Format

Send to

Choose Destination
See comment in PubMed Commons below
J Clin Endocrinol Metab. 2005 Sep;90(9):5377-81. Epub 2005 Jun 28.

PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome.

Author information

1
Pediatric Endocrinology Section, University-Children's Hospital, Hoppe Seyler Strasse 1, 72076 Tubingen, Germany. gerhard.binder@med.uni-tuebingen.de

Abstract

CONTEXT:

Noonan syndrome is frequently associated with an unclear disturbance of GH secretion. Half the individuals with Noonan syndrome carry a heterozygous mutation of the nonreceptor-type protein tyrosine phosphatase, Src homology region 2-domain phosphatase-2 (SHP-2), encoded by PTPN11, which has a role in GH receptor signaling.

OBJECTIVE:

The objective of this study was to compare GH secretion and IGF-I/IGF-binding protein-3 (IGFBP-3) levels of the SHP-2 mutation-positive (mut+ group) vs. mutation-negative individuals (mut- group).

DESIGN, SETTING, AND PATIENTS:

All children presenting to us with short stature plus at least three typical anomalies of Noonan syndrome or pulmonic stenosis during the last 5 yr (n = 29; 10 females and 19 males) were recruited. Auxological data, dysmorphic features, and cardiac morphology were documented. Hormone levels were measured by RIA. All coding exons of PTPN11 were sequenced after PCR amplification.

INTERVENTION:

A prepubertal subgroup (n = 11) was treated with recombinant human GH (rhGH) to promote growth.

RESULTS:

Sequencing yielded 11 different PTPN11 missense mutations in 16 of the 29 patients (55% mut+). Pulmonic stenosis (81 vs. 15%; P = 0.0007) and septal defects (63 vs. 15%; P = 0.02) were more frequently found in the mut+ group, whereas minor anomalies, cryptorchidism, and learning disabilities were as frequent in the mut+ group as in the mut- group. The mut+ group was younger at presentation (mean +/- sd, 5.1 +/- 2.7 vs. 10.3 +/- 5.2 yr; P = 0.002), but not significantly shorter [-3.15 +/- 0.92 vs. -3.01 +/- 1.35 height sd score (SDS)]. IGF-I levels (-2.03 +/- 0.69 vs. -1.13 +/- 0.89 SDS; P = 0.005) and IGFBP-3 levels (-0.92 +/- 1.26 vs. 0.40 +/- 1.08 SDS; P = 0.006) were significantly lower in the mut+ group. In contrast, GH levels showed a tendency to be higher in the mut+ group during spontaneous secretion at night and arginine stimulation (P > or = 0.075, not significant). The mean change in height SDS after 1 yr of rhGH therapy (0.043 mg/kg.d) was +0.66 +/- 0.21 in the mut+ group (n = 8), but +1.26 +/- 0.36 in the mut- group (n = 3; P = 0.007).

CONCLUSIONS:

Our data suggest that SHP-2 mutations in Noonan syndrome cause mild GH resistance by a postreceptor signaling defect, which seems to be partially compensated for by elevated GH secretion. This defect may contribute to the short stature phenotype in children with SHP-2 mutations and their relatively poor response to rhGH.

PMID:
15985475
DOI:
10.1210/jc.2005-0995
[Indexed for MEDLINE]
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Silverchair Information Systems
    Loading ...
    Support Center