Noonan Syndrome

Question 1

A 10-year-old boy is brought to the pediatric clinic for evaluation of short stature. His mother notes that he was born at term with a normal birth weight but has consistently been in the lower percentiles for height. He has mild learning difficulties and struggles with fine motor skills. On physical examination, the boy has hypertelorism, downslanting palpebral fissures, low-set posteriorly rotated ears, a short neck with webbing, and pectus excavatum. A systolic murmur is heard over the left upper sternal border. Echocardiography reveals pulmonary valve stenosis. Family history reveals that the father has similar facial features and a history of heart surgery during childhood.

What is the most likely diagnosis, and what genetic mutation is most commonly associated with this condition?

A. Turner syndrome, SHOX gene mutation
B. Noonan syndrome, PTPN11 mutation
C. Williams syndrome, ELN gene deletion
D. DiGeorge syndrome, 22q11.2 deletion
E. Down syndrome, trisomy 21

Answer 1

Correct Answer: Noonan syndrome, PTPN11 mutation

Explanation: Noonan syndrome is an autosomal dominant disorder caused by mutations in genes involved in the RAS/MAPK pathway, with PTPN11 being the most commonly affected gene. It is characterized by distinctive facial features (broad forehead, hypertelorism, downslanting palpebral fissures, low-set ears, webbed neck), short stature, pectus deformities, and congenital heart defects such as pulmonary valve stenosis or hypertrophic cardiomyopathy. These patients also commonly have congenital lymphatic malformations. The family history of similar features and cardiac issues supports the genetic nature of this condition.

Incorrect Answers:

A. Turner syndrome: Typically affects females and is associated with features such as lymphedema, webbed neck, and coarctation of the aorta, but not pulmonary valve stenosis.
C. Williams syndrome: Associated with elfin facies, hypercalcemia, and supravalvular aortic stenosis, not pulmonary valve stenosis.
D. DiGeorge syndrome: Involves cardiac defects (e.g., tetralogy of Fallot), hypocalcemia, and thymic hypoplasia, but does not present with the distinctive facial and skeletal features of Noonan syndrome.
E. Down syndrome: Associated with intellectual disability, flat facial profile, and atrioventricular septal defects, not pulmonary valve stenosis or webbed neck.

Question 2

What is the genetic basis of Noonan syndrome?

Answer 2

Noonan syndrome is an autosomal dominant disorder caused by mutations in genes involved in the RAS/MAPK pathway, such as PTPN11, SOS1, RAF1, and KRAS.

Question 3

What are the hallmark facial features of Noonan syndrome?

Answer 3

Facial features include a broad forehead, hypertelorism (widely spaced eyes), downslanting palpebral fissures, low-set ears, and a short neck with webbing.

Question 4

What cardiovascular abnormalities are associated with Noonan syndrome?

Answer 4

The most common cardiac defect is pulmonary valve stenosis, but hypertrophic cardiomyopathy and atrial septal defects (ASDs) can also occur.

Question 5

What growth abnormalities are seen in Noonan syndrome?

Answer 5

Patients may have short stature due to growth hormone deficiency or delayed growth.

Question 6

What developmental and intellectual issues are associated with Noonan syndrome?

Answer 6

Mild developmental delays and learning disabilities are common in Noonan syndrome, though intelligence is typically within the normal range.

Question 7

What hematologic findings are associated with Noonan syndrome?

Answer 7

Patients may have coagulation defects such as von Willebrand disease, thrombocytopenia, or clotting factor deficiencies, leading to an increased bleeding tendency.

Question 8

What skeletal and musculoskeletal findings are common in Noonan syndrome?

Answer 8

Skeletal abnormalities include pectus carinatum or excavatum, scoliosis, and cubitus valgus (increased carrying angle of the arms).

Question 9

How is Noonan syndrome diagnosed?

Answer 9

Diagnosis is based on clinical features, family history, and confirmation with genetic testing for mutations in RAS/MAPK pathway genes.

Question 10

What is the treatment approach for Noonan syndrome?

Answer 10

Management includes treatment of specific symptoms, such as surgical correction of cardiac defects, growth hormone therapy for short stature, and special education services for developmental delays.

Question 11

What is the life expectancy for patients with Noonan syndrome?

Answer 11

With appropriate management of complications, patients with Noonan syndrome typically have a normal life expectancy.