Noonan syndrome.ppt

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Diagnosis
• Until recently, diagnosis was made solely on the basis of clinical features, but molecular genetic testing can provide confirmation in 70% of cases. • 46,XX/XY
Yan Hailin
Jan 27th, 2016
Introduction
Noonan syndrome1
• an autosomal dominant, variably expressed, multisystem disorder • It was characterised by Jacqueline Noonan in 1968, who reported nine patients with pulmonary valve stenosis, small stature, mild intellectual disability, ptosis, undescended testes, and skeletal malformations.
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References
1. AE Roberts, JE Allanson, T Marco, et al. Noonan Syndrome[J]. Lancet. 2013 January 26; 381(9863): 333–342. 2. V Bhambhani, M Muenke, et al. Noonan Syndrome[J]. Am Fam Physician. 2014 January 1; 89(1): 37–43. 3. Shaw A C, Kalidas K, Crosby A H, et al. The natural history of Noonan syndrome: a long-term follow-up study.[J]. Archives of Disease in Childhood, 2007, 92(2):128-32. 4. Romano A A, Allanson J E, Dahlgren J, et al. Noonan Syndrome: Clinical Features, Diagnosis, and Management Guidelines[J]. Pediatrics, 2010, 126(4):746-59.
Figure 3. Infant with Noonan syndrome2.
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Clinical features
Figure 4. Child/adolescent with Noonan syndrome2.
Figure 5. Adult with Noonan syndrome.2.
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Clinical features
Table 2. Clinical Features of Noonan Syndrome2.
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Clinical features
• Facial features most often lead to the diagnosis of NS.
Figure 2. Newborn with Noonan syndrome2.
Epidemiology1
• prevalence: 1/1000 to 1/2500 for severe phenotype, mild cases may be 1/100 • familial recurrence is consistent with an autosomal dominant mode of inheritance, but de novo mutations accounting for 60% of cases • risk of transmission to the offspring of an affected individual is 50% • no known predilection by race or sex
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Etiology and Pathogenesis
Figure 1. The RAS–MAPK signaling pathway1.
• growth signals are relayed from activated growth factor receptors to the nucleus • mutations in PTPN11, KRAS, SOS, NRAS, and RAF1 are associated with Noonan syndrome • mutations in SHOC2 and CBL are associated with a Noonan syndrome-like phenotype 3
• A characteristic of the condition is that the phenotype changes considerably with age. • If the diagnosis is missed in childhood, then it may be more difficult to recognise later on.
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In summary
• With a prevalence of one in 1000–2500, NS is not rare. Because presentation can be mild and the typical facial features recede with age, the diagnosis might be overlooked. • Regular detailed follow-up with a multidisciplinary approach is often needed to address the medical and developmental complications of Noonan syndrome. • The targeted pharmacogenomic approaches will be developed on the basis of a detailed understanding of the different disease-causing changes to RAS–MAPK.
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Prognosis3
• Long-term follow-up data are scarce. • The mortality rate in the study by Shaw and colleagues was 9%, with age of death from a few months to 61 years. • 25% of NS patients with hypertrophic cardiomyopathy died of heart failure in first year. • 1/3 have ongoing cardiac disorders requiring drugs for heart failure or arrhythmias, a defibrillator, or a pacemaker.
Etiology and Pathogenesis
Table1. Correlations between genotype and phenotype in Noonan syndrome1.
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Clinicalof NS depends primarily on the identification of characteristic clinical features.
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Table 3.Diagnostic Criteria for Noonan Syndrome2.
Note: 1A+one of 2A-6A/two of 2B-6B 1B+two of 2A-6A/three of 2B-6B
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Management1.4
• early, accurate diagnosis of Noonan syndrome is important • individual treatment regimen • multidisciplinary evaluation and regular follow-up care