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Pediatric GHD
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Noonan Syndrome
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Turner Syndrome
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Children Born Small for Gestational Age (SGA)
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overview of Noonan syndrome

Noonan syndrome is a genetic disorder caused by mutations in four different genes: PTPN11, KRAS, SOS1, and RAF1, occurring in approximately 1:1000 to 1:2500 live births with no gender prominence.¹ Noonan syndrome is identified by a wide spectrum of symptoms and physical features that vary greatly in range and severity, including facial characteristics, congenital heart disease², and short stature.

Several disorders are phenotypically similar to Noonan syndrome, including Turner syndrome, Watson syndrome, Noonan-neurofibromatosis type 1, cardio-facio-cutaneous (CFC) syndrome, and LEOPARD syndrome.³

Diagnosis of Noonan syndrome

Diagnosis of Noonan syndrome can be complex. Cardinal features of Noonan syndrom include*:

^* Not all cardinal features need to be present for a diagnosis.

Diagnosis of Noonan syndrome

Diagnosis of Noonan syndrome is primarily dependent on clinical features, including short stature, typical face dysmorphology, and congenital heart defects⁶. Diagnosis can be difficult due to the wide spectrum of clinical features, not all of which need to be present for diagnosis.

Cardinal features of Noonan syndrome include hypertelorism, ptosis, and low-set, posteriorly rotated ears with a thickened helix.⁵ Cardiac abnormalities most commonly associated with Noonan syndrome include pulmonary stenosis and hypertrophic cardiomyopathy.⁵ Other associated features include the presence of a webbed neck, chest deformity, mild intellectual deficit, cryptorchidism, poor feeding in infancy, bleeding tendencies, and lymphatic issues.⁵

Short stature is one of the main characteristics of the condition, affecting more than 80% of children diagnosed.⁶

Genetic mutations of Noonan syndrome

Genetic mutations and etiology of Noonan syndrome

^* In patients without PTPN11 or KRAS mutations.
KRAS=Kirsten RAt sarcoma; SOS1=Son of Sevenless 1; RAF1=v-raf-1 murine leukemia viral oncogene homolog.⁹

Genetic mutations of Noonan syndrome

Noonan syndrome is a genetic disorder that may be caused by mutations in one of four different genes: PTPN11, KRAS, SOS1, and RAF1.

Approximately 50% of individuals with Noonan syndrome have mutations in the PTPN11 gene, causing pulmonary valve stenosis, characteristic facial dysmorphology⁶, and short stature. Results of long-term studies of growth hormone therapy in patients with Noonan syndrome with short stature demonstrate a significant improvement in adult height.⁸

Five percent of people with Noonan syndrome have mutations in the KRAS gene and usually present more severe symptoms of the condition. Mutations in the SOS1 gene are seen in approximately 17% of those with Noonan syndrome resulting in characteristic facial dysmorphology and cardiac abnormalities. Mutations in the RAF1 gene account for between 3%-17% of patients resulting in hypertrophic cardiomyopathy.

Genetic testing is available to aid in the diagnosis of Noonan syndrome; however, not all patients with Noonan syndrome have an identifiable mutation. Therefore, clinical diagnosis is essential.

References

Osio D, Dahlgren J, Wikland KA, Westphal O. Improved final height with long-term growth hormone treatment in Noonan syndrome. Acta Paediatr. 2005:94:1232-1237.
Roberts A, Toshiyuki A, Swanson K, et al. Germline gain-of-function mutations in SOS1 cause Noonan syndrome. Nature Genetics. 2007;39(1)70-74.
van der Burgt I, Brunner H. Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form. Am J Med Genet. 2000;94(1):46-51.
Norditropin^® cartridges [prescribing information]. Princeton, NJ: Novo Nordisk Inc; 2009.
van der Burgt I. Noonan syndrome [review]. Orphanet J Rare Dis. 2007;2(4):1-6.
Ranke MB, Heidemann P, Knupfer C, Enders H, Schmaltz AA, Bierich JR. Noonan syndrome: growth and clinical manifestations in 144 cases. Eur J Pediatr. 1988;148(3):220-227.
Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nature Genetics. 2007:39(1);75-79.
Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nature Genetics. 2006;38(3):331-336.
Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nature Genetics. 2007;39(8):1007-1012.

Indications and Usage:

Norditropin^® (somatropin [rDNA origin] injection) is indicated for the treatment of children with growth failure due to inadequate secretion of endogenous growth hormone, the treatment of children with short stature associated with Noonan syndrome or Turner syndrome, the treatment of children with short stature born small for gestational age (SGA) with no catch-up growth by age 2-4 years, and for the replacement of endogenous growth hormone in adults with growth hormone deficiency (GHD) who meet either of the following two criteria: 1. Adult Onset: Patients who have GHD, either alone or associated with multiple hormone deficiencies (hypopituitarism), as a result of pituitary disease, hypothalamic disease, surgery, radiation therapy, or trauma; or 2. Childhood Onset: Patients who were growth hormone deficient during childhood as a result of congenital, genetic, acquired, or idiopathic causes.

Important Safety Information:

Somatropin should not be used to treat patients with acute critical illness due to complications following open heart or abdominal surgery, multiple accidental trauma or acute respiratory failure as increased mortality may occur.

Somatropin is contraindicated in patients with Prader-Willi syndrome who are severely obese, have a history of upper airway obstruction or sleep apnea, or have severe respiratory impairment. There have been reports of sudden death when somatropin was used in such patients. Norditropin^® is not indicated for the treatment of patients who have growth failure due to genetically confirmed Prader-Willi syndrome.

Somatropin should not be used or should be discontinued with any evidence of active malignancy. Any preexisting malignancy should be inactive and its treatment complete prior to instituting therapy with somatropin. Somatropin should be discontinued if there is evidence of recurrent activity. Patients with preexisting tumors or GHD secondary to an intracranial lesion should be monitored routinely for progression or recurrence. In childhood cancer survivors, an increased risk of a second neoplasm, particularly meningiomas in patients treated with radiation to the head for their first neoplasm, has been reported in patients treated with somatropin.

Somatropin should not be used in patients with active proliferative or severe non-proliferative diabetic retinopathy, for growth promotion in pediatric patients with closed epiphyses, or in patients with known hypersensitivity to somatropin or any of its excipients.

Somatropin may decrease insulin sensitivity particularly at higher doses in susceptible patients. Glucose levels should be monitored periodically, including close monitoring of patients with preexisting diabetes or glucose intolerance. Doses of anti-hyperglycemic drugs (insulin or oral agents) may require adjustment for patients with diabetes on somatropin therapy.

Intracranial hypertension (IH) with papilledema, visual changes, headache, nausea and/or vomiting, usually occurring within the first eight (8) weeks after initiation of somatropin therapy, has been reported in a small number of patients. In all reported cases, rapid resolution has occurred after therapy cessation or a reduction of dose.

Funduscopic examination should be performed routinely before and during somatropin therapy. If papilledema is observed, somatropin treatment should be discontinued.

Fluid retention during somatropin replacement therapy in adults may frequently occur. Clinical manifestations of fluid retention are usually transient and dose dependent.

In patients with GHD, central (secondary) hypothyroidism may first become evident or worsen during somatropin treatment. Periodic thyroid function tests are recommended and thyroid hormone replacement therapy should be initiated or adjusted as needed.

Slipped capital femoral epiphysis may occur more frequently in patients with endocrine disorders (including GHD and Turner syndrome) or with rapid growth. Onset of a limp or complaints of hip or knee pain in somatropin patients should be carefully evaluated. Rapid growth may also result in progression of preexisting scoliosis. Patients with a history of scoliosis or skeletal abnormalities, which may be present in untreated Noonan, Turner or Prader-Willi syndrome, should be monitored.

Patients with Turner Syndrome should be evaluated carefully for otitis media and other ear disorders since these patients have an increased risk of ear and hearing disorders. Somatropin treatment may increase the occurrence of otitis media in patients with Turner syndrome. Somatropin may also increase the risk of IH in Turner patients. In addition, patients with Turner syndrome should be monitored closely for cardiovascular disorders (e.g., stroke, aortic aneurysm/dissection, hypertension) as these patients are also at risk for these conditions.

Congenital heart disease is an inherent component of Noonan syndrome. Though a clinical study in Noonan syndrome reported no evidence of somatropin-induced ventricular hypertrophy or exacerbation of preexisting ventricular hypertrophy (as judged by echocardiography), the safety of Norditropin^® in children with Noonan syndrome and significant cardiac disease is not known.

Other somatropin-related adverse reactions include injection site reactions/rashes, lipoatrophy and headaches. Subcutaneous injection of somatropin at the same site repeatedly may result in tissue atrophy and can be avoided by rotating the injection site.

Somatropin inhibits 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD-1) in adipose/hepatic tissue, and may significantly impact the metabolism of cortisol and cortisone. In patients treated with somatropin, previously undiagnosed central (secondary) hypoadrenalism may be unmasked requiring glucocorticoid replacement therapy. In addition, patients treated with glucocorticoid replacement therapy, especially with cortisone acetate and prednisone, for previously diagnosed hypoadrenalism may require an increase in their maintenance or stress doses.

Careful monitoring is advisable when somatropin is administered in combination with other drugs known to be metabolized by CP450 liver enzymes (e.g., corticosteroids, sex steroids, anticonvulsants, cyclosporine) as limited published data suggest somatropin may alter clearance of these compounds.

In adult women on oral estrogen replacement, a larger dose of somatropin may be required to achieve the defined treatment goal.

The safety and effectiveness of Norditropin^® in patients age 65 years and older has not been evaluated in clinical studies. Elderly patients may be more sensitive to the actions of somatropin and may be more prone to develop adverse reactions.