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Journal of Clinical Endocrinology & Metabolism, doi:10.1210/jc.2005-0983
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 1 300-306
Copyright © 2006 by The Endocrine Society

Noonan Syndrome: Relationships between Genotype, Growth, and Growth Factors

Jean-Marie Limal, Béatrice Parfait1, Sylvie Cabrol1, Damien Bonnet, Bruno Leheup, Stanislas Lyonnet, Michel Vidaud and Yves Le Bouc

Department of Pediatrics (J.-M.L.), University Hospital, 49933 Angers, France; Molecular Genetics Laboratory (B.P., M.V.), Faculté de Pharmacie, 75006 Paris, France; Pediatric Endocrine Unit (S.C., Y.L.B.), Armand-Trousseau Hospital, 75012 Paris; Université Pierre et Marie Curie, 75005 Paris, France; Pediatric Cardiology Unit (D.B.) and Department of Genetics (S.L.), Necker-Enfants Malades Hospital, 75743 Paris, France; and Department of Pediatrics (B.L.), University Hospital, 54000 Nancy, France

Address all correspondence and requests for reprints to: J. M. Limal, Department of Pediatrics, University Hospital, 4 rue Larrey, 49933 Angers, France. E-mail: jmlimal{at}chu-angers.fr.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Half of the patients with Noonan syndrome (NS) carry mutation of the PTPN11 gene, which plays a role in many hormonal signaling pathways. The mechanism of stunted growth in NS is not clear.

Objective: The objective of the study was to compare growth and hormonal growth factors before and during recombinant human GH therapy in patients with and without PTPN11 mutations (M+ and M–).

Setting, Design, and Patients: This was a prospective multicenter study in 35 NS patients with growth retardation. Auxological data and growth before and during 2 yr of GH therapy are shown. GH, IGF-I, IGF binding protein (IGFBP)-3, and acid-labile subunit (ALS) levels were evaluated before and during therapy.

Results: Molecular investigation of the PTPN11 coding sequence revealed 12 different heterozygous missense mutations in 20 of 35 (57%). Birth length was reduced [mean –1.2 SD score (SDS); six M+ and two M– were < –2 SDS] but not birth weight. M+ vs. M– patients were shorter at 6 yr (P = 0.04). In the prepubertal group (n = 25), GH therapy resulted in a catch-up height SDS, which was lower after 2 yr in M+ vs. M– patients (P < 0.03). The mean peak GH level (n = 35) was 15.4 ± 6.5 ng/ml. Mean blood IGF-I concentration in 19 patients (11 M+, eight M–) was low (especially in M+) for age, sex, and puberty (–1.6 ± 1.0 SDS) and was normalized after 1 yr of GH therapy (P < 0.001), without difference in M+ vs. M– patients. ALS levels (n = 10) were also very low. By contrast, the mean basal IGFBP-3 value (n = 19) was normal.

Conclusions: In NS patients with short stature, some neonates have birth length less than –2 SDS. Growth of M+ is reduced and responds less efficiently to GH than M– patients. The association of low IGF-I and ALS with normal IGFBP-3 levels could explain growth impairment of M+ children and could suggest a GH resistance by a late postreceptor signaling defect.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
NOONAN SYNDROME (NS, OMIM no. 163950) is a congenital autosomal dominant disorder with a wide spectrum of phenotypic expression that was first described in1968 (1). A possible recessive inheritance has been suggested, although many cases are sporadic (2, 3). In 2001, Tartaglia et al. (4) identified heterozygous missense mutations in PTPN11 on chromosome 12q24.1 in about 50% of the tested subjects, which was also commented on by Saenger (5). PTPN11 encodes the protein tyrosine phosphatase SHP-2 (Src-homology 2 domain-containing protein tyrosine phosphatase), a widely expressed protein with a negative effect on intracellular signaling downstream from several growth factors, cytokines, and hormone receptors (6). The structure of SHP-2 consists of two Src-homology (SH) domains (N-SH2 and C-SH2), a single protein tyrosine phosphatase (PTP) domain, and a C-terminal hydrophilic tail. SHP-2 is basally inactive because of interactions between the N-SH2 and PTP domains and has an autoinhibited, closed conformation. Its catalytic activation requires the disruption of the N-SH2/PTP interaction, which is induced by the binding of the N-SH2 domain to phosphotyrosyl-containing motifs of SHP-2 signaling partners (7). The mutations in PTPN11 induce a constitutive activation of PTPN11 and inhibition of intracellular signaling of growth factors.

With the discovery of new mutations, a higher percentage of affected patients has been reported in subsequent series (8, 9, 10, 11). When the selection of patients includes familial cases, the proportion of patients with mutated PTPN11 may reach 60% (12). This new genetic information has allowed investigators to establish genotype-phenotype correlations. Recent data suggest a more prevalent pulmonic stenosis in patients with mutations, whereas hypertrophic cardiomyopathy is more common in patients without mutations (5, 8, 9, 10, 11, 12). Moreover, hematological abnormalities, such as bleeding diathesis and juvenile myelomonocytic leukemia, have been found exclusively in patients with mutations (11).

Proportionate short stature is well recognized as one of the main clinical symptoms and is associated with more than 70% of cases in NS. Nevertheless, some affected subjects have a normal stature, and therefore, the range of adult height is wide (13, 14). This shows that the auxological characteristics of this syndrome are incompletely known (15). The mechanism of stunted growth has been variously reported as insufficient GH secretion (16) or a neurosecretory GH dysfunction (17) and/or low blood IGF-I production (17, 18). These different results make it difficult to link growth retardation to a precise alteration of the GH-IGF-I axis in NS (19). Therefore, we attempted to understand better the mechanism of growth retardation in this syndrome, using a prospective multicenter study designed to evaluate: 1) the percentage of patients with mutated PTPN11 having a short stature; 2) the secretion of GH under pharmacological stimulation; 3) the serum levels of IGF-I, acid-labile subunit (ALS), and IGF binding protein (IGFBP)-3 before and 1 yr after GH treatment; and 4) the correlation between auxological and hormonal data, depending on the genotype of these patients.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

We recruited 35 patients (19 boys and 16 girls) separated according to pubertal development into two groups: group I, 25 prepubertal children at the start of treatment (15 boys, 10 girls), 10.4 ± 3.1 yr (range, 3.8–14.4); and group II, 10 pubertal subjects (four boys, six girls), 14.7 ± 1.7 yr (range, 12.0–17.0). All submitted cases were selected by a group of pediatric geneticists and endocrinologists and one cardiologist. The patient chart included family history, physical evaluation with reference to the criteria of Duncan et al. (20), and photographs of face, neck, and chest. Echographical and electrocardiographical evaluations were performed before and during GH treatment, and subjects with severe congenital heart malformation, hypertrophic cardiomyopathy or both were excluded. Those having NS and neurofibromatosis were also excluded. In all cases, standard karyotype was normal. This prospective study was submitted to the University Hospital Ethics Committee in Angers, which approved the genetic analysis and GH treatment. In all cases, two different informed parental consents were obtained: one for the genetic analysis and the other for the treatment.

Auxological data and GH treatment

Birth length and weight were calculated in SD score (SDS) according to the standards of Usher and McLean (21). Postnatal height measurements (SDS) were evaluated according to French population standards (22). Target height was calculated as follows: (father’s height + mother’s height)/2 + 6.5 cm for boys and –6.5 cm for girls. Only short patients whose height was below –2 SDS were included in this therapeutic study. After at least 1 yr of known spontaneous growth, recombinant human GH (Maxomat; Sanofi-Aventis Laboratory, Paris, France) was administered sc daily in two different dosages: 0.30 mg/kg·wk and 0.46 mg/kg·wk in groups I and II, respectively. Pubertal NS patients were given a higher dose of GH in an attempt to improve their final height because the treatment was started very late.

Mutation screening

Genomic DNA extracted from the peripheral blood leukocytes of the 35 unrelated Noonan probands was amplified using primers specific for the PTPN11 gene coding exons 1–15 and their intron boundaries (exons 1 and 2: AC004086, exon 3–15: AC004216). Primers sequences and PCR conditions for amplification of exons 1–15 are available on request. Mutation screening was performed using bidirectional DNA sequencing of purified PCR products using an ABI BigDye terminator sequencing kit (Applied Biosystems, Applera, France SA) and an automatic ABI Prism 1377 DNA sequencer (Applied Biosystems).

Hormonal assays

Plasma GH concentration. Various pharmacological stimuli were used to test the secretion of GH: ornithine (n = 22 of 35) or betaxolol-glucagon (nine of 35), arginine-insulin hypoglycemia (two of 35), and clonidine-betaxolol (two of 35). Blood GH concentration was measured by RIA before treatment in each pediatric center. A normal response was 10 ng/ml or greater.

IGF-I, IGFBP-3, and ALS. Blood samples were collected at each center, the plasma frozen at –20 C, and then analyzed in a single laboratory (Armand-Trousseau Hospital, Paris, France). Only 19 patient’s samples could be obtained to compare the values before and after 1 yr of GH treatment. IGF-I and IGFBP-3 were calculated in SDS according to the age, sex, and pubertal stage in comparison with control children tested in this laboratory. Plasma IGF-I concentrations were measured by a specific immunoradiometric assay, IGF-I immunoradiometric assay (IM 3516; Immunotech, Marseille, France), including extraction with acid-ethanol. The sensitivity threshold was 3 ng/ml, and the intra- and interassay coefficients of variation were 7.4 and 15.5%, respectively. Plasma IGFBP-3 concentrations were measured by a specific RIA (IGFBP-3 100T; Nichols Institute Diagnostics, San Juan Capistrano, CA). The sensitivity threshold was 0.06 µg/ml, and the intra- and interassay coefficients of variation were 3.8 and 6.3%, respectively. Serum ALS concentrations were measured by a specific ELISA, total ALS ELISA (Diagnostic Systems Laboratories, Webster, TX). The sensitivity threshold was 0.07 µg/ml, and the intra- and interassay coefficients of variation were 7.5 and 8.9%, respectively.

Statistical analysis

Between-group (mutated and nonmutated patients) comparisons were made using the two-tailed test. Changes during treatment were analyzed using a two-tailed pair t test. Results are reported as mean ± SD. Differences were considered statistically significant at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Mutation detection rate and spectrum of identified PTPN11 mutations

We identified 12 different PTPN11 heterozygous missense mutations in 20 of the 35 NS patients. The mutations consisted of two novel N-SH2-associated mutations (c.172A>C and c.178G>T, corresponding to p.Asn58His and p.Gly60Cys, respectively) and 10 recurrent missense mutations located in either the N-SH2 or PTP domain (Fig. 1Go). For five of the sporadic cases, we were able to screen the previously identified PTPN11 mutations on DNA extracted from both parents, confirming their de novo occurrence.



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  		FIG. 1. Distribution of PTPN11 missense mutations identified in 20 of the 35 NS patients. Mutations that have never been described are marked by an asterisk. The number of patients carrying the same mutation is indicated in parentheses.

 
Auxological characteristics and comparison with genotype

Mean father and mother heights were below the mean of the French population (175 ± 6 cm for men and 163 ± 5.6 cm for women) (22). In the mutated group, mean father height (but not mean mother height) and mean target height were significantly greater than in the nonmutated group (Table 1Go). Mean gestational age was 38.8 ± 2.3 wk (32.0–41.0). Mean birth length was 47.7 ± 2.6 cm and 8/34 (6/19 M+ and 2/15 M–) were small for gestational age (SGA). Mean birth weight was normal, 3202 ± 560 g without any difference between mutated and nonmutated patients (Table 1Go and Fig. 2Go). Head circumference at birth obtained in 30 newborns appeared normal in the two groups. Despite a trend of a shorter birth length in mutated vs. nonmutated newborns, we found no significant difference. But SGA tended to be more frequent in mutated than nonmutated patients (32 vs. 13%).


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  		TABLE 1. Auxological data: comparisons in patients with and without mutation

 


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  		FIG. 2. Birth length (A) and birth weight (B) in newborns with NS according to the gestational age. •, Mutated; {circ}, nonmutated. Black lines, ± 2 SD according to the standards of Usher and McLean (21 ).

 
During childhood (at 6 yr of age) and at the inclusion in this study, patients with mutations were significantly shorter than patients without mutations. The difference between the two groups was greater when taking into account target height (Table 1Go).

Evolution of height velocity before and during treatment

Catch-up growth was significant during GH therapy in groups I (prepubertal) and II (pubertal): mean height in SDS before and after 1 yr of GH treatment was –3.3 ± 0.9 vs. – 2.8 ± 1.1 (P < 0.001) for group I and –3.4 ± 0.9 vs. – 2.8 ± 0.9 (P = 0.02) for group II. Only the changes of height during the first 2 yr of GH treatment in the prepubertal group (group I) are shown in Table 2Go because of the small number of pubertal patients (group II, n = 10). Despite a comparable mean age at the start of GH treatment, catch-up growth after the first 2 yr of GH therapy was less pronounced in patients presenting a PTPN11 mutation, especially when taking into account target height. The height (SDS) of the patients with mutations were significantly shorter (P = 0.03) after 2 yr of treatment (Table 2Go). However, height velocity (HV, centimeters per year) was different but not significant in mutated and nonmutated patients. Thus, under GH treatment, there was a different response at the limit of significance after 1 and 2 yr of GH therapy (P = 0.09 and P = 0.13, respectively) in mutated vs. nonmutated patients (Table 2Go).


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  		TABLE 2. Comparison of growth response to GH therapy in the prepubertal patients (group I)

 
During GH therapy, blood glucose was measured every 3 months and remained in the normal limits in all patients. Two echographical examinations a year were performed and were analyzed by the same cardiologist, and none of these patients had an increase in their left ventricular mass index during GH treatment.

Hormonal results

The mean peak blood GH level after pharmacological stimulation in the 35 patients was 15.4 ± 6.5 ng/ml (5.0–34.3). Of the 35 patients, five nonmutated NS had a GH level between 5 and 10 ng/ml, and only two had low IGF-I level. Plasma IGF-I and IGFBP-3 levels were obtained in 19 patients (11 M+ and 8 M–), and ALS measurements were obtained in 10 patients (five M+ and five M–) (Figs. 3Go and 4Go). All patients had IGF-I concentrations at the lower limit or below the normal range before GH treatment, especially in mutated patients, but without significant difference between patients with and without mutations (Table 3Go). ALS levels were extremely low in 10 tested patients. By contrast, the mean IGFBP-3 levels were normal before treatment. After 1 yr during GH treatment, IGF-I and IGFBP-3 concentrations increased significantly (P < 0.001): IGF-I levels became normal and IGFBP-3 levels remained in the normal range (Fig. 3Go). The increase in IGF-I and IGFBP-3 levels during GH treatment in patients with and without mutations was comparable (Table 3Go and Fig. 3Go).



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  		FIG. 3. IGF-I and IGFBP-3 levels before and after 1 yr of GH treatment in 19 patients. • Mutated, {circ}, nonmutated; black lines, ± 2 SD in normal controls.

 


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  		FIG. 4. ALS levels before GH therapy in 10 patients. • Mutated, {circ}, nonmutated; black lines, ± 2 SD in normal controls.

 

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  		TABLE 3. Plasma IGF-I and IGFBP-3 concentrations before and after 1 yr of GH therapy

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
PTPN11 mutation analysis

Sequence analysis of the entire PTPN11 coding sequence led us to identify 20 (57%) missense mutations in 35 index patients with NS. Mutations have been identified, including our data, in 168 of the 377 NS patients (44%) reported to date (4, 8, 9, 10, 11, 12, 23, 24, 25, 26). The higher mutation frequency found in this study may be due to differences in the stringency of the diagnostic criteria and selection of patients for GH treatment. All molecular lesions identified so far correspond to 30 different missense mutations and two in-frame 3-bp deletions. More than 95% of these PTPN11 mutations affect residues located in or close to the N-SH2 and PTP interacting surface. In this study, 10 of 20 (50%) mutations involved exon 3 that codes for the SHP-2 N-SH2 domain. The most common PTP located mutation, c.922A>G in exon 8, previously reported by Tartaglia et al. (4, 9) was present in six patients, representing 30% of the total number of mutations identified. Energetics-based structural analysis and/or in vitro enzymological studies (p.Tyr63Thr, p.Ala72Ser, p.Ile282Val, p.Asn308Asp) for some of the mutations identified in our group of patients have supported the SHP-2 gain of function as a current hypothesis for the molecular pathogenesis of NS (4, 9, 24, 27, 28).

In this study, we also identified two novel c.172A>C/p.Asn58His and c.178G>T/p.Gly60Cys N-SH2-associated mutations. Both these nucleic acid changes affect the interacting region between the N-SH2 and PTP domain and are probably involved in SHP-2 gain of function. Indeed, the crystal structure reported by Hof et al. (7) shows that both residues belong to the NxGDY/F sequence motif, which inserts deep into the PTP catalytic cleft, stabilizing SHP-2 in an inactive conformation. Asn58 in this motif is essential for the SH2-PTP hydrogen-bonding network of the enzyme and Gly60 and Asp61 hydrogen-bond Cys459 of the PTP catalytic cleft. Therefore, a mutation of these residues may destabilize the inactive conformation of the protein. However, further functional investigations are required to address this question.

Pattern of growth: comparisons and correlations with genotype

In this study, in which only patients with a short stature were included, eight of 34 newborns presented asymmetric SGA with low birth length (<–2 SDS) and normal weight and head circumference at birth. This is similar to another study carried out on 22 patients followed in Angers (29). In the large cohort of Ranke et al. (14), weight and length were normal in 119 newborns. However, in the study by Ranke, patients were included on a clinical basis, whatever their growth, and the range of final adult stature was widely spread (150–175 cm in men and 145–165 cm in women). A recent study on Japanese newborns (11) showed a mean birth length of –0.6 SDS and a mean weight of –0.2 SDS for babies with mutations and a mean weight of –0.6 SDS for babies without mutations. In the present cohort, NS patients, and especially patients with mutations, are more frequently SGA for length than patients without mutations. However, a large-scale study is needed to demonstrate whether these mutations are a risk factor for fetal growth retardation. Embryogenesis is affected by the function of SHPs, and experimental models have shown that embryonic lethality in mice was the consequence of homozygotic deletion of SHP2 exon 2 or 3 (see review in Ref.6). Therefore, because PTPN11 mutations induce abnormalities in many growth factor signaling pathways (30, 31), we could suggest that an impaired production of IGF-I and other growth factors in Noonan offspring should lead to their impaired biological activity.

Zenker et al. (12) showed that, after birth, 88% of PTPN11-mutated children older than 3 yr of age had a height less than –2 SDS and that they were significantly shorter than nonmutated children (–3.1 SDS vs. –2.4 SDS). Combined with our results, these data suggest a more severe mechanism acting on growth retardation induced in NS, especially in patients carrying PTPN11 mutation.

Hormonal data

The mechanism of growth retardation in NS is not clear. After pharmacological stimuli, GH secretion was either normal (32, 33, 34, 35) or occasionally subnormal in a small number of patients (16), whereas a neurosecretory GH dysfunction has been described in some cases (17, 18). Moreover, mean IGF-I levels have been measured below normal (17, 18). No study evaluating the GH-IGF-I and IGFBP-3 axis has been systematically undertaken in NS before and during GH therapy, and the hormonal levels have not been correlated with the genotype. Our results show first, a normal GH secretion after pharmacological stimuli and second, low serum IGF-I and ALS concentrations, which contrast with normal IGFBP-3 levels determined by RIA and also by Western-ligand and immunoblotting (data not shown). The hormonal data found in our study may be interpreted in two ways. First, knowing the cellular role of PTPN11 (negative effect on intracellular signaling downstream from several growth factor receptors), a GH postreceptor signaling resistance could represent the mechanism of stunted growth in NS. Some arguments are in favor of this hypothesis. The lower growth response to GH treatment observed in mutated vs. nonmutated patients (this study and Refs.36 and 37) suggest some degree of resistance to GH. Moreover, Binder et al. (36) have recently shown a tendency to higher spontaneous and stimulated GH secretion in mutated vs. nonmutated NS patients, whereas IGF-I levels were low and accompanied by normal IGFBP-3 concentrations, a pattern similar to that observed in the present study. Thus, these data and our results could be in favor of a GH resistance by a late postreceptor signaling defect specific for IGF-I and ALS that doses not affect IGFBP-3 stimulation. However, further studies will be necessary to define the precise site of action of PTPN11 on the GH-induced intracellular signaling pathway.

Second, this is not sufficient to exclude the mechanism of an impaired pituitary dysfunction. Despite a normal response to stimulation tests, a neurosecretory GH dysfunction is frequently observed in NS, as previously described (17, 18). Furthermore, IGFBP-3 levels are in the normal range in 70% of hypopituitary patients (review in Ref.38). Consequently, the IGF-I increase and the significant growth response to GH therapy are also consistent with a neurosecretory dysfunction (38, 39).

In conclusion, a beneficial effect of recombinant human GH on growth was already reported in NS patients (16, 18, 32, 33, 35, 40, 41, 42, 43, 44, 45). The present data confirm this growth improvement with the treatment and could suggest a partial resistance to GH, more severe in PTPN11 mutation-positive patients. Finally, the reason the typical clinical phenotype may be observed in the presence or absence of the PTPN11 mutation remains to be explained. NS is a clinical syndrome consisting of certain phenotypic criteria, presumably caused by different molecular abnormalities, of which PTPN11 mutation is one.


   Acknowledgments
 
We are grateful to the clinicians for including patients in this study: Professor Battin, Dr. Colle (Bordeaux); Dr. Bertrand (Besançon); Dr. Bony-Trifunovic (Amiens); Dr. Cessans (La Rochelle); Professor Chatelain, Professor David, Professor Nicolino (Lyon); Professor Chaussain, Professor Toublanc (Hôpital Saint-Vincent de Paul, Paris); Professor Coutant (Angers); Professor Czernichow, Professor Léger (Hôpital Robert Debré, Paris); Dr. Despert (Tours); Dr. Le Luyer (Le Havre); Professor Lienhardt-Roussie (Limoges); Dr. Parlier (Compiègne); Dr. Pinto (Hôpital Necker-Enfants Malades, Paris); Dr. Simonin (Marseille); Dr. Sulmont (Reims); Professor Tauber, Professor Rochiccioli (Toulouse); and Dr. Weill (Lille). We also thank Dr. Souad Nafa and Annie Serrière (Sanofi-Aventis, France) and, for technical assistance, Laurence Périn and Rémy Christol.


   Footnotes
 
This work was supported by Sanofi-Aventis Laboratory (Paris, France).

First Published Online November 1, 2005

1 B.P. and S.C. contributed equally to this work. Back

Abbreviations: ALS, Acid-labile subunit; HV, height velocity; IGFBP, IGF binding protein; M+ and M–, with and without PTPN11 mutations; NS, Noonan syndrome; PTP, protein tyrosine phosphatase; SDS, SD score; SGA, small for gestational age; SH, Src-homology.

Received May 4, 2005.

Accepted October 14, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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A C Shaw, K Kalidas, A H Crosby, S Jeffery, and M A Patton
The natural history of Noonan syndrome: a long-term follow-up study
Arch. Dis. Child., February 1, 2007; 92(2): 128 - 132.
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