The Role of Somatropin Therapy in Children with Noonan Syndrome
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LEADING ARTICLE
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The Role of Somatropin Therapy in Children with Noonan Syndrome Chris J.H. Kelnar1,2 1 2
Department of Reproductive and Developmental Sciences, University of Edinburgh, Edinburgh, Scotland Royal Hospital for Sick Children, Edinburgh, Scotland
Abstract
Patients with Noonan syndrome, which is thought to have an incidence of 1 : 1000 to 1 : 2500 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.
There are many dysmorphic syndromes with short stature as a [1]
component. In the London Dysmorphology Database
there are
over 850 such syndromes, 20% of which are of prenatal onset. Whilst in some, such as Turner syndrome, somatropin (growth hormone [GH] therapy) is licensed and widely prescribed, in others, such as Noonan syndrome, it has only been used within clinical trials. Treatment in the clinical trial setting raises issues about effectiveness, appropriate outcome measures, safety, and evidence for a broader role and value. In prescribing somatropin (whether or not in licensed indications),
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