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In Noonan syndrome (NS) 30-50% of subjects show cognitive deficits of unknown etiology and with no known treatment. Here, we report that knock-in mice expressing either of two NS-associated mutations in Ptpn11, which encodes the nonreceptor protein tyrosine phosphatase Shp2, show hippocampal-dependent impairments in spatial learning and deficits in hippocampal long-term potentiation (LTP). In addition, viral overexpression of an NS-associated allele PTPN11(D61G) in adult mouse hippocampus results in increased baseline excitatory synaptic function and deficits in LTP and spatial learning, which can be reversed by a mitogen-activated protein kinase kinase (MEK) inhibitor. Furthermore, brief treatment with lovastatin reduces activation of the GTPase Ras-extracellular signal-related kinase (Erk) pathway in the brain and normalizes deficits in LTP and learning in adult Ptpn11(D61G/+) mice. Our results demonstrate that increased basal Erk activity and corresponding baseline increases in excitatory synaptic function are responsible for the LTP impairments and, consequently, the learning deficits in mouse models of NS. These data also suggest that lovastatin or MEK inhibitors may be useful for treating the cognitive deficits in NS.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM 607721) due to a missense mutation c.4A>G in SHOC2 predicting p.Ser2Gly has been described recently. This condition is characterized by facial features similar to Noonan syndrome, reduced growth, cardiac defects, and typical abnormal hair. We report on a patient with molecularly confirmed NS/LAH with coarctation of the aorta. The girl was precipitously born at 37 weeks of gestation at home and required a 3-min resuscitation. Increased nuchal translucency and aortic coarctation with a small ventricular septal defect were described prenatally, hypertrophic cardiomyopathy was detected postnatally. The patient presented with facial dysmorphism typical of NS with redundant skin over the nape and on the back. Short stature, relative macrocephaly, failure-to-thrive together with dystrophic appearance, developmental delay mainly in motor milestones and very thin, sparse, slow-growing hair occurred a few weeks after birth. Endocrine evaluation revealed low IGF-1 levels and borderline growth hormone deficiency. Growth hormone therapy started at 16 months had a partial effect and prevented further growth deterioration. Coarctation of the aorta is not a typical heart defect among individuals with NS/LAH, therefore our observation extends the phenotypic spectrum of this disorder., (© 2014 Wiley Periodicals, Inc.)

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 long-term GH-therapy, and final height (FH) in three of them. They were approximately -3 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 ± 5.72 years. After the 1st year of GH-therapy, IGF1 level and height velocity had increased. Three of 7 patients reached the FH (-2.34 ± 0.12 SDS) at 18.25 ± 0.73 years, after GH administration for 12.39 ± 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-pituitary-gonadal axis, the functional link between SHOC2 and the GH/IGF signaling pathways remains to be clarified., (© 2013 Wiley Periodicals, Inc.)

Activating mutations in PTPN11 (encoding SHP2), a protein tyrosine phosphatase (PTP) that plays an overall positive role in growth factor and cytokine signaling, are directly associated with the pathogenesis of Noonan syndrome and childhood leukemias. Identification of SHP2-selective inhibitors could lead to the development of new drugs that ultimately serve as treatments for PTPN11-associated diseases. As the catalytic core of SHP2 shares extremely high homology to those of SHP1 and other PTPs that play negative roles in cell signaling, to identify selective inhibitors of SHP2 using computer-aided drug design, we targeted a protein surface pocket that is adjacent to the catalytic site, is predicted to be important for binding to phosphopeptide substrates, and has structural features unique to SHP2. From computationally selected candidate compounds, #220-324 effectively inhibited SHP2 activity with an IC50 of 14 μmol/L. Fluorescence titration experiments confirmed its direct binding to SHP2. This active compound was further verified for its ability to inhibit SHP2-mediated cell signaling and cellular function with minimal off-target effects. Furthermore, mouse myeloid progenitors with the activating mutation (E76K) in PTPN11 and patient leukemic cells with the same mutation were more sensitive to this inhibitor than wild-type cells. This study provides evidence that SHP2 is a "druggable" target for the treatment of PTPN11-associated diseases. As the small-molecule SHP2 inhibitor identified has a simple chemical structure, it represents an ideal lead compound for the development of novel anti-SHP2 drugs. Mol Cancer Ther; 12(9); 1738-48. ©2013 AACR.

Growth hormone (GH) is approved by the US Food and Drug Administration (FDA) for use in pediatric patients with disorders of growth failure or short stature and in adults with growth hormone deficiency (GHD) and HIV/AIDS wasting and cachexia. For pediatric patients, guidelines for the use of GH have been developed by several organizations that have identified specific criteria for initiating GH therapy for each FDA-approved indication. Guidelines for adults have also been developed and include recommendations for transition (adolescent) patients with GHD. These patients are often treated with GH as children but may require continued treatment as young adults to attain full skeletal mineralization and improve cardiovascular risk factors. Adult and pediatric guidelines are supported by efficacy and safety studies, which show that, when started at an early age, GH treatment can increase growth velocity and that GH is safe and well-tolerated. We summarize the guidelines that are available for all FDA-approved indications among pediatric and transition patients. Adherence to these guidelines will help to ensure that patients with disorders of growth failure or short stature receive the necessary therapy to increase linear growth and transition smoothly to healthy adulthood.

We report a large infiltrating atypical granular cell tumor in a child with Noonan syndrome. Even though granular cell tumors are rare in childhood, five cases have been reported in children with Noonan syndrome. This study compares these different cases and explores the possibility of activation of the granular cell by the Ras pathway., (© 2012 Wiley Periodicals, Inc.)

Background/aims: The objective of this study was to evaluate the efficacy of recombinant human growth hormone (rhGH) therapy and the influence of genotype on the response to rhGH therapy in children with Noonan syndrome (NS)., Methods: 14 male and 4 female subjects with NS with short stature, whose height was < 3rd percentile, were included. The rhGH was subcutaneously administered at a dose of 66 μg/kg/day. Mutations in the PTPN11 gene were identified in 10 subjects (55.6%). Mutations in the SOS1 (2 children, 11.1%), MEK1 (1 child, 5.6%) and KRAS (1 child, 5.6%) genes were also found., Results: Height SDS increased from –2.8 ± 0.9 at the start of rhGH therapy to –2.0 ± 0.9 12 months later (p < 0.001). Height velocity increased from 5.0 ± 0.9 cm/year in the year before treatment to 8.9 ± 1.6 during treatment (p < 0.001). Changes in height SDS, height velocity, and serum IGF-1 level did not differ significantly between those children with or without PTPN11 mutations., Conclusion: The rhGH therapy significantly improved the growth velocity and increased the serum IGF-1 level. Longterm correlation between genotype and rhGH therapy responsiveness needs to be addressed in a large population.

Noonan syndrome (NS) is a relatively common condition characterized by chest deformation, congenital heart disease, short stature and distinctive facial features. Due to its genetic heterogeneity NS patients exhibit a range of clinical signs. Severe gingivitis and supernumerary teeth are rarely seen in connection with NS. In addition, there has not been a report on NS patients with atypical bilateral enlargement of the mental foramens and inferior-alveolar canals. This case report describes a NS patient who has undergone growth hormone (GH) therapy and is presenting with classical and rare NS phenotypes.

This review will summarize the effects of growth hormone (GH) on height, body composition, bone and psychosocial parameters in children with Turner syndrome or Noonan syndrome and those born small for gestational age. The safety of GH treatment in children with these diagnoses is also reported. Despite the reported efficacy and safety of GH in these indications, however, not all children achieve their target height potential, due in some part to poor adherence to GH therapy regimens; indeed up to 50% of children are less than fully compliant with treatment. With this in mind the present and future administration of GH therapy is discussed with respect to advances being made in the presentation of GH for injection and advances in GH injection devices. It is hoped that such progress, aimed at making the administration of GH easier and less painful for the patient will improve treatment adherence and outcome benefits., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Growth hormone is a widely used hormone. This article describes its historical use, current indications and studies for possible future uses., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Although recombinant human GH (rhGH) has been available since 1985, there are several questions related to its use that remain unanswered. The Entrez-PubMed search engine was used to conduct a review of publications appearing since 2007 that address growth and GH treatment. Recent publications related to the diagnosis of GH deficiency, genetics of growth, the use of rhGH in different genetic conditions, in idiopathic short stature, and in puberty, and strategies to adjust rhGH dose were reviewed. New studies investigating the genetics of growth and the response to rhGH therapy in different groups are helping in the understanding of the physiology of normal growth. Although in most children treated with rhGH there is a short-term benefit, the clinical relevance of the benefits after long-term treatment in some conditions remains unclear. The challenges are to define milder forms of GH deficiency and to assess the relevance of the benefits, if any, caused by rhGH in different patient populations and the best therapeutic approach for these patients. Well-designed long-term studies using anthropometric, genetic, and laboratory data that will also assess long-term quality of life benefits are needed to help clinicians select patients to initiate treatment with rhGH and to adjust treatment to improve outcome.

Growth hormone (GH) therapy has been appropriate for severely GH-deficient children and adolescents since the 1960s. Use for other conditions for which short stature was a component could not be seriously considered because of the small supply of human pituitary-derived hormone. That state changed remarkably in the mid-1980s because of Creutzfeldt-Jakob disease associated with human pituitary tissue-derived hGH and the development of a (nearly) unlimited supply of recombinant, 22 kDa (r)hGH. The latter permitted all GH-deficient children to have access to treatment and one could design trials using rhGH to increase adult height in infants, children and adolescents with causes of short stature other than GH deficiency, as well as trials in adult GH-deficient men and women. Approved indications (US Food and Drug Administration) include: GH deficiency, chronic kidney disease, Turner syndrome, small-for-gestational age with failure to catch up to the normal height percentiles, Prader-Willi syndrome, idiopathic short stature, SHOX gene haploinsufficiency and Noonan syndrome (current to October 2008). The most common efficacy outcome in children is an increase in height velocity, although rhGH may prevent hypoglycemia in some infants with congenital hypopituitarism and increase the lean/fat ratio in most children - especially those with severe GH deficiency or Prader-Willi syndrome. Doses for adults, which affect body composition and health-related quality of life, are much lower than those for children, per kilogram of lean body mass. The safety profile is quite favorable with a small, but significant, incidence of raised intracranial pressure, scoliosis, muscle and joint discomfort, including slipped capital femoral epiphysis. The approval of rhGH therapy for short, non-GH-deficient children has validated the notion of GH sensitivity, which gives the opportunity to some children with significant short stature, but with normal stimulated GH test results, to benefit from rhGH therapy and perhaps attain an adult height within the normal range and appropriate for their mid-parental target height (genetic potential)., (Copyright 2010 S. Karger AG, Basel.)

Growth hormone treatment in Noonan syndrome increases growth velocity significantly during the first 2 years of treatment and, to some extent, until puberty. This increase is more pronounced if treatment is started at an early age. Treatment before the age of 5 years is not recommended due to an increased risk of malignancies. In contrast to other growth hormone-treated patients, a slight but significant further increase in height gain can be expected during pubertal growth (at least in boys). Final height improvement varies between 1 and 2 SDS in different studies. Cardiac function does not seem to be impaired during treatment. No significant adverse events have been reported., (2009 S. Karger AG, Basel.)

Short stature is one of the key features of Noonan syndrome (NS). Attempts have therefore been made to improve height by means of recombinant human growth hormone (rhGH) treatment. Most of these endeavors were carried out either as case studies or observational studies. The overall experience in treating NS is still rather limited, and, in general, it can be said that the NS patients who received GH treatment represent a very narrow segment. The dosages applied in both the case studies and observational studies tended to be higher than those used in the replacement therapy of GH-deficient patients, but lower than in Turner syndrome patients. The NS studies have shown that the overall height gain of patients is small (5-10 cm), and that treatment usually begins at the age of about 10 years, at a height of approximately -3.0 SDS. This small response to treatment reflects the external treatment conditions (i.e. late age at GH start, low GH dose), but may also be associated with the fact that impaired sensitivity to GH is common in NS. Both case studies and observational studies are necessary in order to obtain further evidence about the efficacy and safety of GH treatment in NS., (2009 S. Karger AG, Basel.)

Short stature is a major characteristic of Noonan syndrome (NS), the biological basis of which is not yet clear. In around half of all individuals with NS, the cytoplasmic tyrosine phosphatase SHP2 encoded by PTPN11 is mutated and predicted to be overactive. While SHP2 enhances Ras-MAPK signaling, it downregulates Jak2/STAT5b signaling of the growth hormone (GH) receptor, according to in vitro data. Decreased IGF-I levels have been measured in those children with NS who carried PTPN11 mutations suggesting a mode of mild GH insensitivity. The short-term responsiveness to GH therapy in NS with respect to PTPN11 mutations has been addressed in 3 studies in the past. The number of treated children was small and gene analysis was restricted to PTPN11, excluding the recent discovered candidate genes KRAS, RAF1 and SOS1. All 3 studies showed that GH responsiveness was mildly reduced in the presence of PTPN11 mutations; relevant long-term data, however, are missing. In a small subgroup of patients with NS, tumor risk is increased and related to specific mutations of Ras-MAPK pathway genes, including PTPN11. Therefore, when long-term GH therapy is intended to promote growth in children with NS, it has to be considered in relation to the genotype, the effective promotion of growth and the potentially increased tumor risk. Progress in the understanding of cell regulation by Ras-MAPK signaling will hopefully provide more evidence on which therapy might be helpful in the care of children with NS., (2009 S. Karger AG, Basel.)

Background and Aims: Several studies, despite using small cohorts, have shown a short-term improvement in the height velocity of short children with Noonan syndrome (NS) when treated with recombinant growth hormone (GH). However, the question is whether or not this improvement is sustained until adult height is reached. This paper reviews the few studies reporting final height data of GH treatment in individuals with NS., Methods: Review of published papers from 4 main and several small studies with final height data after GH treatment in NS., Results: The range of height gain to adult age varies between 0.6 and 2.0 SDS, depending on genotype, age at start of treatment, duration of treatment and which growth charts are used. The younger the age at which treatment is started, the better the result. There seems to be a correlation between growth response and genotype, with a diminished growth response when the PTPN11 mutation is present., Conclusion: Data on the benefits of GH treatment during childhood and adolescence upon the final height are encouraging in individuals with NS. There is a substantial height gain during prepubertal years, which continues during the pubertal period, reaching a final height within the normal population in the majority of previously short individuals with NS., (2009 S. Karger AG, Basel.)

Background: The clinical hallmarks of Noonan syndrome (NS) are facial dysmorphism, short stature and cardiac defects. As one of the common cardiac defects in NS is hypertrophic cardiomyopathy, there have been concerns regarding cardiac safety since the start of human growth hormone (hGH) therapy for NS., Methods: Review of currently available data on the prevalence of cardiac defects, the theoretical effects of hGH on the heart and the results of studies on the effects of hGH on the heart., Results: The prevalence of cardiac defects in NS is high, and the spectrum is very broad. Progression of ventricular wall thickness during hGH therapy has never been reported. There are barely any data available on children with NS and hypertrophic cardiomyopathy collected during hGH therapy. In post-marketing surveillance studies, there are no reports of adverse cardiac events related to hGH therapy., Conclusion: The reported absence of negative effects of hGH therapy on the heart in NS and especially on ventricular wall thickness is reassuring. Still, keeping in mind the current limited experience, any effects on the heart resulting from hGH therapy should be monitored carefully in NS., (2009 S. Karger AG, Basel.)

A 17-year-old boy with chromosomal mosaicism resulting in a 45,X/46,X,idic(Y)(p11) karyotype came to medical attention at the age of 10 years because of short stature. He was treated with recombinant growth hormone for 6.6 years and has achieved a near final adult height of 172.5 cm. His clinical features included second-degree hypospadias, some stigmata of Turner syndrome, and spontaneous progression through puberty. We report long-term use of growth hormone in a male adolescent with isodicentric Yq.

Context: Noonan syndrome (NS) is a heterogeneous genetic disorder characterized by short stature., Setting: The National Cooperative Growth Study (NCGS), a postmarketing observational study of recombinant human GH (rhGH)-treated children, includes a large cohort of children with NS., Patients: We studied NCGS-enrolled prepubertal and pubertal children with NS., Main Outcomes: Baseline characteristics and growth responses in NS patients with reported near-adult height (NAH) (n = 65) were compared to patients with idiopathic GH deficiency (n = 3007) and Turner syndrome (TS; n = 1378) with reported NAH to identify factors contributing to NAH optimization in NS., Results: NS patients (mean enrollment age, 11.6 yr) received rhGH (mean, 0.33 mg/kg . wk) for a mean of 5.6 yr. No significant difference was observed in Delta height sd score (SDS) between NS (+1.4 +/- 0.7) and TS (+1.2 +/- 0.9). However, Delta height SDS for NS and TS differed significantly from idiopathic GH deficiency (+1.7 +/- 1.0) (P < 0.0001). Mean gain in NAH above projected was 10.9 +/- 4.9 cm (males) and 9.2 +/- 4.0 cm (females). Duration of prepubertal rhGH was an important contributor to prepubertal change in height SDS (r(2) = 0.97). Height SDS at pubertal onset highly correlated with NAH SDS (rho = 0.783; P < 0.0001). Duration of puberty highly correlated with pubertal height gain in centimeters for males (rho = 0.941) and females (rho = 0.882) (P < 0.01). No new adverse events were observed., Conclusions: rhGH significantly improved height SDS for children with NS at NAH. Duration of prepubertal rhGH and height SDS at puberty were important contributors to NAH. Because starting age of the patients in this report was 11.6 yr, these data suggest that greater growth optimization is possible with earlier initiation of therapy.

Noonan syndrome (NS) is a phenotypically heterogeneous condition frequently associated with short stature. Genetic investigations have identified mutations in several genes, e.g. PTPN11, KRAS, RAF and SOS1 in patients with the NS phenotype and related disorders such as LEOPARD, Costello and Cardiofacio- cutaneous syndromes. In NS, PTPN11 mutations are present in 29-60% of cases. The degree of short stature does not associate closely with the presence of a mutation; however, some PTPN11-positive patients have decreased growth hormone (GH)-dependent growth factors consistent with mild GH insensitivity. GH therapy induces short-term increases in height velocity over 1-3 years, and is likely to improve adult height.

Background: Patients with mutations or deletions of the Short Stature Homeobox-containing(SHOX) gene have variable degrees of growth impairment, with or without mesomelic skeletal dysplasia. If untreated, short patients with SHOX deficiency remain short in adulthood. Growth hormone (GH) treatment improves short-term linear growth; however, there are no data on GH treatment effects on final height., Patients: In a retrospective study, we assessed the relative effects of GH on final height gain in patients with SHOX deficiency (n = 14; 12 females) and Turner syndrome (TS) (n = 158). Patients were included if they fulfilled the following criteria: genetically-confirmed SHOX deficiency or TS, baseline height SDS <1.5, GH treatment started at Tanner stage < or =2, duration of GH treatment >2 years, and final height attained., Results: Both groups of patients were short at baseline (height SDS [mean +/- SD]: SHOX deficiency, -3.3 +/- 0.9; TS, -2.9 +/- 0.8). Height SDS gain from baseline to final height was significant for each patient group (SHOX deficiency, 1.1 +/- 0.7; TS, 1.2 +/- 0.8; p < 0.001); however, it was not significantly different between groups (p = 0.708)., Conclusions: Patients with SHOX deficiency receive similar final height benefit from GH treatment to those with TS., (Copyright 2009 S. Karger AG, Basel.)

Noonan syndrome is an autosomal dominant condition with variable phenotypic expression. Although an association between Noonan syndrome and various neoplasms has been identified, a relationship with primary glial or neuronal tumors of the central nervous system (CNS) has not yet been established. We describe the case of a 6-year-old male patient with Noonan syndrome and leptomeningeally disseminated low-grade mixed glioneuronal tumor. After a literature review, this case emerges as the third patient to present with Noonan syndrome and primary CNS glial tumor and the first with mixed glioneuronal tumor, indicating the possible association between these individual entities.

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 -2.8 (-4.1 to -1.8) and 0.0 (-1.4 to +1.2), 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 +1.3 (+0.2 to +2.7) and +1.3 (-0.6 to +2.4), based on national and Noonan standards respectively. In 22 children with a mutation in PTPN11 mean gain in H-SDS for National standards was +1.3, not different from the mean gain in the five children without a mutation in PTPN11+1.3 (P=0.98)., Conclusion: Long-term GH treatment in NS leads to attainment of adult height within the normal range in most patients.

Noonan's syndrome is a clinical entity associating short stature, facial dysmorphy and congenital cardiomyopathy. In 50 % of cases, PTPN11 mutations are found, transmitted as an autosomal dominant trait. Mutations of other genes (KRAS, SOS1) were also recently reported. Short stature could be due to GH deficiency, abnormal neurosecretory function or GH insensitivity. GH treatment induces height gain, even if only few studies reported data on final height. Response to GH varies, depending on the presence of PTPN11 mutations. No cardiac adverse effects were reported to date with GH treatment in Noonan's syndrome.

Noonan Syndrome (NS) is one of the most common genetic syndromes and it is an important differential diagnosis in children with short stature, delayed puberty and cryptorchidism. NS is characterized by dysmorphic facial features, congenital heart defects and short stature, but there is a great variability in phenotype. NS may occur in a pattern consistent with autosomal dominant inheritance with almost complete penetrance. The diagnosis is based on a clinical score system proposed by van der Burgt e cols. in 1994. In recent years, germline mutations in the components of RAS-MAPK (mitogen activated protein kinase) pathway have been shown to be involved in the pathogenesis of NS. Mutations in PTPN11, KRAS, SOS1, RAF1 and MEK1 can explain 60-70% of NS molecular cause. Growth hormone therapy is proposed to correct the short stature observed in these patients. Recent studies suggest that the presence of PTPN11 mutations in patients with NS indicates a reduced growth response to short-term hrGH treatment. In this article, it is reviewed clinical and molecular aspects of NS and hrGH treatment for short stature.

Background: Noonan syndrome (NS) is an autosomal dominant inherited disease, characterized by a distinctive facial appearance, congenital heart defects, and short stature. Treatment with growth hormone (GH) is an option to enhance height, but long-term effects are still unclear., Patients and Methods: A cohort of 402 patients (269 males, 133 females), mean age 9.7 years at start with GH, was studied within the KIGS International growth database with respect to long-term response to GH therapy and final height after GH therapy., Results: At the start of GH therapy median height was -2.61 SDS (Tanner 1966 standards). Seventy-three patients who were followed longitudinally for 3 years had an increment in height SDS (Ht SDS) over the first 3 successive years of 0.54, 0.13 and 0.13, respectively. Twenty-four patients had reached their final height after 4-12 years of GH treatment. Their Ht SDS increased from a median of -3.28 to a median of -2.41 at final height., Conclusion: This group of patients with NS showed an early response to GH treatment, with an attenuation of this effect thereafter. At final height the median increment of final height was 0.61 SDS according to Tanner standards and 0.97 SDS according to Noonan standards. No serious side effects were reported.

Noonan syndrome (NS) is a phenotypically heterogeneous syndrome which is frequently associated with short stature. Recent genetic investigations have identified mutations in five genes, namely PTPN11, KRAS, SOS1, NF1 and RAF1 in patients with the NS phenotype. PTPN11 is the commonest, being present in approximately 50% of cases. The degree of short stature in children does not associate closely with the presence of mutations, however some PTPN11-positive patients have decreased GH-dependent growth factors consistent with mild GH insensitivity. GH therapy, using doses similar to those approved for Turner syndrome (TS), induced short-term increases in height velocity over 1-3 years, and may improve final adult height with longer-term treatment., (Copyright 2008 S. Karger AG, Basel.)

Growth hormone (GH) is a polypeptide hormone, secreted by somatotropic cells of the anterior part of the hypophysis. Its application in therapy, first limited to GH deficient children, has now been widened to various other clinical conditions, not necessarily related to short stature. Clinical trials conducted in recent years have proved the safety of its administration in both children and adults. The efficacy of this form of therapy varies, according to different authors, from enthusiastic data to very critical opinions. For many pediatric diseases, such as GH deficiency or Turner syndrome, GH is regarded by many experts, despite the high costs of the therapy, as the first-line treatment. Mounting evidence suggests that GH is safe and effective also in children with chronic renal failure and cystic fibrosis. Recently, it has also been administered to adults with GH deficiency and short bowel syndrome. The aim of this paper is to summarize the current data on GH administration in modern pharmacotherapy. In this paper we have included the results of the recently published studies and discussed not commonly known indications for GH therapy, as well as its experimental administration in both children and adults.

We report a child with Noonan syndrome, referred with severe short stature (height--5.4 SD) and biochemical features of GH resistance. The Noonan syndrome phenotype was confirmed by a clinical geneticist, however analysis of the protein tyrosine phosphatase nonreceptor type 11 (PTPN11) gene showed no mutation. Baseline serum IGF-I, IGFbinding protein 3 (IGFBP-3) and acid-labile subunit (ALS) were low, and in an IGF-I generation test, IGF-I did not increase into the normal range and IGFBP-3 and ALS did not change. These results are consistent with GH resistance. Treatment with human GH (hGH) was given in a dose of 0.05 mg/kg/day and height velocity increased from 5.6 to 10.7 cm/yr during the first year, and 8.9 cm/yr during the second year of therapy. Height standard deviation score has increased by 1.85 after 2 and a half yr of therapy. Serum IGF-I, IGFBP-3 and ALS values increased well into the normal range. This case shows that the potential value of GH therapy must be evaluated in each patient individually and that an excellent response may occur in a child with a PTPN11-negative genotype.

Introduction: Around 50% of Noonan syndrome (NS) patients present heterozygous mutations in the PTPN11 gene., Aim: To evaluate the frequency of mutations in the PTPN11 in patients with NS, and perform phenotype-genotype correlation., Patients: 33 NS patients (23 males)., Methods: DNA was extracted from peripheral blood leukocytes, and all 15 PTPN11 exons were directly sequenced., Results: Nine different missense mutations, including the novel P491H, were found in 16 of 33 NS patients. The most frequently observed features in NS patients were posteriorly rotated ears with thick helix (85%), short stature (79%), webbed neck (77%) and cryptorchidism (60%) in boys. The mean height SDS was -2.7 +/- 1.2 and BMI SDS was -1 +/- 1.4. Patients with PTPN11 mutations presented a higher incidence of pulmonary stenosis than patients without mutations (38% vs. 6%, p< 0.05). Patients with and without mutations did not present differences regarding height SDS, BMI SDS, frequency of thorax deformity, facial characteristics, cryptorchidism, mental retardation, learning disabilities, GH peak at stimulation test and IGF-1 or IGFBP-3 SDS., Conclusion: We identified missense mutations in 48.5% of the NS patients. There was a positive correlation between the presence of PTPN11 mutations and pulmonary stenosis frequency in NS patients.

Growth hormone (GH) is a polypeptide secreted by somatotropic cells of the anterior part of the hypophysis. Its usage was firstly restricted to children with growth hormone deficiency. Because of molecular biology development and greater availability of GH, the range of its therapeutic applications has widened. Apart from supplementary management of GH deficiency in children and adults, nowadays it is commonly used as first-line therapy in many disorders associated with short height. The aim of this paper is to present the exact role of GH in contemporary pharmacotherapy and adverse effects of treatment with GH. We review both well-known and less-commonly known indications for this form of treatment. Suggested dosage and the time of the beginning and duration of therapy are also discussed.

Background: The autosomal-dominant Noonan syndrome (MIM 163950) is characterized by short stature, typical facial dysmorphology and heart defects. Noonan syndrome is genetically heterogeneous. Over the last few years, germline mutations in four genes have been found in people with clinical signs of Noonan syndrome, accounting for approximately 65% of cases. All four genes encode proteins involved in the Ras-mitogen-activated protein kinase pathway and result in upregulation of this pathway. Recently, more data on final height after long-term growth hormone (GH) therapy has become available that shows its effectiveness in increasing final height for individuals with Noonan syndrome., Conclusions: The genetics underlying Noonan syndrome has been partially clarified over the last 5 years and further findings will undoubtedly be reported in the next few years. GH therapy has been used to treat patients with Noonan syndrome for approximately 15 years and is effective in improving adult height in affected children., (Copyright (c) 2007 S. Karger AG, Basel.)

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.

Aim: To assess whether children with Noonan syndrome on long-term growth hormone (GH) therapy improve their final height to near mid-parental height., Methods: Twenty-five prepubertal children (13 girls) with Noonan syndrome (NS) were studied. A single clinician made the diagnosis based on clinical criteria. GH treatment started at an age ranging from 3.1 to 13.8 y and was continued for at least 2 y. Improvement or "gain" in final height (FH) was defined as either the difference between adult height SD scores (SDS) and pre-treatment height SDS (the childhood component of the Swedish reference) or height SDS compared to the Noonan reference., Results: Ten children received a GH dose of 33 microg/kg/d (mean age at start 7.7+/-2.1 y, mean age at stop 17.6+/-1.7 y) and 15 received a dose of 66 microg/kg/d (mean age at start 8.6+/-3.3 y, mean age at stop 18.4+/-2.1 y). Eighteen out of 25 patients reached FH. A substantial improvement in FH of 1.7 SDS, equivalent to 10.4 cm compared to pre-treatment height, was observed. No significant difference was seen between the two GH doses. Females gained a mean height of 9.8 cm and males 1-13 cm (FH 174.5+/-7.8 cm vs mean adult height of 162.5+/-5.4 cm for males with NS) at final height. Moreover, 60% reached a mid-parental height of+/-1 SD., Conclusion: GH treatment improves final height in patients with Noonan syndrome, with a mean gain of 1.7 SDS. The prepubertal height gain is maintained to final height and the children achieve a height close to their mid-parental height.

Context: 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., Setting: This study was performed at a university hospital., Design: The study design was to conduct a retrospective analysis of 3 yr of hGH treatment and genotyping of PTPN11 in patients with NS., Patients: 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., Intervention: Patients were treated with hGH (47 microg/kg.d)., Main Outcome Measures: 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.

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.

Unlabelled: A male infant with clinical features of Noonan syndrome and rapidly progressive hypertrophic cardiomyopathy is reported. He manifested severe heart failure and failure to thrive. Administration of propranolol and cibenzoline improved ventricular outflow tract obstruction, leading to catch-up growth. Genetic analysis of the patient revealed a novel missense mutation in the PTPN11 gene., Conclusion: This is the first description of a patient with a Gln510Glu mutation in the protein-tyrosine phosphatase, non-receptor type 11 gene. This specific mutation may be associated with a rapidly progressive hypertrophic cardiomyopathy.

The objective of this study was to investigate the effect of administration of recombinant human growth hormone (hGH) in patients with Noonan syndrome. hGH was administered (0.5 IU/kg/week) to 15 patients with Noonan syndrome over a 2 year period. Average patient age prior to therapy was 7.5 +/- 2.5 (mean +/- SD) yr, the height SD score was -2.8 +/- 0.7, and the pretreatment height velocity and bone age were 4.8 +/- 1.0 cm/yr and 5.8 +/- 2.1 yr, respectively. The height velocity in the year prior to treatment, and 0-12 and 12-24 months after commencing treatment was 4.8 +/- 1.0 cm/yr, 7.0 +/- 1.2 cm/yr, and 5.5 +/- 0.6 cm/yr, respectively. The height velocity in the first year of treatment was significantly greater (P = 0.0001, n = 14) than the pretreatment value, but there was no significant difference in the second year. The height SD scores at the commencement of treatment, and after 12 and 24 months of treatment were -2.8 +/- 0.7, -2.4 +/- 0.7, and -2.2 +/- 0.5, respectively. Bone age advanced by 1.1 +/- 0.5 yr in the 12 months after commencing treatment. We conclude that the use of hGH may be beneficial in the treatment of Noonan syndrome, although further research is required.

Aim: To evaluate the possible effects of recombinant growth hormone (rhGH) therapy on mineral homeostasis and bone turnover, the authors studied calcium-phosphate metabolism parameters, including some bone markers, in 2 prepubertal subjects with Noonan's syndrome (NS)., Methods: Two prepubertal males suffering from NS, short stature (-3.9 and -5.4 SDS respectively) and low growth velocity (3.9 and 3.3 cm/year), were treated with rhGH (0.85 U/kg/week) for 1 year. Serum levels of total calcium (Ca), inorganic phosphate (P), magnesium (Mg), parathyroid hormone (PTH), calcitonin (CT), 25OH vitamin D, 1.25(OH)(2)D, osteocalcin (BGP), type I procollagen carboxy-terminal propeptide (PICP) and its telopeptide (ICTP) were measured., Results: The baseline values were in the normal range; during the treatment no remarkable difference in the values of every one parameters was detected in the 2 patients studied. In one of them, who responded to GH treatment with significantly improved growth velocity, serum levels of the BGP increased during the first semester, and then progressively declined; conversely, serum levels of the ICTP remained stable during the first 6 months of GH-therapy, whereas increased in the following 6 months., Conclusion: The results suggest that in Noonan's syndrome patients responding to GH-therapy, a stimulation of bone turnover, with ensuing increase of height velocity, takes place, at least during the first year of GH-therapy. The authors underline the necessity of confirming their results on a larger group of patients with Noonan's syndrome.

Noonan syndrome is a relatively common autosomal dominant condition characterised by cardiac defects, short stature, feeding difficulties during the first year of life, and learning and behavioural problems later in life. The diagnosis is clinical and in 50% of cases it can be confirmed by a mutation in the PTPN11 gene. Studies into the effect of growth hormone treatment on final height have yet to provide any definite conclusions. Therefore, for the time being this treatment should be carried out in a research setting. Early-childhood feeding difficulties are troublesome. However, these disappear spontaneously and do not seem to negatively affect growth. Specific developmental patterns, resulting in behavioural and learning problems (non-verbal learning disability) are frequently encountered and require a specific approach.

Patients with Noonan syndrome, which is thought to have an incidence of 1 : 1,000 to 1 : 2,500 live births, have variable hypogonadism together with features such as pulmonary valvular stenosis, dysmorphism, deafness, visual problems, cryptorchidism, clotting disorders, and short stature. Noonan syndrome is now known to be associated with mutations in the PTPN11 gene encoding the protein tyrosine phosphatase SHP-2 on chromosome 12 (12q24.1). This discovery will facilitate both knowledge of the true incidence and phenotypic diversity. There are poor genotype-phenotype correlations in Noonan syndrome, and the currently defined gene abnormalities only account for a minority of those identified on a clinical basis. Puberty in patients with Noonan syndrome generally occurs spontaneously but is typically delayed. Mean adult height is 162.5cm (men) and 153cm (women), although standards are based on relatively small samples of largely cross-sectional data and are subject to ascertainment bias. Available evidence suggests that there may be disturbance of the growth hormone/insulin-like growth factor axis in Noonan syndrome and that somatropin (growth hormone therapy) dose-dependently improves vertical growth in the short to medium-term. Final height data from a number of European studies will be available later in 2003. Noonan syndrome patients with echocardiographic features of hypertrophic cardiomyopathy may be at particular risk from somatropin therapy because of its known effects on cardiac muscle mass; these patients have generally been excluded from trials of somatropin. Unbiased evidence for the efficacy and safety of somatropin therapy in Noonan syndrome will come from appropriately controlled studies of sufficiently large numbers of patients defined on such a basis and followed to final height. This is now possible but will require international cooperation. Nevertheless, the clinical relevance of somatropin therapy in Noonan syndrome and other short stature syndromes will be dependent on looking beyond improvement in final height (even if achievable) to psychological and quality of life outcomes.

Skeletal dysplasias comprise a diverse group of conditions that usually compromise both linear growth and body proportions. It is of theoretical interest to evaluate the effect of GH treatment on linear growth, body proportion and final height in the different skeletal dysplasias. Reported experience of GH treatment in short children with skeletal dysplasia is sparse and often limited to short treatment periods and knowledge of its effects on final height and body proportion is generally lacking. Formal studies are almost all confined to achondroplasia as the most common entity. First-year response is typically a 2-3 cm increase in growth velocity in prepubertal children, or a gain of about 0.5 SDS or less in relative height from a baseline level of -4 to -5 SDS. GH treatment for up to 5 years in achondroplasia can produce a total height gain of about 1 SDS. Apart from achondroplasia, treatment of hypochondroplasia and dyschondrosteosis with GH has been reported in a small number of patients. Long-term data are, however, lacking. Of theoretical interest is that in many syndromic or non-syndromic short-statured children body proportion, i.e. trunk to leg length ratio, does not seem to be dependent on the degree of GH sufficiency and does not seem to be changed by GH treatment. GH treatment, at least in the prepubertal period, does seem to influence degree of disproportion., (Copyright 2003 S. Karger AG, Basel)

Twenty-three children with Noonan's syndrome were treated with growth hormone (GH) and followed for at least three years. The presence of cardiomyopathy was a contraindication to treatment. Height SDS and velocity increased during treatment. None of the 23 children developed hypertrophic cardiomyopathy during GH treatment. Children with any cardiac abnormality at the start of treatment did not show a reduced growth trend when compared with patients with normal hearts.

Short stature is one of the major features of Noonan's syndrome (NS). In a multicentre trial of growth hormone (GH) therapy in 25 children with NS, we observed a large inter-individual variation in first-year response to GH treatment. This suggested that subgroups might exist in NS that differ in either endogenous GH status or responsiveness to GH therapy. We therefore related growth, GH secretion and 2 years response to GH treatment to subtypes of phenotypic expression of NS. Twelve patients were moderately affected and 13 had a severe clinical phenotype of NS. The variability in phenotype did not correlate with significant differences in intra-uterine growth, infancy growth or childhood growth, and response to GH treatment. However, the variability in phenotype severity did account for striking differences in endogenous GH secretion.

We assessed bone mineral density (BMD) and body composition in children with Noonan's syndrome (NS) before and during growth hormone (GH) treatment. Sixteen children (12 boys, 4 girls) with NS aged 5.8-14.2 (mean 10.0) years were studied for 2 years. Anthropometry, BMD measurements by radiographic absorptiometry and bioimpedance measurements (Akern-BIA 101/S) were performed at baseline and after 3, 6, 12 and 24 months. Daily GH dosage was 0.05 mg/kg. Trabecular volumetric BMD was normal; cortical BMD was in the lower normal range at baseline and slightly increased over the 2 years. Fat free mass and total body water were below normal at the start and increased significantly over the first 3 months, with a slight increment thereafter. Percentage fat mass decreased over the first 6 months and increased thereafter. These findings are comparable to the data on body composition in short normal children and girls with Turner's syndrome treated with GH.