eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics
Noonan Syndrome
Updated: Jul 24, 2009
Introduction
Background
Noonan syndrome was first recognized as a unique entity in 1963 when Noonan and Ehmke described a series of patients with unusual facies and multiple malformations, including congenital heart disease. These patients were previously thought to have a form of Turner syndrome, with which Noonan syndrome shares numerous clinical features. The observation that patients with Noonan syndrome have normal karyotypes was important in allowing the distinction to be made between the Turner and Noonan syndromes.
The cardinal features of Noonan syndrome include unusual facies (ie, hypertelorism, down-slanting eyes, webbed neck), congenital heart disease (in 50%), short stature, and chest deformity. Approximately 25% of individuals with Noonan syndrome have mental retardation. Bleeding diathesis is present in as many as half of all patients with Noonan syndrome. Skeletal, neurologic, genitourinary, lymphatic, eye, and skin findings may be present to varying degrees.
Pathophysiology
The pathophysiology of Noonan syndrome is not fully understood. Four disease-causing genes (PTPN11, SOS1, RAF1, and KRAS) have been identified. All 4 genes are part of the RAS/RAF/MEK/ERK signal transduction pathway, which is an important regulator of cell growth.
Frequency
United States
The incidence of Noonan syndrome is estimated to be 1 case per 1000 to 1 case per 2500 live births.
International
The incidence of Noonan syndrome appears to be consistent worldwide.
Mortality/Morbidity
The primary source of morbidity and mortality in these patients depends on the presence and type of congenital heart disease.
Race
Noonan syndrome is panethnic.
Sex
Noonan syndrome occurs in either a sporadic or autosomal dominant fashion. In either case, males and females are equally affected.
Age
The disorder is present from birth, but age impacts the facial phenotype. Infants with Noonan syndrome can be difficult to recognize by facial appearance alone. The phenotype becomes more striking in early childhood, but with advancing age, it may again become quite subtle. Careful examination of an affected child's parents may in fact reveal that they are mildly affected.
Clinical
History
The prenatal history is typically unremarkable; however, some cases are complicated by polyhydramnios, fetal edema, or cystic hygroma.
- A careful family history should be obtained, paying particular attention to the presence of congenital heart disease, mental retardation, short stature, or unusual facies among the parents or siblings of an affected child.
- A child with mild expression of the facial phenotype might only present with developmental delay and history of congenital heart disease. A history of abnormal bleeding is present in as many as 50% of patients.
Physical
- Growth parameters
- Size at birth is usually within the reference range.
- Short stature is present in as many as 80% of patients. Average adult height for is 5 ft 5 inches in males and 5 ft in females.
- Facial features
- Triangular-shaped face
- Hypertelorism
- Down-slanting eyes
- Ptosis
- Strabismus (48%)
- Amblyopia (33%)
- Refractive errors (61%)
- Low-set ears with thickened helices
- High nasal bridge
- Short webbed neck
- Chest/back features
- Pectus carinatum or excavatum
- Scoliosis
- Cardiac features: The characteristic lesion is dysplastic/stenotic pulmonic valve, but virtually all types of congenital heart defects have been described in patients with Noonan syndrome. Hypertrophic cardiomyopathy (obstructive and nonobstructive types) is present in as many as 30% of patients.
- Abdominal features: Hepatosplenomegaly unrelated to cardiac status is present in approximately 25% of patients.
- Genitourinary features
- Renal anomalies are present in 10% of patients but are not clinically significant.
- More than half of male patients have undescended testes.
- Skeletal features
- Joint laxity is present in more than half of patients.
- Talipes equinovarus, radioulnar synostosis, cervical spine fusion, and joint contractures are less common findings.
- Skin findings
- Lymphedema
Lymphedema of the feet in an infant is shown. The toes have the characteristic sausagelike appearance.
Generalized lymphedema is seen here in an infant. The loose skin folds around the neck will form a webbed neck later in life.
- Prominent pads of fingers and toes (67%)
- Follicular keratosis of face and extensor surfaces (14%)
- Multiple lentigines (3%)
- Lymphedema
- Neurologic findings
- Hypotonia
- Seizure disorder (13%)
- Unexplained peripheral neuropathy (infrequent)
Causes
Both sporadic and autosomal dominant cases have been identified. At least 4 disease-causing genes have been found.1,2,3,4,5
- PTPN11 mutations account for approximately 50% of clinically recognized cases.
- SOS1 mutations account for approximately 10% of cases.
- RAF1 mutations account for 3-17% of cases.
- KRAS mutations account for approximately 1% of cases.
- Cases due to SOS1 mutations are generally associated with better cognitive function than those associated with PTPN11 mutations.6
More on Noonan Syndrome |
 Overview: Noonan Syndrome |
| Differential Diagnoses & Workup: Noonan Syndrome |
| Treatment & Medication: Noonan Syndrome |
| Follow-up: Noonan Syndrome |
| Multimedia: Noonan Syndrome |
| References |
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References
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Tartaglia M, Pennacchio LA, Zhao C, et al. Gain-of-function SOS1 mutations cause a distinctive form of Noonan syndrome. Nat Genet. Jan 2007;39(1):75-9. [Medline].
Pandit B, Sarkozy A, Pennacchio LA, et al. Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy. Nat Genet. Aug 2007;39(8):1007-12. [Medline].
Schubbert S, Zenker M, Rowe SL, et al. Germline KRAS mutations cause Noonan syndrome. Nat Genet. Mar 2006;38(3):331-6. [Medline].
Carta C, Pantaleoni F, Bocchinfuso G, et al. Germline missense mutations affecting KRAS Isoform B are associated with a severe Noonan syndrome phenotype. Am J Hum Genet. Jul 2006;79(1):129-35. [Medline].
Pierpont EI, Pierpont ME, Mendelsohn NJ, Roberts AE, Tworog-Dube E, Seidenberg MS. Genotype differences in cognitive functioning in Noonan syndrome. Genes Brain Behav. Apr 2009;8(3):275-82. [Medline].
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Ferrero GB, Baldassarre G, Delmonaco AG, Biamino E, Banaudi E, Carta C, et al. Clinical and molecular characterization of 40 patients with Noonan syndrome. Eur J Med Genet. Nov-Dec 2008;51(6):566-72. [Medline].
Marino B, Digilio MC, Toscano A, et al. Congenital heart diseases in children with Noonan syndrome: An expanded cardiac spectrum with high prevalence of atrioventricular canal. J Pediatr. Dec 1999;135(6):703-6. [Medline].
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Noonan JA. Noonan syndrome revisited. J Pediatr. Dec 1999;135(6):667-8. [Medline].
Noonan JA. Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr (Phila). Sep 1994;33(9):548-55. [Medline].
Qiu WW, Yin SS, Stucker FJ. Audiologic manifestations of Noonan syndrome. Otolaryngol Head Neck Surg. Mar 1998;118(3 Pt 1):319-23. [Medline].
Sharland M, Burch M, McKenna WM, Paton MA. A clinical study of Noonan syndrome. Arch Dis Child. Feb 1992;67(2):178-83. [Medline].
Sharland M, Morgan M, Smith G, et al. Genetic counseling in Noonan syndrome. Am J Med Genet. Feb 15 1993;45(4):437-40. [Medline].
Singer ST, Hurst D, Addiego JE Jr. Bleeding disorders in Noonan syndrome: three case reports and review of the literature. J Pediatr Hematol Oncol. Mar-Apr 1997;19(2):130-4. [Medline].
van der Burgt I, Thoonen G, Roosenboom N, et al. Patterns of cognitive functioning in school-aged children with Noonan syndrome associated with variability in phenotypic expression. J Pediatr. Dec 1999;135(6):707-13. [Medline].
Further Reading
Keywords
Noonan syndrome, Noonan's syndrome, hypertelorism, down-slanting eyes, webbed neck, congenital heart disease, congenital heart disease, short stature, chest deformity, polyhydramnios, fetal edema, cystic hygroma, ptosis, strabismus, amblyopia, high nasal bridge, pectus carinatum, pectus excavatum, scoliosis, hepatosplenomegaly, talipes equinovarus, radioulnar synostosis, cervical spine fusion, lymphedema, LEOPARD syndrome, bleeding diatheses, treatment, diagnosis
