AUTHOR INFORMATION

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Authored by Jennifer Ibrahim, MD, Fellow, Department of Pediatrics, Division of Genetics, Children's Hospital of New Jersey and Mount Sinai School of Medicine

Coauthored by Margaret McGovern, MD, PhD, Vice Chair, Professor, Department of Human Genetics, Mount Sinai School of Medicine

Jennifer Ibrahim, MD, is a member of the following medical societies: American Society of Human Genetics

Edited by Elaine H Zackai, MD, Director of Clinical Genetics Center, Professor of Pediatrics, Department of Pediatrics, Division of Human Genetics and Molecular Biology, University of Pennsylvania, Children's Hospital of Philadelphia; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Daniel Rauch, MD, FAAP, Director, Pediatric Hospitalist Program, Associate Professor, Department of Pediatrics, New York University School of Medicine; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Jennifer Ibrahim, MD
Editor's Email:	Elaine H Zackai, MD

eMedicine Journal, February 24 2006, VOLUME 7, Number 2

INTRODUCTION

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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 a number of 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 are 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. A disease-causing gene, PTPN11, has been identified. The gene product, SHP2, plays an important role in cardiac semilunar valve development.

Frequency:

• In the US: The incidence of Noonan syndrome is estimated at 1 in 1000 to 1 in 2500 live births.

• Internationally: 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 affected equally.

Age: The disorder is present from birth, but age impacts upon 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 affected mildly.

CLINICAL

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History: The prenatal history typically is 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 up to 80% of patients. Average adult height for males is 5'5" and for females is 5'.
  
  
  
• 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/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 up to 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

  • Prominent pads of fingers and toes (67%)

  • Follicular keratosis of face and extensor surfaces (14%)

  • Multiple lentigines (3%)



• Neurologic findings


• • Hypotonia
  
  
  
  • Seizure disorder (13%)
  
  
  
  • Unexplained peripheral neuropathy (infrequent)
  
  
  

Causes: Both sporadic and autosomal dominant cases have been identified. At least one disease-causing gene, PTPN11, has been found. Mutations in PTPN11 are found in approximately 59% of familial cases and in 37% of sporadic cases.

DIFFERENTIALS

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Fetal Alcohol Syndrome

Other Problems to be Considered:

Fetal hydantoin syndrome
LEOPARD (multiple lentigines syndrome)
Cardio-facial-cutaneous syndrome
XO/XY mosaicism
Turner syndrome

WORKUP

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Lab Studies:

• Bleeding diatheses are common among patients with Noonan syndrome. The most frequent abnormality is factor XI deficiency, but various disorders have been reported in patients with Noonan syndrome. All patients should have a CBC count with platelet count, coagulation profile, and measurement of factor XI level at the minimum.



• If full phenotypic expression is not apparent, karyotyping may be necessary.



• Mutation analysis may confirm the diagnosis. However, the failure to identify a germline PTPN11 mutation does not rule out Noonan syndrome. This entity remains a clinical diagnosis.

Other Tests:

• Any child suspected of having Noonan syndrome requires a detailed cardiac workup. This includes ECG, echocardiogram (ECHO), and consultation with a pediatric cardiologist.



• Assessment of development is necessary to identify any delays and allow for intervention. Full-scale IQ ranges from 48-130, with a mean of 86.1 (approximately 1 standard deviation [SD] below the general population mean). Approximately 25% of patients with Noonan syndrome have mental retardation.



• Audiologic evaluation: The incidence of progressive high-frequency sensorineural hearing loss may be as high as 50%.

TREATMENT

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Medical Care: Growth hormone has been used to accelerate growth in some patients with Noonan syndrome. To date, no effect on final adult height has been documented.

Surgical Care: Certain types of congenital heart lesions are amenable to surgical correction.

Consultations:

• Geneticist



• Cardiologist



• Hematologist



• Ophthalmologist



• Neurologist



• Audiologist

Diet: No special dietary restrictions apply.

Activity: Activity may be limited by cardiac status and the presence of hematologic abnormalities.

MEDICATION

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No specific pharmacologic therapy is available.

FOLLOW-UP

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Further Outpatient Care:

• All patients require ongoing developmental, audiologic, and ophthalmologic follow-up. Direct other follow-up at specific findings (eg, hematology follow-up for patients with bleeding disorders).

Deterrence/Prevention:

• If a causative mutation is found in the affected individual, parental studies should be offered in order to distinguish familial cases from sporadic cases. If an individual carries a germline mutation, prenatal diagnosis can be offered in future pregnancies. The presentation varies widely in families, and clear genotype-phenotype correlations have not yet been identified.

Patient Education:

• Once the pattern of inheritance has been identified, parents need to be counseled regarding recurrence risk with each pregnancy. Sporadic cases present minimal recurrence risk to the siblings of the affected child; the exception is parental gonadal mosaicism. Offspring of an affected individual have a 50% chance of developing Noonan syndrome.



• Patients with bleeding disorders must be advised against the use of aspirin and aspirin-containing products or other medications that may interfere with coagulation or platelet function.

MISCELLANEOUS

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Medical/Legal Pitfalls:

• Recurrence risk for parents who do not appear to be affected or who have only some facial features of Noonan Syndrome is 5%. Gonadal mosaicism may account for this increase over population risk. Affected individuals have a 50% chance of passing on the disorder with each pregnancy.

Special Concerns:

• Before any patient with Noonan syndrome can undergo a surgical procedure, a full hematologic workup must be performed.



• Female patients have normal pubertal development and fertility. Fertility in males with undescended testes may be decreased. For this reason, the mother is more frequently the transmitting parent in familial cases.

TEST QUESTIONS

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CME Question 1: An adult woman with Noonan syndrome is planning to become pregnant. Which of the following reflects the risk that her children will have Noonan syndrome?

A: No increased risk above that of the general population
B: 25%
C: 50%
D: 75%
E: 100%

The correct answer is C: The correct answer is 50%. Noonan syndrome can be inherited in an autosomal dominant fashion.

CME Question 2: Which of the following is not consistent with the diagnosis of Noonan syndrome?

A: Abnormal karyotype
B: History of bleeding problems
C: Normal intellect
D: Absence of congenital heart disease
E: Chest deformity

The correct answer is A: Patients with Noonan syndrome have normal karyotypes.

Pearl Question 1 (T/F): In familial cases of Noonan syndrome, the mother is more likely to be the transmitting parent.

The correct answer is True: Although autosomal dominant diseases affect equal numbers of males and females, male patients with Noonan syndrome frequently have infertility secondary to cryptorchidism.

Pearl Question 2 (T/F): Children with Noonan syndrome must have coagulation studies performed prior to any surgical procedure.

The correct answer is True: Many children with Noonan syndrome have a bleeding diathesis. Before any surgical procedure can be performed safely, bleeding disorders must be identified and treated.

Pearl Question 3 (T/F): Atrioventricular (AV) canal is the most common type of congenital heart lesion associated with Noonan syndrome.

The correct answer is False: A dysplastic or stenotic pulmonic valve is most frequently associated with Noonan syndrome. However, virtually all types of congenital heart lesions have been described among patients with Noonan syndrome.

Pearl Question 4 (T/F): Bleeding diathesis is the most common cause of death among patients with Noonan syndrome.

The correct answer is False: The presence of congenital heart disease is the primary cause of mortality among patients with Noonan syndrome.

BIBLIOGRAPHY

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• Allanson JE: Noonan syndrome. J Med Genet 1987 Jan; DA - 19870320(1): 9-13[Medline].
• Allanson JE, Hall JG, Hughes HE, et al: Noonan syndrome: the changing phenotype. Am J Med Genet 1985 Jul; 21(3): 507-14[Medline].
• Bader-Meunier B, Tchernia G, Mielot F, et al: Occurrence of myeloproliferative disorder in patients with Noonan syndrome. J Pediatr 1997 Jun; 130(6): 885-9[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 1999 Dec; 135(6): 703-6[Medline].
• Noonan JA: Noonan syndrome revisited. J Pediatr 1999 Dec; 135(6): 667-8[Medline].
• Noonan JA: Noonan syndrome. An update and review for the primary pediatrician. Clin Pediatr (Phila) 1994 Sep; 33(9): 548-55[Medline].
• Noonan JA: Hypertelorism with Turner phenotype. A new syndrome with associated congenital heart disease. Am J Dis Child 1968 Oct; 116(4): 373-80[Medline].
• Qiu WW, Yin SS, Stucker FJ: Audiologic manifestations of Noonan syndrome. Otolaryngol Head Neck Surg 1998 Mar; 118(3 Pt 1): 319-23[Medline].
• Sharland M, Burch M, McKenna WM, Paton MA: A clinical study of Noonan syndrome. Arch Dis Child 1992 Feb; 67(2): 178-83[Medline].
• Sharland M, Morgan M, Smith G, et al: Genetic counseling in Noonan syndrome. Am J Med Genet 1993 Feb 15; 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 1997 Mar-Apr; 19(2): 130-4[Medline].
• Tartaglia M, Kalidas K, Shaw A, et al: PTPN11 mutations in Noonan syndrome: molecular spectrum, genotype-phenotype correlation, and phenotypic heterogeneity. Am J Hum Genet 2002 Jun; 70(6): 1555-63[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 1999 Dec; 135(6): 707-13[Medline].

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