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See updated Article: Noonan syndrome; Author Judith Allanson, MD Last revision 1 May 2006

Noonan Syndrome: Evaluation and Treatment of Associated Health Issues

J E Allanson

Adapted from “Management of Common Genetic Syndromes”

Editors: S B Cassidy and J E Allanson. Wiley 2005.  

Index

• Growth Evaluation Treatment	Neurology Evaluation Treatment	Lymphatics Evaluation Treatment	Skin Evaluation Treatment
  Development Evaluation Treatment	Ophthalmology Evaluation Treatment	Genitourinary Evaluation Treatment	Ears and Hearing Evaluation Treatment
  Cardiology Evaluation Treatment	Hematology Evaluation Treatment	Musculoskeletal Evaluation Treatment	Neoplasia Evaluation Treatment

Growth

Evaluation

• Growth velocity should be monitored for 6-12 months, using regular, not syndrome specific, growth charts. If growth velocity is normal, height should be measured every 6 months.

·        If deficiency is noted, nutritional status should be evaluated and chronic illness ruled out.

·        Initial testing for growth deficiency should include thyroid function tests, bone age, complete blood count, blood chemistries, sedimentation rate, and IGF-1 and usually IGFBP-3.

·        Provocation testing should be performed using standard methods.

·        If growth hormone deficiency is found, panhypopituitarism should be assessed by specific hormone testing and magnetic imaging of the brain.

·        Cardiac status must be evaluated in the child on growth hormone treatment. Cardiomyopathy is not a complete contraindication to treatment, but close monitoring with echocardiography must be put in place.

• The child on growth hormone should have periodic assessment of growth velocity (every 6 months), bone age (every 12 months), and thyroid function tests and blood chemistries (annually).

Treatment

• There are significant differences in the utilization of growth hormone and in the approach to treatment between countries. In Canada and some European countries, growth hormone deficiency must be documented before growth hormone treatment is sanctioned. In the United States and Britain, some endocrinologists may choose to treat any small individual with growth hormone, irrespective of growth hormone testing results, beginning at age 7-8 years (Romano, personal experience).
• Initiation of treatment with growth hormone should be considered once deficiency is proven. Some clinicians would institute treatment in any child with Noonan syndrome who is small, irrespective of results, beginning at 7 or 8 years (Romano, personal experience). Treatment is currently a daily injection or application to the skin surface using a gunlike device. Alternate vehicles are under development.
• Feeding difficulties and associated failure to thrive should be managed as in the general population.

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Development

Evaluation

• A screening developmental assessment, with such tools as the Denver Developmental Screening Test, should be done at diagnosis and at least annually.

·        A full developmental assessment should be done if delays are ascertained.

·        School difficulties deserve formal psychological assessment to determine whether a specific cognitive disability is present that might respond to an alternate teaching method.

·        Any delay in speech acquisition should prompt an assessment by speech pathology.

Treatment

• Hypotonia will respond to physical and occupational therapies over time.

·        An infant stimulation program should be initiated if delays are noted early.

·        Special individualized education strategies are needed if indicated by detailed testing.

·        Speech therapy is suggested where delays or articulation deficiencies are identified.

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Cardiology

Evaluation

• Clinical assessment, electrocardiogram (with particular attention to the QRS axis), and echocardiogram are recommended at the initial assessment. Subsequent follow-up is dictated by these investigations and the clinical course.

·        A malformed pulmonary valve should be evident at initial assessment but may become more stenotic with time. Cardiac hypertrophy may progress without changes in clinical status. Therefore, echocardiographic follow-up, at least every 2 years, is important regardless of the finding of a normal myocardium at presentation.

Treatment

• b-Blockade or calcium channel blockers have been used most frequently in the treatment of obstructive cardiomyopathy, although attempts to improve diastolic function with both classes of drug are often contemplated (Ishizawa et al., 1996).

·        If there is no response to drug therapy, surgery is indicated for left ventricular outflow obstruction. Both surgical myomectomy and transplantation are reported (Sharland et al., 1992a).

·        Intervention for pulmonary outflow tract obstruction caused by valvular dysplasia is recommended at any age if right ventricular pressure exceeds 80 mmHg. Results are good. The initial palliative surgery of choice (Ishizawa et al., 1996) is balloon valvuloplasty, although it is widely accepted that results in the presence of a dysplastic valve may not be as good as in non-syndromic pulmonary valve stenosis. Frequently, open pulmonary valvotomy, with annulus enlargement, is needed. Severe cases may require pulmonary valve debridement or replacement, typically with a bioprosthesis (Ishizawa et al., 1996). Recurrent stenosis rarely occurs, although a mild decease in gradient may occur in the late postoperative period.

·        Subacute bacterial endocarditis prophylaxis is required in all individuals with a cardiac structural defect for dental work, surgery, catheterization, and other circumstances likely to promote a bacteremia.

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 Neurology

Evaluation

·        Neurological investigation should be prompted by signs and symptoms and may include thorough neurological examination, magnetic resonance imaging, electroencephalogram, electromyogram, and/or nerve conduction velocities.

·        Creatine kinase analysis is recommended before anesthesia or dental work.

 Treatment

• Anticonvulsant therapy is indicated for a seizure disorder, and treatment does not differ from that in the general population.

·        Dantrolene prophylaxis should be used during anesthesia when creatine kinase levels are increased or if there is a clinical suspicion of malignant hyperthermia or myopathy.

·        Surgery may be required for a rare brain structural anomaly such as hydrocephalus.

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Ophthalmology

Evaluation

·        A detailed visual assessment in infancy or at diagnosis is indicated.

·        Continuing periodic ophthalmologic evaluation should be done if anomalies are found (Lee et al., 1992).

Treatment

·        Most ocular defects require nonsurgical treatment, such as glasses and occlusion for amblyopia and correction of refractive errors.

·        Surgery may be required for cataracts or ptosis (in 10%).

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Hematology

Evaluation

• Inquiries should be made about a history of easy bruising or prolonged bleeding at menstruation or after venipuncture.

·        Clinical evidence of abnormal bleeding should be sought.

·        Routine screening tests at diagnosis should include prothrombin time, activated partial thromboplastin time, bleeding time, and platelet count. Recent aspirin exposure must be excluded.

·        Additional specific testing of coagulation factors, von Willebrand factor antigen, and functional epitope and platelet function is advised if indicated by the screening results (Witt et al., 1987; Sharland et al., 1992b).

 Treatment

• Aspirin and aspirin-containing medications should be avoided.

·        Individualized hemostatic support may be required, depending on the specific hemorrhagic diathesis identified.

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Lymphatics

Evaluation

·        Prenatal: In the presence of a cystic hygroma or thickened nuchal fold, maternal serum screening or invasive testing with chromosome analysis should be pursued. A detailed sonographic search for other anomalies should be carried out.

·        Postnatal: The objectives of evaluation of lymphedema are twofold-to discover the cause of the lymphatic problem and to define the type. Radionuclide scanning is advocated by many as a first step. Intradermal injection in the first interdigital web space of the lower limb is followed by serial scintiscans of the ilioinguinal region. Direct lymphangiography can then be used to define the type of anomaly.

·        The majority of individuals with intestinal lymphangiectasia manifest diarrhea, with or without steatorrhea, and diagnosis often begins, as a consequence, with studies to detect and quantify protein loss. Barium meal appearance is characteristic, and peroral jejunal biopsy and lymphography provide definitive diagnosis.

·        Chylous complications often are related to lymph vessel hyperplasia with abnormalities of the thoracic duct or presence of megalymphatics. Diagnosis of chylothorax depends on accurate assessment of clinical features, chest radiographs, and demonstration of chyle in pleural fluid obtained by thoracocentesis. Computerized tomographic scanning and lymphoscintigraphy are useful adjuncts that may delineate obstruction to the cisterna chyli with chylous reflux in both chylothorax and chylous ascites.

 Treatment

• Chronic lymphedema of the lower extremities, albeit rare, is frequently associated with infection. Foot hygiene is extremely important. Carefully fitting shoes and support stockings are useful, along with antibacterial cleaning solutions. Daily examination for webspace fissures, paronychias, impetigo, and folliculitis should be instituted, with prompt use of systemic antibiotics where indicated to decrease the incidence of severe infection. Prophylactic penicillin may be warranted when hygiene measures alone are inadequate (White, 1984).

·        Treatment options for chylothorax include drainage by repeated thoracentesis, chest tube, or pleuroperitoneal shunt; reduction of chyle production by low-fat diet or parenteral nutrition; and, if conservative measures fail, surgical modification of lymph flow by thoracic duct ligation, chemical pleurodesis, or pleurectomy. Most chylothoraces resolve with drainage and dietary modification. Long periods of drainage are complicated by weight loss, hypoalbuminemia, lymphopenia, and infection, which can be fatal. Successful prednisone therapy has been reported. The effect of steroids may be to increase plasma oncotic pressure through increased rate of breakdown of extrahepatic proteins, freeing amino acids and facilitating liver synthesis of more plasma proteins.

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Genitourinary

Evaluation

• Renal ultrasound is recommended in newborns or at diagnosis to assess for malformations and disruptions.

·        Serial re-evaluation may be suggested, depending on the findings.

·        Periodic urinalysis is warranted if the genitourinary tract is abnormal, because of increased frequency of urinary tract infection in these circumstances.

·        Evaluation of the pituitary-gonadal axis before puberty is suggested to assess the need for hormone replacement therapy.

Treatment

• The presence of cryptorchidism at birth should lead to a referral to an appropriate surgeon for consideration of a trial of human chorionic gonadotrophin injection and/or surgery before school entry. The approach to treatment is the same as in the general population.

·        Urinary tract infection should be treated with appropriate antibiotics.

·        Testosterone replacement should be considered in males with primary hypogonadism.

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Musculoskeletal

Evaluation

• Annual assessment of chest cage and spine, both clinical and radiological, is recommended.

·        Dental evaluation and monitoring should begin in early childhood, so that appropriate referral to orthodontics can be facilitated.

 Treatment

• Scoliosis may require bracing or surgery, as in the general population.

·        Malocclusion may need orthodontic intervention, as in the general population.

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Skin

Evaluation

·        Dermatological problems should be referred to a specialist and management planned as in the general population.

Treatment

·        Local medication for keratosis pilaris atrophicans faciei is usually unsuccessful.

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Ears and Hearing

Evaluation

·        Hearing testing should begin in infancy and continue annually through early childhood.

 Treatment

·        Aggressive treatment of otitis media with antibiotics is recommended.

·        Sensorineural hearing loss may require hearing aids.

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Neoplasia

Evaluation

·        Juvenile myelomonocytic leukemia is seen with slightly increased frequency. Given the rarity of this malignancy, no particular screening is recommended.

Treatment

·        Juvenile myelomonocytic leukemia should be treated in a standard manner

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