Etiology and Treatment of Growth Delay in Noonan Syndrome

Noonan syndrome is characterized by multiple phenotypic features, including growth retardation, which represents the main cause of consultation to the clinician. Longitudinal growth during childhood and adolescence depends on several factors, among them an intact somatotrophic axis, which is characterized by an adequate growth hormone (GH) secretion by the pituitary, subsequent binding to its receptor, proper function of the post-receptor signaling pathway for this hormone (JAK-STAT5b and RAS/MAPK), and ultimately by the production of its main effector, insulin like growth factor 1 (IGF-1). Several studies regarding the function of the somatotrophic axis in patients with Noonan syndrome and data from murine models, suggest that partial GH insensitivity at a post-receptor level, as well as possible derangements in the RAS/MAPK pathway, are the most likely causes for the growth failure in these patients. Treatment with recombinant human growth hormone (rhGH) has been used extensively to promote linear growth in these patients. Numerous treatment protocols have been employed so far, but the published studies are quite heterogeneous regarding patient selection, length of treatment, and dose of rhGH utilized, so the true benefit of GH therapy is somewhat difficult to establish. This review will discuss the possible etiologies for the growth delay, as well as the outcomes following rhGH treatment in patients with Noonan syndrome.

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Adult growth hormone deficiency

Oxford Textbook of Endocrinology and Diabetes ◽

10.1093/med/9780199235292.003.2086 ◽

2011 ◽

pp. 152-165

Author(s):

Aurora Aragon-Alonso ◽

Mark Sherlock ◽

Andrew A. Toogood

Keyword(s):

Growth Hormone ◽

Growth Hormone Deficiency ◽

Replacement Therapy ◽

Recombinant Human Growth Hormone ◽

Hormone Replacement ◽

Adult Life ◽

Growth Failure ◽

Clinical Syndrome ◽

Hormone Deficiency ◽

Recombinant Dna Technology

It has been known for many years that growth hormone is essential for normal linear growth, but over the past few years, with the advent of recombinant human growth hormone therapy, the importance of growth hormone during adult life has been described in detail. The growth hormone peptide was first isolated from bovine pituitaries in the 1940s (1), but was found to be species specific and inactive in humans. In 1956, growth hormone was extracted from human cadaveric pituitary tissue (2) and a year later was administered to a 13-year-old boy with hypopituitarism, resulting in an increased growth velocity (3). The first report suggesting growth hormone could have beneficial actions in adulthood was published in 1962 in which a 35-year-old woman with hypopituitarism reported increased vigour, ambition, and wellbeing after 2 months treatment with cadaveric growth hormone (4). However, the limited supply of pituitary-derived growth hormone confined its use to the treatment of children with severe growth failure caused by proven growth hormone deficiency (GHD). In 1985, the association of cadaveric growth hormone treatment with Creutzfeldt–Jakob disease led to its withdrawal from use worldwide (5). Since then, all growth hormone in clinical use has been produced using recombinant DNA technology. The first placebo-controlled trials of growth hormone replacement therapy in adults with GHD were published in 1989 (6, 7). These and subsequent studies have led to the recognition of adult GHD as a specific clinical syndrome and the impact of GHD and replacement therapy in adults with GHD has been studied in detail.

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Long Term Experience with Growth Hormone Treatment in Children with Chronic Renal Failure

Peritoneal Dialysis International ◽

10.1177/089686089901902s77 ◽

1999 ◽

Vol 19 (2_suppl) ◽

pp. 467-472 ◽

Cited By ~ 7

Author(s):

Franz Schaefer ◽

Dieter Haffner ◽

Elke Wühl ◽

Otto Mehls

Keyword(s):

Growth Hormone ◽

Renal Failure ◽

Chronic Renal Failure ◽

Final Height ◽

Recombinant Human Growth Hormone ◽

Growth Failure ◽

Skeletal Maturation ◽

Height Velocity ◽

Benign Intracranial Hypertension

After a decade of experience with recombinant human growth hormone (rhGH) in children with chronic renal failure (CRF), the long-term efficacy and safety of the drug is now established. In prepubertal children, partial catch-up growth is achieved during the first three treatment years, followed by sustained percentile-parallel growth. Discontinuation of rhGH treatment results in catch-down growth in 75% of patients. Treatment efficacy is inversely correlated with age and baseline height velocity, and positively influenced by genetic target height and residual renal function. Skeletal maturation is not accelerated, suggesting a true increase in final height potential. Side effects are limited to a stimulation of insulin secretion, which is not associated with changes in glucose tolerance, and occasional cases of benign intracranial hypertension. In summary, the advent of rhGH has opened a new era in the management of growth failure in CRF. Available evidence suggests that treatment should start in early childhood and early in the course of renal failure, and should be continued at least until renal transplantation. It remains to be seen whether the beneficial effect of rhGH on height observed during the prepubertal period will result in an eventual increase in adult height.

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