Hormone Research (Horm Res)

Publications in this journal

• Article: Growth hormone and the heart in Noonan syndrome.

  C Noordam
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  ABSTRACT: 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. 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. 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. 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.
  Hormone Research 12/2009; 72 Suppl 2:49-51.
• Article: Response to growth hormone in short children with Noonan syndrome: correlation to genotype.

  Gerhard Binder
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  ABSTRACT: 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.
  Hormone Research 12/2009; 72 Suppl 2:52-6.
• Article: Genetic and pathogenetic aspects of Noonan syndrome and related disorders.

  Martin Zenker
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  ABSTRACT: Noonan syndrome (NS) and the clinically overlapping disorders cardio-facio-cutaneous syndrome, LEOPARD syndrome, Costello syndrome and Neurofibromatosis-Noonan syndrome share the clinical features of short stature, the same spectrum of congenital heart defects, and a similar pattern of craniofacial anomalies. It is now known that all these disorders are caused by mutations in components of the RAS-MAPK signaling pathway. This pathway was previously known for its involvement in tumorigenesis. This article reviews the current knowledge on underlying genetic alterations and possible pathogenetic mechanisms responsible for NS and related disorders. It discusses the relationship between a group of developmental disorders and oncogenes. Potential future treatment prospects are based on the possibility of inhibiting RAS-MAPK signaling by pharmaceuticals.
  Hormone Research 12/2009; 72 Suppl 2:57-63.
• Article: GH therapy in Noonan syndrome: Review of final height data.

  Jovanna Dahlgren
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  ABSTRACT: 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. Review of published papers from 4 main and several small studies with final height data after GH treatment in NS. 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. 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.
  Hormone Research 12/2009; 72 Suppl 2:46-8.
• Article: Growing news on Noonan and related syndromes.

  Joachim Woelfle, Berthold P Hauffa
  Hormone Research 12/2009; 72 Suppl 2:1-2.
• Article: Noonan syndrome: the hypothalamo-adrenal and hypothalamo-gonadal axes.

  Christopher J H Kelnar
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  ABSTRACT: The hypothalamo-pituitary-adrenal axis has not been studied systematically in Noonan syndrome (NS), despite potential concerns about other aspects of hypothalamo-pituitary function. While adrenarche may be delayed in children with constitutional growth of puberty and in isolated GH deficiency, this does not generally seem to be the case in hypergonadotrophic hypogonadism due to Turner syndrome (TS) and this is (anecdotally) the usual hormonal profile in NS children and adults. Precocious or 'exaggerated' adrenarche can be associated with intrauterine growth retardation and is a forerunner of syndrome X. Although NS neonates often have 'normal' birth weights, in some it can be artificially inflated by subcutaneous edema (as in TS, where intrauterine growth retardation is characteristic). Overall, however, a controlling role for adrenarche (whether precocious or delayed) in gonadarche in NS seems unlikely. Neither normally descended testes nor normal (even if delayed) pubertal development implies normal fertility in NS men. Interactions between fetal, neonatal, childhood and pubertal testis development and gonadal axis maturation are complex. There is probably a spectrum of abnormalities in NS, but most commonly primary gonadal failure and hypergonadotrophic hypogonadism - characteristic NS molecular genetic abnormalities - may be important for normal germ cell proliferation, development and migration. The identification of different gene defects facilitates understanding of NS phenotypic diversity and provides opportunities for prospective studies on gonadal and adrenal axes in better defined populations less subject to ascertainment bias. At a clinical level, more longitudinal data are still needed with regard to the natural history of pubertal timing, its tempo of progression and the pattern of pubertal growth.
  Hormone Research 12/2009; 72 Suppl 2:24-30.
• Article: Malignant diseases in Noonan syndrome and related disorders.

  Henrik Hasle
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  ABSTRACT: The overall risk of cancer in children with Noonan (NS), cardio-facial-cutaneous, Costello or LEOPARD syndrome is high, although no precise estimates are available. There are few data on cancer in adults with NS, but the reported numbers of malignancies in adults do not seem excessive. Juvenile myelomonocytic leukemia (JMML) is a rare aggressive leukemia in young children. A JMML-like myeloproliferative disorder has been described in about 30 neonates with NS and the PTPN11 mutation. The disorder often regresses spontaneously, but fatal complications may occur. A review of the literature indicates an increased risk of acute lymphoblastic leukemia and acute myeloid leukemia in NS. Young children with Costello syndrome have an extremely high risk of rhabdomyosarcoma, and also an increased risk of neuroblastoma and bladder carcinoma. Registry-based studies of patients with NS and related disorders diagnosed with molecular genetics and a high-quality long-term follow-up are necessary to further estimate the incidence of malignancy.
  Hormone Research 12/2009; 72 Suppl 2:8-14.
• Article: Growth in Noonan syndrome.

  B J Otten, C Noordam
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  ABSTRACT: Growth failure in Noonan syndrome is mainly postnatal of character and is dominated by slow maturation and late puberty. The postnatal early decline seems to be an intrinsic part of the syndrome. Reported adult heights are about -2 SD and are indicative of a secular trend.
  Hormone Research 12/2009; 72 Suppl 2:31-5.
• Article: Noonan syndrome: growth to growth hormone - the experience of observational studies.

  Michael B Ranke
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  ABSTRACT: 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.
  Hormone Research 12/2009; 72 Suppl 2:36-40.
• Article: Noonan syndrome: introduction and basic clinical features.

  T Rohrer
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  ABSTRACT: Noonan syndrome (NS) is a fairly common (1 per 1,000-2,500 live births) autosomal dominantly inherited disorder and the most common syndromal cause of congenital heart disease after Down's syndrome. The clinical features vary with age, but typical signs of NS include characteristic facial features with hypertelorism, down-slanting palpebral fissures, low-set posteriorly rotated ears, chest and spinal deformities, short stature, specific heart defects, learning disabilities and mild mental retardation. This article gives a brief introduction to NS and its basic clinical features using the established and generally accepted NS scoring system based on family history and facial, cardiac, growth, chest wall and other criteria. Aspects discussed include the definition, epidemiology, etiology, diagnosis and genetics of NS, as well as growth, skeletal and gonadal anomalies, pubertal development, ophthalmic and cutaneous abnormalities and the incidence of cancer in patients with NS.
  Hormone Research 12/2009; 72 Suppl 2:3-7.
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  Article: Neuropsychological and behavioral aspects of Noonan syndrome.

  Ellen Wingbermuehle, Jos Egger, Ineke van der Burgt, Willem Verhoeven
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  ABSTRACT: The current paper introduces concise neuropsychological assessment as an essential tool for studying the contribution of cognition and behavior in the expression of genetic syndromes, like Noonan syndrome (NS). Cognitive and behavioral findings in NS show intelligence scores across a wide range, with a mildly lowered average level. Language and motor development are often delayed, but no longer dysfunctional in adulthood. Continuing mild problems in selective and sustained attention are noted, as well as suboptimal organization skills and compromised abilities to structure complex information. These problems seem to culminate in learning difficulties, requiring attention for special needs in education. It seems that a complex of psychosocial immaturity, alexithymia and amenable traits is typical of NS patients. Consequently, psychopathology or psychological problems in leading a self-serving life may often remain underreported. This is why the authors advocate the integration of the domain of social cognition and personality in NS assessment.
  Hormone Research 12/2009; 72 Suppl 2:15-23.
• Article: Growth hormone therapy in Noonan syndrome: growth response and characteristics.

  Otto Westphal
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  ABSTRACT: 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.
  Hormone Research 12/2009; 72 Suppl 2:41-5.
• Article: Juvenile idiopathic arthritis: classification, clinical presentation and current treatments.

  Gunther E Dannecker, Pierre Quartier
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  ABSTRACT: BACKGROUND: The term juvenile idiopathic arthritis (JIA) describes a clinically heterogeneous group of arthritides. The onset in all subgroups is before 16 years of age, but each group presents with different clinical signs and symptoms. The cause of the disease is unknown, but both genetic and environmental factors are believed to be involved. Management of the disease has greatly improved in recent years due to advances in pharmacologic treatment options (especially with new biologic agents) and the prognosis for patients is better than ever before. However, none of the available drugs has a curative potential. This review provides an overview on the classification and the clinical symptoms of the defined subgroups of JIA as well as pharmacotherapies for it. CONCLUSIONS: Treatment of children with JIA is challenging and complex. Since lengthy therapy might be necessary, a multidisciplinary pediatric rheumatology team is crucial for optimal treatment. Although a cure is unknown at this time, adequate treatment aims to preserve function of the joints as well as normal childhood development.
  Hormone Research 11/2009; 72 Suppl 1:4-12.
• Article: Mechanisms of impaired growth: effect of steroids on bone and cartilage.

  Robert C Olney
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  ABSTRACT: BACKGROUND: Long-term treatment with high-dose glucocorticoids (GCs) has profound effects on bone metabolism and linear growth. Bone metabolism is a balance between bone resorption by osteoclasts and new bone formation by osteoblasts. Systemically, GC treatment reduces circulating levels of estrogen and modestly increases parathyroid hormone levels. At the local level, GCs decrease insulin-like growth factor I (IGF-I) production, induce IGF-I resistance and increase nuclear factor kappaB ligand production by osteoblasts. These alterations inhibit new bone formation and stimulate bone resorption, with a net loss of bone over time. Clinically, this results in decreased bone mineral density, osteoporosis and increased risk for fracture. Local effects of GCs at the growth plate include reduction of IGF-I production, inducing IGF-I resistance and reducing production of C-type natriuretic peptide, which results in a reduction of chondrocyte proliferation, matrix synthesis and hypertrophy. These reductions in chondrocyte function result in decreased linear growth. CONCLUSIONS: The effects of GCs on bone metabolism and linear growth are sensitive and specific and represent an evolutionary adaptation to redirect resources during times of physiologic stress. Since many of these effects result from alterations in IGF-I production, growth hormone therapy is a potential approach to ameliorate these problems.
  Hormone Research 11/2009; 72 Suppl 1:30-5.
• Article: Mechanisms of muscle atrophy induced by glucocorticoids.

  O Schakman, H Gilson, S Kalista, J P Thissen
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  ABSTRACT: BACKGROUND: Many pathological states characterized by muscle atrophy (e.g., sepsis, cachexia, starvation, metabolic acidosis and severe insulinopenia) are associated with an increase in circulating glucocorticoid (GC) levels, suggesting that GC could trigger the muscle atrophy observed in these conditions. GC-induced muscle atrophy results from decreased protein synthesis and increased protein degradation. The inhibitory effect of GCs on protein synthesis is thought to result mainly from the inhibition of the p70 ribosomal S6 protein kinase. The stimulatory effect of GCs on muscle proteolysis results from the activation of two major cellular proteolytic systems: ubiquitin proteasome and lysosomal systems. The decrease in muscle production of insulin-like growth factor I (IGF-I), a muscle anabolic growth factor, could contribute to GC-induced muscle atrophy. By activating the phosphatidylinositol-3-kinase/Akt pathway, IGF-I overrides GC action to stunt muscle atrophy. Evidence also indicates that increased production of myostatin, a catabolic growth factor, could play a critical role in GC-induced muscle atrophy. CONCLUSIONS: Recent progress in understanding the role of growth factors in GC-induced muscle atrophy allows investigation into new therapies to minimize this myopathy.
  Hormone Research 11/2009; 72 Suppl 1:36-41.
• Article: Promoting growth in chronic inflammatory disease: lessons from studies of the growth plate.

  S F Ahmed, L Sävendahl
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  ABSTRACT: BACKGROUND: Growth disorders are commonly observed in children with chronic inflammatory disease. It is likely that these disorders are mediated by a combination of factors, including the disease process and its treatment (with drugs such as glucocorticoids [GCs]). These factors affect the growth hormone-insulin-like growth factor I (IGF-I) axis, which is crucial for promoting linear growth at the level of the growth plate. Recent advances in our knowledge of the effects of GCs and proinflammatory cytokines on the growth plate have led to an improved understanding of the biological rationale for the use of growth-promoting therapy in children with chronic inflammatory disease and concurrent growth retardation. CONCLUSIONS: Both GCs and proinflammatory cytokines can adversely affect a number of components of growth plate chondrogenesis, and these effects can be ameliorated by raising local IGF-I exposure. However, this intervention does not lead to complete normalization of the growth plate. In children with chronic inflammation, the cornerstone of improving growth remains the judicious use of GCs while ensuring effective control of the disease process.
  Hormone Research 11/2009; 72 Suppl 1:42-7.
• Article: Effects of growth hormone treatment on growth in children with juvenile idiopathic arthritis.

  D Simon, S Bechtold
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  ABSTRACT: BACKGROUND: Several therapeutic trials have been conducted over the past decade to evaluate the role of exogenous growth hormone (GH) as a means of correcting the growth deficiency seen in children with juvenile idiopathic arthritis (JIA). Early studies showed the benefit of GH treatment with respect to final height in patients with JIA. Of 13 patients receiving GH, 84% (11 patients) achieved a final height within their target range compared with only 22% (4 of 18 patients) of untreated patients. There are, however, factors that may limit the statural gains achieved with GH therapy including severe inflammation, severe statural deficiency at GH therapy initiation, long disease duration and delayed puberty. Data on the efficacy of GH replacement therapy in children with JIA and factors that influence the statural growth response will be reviewed. CONCLUSIONS: Results from therapeutic trials show that treatment with GH can decrease the statural deficit that occurs during the active phase of JIA, producing an adult height that is close to the genetically determined target height.
  Hormone Research 11/2009; 72 Suppl 1:55-9.
• Article: Growth and development abnormalities in children with juvenile idiopathic arthritis: treatment and prevention.

  Paul Czernichow
  Hormone Research 11/2009; 72 Suppl 1:1-3.
• Article: Natural history of growth and body composition in juvenile idiopathic arthritis.

  S Bechtold, J Roth
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  ABSTRACT: BACKGROUND: In patients with juvenile idiopathic arthritis (JIA), growth impairment and altered body composition, including disturbed skeletal development, are well-known long-term complications. Data on longitudinal growth in patients with systemic and polyarticular JIA reveal growth impairment in the active phases of the disease. With reduction in disease activity and lower glucocorticoid (GC) doses, some patients experience 'catch-up' growth; however, many have only a slight improvement in height standard deviation during puberty or after cessation of GC treatment. The consequence is a final height below the 3rd percentile and below the genetic height potential. Although few studies have specifically addressed body composition in children with JIA, studies on the development of bone mass have described notable deficits in both GC-treated and GC-naïve children. In recent years, the deficits in bone mass have been related, in part, to the deficits in muscle mass, which are prevalent in these patients. CONCLUSIONS: The major goal for physicians caring for patients with JIA is optimal disease control while maintaining normal growth. Early recognition of patients who develop prolonged growth disturbances and altered body composition is important as these abnormalities contribute to long-term morbidity and need to be addressed both diagnostically and therapeutically when treating children with JIA.
  Hormone Research 11/2009; 72 Suppl 1:13-9.
• Article: Effects of growth hormone treatment in juvenile idiopathic arthritis: bone and body composition.

  S Bechtold, R Dalla Pozza, H P Schwarz, D Simon
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  ABSTRACT: BACKGROUND: Inflammation and glucocorticoid therapy are major factors influencing growth and bone maturation in patients with juvenile idiopathic arthritis (JIA). In addition to alterations in total bone mineral density and bone geometry, longitudinal data confirm that the main contributors to errant bone maturation in patients with JIA are reductions in muscle mass and force. Growth hormone (GH) therapy, which has shown efficacy in controlling disease, may also positively influence body composition. For several years, GH therapy has been used to treat growth retardation in patients with JIA receiving glucocorticoids. GH therapy normalizes growth velocity, increases height, bone mineral density and bone mass and changes bone geometry. Despite ongoing glucocorticoid therapy, muscle mass and bone size substantially increase with GH therapy. Increased bone size suggests improved bone stability, which may reduce fracture risk. Along with the increase in muscle mass, patients experience stabilized or slightly decreased fat mass during GH therapy. CONCLUSIONS: All these effects suggest an anabolic effect of GH therapy on bone and body composition.
  Hormone Research 11/2009; 72 Suppl 1:60-4.