Noonan Syndrome: A Rare Disorder

Thousands of genes make up the human body. Various combinations of DNA (building blocks of genes) are the reason why you have brown hair and I have blue eyes. Sometimes there are permanent alternations in a gene called mutations. Conditions such as Noonan syndrome cause widespread symptoms in development occur because of genetic mutations.

Noonan Syndrome
Noonan Syndrome Genetic Mutation

What is Noonan Syndrome?

Noonan syndrome is a rare genetic disorder impacting growth and development. Jacqueline Noonan founded the syndrome in 1962 after discovering a subset of patients with similar facial features, musculoskeletal deformities, and cardiac abnormalities. An estimated 1 in 1,000 to 1 in 2,500 is diagnosed with the condition. Symptoms are apparent from birth in both genders and various ethnic backgrounds.

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Causes of Noonan Syndrome

As previously stated, it is caused by a genetic mutation. It follows an autosomal dominant inheritance pattern, which indicates that only one copy of the mutation gene is needed to have symptoms of the syndrome. Although Noonan syndrome commonly runs in families, there are cases where of spontaneous mutations that occur without a family history.

At least 8 gene mutations have been associated with Noonan syndrome. According to the National Human Genome Research Institute, the top 5 causing genes are SOS1, RIT1, RAF1, KRAS, and the PTPN11 gene that is responsible for half of all the cases.

Symptoms of Noonan Syndrome: Facial Features

The most obvious symptoms of Noonan syndrome manifest as unique facial features. Beginning with the head, characteristics begin with a large skull and low hairline. They also include wide-set eyes with pale blue or green irises, low-set ears that are rotated, and a wide nose. Their lips are grooved, and teeth crooked due to a high palate and small jaw. Skin appears thin and transparent. Facial features are considerably pronounced in infancy and early childhood.

Noonan Syndrome
Noonan Characteristics

Symptoms of Noonan Syndrome: Musculoskeletal and Development

Noonan syndrome is a disorder of development. Patients with this syndrome are considered failure to thrive—meaning they struggle to gain adequate weight due to eating difficulties. Despite normal birth weight, insufficient levels of growth hormones delay bone growth. As a result, bone maturity is delayed and growth spurts occur later than what is typical. They rarely reach normal stature.

Musculoskeletal issues are a consequence of the Noonan syndrome interfering with development. Deformities of the spin, like scoliosis and kyphosis, are common. A protruding sternum (pectus carinatum) or a sunken in chest (pectus excavatum) accompany wide set nipples and a short webbed neck.

Symptoms of Noonan Syndrome: Cardiovascular

While the physical characteristics of Noonan syndrome are relatively benign, it can affect the cardiovascular system too. Nearly all patients have congenital heart disease that is present at birth. In some cases, the defects are evident before birth.

  • Arrhythmias—The heart beats out of a normal rhythm ranging from beating too fast or in an irregular pattern.  
  • Thickening of the heart muscle—Also termed hypertrophic cardiomyopathy, the heart has to work harder to pump blood past thickening heart cells which enlarges the ventricles.  
  • Pulmonary valve stenosis—Blood flow to the lungs is reduced because the valve allowing the passage of blood from the heart to the lungs becomes narrow.
  • Ventricular septal defect—A ventricular septal defect is a hole in the wall that separates the heart’s two chambers. Most holes in the regular population close on their own, but in those with this syndrome holes in the septum lead to fast breathing, a bluish tint to skin, lips, and nails, and failure to thrive.
  • Pulmonary artery stenosis—The pulmonary artery, located above the pulmonary valve, carries blood from the right ventricle to the lungs. Pulmonary artery stenosis is the narrowing of the pulmonary artery. Complications are high blood pressure and an enlarged heart from the cardiovascular system having to work harder to pump blood from the heart to the lungs.  
  • Aortic coarctation—Part of the heart known as the aorta narrows, reducing the amount of blood pumped from the heart to the rest of the body.

Other Symptoms of Noonan Syndrome

The severity of this syndrome differs in each individual. Many have signs other than solely unique facial features, cardiovascular defects, growth and developmental delays, and musculoskeletal symptoms.

  • Lymphedema—This syndrome also prevents the lymphatic system from filtering infection and fluids. Lymphedema is the swelling of the body from excessive lymph fluid. The swelling occurs in the tops of hands and in the feet.
  •  Learning disabilitiesSome patients exhibit cognitive deficits along with emotional and behavioral problems.
  • Strabismus (cross-eye)—Noonan syndrome interferes with coordination of the eye muscles. When cross-eyed, one eye is misaligned inward and the other remains in proper focus.    
  • Ptosis—Ptosis is the drooping of the eyelid.
  • Cataracts—Although common amongst the older population, this syndrome causes cataracts at an early age. Clouding of the lens effects vision.
  • Myopia or Hyperopia—Nearsightedness or farsightedness
  • Astigmatism—An abnormal curvature of the eye’s lens or an abnormally shaped cornea results in blurry vision.
  • Hearing difficulties—Poor hearing can be from nerve issues or structural defects in the ear.
  • Excessive bleeding—Secondary clotting disorders or a decrease in platelets causes easy bleeding.
  • Cryptorchidism—In males, one or both of the testicles fail to drop from the scrotum. Fertility can be effected.

How Noonan Syndrome Affects the Brain

Genetic mutations causing Noonan syndrome affect the RAS pathway. The RAS pathway is a group of proteins in a cell that communicates “a signal from a receptor on the surface of the cell to the DNA in the cell’s nucleus” (Brett, 2018). The theory is that this syndrome affects the brain because the mutation interferes with hippocampus function. Cognitive delays in executive functioning are prevalent cognitive deficits in this syndrome.

Memory Impairment in Noonan Syndrome

Memory impairments involve mainly visual memory and working memory. The latter is a form of short-term memory involving immediate processing. It is crucial for day-to-day tasks. Those with Noonan syndrome might forget steps to an activity like completing homework or making a sandwich. With significant impairments in visual memory, presenting information verbally is ideal.

Attention-Deficit-Hyperactivity Disorder (ADHD) in Noonan Syndrome

Studies reflect that 30% of patients with Noonan syndrome have attention deficit hyperactivity disorder (ADHD). Impulsivity, forgetfulness, distractibility, and disorganization are symptoms indicative of ADHD. However, not all symptoms pertaining to attention are from ADHD. Memory deficits have a role in distractibility.

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Language Development and Communication in Noonan Syndrome

Extensive communication barriers arise in this syndrome. Verbal skills are lacking in the majority of patients beginning in infancy. As per the Noonan Syndrome Awareness Association, spoken first words are delayed until 15 to 31 months (Brett, 2018). Low muscle tone of the mouth muscles precipitates problems with articulation. Hearing deficits complicate conversation if unable to hear what is being said.

Noonan Syndrome and Autism

A large portion of patients with Noonan syndrome meets at least part of the criteria for an autism diagnosis. Shortfalls of social skills are due to multiple factors. Metaphors and inferred information are misinterpreted and misunderstood because language difficulties are partly responsible for social cognition. Knowing appropriate behavior in social settings is related to social immaturity from developmental delays.

Diagnosing Noonan Syndrome

Noonan syndrome patients vary in presentation. The severely afflicted show obvious symptoms at birth, but those with milder cases may go until adulthood before reaching the consensus of a diagnosis. Overall, the diagnosis relies on medical professionals recognizing the key signs. If Noonan syndrome is suspected, patients are referred to a geneticist for genetic sequencing to isolate the causing gene. 1 in 5 with Noonan syndrome are unable to locate a specific mutation and must depend on a clinical evaluation.

Treatment for Noonan Syndrome

Treatment for Noonan Syndrome is tailored to the individual patient’s presentation. Patients are closely monitored by a series of specialists—cardiologists, endocrinologists, hematologists, ophthalmologist, and hearing doctors. A combination of therapies is generally necessary to manage the symptoms.

Early Intervention for Noonan Syndrome

Early intervention consists of physical and occupational therapy. Therapies are essential for those diagnosed with Noonan Syndrome. The condition causes nerve issues and decreased muscle tone, so trained physical therapists pinpoint problem areas and work on safe strengthening exercises. Cardiac defects must be considered when implementing an exercise regimen.

Occupational Therapy for Noonan Syndrome
Occupational Therapy for Noonan Syndrome

Occupational therapists teach patients effective strategies for improving daily functions. This ranges from ways to sit to reduce pain to cognitive interventions. Examples of occupational therapy interventions include:

  • Speech therapy—Therapists train the patient to develop their mouth muscles, as low muscle tone causes difficulties speaking and eating.
  • Fine motor activities—Playing with playdough, legos, and beading increases fine motor skills.
  • Appropriate seating Musculoskeletal involvement and short stature makes certain positions uncomfortable. Occupational therapists lend soft cushions and adjustable chairs to ease pain. Musculoskeletal involvement and short stature makes certain positions uncomfortable. Occupational therapists lend soft cushions and adjustable chairs to ease pain.
  • Thickened utensils—Fine motor problems make it harder to grasp objects. Thickened utensils (i.e. pen, pencils, scissors, silverware) are easier to use.
  • Practicing skills—Occupational therapists practice everyday skills like writing, cutting, folding, and tracing.
  • Visual and verbal cues—Cognitive development benefits from visual and verbal cues given with instructions.
  • Emotional monitoring—Processing emotions is more difficult with cognitive delays. Therapists demonstrate how to monitor emotions with calendars and charts.

An occupational therapist’s role is to facilitate all of these needs in the home and in a classroom setting to ensure success.

Cardiovascular Monitoring for Noonan Syndrome

The cardiovascular symptoms of Noonan syndrome are treated in the same manner as those without the condition. Frequent monitoring is required for doctors to discern the progression of cardiac abnormalities. Medications such as beta-blockers are first prescribed to help control irregular heart rate, stabilize arrhythmias, and reduce stress on the heart muscle from thickening and dilation.

Growth Therapies Used for Noonan Syndrome

As suggested by the Mayo Clinic, height should be recorded 3 times a year. For children with stunted growth because of Noonan syndrome, specialists suggest that hormone levels are checked through blood work. If hormone levels are low, growth hormone therapy can restore levels. Growth hormone therapy is an injectable hormone that promotes growth.

Surgery for Noonan Syndrome

Unfortunately, the severe cases of Noonan syndrome do not respond favorably to less invasive treatments. They require the surgical interventions discussed below.

Cardiovascular

Surgeries for the cardiovascular symptoms of Noonan syndrome are geared toward correcting congenital heart defects. For example, many undergo an operation to close the hole in the heart’s septum if it does not close on its own. Secondary pulmonary stenosis is treated by widening and replacing the valve/artery. Removing part of the heart muscle is used to treat hypertrophic cardiomyopathy in the Noonan syndrome patients who are unresponsive to medication.

Undescended Testicles

Males with Noonan syndrome cryptorchidism, or undescended testicles, need surgery to move the testicles into position. It is best that this is done in the first one to two years of life to avoid infertility complications.

Lymphedema

Specialists also treat lymphedema with surgery in rare situations. The lymphatic system is connected to a nearby artery. Surgery restores the flow of lymph in various sections of the lymphatic system by rerouting the path.

Noonan Syndrome is a rare disorder, but with awareness, it does not have to be rarely known.

References

Brett. (2018, March 18). Intellectual Difficulties in Noonan Syndrome. Retrieved from https://noonansyndrome.com.au/intellectual-difficulties-in-noonan-syndrome/

Digilio, M., & Marino, B. (2001). Clinical manifestations of Noonan syndrome. Images in paediatric cardiology, 3(2), 19-30.

Roelofs, R. L., Janssen, N., Wingbermühle, E., Kessels, R. P., & Egger, J. I. (2016). Intellectual development in Noonan syndrome: a longitudinal study. Brain and behavior, 6(7), e00479. doi:10.1002/brb3.479