Noonan Syndrome
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Direct answer
Noonan syndrome is an autosomal dominant RASopathy that mimics Turner syndrome in a normal karyotype, causing short stature, characteristic facial features, pulmonary valve stenosis and a bleeding tendency. It results from gain-of-function variants in genes of the RAS-MAPK pathway, most often PTPN11. Unlike Turner syndrome, it affects males and females equally and does not cause ovarian failure.
What you must remember
- Inheritance: autosomal dominant, with many cases arising de novo, and both sexes equally affected.
- Genetics: RAS-MAPK pathway variants, with PTPN11 the most common, and SOS1, RAF1 and KRAS also implicated.
- Heart: pulmonary valve stenosis, often dysplastic, is the commonest lesion, and hypertrophic cardiomyopathy is also common.
- Face and neck: hypertelorism, down-slanting palpebral fissures, ptosis, low-set posteriorly rotated ears and a webbed neck.
- Chest and growth: pectus deformity and short stature, with growth hormone considered in suitable children.
- Male genitalia: cryptorchidism is common and may need orchidopexy.
- Bleeding: factor XI deficiency and platelet dysfunction cause bruising and bleeding, so a coagulation screen is needed before surgery.
- Intelligence: usually normal, though mild learning difficulties can occur.
Noonan and Turner, side by side
Noonan and Turner syndromes overlap in short stature and webbed neck, so the karyotype and the heart lesion decide most cases. The table sets out the features that separate them.
| Feature | Noonan syndrome | Turner syndrome |
|---|---|---|
| Karyotype | Normal, 46,XX or 46,XY | 45,X or mosaic |
| Sex affected | Males and females | Females only |
| Typical heart lesion | Pulmonary valve stenosis, hypertrophic cardiomyopathy | Bicuspid aortic valve, coarctation |
| Gonads | Normal or small testes, normal ovaries | Streak gonads, ovarian failure |
| Bleeding tendency | Common, from factor XI or platelet defects | Not a typical feature |
Coarctation and streak gonads point towards Turner syndrome. Pulmonary stenosis and a bleeding history point towards Noonan syndrome, even in a girl with a webbed neck.
Echocardiography at diagnosis is the practical tool for defining the heart lesions. A bleeding history and a coagulation screen complete the workup. Genetic testing confirms the diagnosis when the phenotype is atypical or the features are mild.
Where the exam tries to catch you
Noonan questions usually hinge on the karyotype, the heart lesion and the bleeding history.
- Trap: diagnosing Turner syndrome in a short girl with a webbed neck and a pulmonary stenosis murmur. Correct: Noonan syndrome with a normal karyotype fits, since pulmonary stenosis is the Noonan lesion and coarctation is the Turner lesion.
- Trap: calling Noonan syndrome X-linked because boys are often reported. Correct: it is autosomal dominant and affects males and females equally.
- Trap: proceeding to surgery or dental extraction without a bleeding check. Correct: screen for factor XI deficiency and platelet dysfunction, and plan haemostasis before the procedure.
- Trap: stopping at the murmur of pulmonary stenosis. Correct: echocardiography must also look for hypertrophic cardiomyopathy, which is common in Noonan syndrome.
Frequently asked questions
Which karyotype is seen in Noonan syndrome?
Noonan syndrome occurs with a normal karyotype, either 46,XX or 46,XY. This normal chromosome count is what separates it from Turner syndrome. Diagnosis rests on the clinical features, with molecular testing of RAS-MAPK genes when the picture is unclear.
Which gene is most commonly mutated in Noonan syndrome?
PTPN11 is the most commonly mutated gene in Noonan syndrome, and its variants cause gain of function in the RAS-MAPK pathway. Other genes, including SOS1, RAF1 and KRAS, account for other cases. Molecular testing can confirm the diagnosis when features are equivocal.
What cardiac lesion is most typical of Noonan syndrome?
Pulmonary valve stenosis, usually with a dysplastic valve, is the most typical cardiac lesion of Noonan syndrome. Hypertrophic cardiomyopathy is also recognised. Echocardiography is therefore needed at diagnosis and periodically afterwards.
Why do children with Noonan syndrome bleed easily?
Children with Noonan syndrome may bleed easily because of factor XI deficiency or platelet dysfunction. Bruising, nosebleeds and prolonged bleeding after procedures are the clues. A coagulation screen before surgery or dental extraction helps plan safe management.
How does Noonan syndrome differ from Turner syndrome?
Noonan syndrome affects both sexes with a normal karyotype, whereas Turner syndrome affects females with a 45,X karyotype. Noonan characteristically causes pulmonary stenosis, while Turner causes coarctation or bicuspid aortic valve. Fertility and ovarian function also differ sharply between the two.