Noonan Syndrome

Noonan syndrome is typically caused by a genetic mutation in one of several genes involved in the Ras-MAPK pathway that regulates gene expression. Children with Noonan syndrome may inherit a copy of a defective gene from their parents or acquire it in their lifetime through spontaneous mutation in a gene.

In 50% of cases, mutations occur on the PTPN11 gene. Less commonly, the SOS1, RAF1, RIT1, and KRAS genes can be affected by mutations. Rarely mutations of the NRAS, BRAF, MEK2, RRAS, RASA2, A2ML1 and SOS2 genes can occur. Once mutated, the affected gene(s) may produce active proteins that disrupt cellular division and tissue formation.  

In most cases, Noonan syndrome is inherited in an autosomal dominant pattern, in which an individual only needs one copy of an altered gene to be affected. If one parent has Noonan syndrome, there is a 50% chance of passing the defective gene to each child. Because Noonan syndrome can present with various symptoms, the severity of the presentation may differ between the affected parent and the affected offspring.

Signs and symptoms of Noonan syndrome vary greatly among individuals depending on the gene(s) affected by the mutation and may range from mild to severe. Patients with Noonan syndrome may have specific facial features noticeable at birth, including a large head; widely spaced, downward-slanting eyes with pale blue or green irises; low-set ears that are rotated backward; and a nose that is depressed at the top with a broad base. Non-facial features of Noonan syndrome include a short neck with extra folds of skin, a sunken or bulging sternum, wide-set nipples, and short stature. Developmental delays associated with Noonan syndrome include failure to thrive, delayed walking, talking, and growth; difficulty feeding; slow weight gain; increased risk of learning disabilities; and delayed puberty. Because of its various features, Noonan syndrome might resemble other congenital disorders, like Turner syndrome.

People with Noonan syndrome may present with different complications depending on the organ system(s) affected by the disorder. Individuals with Noonan syndrome may have a visual impairment and eye conditions such as strabismus, near-sightedness, far-sightedness, or cataracts. They might also experience hearing loss due to structural abnormalities in the inner ear bones that affect their function. Heart defects, including different forms of congenital heart disease, such as pulmonary valve stenosis, characterized by the narrowing of the pulmonary valve; atrial septal defect, which is an opening in the wall that separates the left and the right atria; hypertrophic cardiomyopathy, which involves thickening of the heart muscle; and irregular heart rhythm, may also present in Noonan syndrome. 

Additionally, individuals with Noonan syndrome have a higher risk of complications like excessive bleeding or bruising in trauma due to low platelet counts or clotting defects; leukemia; and lymphatic complications, leading to excessive fluid collections that cause swelling of hands and feet. There may also be an increased risk of urinary tract infections due to structural abnormalities in the urinary tract and fertility concerns in males due to undescended testicles.

Diagnosis of Noonan syndrome may occur before birth, at birth, in infancy, or even in early adulthood. Before birth, Noonan syndrome may be suspected if there is a family history of Noonan syndrome, if one or both biological parent(s) has a genetic mutation associated with Noonan syndrome, or during a routine fetal ultrasound. On ultrasound, Noonan syndrome may be suspected if findings reveal excessive amniotic fluid surrounding the fetus, build-up of fluid around other parts of the fetus, such as the lungs, or characteristic structural heart abnormalities. During pregnancy, in some cases, fetal DNA may be tested via chorionic villus sampling, where a sample of cells is removed from the placenta, or via amniocentesis, where a sample of amniotic fluid is removed for genetic testing. If the fetus is found to have genetic mutations associated with Noonan syndrome, a genetic counselor may be consulted to discuss the results and options. 

At birth or in early infancy, Noonan syndrome diagnosis typically involves identifying signs and symptoms during a physical examination. However, many signs and symptoms of Noonan syndrome are non-specific or indicative of closely related disorders (e.g., Costello syndrome or Turner syndrome); therefore, signs and symptoms alone may not be sufficient for diagnosis. Healthcare professionals may use the van der Burgt scoring system to diagnose Noonan syndrome, which calculates an individual’s score based on major and minor criteria, including facial, cardiac, height, chest wall, family history, and other features.

Noonan syndrome may also be diagnosed through genetic testing, which involves the collection of blood samples. Many individuals with Noonan syndrome have normal chromosome studies; however, in some cases, no mutations may be found, indicating that negative genetic tests do not rule out Noonan syndrome.

There is currently no cure for Noonan syndrome; therefore, treatment is generally focused on managing any signs, symptoms, and complications associated with Noonan syndrome.

Visual impairment associated with Noonan syndrome may be managed with close monitoring of eye health, prescription glasses, or surgery in certain circumstances, such as if the individual develops cataracts. Hearing impairment may be monitored closely with auditory exams and hearing aids depending on the degree of hearing loss. 

Short stature may be managed by monitoring growth rates closely until adulthood, ensuring adequate nutrition, and measuring growth hormone levels. In individuals with insufficient growth hormone levels, treatment with growth hormone therapies, such as somatropin, may be an option that starts around four or five years of age and continues until the child stops growing. 

Genital problems, such as undescended testicles, may be managed with a surgical procedure called an orchidopexy, in which the undescended testicle is surgically moved into the scrotum, typically before two years of age, to avoid future fertility issues.

Heart defects may involve various treatments, including medications or surgery, depending on the nature and severity of the heart defect. In many mild cases, treatment involves close monitoring of heart function, such as through routine ECGs and echocardiograms.  Irregular heart rate may be managed using medications such as beta-blockers (e.g., metoprolol), while surgery may be required to repair heart valves. 

Treatment of bleeding and clotting disorders may be managed by avoiding blood thinners, such as aspirin, or with blood transfusions, depending on the degree of blood loss.

Finally, learning disabilities may be managed using simulation programs, physical and speech therapies, and special education using individualized teaching strategies.