DESCRIPTION

• Noonan syndrome is a Mendelian inherited syndrome characterized by phenotypic stigmata differentiated from those seen with the genotype of Turner syndrome (XO).
• System(s) affected: Cardiovascular; endocrine; urologic; otologic; neurologic; hematologic
• Synonym(s): Female pseudo-Turner syndrome; Male Turner syndrome; Bonnevie Ullrich syndrome

EPIDEMIOLOGY

• Age at presentation: Fetal to adult; the mean age at diagnosis is ~9 yr.
• Sex: Male = Female

Prevalence

Overall prevalence is not well established, but is ~1/2,000 newborns, with males affected as often as females.

RISK FACTORS

Genetics

• An autosomal-dominant and recessive patterns of inheritance has been established. Many cases may be new stigmata. Normal karyotype.
• Marked genetic heterogeneity
• To date, familial pedigree studies have isolated the locus of Noonan syndrome to several chromosomes, including 12 and 18.
• A large proportion (20–30%) of 1st-generation family members of individuals with Noonan syndrome also are affected with Noonan syndrome. Affected parents 30–75%.

PATHOPHYSIOLOGY

Depends on associated cardiac defects.

ETIOLOGY

Hormonal: Mutations in PTPN11 gene on chromosome 12 resulting in interference with growth hormone and IGF-I signaling in 50% of patients.

COMMONLY ASSOCIATED CONDITIONS

• Cardiovascular (50% of cases):
  • Pulmonary valve dysplasia and stenosis is the most common lesion (50–75% of cases).
  • Hypertrophic cardiomyopathy: Typically asymmetric; can be associated with subaortic or subpulmonic stenosis (25–33% of affected individuals)
  • Atrial septal defect (ASD): 27% of cases
  • Tetralogy of Fallot
  • Conduction abnormalities
  • Rarely aortic stenosis and coarctation
• Endocrine/urologic:
  • Gonadal dysfunction: Hypofunction of testes in males
  • Cryptorchidism
  • Short stature
  • Renal/Genitourinary abnormalities
• Otologic/Ophthalmologic:
  • Progressive sensorineural hearing deficits (50% of cases)
  • Strabismus, refractive errors, amblyopia, and nystagmus (95%)
• Neuropsychological:
  • Mental retardation (25% of cases)
  • Developmental delay
• Hematologic/Oncologic:
  • Coagulopathies
  • Chronic myelomonocytic leukemia or "benign" monoclonal gammopathy
  • Malignant schwannoma
• Neurologic:
  • Cerebrovascular disease such as moyamoya
• Lymphatic:
  • Postnatal: Dorsal limb lymphedema, organ lymphangiectasias, chylous effusions
  • Prenatal: Cystic hygroma, polyhydramnios, hydrops fetalis

Outline

• Description
• Epidemiology
  • Prevalence
• Risk Factors
  • Genetics
• Pathophysiology
• Etiology
• Commonly Associated Conditions

Signs and symptoms:

The phenotype varies with the age at presentation

• Fetal:
  • Increased nuchal fluid
  • Possible hydrops
  • Pleural effusions
  • Normal karyotype on amniocentesis
  • Brachycephaly or growth retardation
  • Shortened femora
  • Renal abnormalities
• Infant:
  • Cardiac abnormalities:
    • Systolic ejection murmur of pulmonary stenosis
    • Ejection click usually not present
    • If LV cardiomyopathy is present, the patient may have typical symptoms of exertional dyspnea, chest pain, palpitations, postural hypotension, or syncope.
  • Edema of hands and feet
  • High-arched palate
  • Short or webbed neck
  • Pectus carinatum or excavatum
  • Cubitus valgus
  • Typical facies: Malformed posteriorly rotated ears, antimongoloid palpebral slant, ptosis, broad flat nose, vivid blue or blue-green irises, thick/droopy eyelids
  • Undescended testes with possible hypogonadism
  • Cardiovascular malformations: Predominantly ASD, pulmonary stenosis, and hypertrophic cardiomyopathy may result in symptoms if severe.
• Childhood and adolescence:
  • Short stature
  • Developmental delay
  • Characteristic cardiac malformations
  • Sexual maturation delay of ~2 yr

DIAGNOSTIC TESTS & INTERPRETATION

• Echo:
  • Isolated pulmonary stenosis or peripheral pulmonary artery stenosis may result in RV hypertrophy.
  • If associated with asymmetric LV hypertrophy, left-axis deviation with LV hypertrophy may be seen.
  • Conduction abnormalities: Typically 1st-degree atrioventricular block
• Audiometry:
  • Sensorineural or conductive hearing losses
• Developmental/psychosocial testing:
  • May reveal varying degrees of cognitive, behavioral, and psychosocial deficits

Imaging

• Fetal US:
  • Subcutaneous edema of nuchal skin folds
  • Generalized fetal edema
  • Renal abnormalities
  • Short femora
  • Cardiac abnormalities
• Transthoracic or fetal echo:
  • Pulmonary stenosis, ASD, asymmetric hypertrophic cardiomyopathy, tetralogy of Fallot, rarely aortic stenosis
• Radiographs:
  • Chest: Enlarged cardiac silhouette secondary to LV or RV hypertrophy
  • Extremity: Bone age studies in association with growth hormone therapy for growth retardation

Lab

Genetic testing:

• PTPN11 gene on Chr 12q24.1 (50%), KRAS gene mutations (<5%), SOS1 (13%), RAF1 (3–17%)
• Sources: Blood, chorionic villi and amniotic fluid, coagulation profiles, platelet count, VWF levels, coagulation factor levels

Diagnostic Procedures/Surgery

Cardiac catheterization:

• Diagnostic catheterization rarely required
• Pulmonary stenosis with doming or dysplastic pulmonary valve
• Hypertrophic cardiomyopathy with possible ventricular outflow tract obstruction

DIFFERENTIAL DIAGNOSIS

• Turner syndrome
• Cardio-facial-cutaneous syndrome
• LEOPARD syndrome
• Costello syndrome
• Watson syndrome
• Neurofibromatosis: In the context of isolated pulmonary stenosis or peripheral artery stenosis, may display right-axis deviation and RV hypertrophy

Outline

• Information
• Diagnostic Tests & Interpretation
  • Imaging
  • Lab
  • Diagnostic Procedures/Surgery
• Differential Diagnosis

• In symptomatic patients with hypertrophic cardiomyopathy, treatment may include:
  • -Adrenergic receptor–blocking agents such as propranolol
  • Calcium channel blockers such as verapamil or diltiazem
  • Disopyramide
• Growth hormone therapy beginning as early as 8 yr of age for children with growth retardation/short stature

ADDITIONAL TREATMENT

General Measures

• See also: Hypertrophic Cardiomyopathy; Cardiomyopathy, Pediatric
• Prenatal:
  • Parental counseling is advised regarding potentially affected systems, especially cardiac and renal. Timing and mode of delivery should be organized through the efforts of a high-risk perinatal team.
• Newborn:
  • Patients with fetal hydrops should receive supportive, nutritional, and respiratory care in an experienced center where neonatal, renal, and cardiac care can be provided.
• Infancy and childhood:
  • Early recognition of and intervention for cognitive or developmental delays
  • Identification and management of hearing deficits
• Adolescence and adulthood:
  • Early evaluation and recognition of growth delay
  • Appropriate referral for management of pubertal delay

SURGERY

• Cardiac:
  • Interventional cardiac catheterization with balloon dilation of pulmonary valvar stenosis or peripheral pulmonary artery stenosis; often poor results for dysplastic pulmonary valve stenosis; surgery for severe obstruction is usually required
  • Myotomy or myomectomy for severe LV outflow tract obstruction due to hypertrophic cardiomyopathy
  • Surgical or transcatheter device ASD closure
  • Surgical repair of pulmonary stenosis, tetralogy of Fallot, or other lesions
• Orthopedic:
  • Leg-lengthening procedures for short stature
• Otologic:
  • Placement of hearing aid devices for sensorineural deficits or myringotomy tubes for conductive hearing loss

Outline

• Additional Treatment
  • General Measures
• Surgery

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• Routine lifelong outpatient visits are recommended, with attention to systems discussed, especially cardiovascular, renal, endocrine, and otologic.
• A well-coordinated multidisciplinary approach is required.

DIET

No dietary restrictions

PATIENT EDUCATION

Activity: No restrictions in the absence of cardiac disease

PROGNOSIS

Overall, the prognosis and outcomes have improved significantly due to early recognition and treatment of associated cardiac malformations, short stature, and cognitive delays.

Pregnancy Considerations

Pregnancy is possible, but may be of high risk in women with severe manifestations; 50% of offspring of affected mothers or fathers will have Noonan syndrome.

Outline

• Follow-Up Recommendations
  • Patient Monitoring
• Diet
• Patient Education
• Prognosis
  • Pregnancy Considerations

CODES

ICD9

• 425.8 Cardiomyopathy in other diseases classified elsewhere
• 759.89 Other specified congenital anomalies

SNOMED

• 205824006 Noonan's syndrome (disorder)
• 195029002 cardiomyopathy associated with another disorder (disorder)

ADDITIONAL READING

• Allason JE. Noonan Syndrome. Gene Reviews, NCBI Bookshelf. 2008;1–20.
• Ferreira LV, Souza SAL, Arnold IJP, et al. PTPN11 (protein tyrosine phosphatase, nonreceptor type 11) mutations and response to growth hormone therapy in children with Noonan syndrome. J Clin Endocrinol Metabol. 2005;90:5156–5160.
• Grange CS, Heid R, Lucas SB, et al. Anesthesia in a parturient with Noonan syndrome. Can J Anaesth. 1998;45:332–336.
• Harland M, Burch M, McKenna WM, et al. A clinical study of Noonan syndrome. Arch Dis Child. 1992;67:178–183.
• Ishizawa A, Oho S, Dodo H, et al. Cardiovascular abnormalities in Noonan syndrome: The clinical findings and treatments. Acta Pediatr Jpn. 1996;38:84–90.
• Moss and Adams’ Heart Disease in Infants, Children and Adolescents, 6th ed. Lippincott, Williams & Wilkins, 2001.
• Nisbet DL, et al. Prenatal features of Noonan syndrome. Prenatal Diagn. 1999;19:642–647.
• Rudolph AM. Rudolph’s Pediatrics, 19th ed. East Norwalk, CT: Appleton & Lange, 1991.
• Shaw AC, Kalidas K, et al. The natural history of Noonan Syndrome: A long-term follow-up study. Arch Dis Child. 2007;92:12–132.
• Van der Burgt I. Noonan Syndrome. Orphanet J Rare Dis. 2007;2:2–4.

Eric D. Fethke

Welton M. Gersony