Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

Rohrer, Tilman; Abuzzahab, Jennifer; Backeljauw, Philippe; Birkegård, Anna Camilla; Blair, Joanne; Dahlgren, Jovanna; Júlíusson, Pétur Benedikt; Ostrow, Vlady; Pietropoli, Alberto; Polak, Michel; Romanò, Alicia; Ross, Judith L.; Sävendahl, Lars; Miller, Bradley S.

doi:10.1159/000512429

Cited by 19 publications

(31 citation statements)

References 60 publications

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“…This analysis assessed the impact of PTPN11 mutation status on long-term effectiveness outcomes in NS patients treated with rhGH. The effectiveness of GHT in treating short stature due to NS has been previously demonstrated (8,29,30,31,32,33,34). The impact of PTPN11 mutation status on long-term GHT response has previously been discussed, but additional studies are needed to further clarify the role of the different RAS/MAPK pathway aberrations in growth and in GH responsiveness.…”

Section: Discussionmentioning

confidence: 94%

“…HSDS (general population reference) was calculated using CDC national reference growth charts (27) for the ANSWER program® and using Japanese national reference data for the GHLIQUID-4020 trial (26). HSDS (NS-specific) was calculated using reference data reported by Ranke et al (28) for the ANSWER program® and using data reported by Isojima et al (29) for the GHLIQUID-4020 trial.…”

Section: Discussionmentioning

confidence: 99%

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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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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

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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“…There are a few studies that have reported long-term results on the efficacy of rhGH treatment in NS (34)(35)(36). Recently, in two complementary non-interventional studies, NordiNet ® IOS and ANSWER, it has been demonstrated that NS children treated with rhGH achieved significant height gain during the first 3 years of follow-up (37).…”

Section: Discussionmentioning

confidence: 99%

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height

et al. 2021

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ObjectivesGrowth impairment is a common manifestation in Noonan syndrome (NS). Recombinant human GH (rhGH) treatment has been shown to increase growth and adult height (AH) in a few studies. We aimed to evaluate the growth trajectory towards the AH, and the effects of rhGH treatment in a large cohort of NS children.MethodsRetrospective, multicenter, cohort study including subjects with genetic diagnosis of NS. A total of 228 NS patients, 154 with PTPN11 mutations, 94 who reached AH, were recruited. Auxological data were collected at 2, 5, and 10 years, at pubertal onset, at AH. Sixty-eight NS subjects affected with GH deficiency (GHD) were treated with rhGH at a mean dose of 0.24 mg/kg per week until AH achievement.ResultsANOVA analysis showed a significant difference between birth length and height standard deviation scores (HSDS) at the different key ages (p<0.001), while no significant differences were found between HSDS measurements at 2, 5, and 10 years, at pubertal onset, and at AH. HSDS increased from −3.10 ± 0.84 to −2.31 ± 0.99 during rhGH treatment, with a total height gain of 0.79 ± 0.74, and no significant difference between untreated and treated NS at AH.ConclusionsrhGH treatment at the standard dose used for children with GH idiopathic deficiency is effective in improving growth and AH in NS with GHD. Further studies are needed to assess genotype-specific response to rhGH treatment in the different pathogenic variants of PTPN11 gene and in the less common genotypes.

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“…While in children with biallelic IGFALS variants, rhGH and rhIGF appear ineffective, preliminary reports have suggested that rhGH could be effective to accelerate growth velocity in children who are heterozygous carriers of IGFALS variants [164, 189]. rhGH is registered for the treatment of Noonan syndrome, based on the moderate effect on height velocity and adult height [190]. The growth response to rhGH treatment in children with 3M syndrome is variable and modest [185].…”

Section: Conditions With Decreased Gh Sensitivitymentioning

confidence: 99%

Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

et al. 2021

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The current differential diagnosis for a short child with low insulin-like growth factor I (IGF-I) and a normal growth hormone (GH) peak in a GH stimulation test (GHST), after exclusion of acquired causes, includes the following disorders: (1) a decreased spontaneous GH secretion in contrast to a normal stimulated GH peak (“GH neurosecretory dysfunction,” GHND) and (2) genetic conditions with a normal GH sensitivity (e.g., pathogenic variants of GH1 or GHSR) and (3) GH insensitivity (GHI). We present a critical appraisal of the concept of GHND and the role of 12- or 24-h GH profiles in the selection of children for GH treatment. The mean 24-h GH concentration in healthy children overlaps with that in those with GH deficiency, indicating that the previously proposed cutoff limit (3.0–3.2 μg/L) is too high. The main advantage of performing a GH profile is that it prevents about 20% of false-positive test results of the GHST, while it also detects a low spontaneous GH secretion in children who would be considered GH sufficient based on a stimulation test. However, due to a considerable burden for patients and the health budget, GH profiles are only used in few centres. Regarding genetic causes, there is good evidence of the existence of Kowarski syndrome (due to GH1 variants) but less on the role of GHSR variants. Several genetic causes of (partial) GHI are known (GHR, STAT5B, STAT3, IGF1, IGFALS defects, and Noonan and 3M syndromes), some responding positively to GH therapy. In the final section, we speculate on hypothetical causes.

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Long-Term Effectiveness and Safety of Childhood Growth Hormone Treatment in Noonan Syndrome

Cited by 19 publications

References 60 publications

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

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

Growth in Children With Noonan Syndrome and Effects of Growth Hormone Treatment on Adult Height

Differential Diagnosis of the Short IGF-I-Deficient Child with Apparently Normal Growth Hormone Secretion

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