PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome.
BACKGROUND
The cause of growth impairment in Noonan syndrome (NS) remains unclear. Mutations in PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) that codify constitutively activated Src homology protein tyrosine phosphatase-2 tyrosine phosphatase and may interfere with GH and IGF-I signaling were identified in approximately 40% of patients with NS.


OBJECTIVE
The objective of this study was to evaluate the influence of PTPN11 status on response to human GH (hGH) treatment in NS children with short stature.


METHODS
This study was performed at a university hospital.


METHODS
The study design was to conduct a retrospective analysis of 3 yr of hGH treatment and genotyping of PTPN11 in patients with NS.


METHODS
Fourteen NS patients, half of them with PTPN11 mutations in heterozygous state, were studied. At the beginning of treatment, there were no clinical or laboratory differences between groups with and without mutations in the PTPN11 gene.


METHODS
Patients were treated with hGH (47 microg/kg.d).


METHODS
The main outcome measures were PTPN11 genotype, change in IGF-I levels, and change in height sd score.


RESULTS
Patients with mutations in PTPN11 presented a significantly smaller increment in IGF-I levels during the treatment compared with patients without mutations (86 +/- 67 and 202 +/- 93 microg/liter, respectively; P = 0.03). hGH treatment significantly improved growth velocity in both groups, with slightly better results observed in patients without mutations. This was translated into greater gains in height sd score relation to baseline during the 3 yr of treatment in patients without mutations (+1.7 +/- 0.1) compared with those with mutations (+0.8 +/- 0.4; P < 0.01).


CONCLUSIONS
Our findings suggest that the presence of PTPN11 mutations in patients with NS indicates a reduced growth response to long-term hGH treatment.
Ferreira
Lize V
LV
Hospital das Clinicas, Labaratorio de Hormonios, Avenue Dr. Eneas de Carvalho Aguiar 155 PAMB, 2 Andar Bloco 6, 05403-900 Sao Paulo, Brazil.
Souza
Silvia A L
SA
Arnhold
Ivo J P
IJ
Mendonca
Berenice B
BB
Jorge
Alexander A L
AA
D001827:Body Height / Q000187:drug effects; D002648:Child; D005260:Female; D005838:Genotype; D006579:Heterozygote; D019382:Human Growth Hormone / Q000627:therapeutic use*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009634:Noonan Syndrome / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology; D054648:Protein Phosphatase 2; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D012189:Retrospective Studies; D016896:Treatment Outcome
D047908:Intracellular Signaling Peptides and Proteins; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I; D054648:Protein Phosphatase 2; C516724:PTPN11 protein, human; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases