dysfunction, and GH insensitivity (GHI) ( 17 , 21 ). Decreases in IGF-I and IGF-binding protein 3, together with low responses to provocation tests, suggest impaired GH release, or disturbance of the GH/IGF-I axis, at least in a proportion of affected individuals ( 21 ).…”

Section: Growth and Growth Hormone-igf-1 Axis In Noonan Syndromementioning

confidence: 99%

“…From an auxological point of view, NS is one of the most prevalent non-chromosomal disorders affecting development and growth ( 17 , 18 ). In affected subjects, birth weight and length are generally normal, although postnatal growth failure is observed ( 19 , 20 ).…”

Section: Introductionmentioning

confidence: 99%

“…After 2007, when the Food and Drug Administration (FDA) approved recombinant human GH (rhGH) treatment for short stature in NS, the treatment was subsequently approved in Brazil, Israel, Japan, South Korea, Switzerland and some European countries ( 8 , 17 ). For this reason, many studies conducted in the past evaluating the response and safety of rhGH treatment in NS patients were performed in subjects with concomitant GH deficiency (GHD) who were therefore treated with standard doses for this diagnosis.…”

Section: Introductionmentioning

confidence: 99%

“…To date, most studies on rhGH treatment for NS have been retrospective and observational, involving small numbers of patients, with variable ages at the start of treatment and treated with different doses. Unfortunately, molecular characterization is available for only a small number of these cohorts ( 8 , 17 ).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

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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