The efficacy and safety of growth hormone therapy in children with noonan syndrome: a review of the evidence.

Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited.

Cardiac findings in Noonan syndrome on long-term follow-up.

OBJECTIVE: Noonan syndrome (NS) is the second most common genetic syndrome associated with cardiac abnormalities, including, most notably, pulmonary stenosis (PS) and hypertrophic cardiomyopathy (HCM). Little is known about the natural history of heart disease in this unique subset of patients. We sought to contribute information on the natural history of NS by looking at how the cardiac disease progresses with time. DESIGN: This is a retrospective review of the medical records of patients with NS seen at our institution between 1963 and 2011. RESULTS: Records were available for 113 patients. Average length of follow-up was 14.16 years (2 months to 44 years, median 12.5 years). Sixty-six percent (75/113) of our patients had PS; within this subset, 57% (43) were classified as mild, 9% (7) moderate, and 33% (25) severe. None of the cases of mild PS worsened with time. All of the severe cases had an intervention, as did some moderate cases. Fourteen percent (16/113) of our patients had HCM; 56% (9/16) were mild, diagnosed at an average age of 3.8 years. Seven of these were stable with time, while one did progress. Forty-four percent (7/16) of cases were classified as severe, diagnosed at an average age of 4.2 months, and all were managed medically, surgically, or both. Our cohort had seven deaths (ages 6 months and 6, 10, 20, 40, 49, and 50 years). CONCLUSION: Mild PS in patients with NS is nonprogressive. Severe, and in some cases moderate, PS will invariably require a therapeutic intervention. It is uncommon for HCM to progress or have new onset beyond early childhood. Prognosis of heart disease in NS is influenced most by the findings on presentation.

Noonan syndrome: clinical features, diagnosis, and management guidelines.

Noonan syndrome (NS) is a common, clinically and genetically heterogeneous condition characterized by distinctive facial features, short stature, chest deformity, congenital heart disease, and other comorbidities. Gene mutations identified in individuals with the NS phenotype are involved in the Ras/MAPK (mitogen-activated protein kinase) signal transduction pathway and currently explain ∼61% of NS cases. Thus, NS frequently remains a clinical diagnosis. Because of the variability in presentation and the need for multidisciplinary care, it is essential that the condition be identified and managed comprehensively. The Noonan Syndrome Support Group (NSSG) is a nonprofit organization committed to providing support, current information, and understanding to those affected by NS. The NSSG convened a conference of health care providers, all involved in various aspects of NS, to develop these guidelines for use by pediatricians in the diagnosis and management of individuals with NS and to provide updated genetic findings.

Cardiomyopathy of unknown etiology: Barth syndrome unrecognized.

This is a report of a child who died at 20 months from what was clinically thought to be cardiomyopathy of unknown etiology. Barth syndrome, an X-linked mitochondrial cardioskeletal myopathy, was diagnosed by genetic testing at autopsy. Barth syndrome presents in infancy or childhood with cardiomyopathy, hypotonia, growth delays, and cyclic neutropenia. Other associated laboratory findings can include hypocholesterolemia, relative monocytosis, low prealbumin, low plasma carnitine, and lactic acidosis. The classic echocardiogram finding is left ventricular noncompaction, although not always present. Until recently, the most reliable biochemical finding has been 3-methylglutaconic aciduria. However, quantitative analysis must be specifically requested for results to be reliable. Recently, a confirmatory tetralinoleoyl cardiolipin high-pressure liquid chromotography-tandem mass spectrometry blood test has become available. Genetic testing is also confirmatory and details the underlying mutation. Diagnosis is often missed or delayed and early diagnosis improves survival. The purpose of this case report is to encourage physicians to include Barth syndrome in the differential for cardiomyopathy of uncertain etiology in males, especially in the presence of growth delays, hypotonia, neutropenia, and/or family history of pediatric male death of unknown etiology.

Life-long follow-up in congenitally corrected transposition.

A male patient with congenitally corrected transposition, with no associated cardiac malformations, was diagnosed in childhood and followed until his death at age 28. He underwent two cardiac gated single photon emission computed tomographies over a two year period, which demonstrated progression of ischaemia and reduction of systolic function. The findings suggest that, when the systemic ventricle is perfused by the morphologically right coronary artery, there may be inadequate perfusion to supply any subsequent extensive hypertrophy.

Noonan syndrome and related disorders: alterations in growth and puberty.

Noonan syndrome is a relatively common multiple malformation syndrome with characteristic facies, short stature and congenital heart disease, most commonly pulmonary stenosis (Noonan, Clin Pediatr, 33:548-555, 1994). Recently, a mutation in the PTPN11 gene (Tartaglia, Mehler, Goldberg, Zampino, Brunner, Kremer et al., Nat Genet, 29:465-468, 2001) was found to be present in about 50% of individuals with Noonan syndrome. The phenotype noted in Noonan syndrome is also found in a number of other syndromes which include LEOPARD (Gorlin, Anderson, Blaw, Am J Dis Child, 17:652-662, 1969), Cardio-facio-cutaneous syndrome (Reynolds, Neri, Hermann, Blumberg, Coldwell, Miles et al., Am J Med Genet, 28:413-427, 1986) and Costello syndrome (Hennekam, Am J Med Genet, 117C(1):42-48, 2003). All three of these syndromes share similar cardiac defects and all have postnatal short stature. Very recently, HRAS mutations (Aoki, Niihori, Kawame, Kurosawa, Ohashi, Tanaka et al., Nat Genet, 37:1038-1040, 2005) have been found in the Costello syndrome and germline mutations in KRAS and BRAF genes (Rodriguez-Viciana, Tetsu, Tidyman, Estep, Conger, Santa Cruz et al., Nat Genet, 2006; Niihori, Aoki, Narumi, Neri, Cave, Verloes et al., Nat Genet, 38:294-296, 2006) in the Cardio-facio-cutaneous syndrome. Phenotypic overlap between these genetic disorders can now be explained since each is caused by germline mutations that are major components of the RAS-MAPK pathway. This pathway plays an important role in growth factor and cytokine signaling as well as cancer pathogenesis.

Quality of life and social outcomes in adults with congenital heart disease living in rural areas of Kentucky.

As revealed by a quality-of-life survey done in a small rural Kentucky cohort, adults who live in rural areas who have congenital heart disease have a relatively poor health-related quality of life and face unique challenges in gaining employment, maintaining health insurance, and overcoming the perceived childhood stigma of being "different."

A history of pediatric specialties: the development of pediatric cardiology.

Pediatric cardiology, as a discipline, arose from early descriptive studies of congenital cardiac defects. The development of the stethoscope allowed some clinical diagnoses to be made during life. Cardiology as a medical specialty was limited, mainly, to internists. When Robert Gross ligated a patent ductus in 1938, pediatric cardiology, as a discipline, was born. Physiologic studies, angiography, and the development of extracorporeal circulation allowed congenital cardiac lesions previously considered a curiosity to be diagnosed and treated successfully. The few pediatricians who were interested in cardiology taught themselves, and soon pediatric cardiology training programs developed. By 1961, pediatric cardiology became the first subspecialty board in pediatrics. The past 60 y has brought enormous progress. Cardiac ultrasound, color-flow Doppler, and magnetic resonance imaging have made diagnostic cardiac catheterization almost unnecessary. Instead, interventional cardiac catheterization rapidly developed and is already able to replace surgery in the treatment of a number of cardiac defects. The first 50 y of cardiology has been focused on patient care, education, and clinical research, but the last 10 y has added exciting, basic research discoveries, which are elucidating the cause of cardiac defects with hope for prevention in the future. As a discipline, pediatric cardiology has always required a team-pathologists, physiologists, cardiologists, surgeons, intensivists, interventionists, and anesthesiologists-all playing an important role in the treatment of children with cardiac problems. Today the geneticists, molecular biologists, and other basic scientists are joining the team to ensure an exciting future for pediatric cardiology and the children yet to be born.

Adult height in Noonan syndrome.

Short stature is a very common manifestation of Noonan syndrome (NS) and is accompanied by a variable delay in bone age. Although reports of adult height in NS are uncommon, some feel growth hormone therapy will increase adult height. We report our findings in 73 adults over 21 years of age with NS. Thirty percent of this group had an adult height in the normal range between 10th percentile and 90th percentile. Over half of the females and nearly 40% of males had an adult height below the 3rd percentile. The presence or severity of heart disease was not a factor, and none of the adults with a normal height had been treated with growth hormone. Serial measurements of height for many years through childhood to adulthood were available in only a few patients, but their pattern of growth suggests catch up may occur in late adolescence. To evaluate the benefit of growth hormone therapy, long term serial height measurements over a period of years comparing treated and untreated patients are needed. It will be important to determine what role, if any, the mutated PTPN 11 gene plays in the short stature common in NS.

Fatal Kawasaki disease due to coronary aneurysm rupture with massive cardiac tamponade.

Kawasaki disease (KD), an acute febrile childhood vasculitis of unknown etiology, preferentially involves the coronary arteries. Diagnosis typically rests on strict clinical criteria. If untreated, KD may be complicated by coronary arteritis and progress to aneurysm formation, thereby predisposing the child to a small but significant risk of death. We report a case of atypical KD causing death due to rupture of a coronary artery aneurysm with massive cardiac tamponade. The clinical challenge to recognize KD during the acute phase--especially in atypical cases when the diagnostic criteria are incomplete--is critical. Therapeutic intervention with intravenous gamma-globulin (IVIG) and aspirin during the first 10 days of onset is highly effective not only in reducing nearly tenfold such potentially fatal cardiac complications by arresting the immune-mediated necrotizing arteritis, but also in alleviating the acute symptoms related to systemic inflammation.