We searched PubMed for reports published between 2000, and 2011, with the terms “Noonan syndrome”, “clinical features”, “molecular genetics”, “treatment”, “PTPN11”, “KRAS”, “SOS1”, “RAF1”, “SHOC2”, “NRAS”, “BRAF”, and “CBL”. Only articles published in English were reviewed. Selection criteria were the novelty and importance of studies, judged by AER and confirmed by the other authors, and their relevance to general medical doctors, paediatricians, cardiogists, endocrinologists, haematologists,
SeminarNoonan syndrome
Introduction
Noonan syndrome is an autosomal dominant, variably expressed, multisystem disorder with an estimated prevalence of 1 in 1000–2500.1 It was characterised by Jacqueline Noonan, who reported nine patients with pulmonary valve stenosis, small stature, hypertelorism, mild intellectual disability, ptosis, undescended testes, and skeletal malformations.2 Understanding of the molecular genetic causes of Noonan syndrome has increased greatly in the past decade, enabling study of the pathophysiological mechanisms underlying the varied medical and developmental features of the disorder.
The RAS–MAPK pathway is a well-studied, widely important signal transduction pathway through which extracellular ligands—such as some growth factors, cytokines, and hormones—stimulate cell proliferation, differentiation, survival, and metabolism (figure 1). Cell surface receptors are phosphorylated at sites within their cytoplasmic region after ligand binding. This binding leads to recruitment of adaptor proteins (eg, GRB2), which form a constitutive complex with guanine nucleotide exchange factors (eg, SOS) that convert inactive, GDP-bound RAS to its active GTP-bound form. Activated RAS proteins then activate the RAF–MEK–ERK cascade through a series of phosphorylation events, ending with activated ERK entering the nucleus to alter gene transcription and modulating the activity of cytoplasmic targets to cause the appropriate short-term and long-term cellular response to the stimulus. All the genes implicated in Noonan syndrome encode proteins integral to this pathway and disease-causing mutations usually enhance signal flow through this pathway.3, 4
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Signs and symptoms
Roughly 10% of affected individuals have auditory deficits in the low frequency range caused by sensorineural hearing loss and 25% have deficits in the high frequency range.5 Inner ear structural abnormalities, including temporal bone abnormalities, have been reported.6, 7
Noonan syndrome is the second most common syndromic cause of congenital heart disease, exceeded in prevalence only by trisomy 21.8 Several cardiovascular phenotypes occur in Noonan syndrome. The most common are pulmonary
Natural history
Long-term follow-up data are scarce. Shaw and colleagues10 studied 112 British individuals with a clinical or molecular genetic diagnosis of Noonan syndrome (mean age at assessment 25·3 years, mean follow-up 12 years) in the largest study of its kind. The mean final adult height was 1·70 m for men and 1·53 m for women. Feeding difficulties in infancy were an early marker of delayed language development and long-term educational achievement. Most patients gained a diploma: 43% gained a General
Diagnosis
Many of the recognisable features of Noonan syndrome could be the consequence of lymphatic obstruction or dysfunction during development, including webbing of the neck and prominence of the trapezius, cryptorchidism, widely spaced nipples, low-set and posteriorly rotated ears, hypertelorism, and ptosis.38 Other key features of Noonan syndrome include congenital heart defects, superior pectus carinatum with inferior pectus excavatum, developmental delay, short stature, and lymphatic dysplasias.
Management and differential diagnosis
Management guidelines for Noonan syndrome have been developed (table 3).38, 103, 104 Although the facial features and many of the medical and developmental complications associated with Noonan syndrome-like disorders are the same for Noonan syndrome, mutations in two genes—SHOC2 and CBL—are associated with additional features not seen in Noonan syndrome.
SHOC2 is a widely expressed protein and positive modulator of the RAS–MAPK signalling cascade. The recurrent missense SHOC2 mutation, 4A→G
Conclusion
With a prevalence of one in 1000–2500, Noonan syndrome is a disorder that most doctors will encounter during their careers. 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. Much progress has been made in our understanding of the molecular genetic causes of Noonan syndrome in the
Search strategy and selection criteria
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