RASopathies:

Noonan Syndrome Spectrum Disorders

Developmental Disorders

What are RASopathies?

RASopathies are rare and include several different conditions. The most common is Noonan Syndrome. These syndromes are typically found in childhood, but later diagnosis is possible. Most RASopathy patients (up to 80%) have heart problems, including congenital heart defects and "HCM". Other organs and systems are affected, such as the face, head, and kidneys. Those with RASopathies may have slow growth, developmental delay, and bleeding disorders.

The group of conditions called RASopathies are developmental disorders. They are caused by mutations in genes linked to the RAS/MAPK pathway. These disorders occur in about 1 in 1000 to 1 in 2500 live births. The most common RASopathy is Noonan Syndrome, so they're called Noonan Syndrome Spectrum Disorders. These syndromes affect many body systems, and heart problems are often part of that.

What are the different RASopathies?

The RASopathies include Noonan Syndrome with multiple lentigines (NSML, formerly LEOPARD syndrome). Also, Cardiofaciocutaneous Syndrome (CFCS), Mazzanti Syndrome (MS), Costello Syndrome (CS), Type 1 Neurofibromatosis, and Legius Syndrome. Other related syndromes are being investigated.

How are RASopathies similar to each other?

Each RASopathy has a unique clinical type, but they have overlapping signs and symptoms. These include slow growth, changes in the bones of the face and head, undescended testicles, cognitive deficits, kidney problems, bleeding disorders, and congenital heart defects.

What causes RASopathies?

Mutations in various genes can cause RASopathy. More than 10 genes are associated with Noonan Syndrome alone. Some of these mutations lead to a higher chance of hypertrophic cardiomyopathy (HCM). Others have a higher chance of learning disabilities or growth problems.

Other heart problems in RASopathies

Congenital heart defects (CHD) are often part of RASopathies. These include pulmonary valve stenosis, mitral valve problems, ASD (hole between the atria), VSD (hole between the ventricles), AVSD (hole in the center of the heart), aortic coarctation (narrowing of the artery leaving the heart), and coronary artery issues.

Monitoring heart problems in RASopathies

EKG/ECG and Holter Monitor

Abnormal heart rhythms are common in RASopathies. Regular evaluations using EKG and Holter or ambulatory monitoring are important.

Echocardiogram

It's important to have regular echocardiograms. They can detect issues with the heart anatomy and LVOTO. They can also detect heart failure. How often patients need an echo depends on their individual hearts. Your cardiologist will tell you how often you need an echo.

LVOTO is common among patients with RASopathies. This may be due to problems other than LVH. Things like issues with papillary muscles, or abnormal mitral chordae. Fibrous tissue can cause midventricular obstruction. The mitral valve leaflets can be long in patients with R-HCM. Displacement of the papillary muscles may pull the mitral valve out of alignment. These causes of obstruction can be seen on an echo.

Hypertrophy in both the right and left ventricle may be a clue that this is R-HCM. Thickening in the right ventricle may cause right ventricular outflow tract obstruction.

MRI/CMR

Cardiac MRI (CMR) can measure the thickness of the septum and walls of the heart more accurately than echo. Late gadolinium enhancement shows how much fibrosis (scarring) is in the heart.

Genetic Testing and Family Screening

Genetic testing helps to understand which RASopathy is present and what problems it may cause. It can help screen family members of the patient so they know if they are affected. It can also help people make choices about having children. When someone is diagnosed with RASopathy, their family will be offered genetic testing. A genetic counselor can help your family understand your genetic information.

Medical Management

Medical therapy is the first option in patients with R-HCM. 

Nonvasodilating beta-blockers and diuretics can reduce congestive status and heart failure (HF) symptoms. Be careful not to overdo diuretics as they can cause low blood volume, which can increase LVOTO. If beta-blockers have too many side effects, nonvasodilating calcium channel blockers can be tried. 

There are some reports of low heart rate and worse HF in infants with LVOT gradients over 100 mmHg. Verapamil could be harmful to this group. In patients who still have symptoms on beta-blockers, disopyramide can help reduce obstruction.

In some cases, rapamycin or MEK1 inhibitors may reduce LVH and should be considered.

Myectomy Surgery

In cases where obstruction can't be reduced by medications, septal myectomy surgery is an option to remove the obstruction.

Heart Transplant

Heart transplant is rarely done in patients with NS. It may be considered in patients with severe HF symptoms who don't respond to medications. If a heart transplant is needed and the wait is too long, especially in infants, the outcome is often poor. Evaluation for heart transplants should be done as early as possible in R-HCM patients with severe heart failure.

Clinical Trials

There are ongoing clinical trials of medications for heart problems in RASopathies. A small trial with trametinib had promising results, reversing LVH in two NS patients. More studies are on the horizon.