PTPN11 (Protein Tyrosine Phosphatase, Nonreceptor Type 11) Mutations and Response to Growth Hormone Therapy in Children with Noonan Syndrome

Ferreira, Lize Vargas; Souza, Silvia A.L.; Arnhold, Ivo Jorge Prado; Mendonca, Berenice B.; Jorge, Alexander A L

doi:10.1210/jc.2004-2559

Cited by 84 publications

(84 citation statements)

References 29 publications

(33 reference statements)

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“…In agreement with this, individuals mutated in PTPN11 appeared to respond less to GH therapy than other NS patients [25,27]. Supporting the concept of GH resistance in patients with PTPN11 mutations, other clinicians subsequently reported that these individuals display, under GH therapy, smaller increments in IGF-1 levels or in short-term growth, compared with subjects without PTPN11 mutations [28,53]. However, in one of these studies which also measured patients growth, long-term GH treatment was not found to make a significant difference on the growth of children harboring PTPN11 mutations, in comparison with other NS patients [28].…”

Section: Signs Of Gh Resistancementioning

confidence: 58%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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Short stature is a frequent feature of Noonan syndrome (NS), a disease caused by mutations of genes encoding components of the Ras/mitogen-activated protein kinases (MAPK) signalling pathway. To date numerous patients have been treated with growth hormone (GH) in various countries. However this treatment is still controversial, as its efficacy is a matter of debate. The final height gain of GH therapy represents 5 to 10 cm, at best, which is disappointing considering the length and burden of the treatment. The reasons explaining this lack of efficiency are poorly understood and they seemed to involve a waning effect after the first year of GH treatment or acceleration of bone maturation in patients on GH. Moreover, GH therapy raises questions about its safety, especially in subjects with NS who are at risk for cardiac defects and malignancies. Cases of severe adverse effects were described, yet too sporadically to conclude that they were certainly caused by GH therapy. Novels insights in understanding the dysfunction of GH-dependent processes in NS were recently reported and this manuscript aims at reviewing the latest advances. Clinical data suggested that growth retardation could be caused by a partial postreceptor resistance to GH, an impaired sensitivity to GH which could also explain the modest efficiency of GH therapy in NS patients. Similar observations were also obtained in a NS mouse model harboring a mutation in the gene encoding the tyrosine phosphatase Shp2. In the mouse, the mechanism of GH resistance is thought to involve upregulation by mutated Shp2 of GH-induced Ras/MAPK, a signaling pathway which seemed to play a negative regulatory role in the production of GH mediators involved in bone growth. Despite these recent finding, the underlying mechanisms of growth retardation and GH therapy in NS remain to be further explored in order to improve treatment for short stature.

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Section: Signs Of Gh Resistancementioning

confidence: 58%

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Raynal¹

2014

Horm Stud

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“…The relevance of RAS signaling in GH and IGF signal transduction is well-known [Padidela et al, 2008], but the mechanism by which aberrant targeting of SHOC2 dysregulates growth remains to be elucidated. In the literature, impaired response to GH stimulating test has been described in patients affected by RASopathies [Noordam et al, 2001;Mazzanti et al, 2009] as well as the occurrence of peripheral GH insensitivity [Ferreira et al, 2005]. Final height (FH) data in NS after GH therapy have also been reported [Ferreira et al, 2005].…”

Section: Introductionmentioning

confidence: 99%

“…In the literature, impaired response to GH stimulating test has been described in patients affected by RASopathies [Noordam et al, 2001;Mazzanti et al, 2009] as well as the occurrence of peripheral GH insensitivity [Ferreira et al, 2005]. Final height (FH) data in NS after GH therapy have also been reported [Ferreira et al, 2005]. At present, only a few NS/LAH patients treated with GH-therapy have been described [Mazzanti et al, 2003;Capalbo et al, 2012b], and no FH data are available.…”

Section: Introductionmentioning

confidence: 99%

GH Therapy and first final height data in Noonan‐like syndrome with loose anagen hair (Mazzanti syndrome)

Mazzanti

Tamburrino

Scarano

et al. 2013

American J of Med Genetics Pt A

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Noonan-like syndrome with loose anagen hair (NS/LAH or Mazzanti Syndrome) is caused by a single missense mutation in SHOC2 promoting tN-myristoylation of the encoded protein.Cardinal features include facial features resembling NS, short stature often associated with proven growth hormone deficiency (GHD), typical ectodermal anomalies, and distinctive behavior. Overall, the clinical features are more severe than those generally observed in NS, even though the phenotype improves with age. We report on growth and pubertal trend in seven patients heterozygous for a mutated SHOC2 allele, treated with longterm GH-therapy, and final height (FH) in three of them. They were approximately À3 SDS below the Italian general population standards, they had very low IGF1 levels at baseline and GHD at pharmacological tests. All patients were treated with GH (0.035 mg/kg/day) for a mean period of 8.49 AE 5.72 years. After the 1st year of GH-therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (À2.34 AE 0.12 SDS) at 18.25 AE 0.73 years, after GH administration for 12.39 AE 2.12 years. Pubertal development was variable, showing a prolonged and delayed puberty or rapid pubertal progression that could impair the FH. Overall, our data in this small cohort suggest that NS/LAH patients benefit from long-term GH-therapy, although they do not show the characteristic catch-up growth of isolated GHD. While the observed growth and pubertal behavior is consistent with a dysfunction of the hypothalamic-pituitarygonadal axis, the functional link between SHOC2 and the GH/ IGF signaling pathways remains to be clarified.

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“…With regard to safety of long-term GH treatment, we showed that there were no changes in cardiac dimensions and insulin-like growth factor-I (IGF-I) levels remained in the normal range during short-term GH treatment (14,15). Short-term results seem less favourable in children with NS with mutations in PTPN11 than without mutations in PTPN11 (16)(17)(18). Data on adult height after GH treatment in relation to the presence or absence of this mutation are not available.…”

Section: Introductionmentioning

confidence: 99%

Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11

Noordam

Peer

François

et al. 2008

European Journal of Endocrinology

120

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Context: Noonan syndrome (NS) is characterized by short stature, typical facial dysmorphology and congenital heart defects. Short-term effect of GH therapy in NS is beneficial, reports on the effect on adult height are scarce. Objective: To determine the effect of long-term GH therapy in children with NS. Design: Twenty-nine children with NS were treated with GH until final height was reached. Setting: Hospital endocrinology departments. Patients: Children with the clinical diagnosis of NS, with mean age at the start of therapy of 11.0 years, 22 out of 27 tested children had a mutation in the protein tyrosine phosphatase, non-receptor-type 11 gene (PTPN11 gene). Interventions: GH was administered subcutaneously at 0.05 mg/kg per day until growth velocity was 1 cm/6 months. Main outcome measure: Linear growth (height) was measured at 3-month intervals in the first year and at 6-month intervals thereafter until final height. Results: At the start of treatment, median height SDS (H-SDS) was K2.8 (K4.1 to K1.8) and 0.0 (K1.4 to C1.2), based on national and Noonan standards respectively. GH therapy lasted for 3.0-10.3 years (median, 6.4), producing mean gains in H-SDS of C1.3 (C0.2 to C2.7) and C1.3 (K0.6 to C2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was C1.3, not different from the mean gain in the five children without a mutation in PTPN11C1.3 (PZ0.98). Conclusion: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

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PTPN11 (Protein Tyrosine Phosphatase, Nonreceptor Type 11) Mutations and Response to Growth Hormone Therapy in Children with Noonan Syndrome

Cited by 84 publications

References 29 publications

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

Growth hormone and noonan syndrome: update in dysfunctional signaling aspects and in therapy for short stature

GH Therapy and first final height data in Noonan‐like syndrome with loose anagen hair (Mazzanti syndrome)

Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, non-receptor-type 11

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