Tuberous sclerosis: Clinical clues for early diagnosis

A scan of the brain of a tuberous sclerosis patient.

Tuberous sclerosis is a rare neurological condition characterized by benign tumor growth in various parts of the body. It often affects the brain, eventually causing epilepsy and neurodevelopmental disorders. One challenge has been diagnosing the condition in infants, as they often don’t present with many clinical signs. However, a recent study published in Pediatrics has shed some light on early manifestations of this condition that may help lead to earlier diagnosis — and possibly earlier and more aggressive treatment.

To better understand clinical clues that may be seen in pediatric practice, Notes sat down with principal investigator of the study, Mustafa Sahin, MD, PhD, director of the Translational Neuroscience Center at Boston Children’s Hospital. He and his team in the Tuberous Sclerosis Program at Boston Children’s follow about 300 children with the condition.

What are the main takeaways of your research?

We started a national consortium to look at the manifestations of tuberous sclerosis in different organs in the first three years of life. Of the 130 children enrolled in this particular study, we found that a few manifestations of tuberous sclerosis can actually be detected early, often in infancy.

What are the specific clinical signs that might be seen in infants?

We found the two most prevalent presenting features in infants were heart tumors and hypomelanotic macules, white spots on the skin where there is a lack of pigmentation. About 85 percent of the infants in our study had heart tumors, hypomelanotic macules or both.

Ultrasound images of cardiac and lung tumors found in tuberous sclerosis.
Cardiac tumors and lymphangiomyomatosis are clinical signs of tuberous sclerosis.

Heart tumors seem to develop earliest, before any other manifestations develop on the skin or in the brain. This study confirmed that infants who have multiple heart tumors, either prenatally or shortly after birth, have a high prevalence of tuberous sclerosis. Although heart tumors may not be detected by ultrasound prenatally in all patients, something as benign as a heart murmur after birth could also be a sign of tumors.

The hypomelanotic macules may develop anywhere on the body and may be seen at birth. However, they can sometimes be missed on light-skinned people, and are best viewed using a Wood lamp.

What other clinical signs might be present in children?

Most children with tuberous sclerosis have other skin manifestations, though they don’t usually show up until after the first year. Many have raised lesions on the face, called angiofibromas. Older children may also present with a shagreen patch, a raised, collagen-filled lesion that resembles an orange peel, usually found on the lower back.

Another sign that occurs quite frequently in the first year of life is the onset of seizures. About 80 percent of kids with tuberous sclerosis will have seizures. Babies ages 3 to 9 months often have a type of seizure called infantile spasms, which is a symmetric jerking of the upper or lower body that occurs in clusters. It’s a very stereotypical movement that is often mistaken for colic, as the child can look like they are in pain. These seizures can occur in clusters up to 30 times in a row, and most often occur when a child is going into sleep or coming out of sleep.

Why is early diagnosis so important?

We’ve found that early treatment may help alleviate seizures, one of the most severe complications of tuberous sclerosis.

We recently discovered that a significant number of patients start having abnormalities on their EEGs about two to three months before their seizures begin. That has led us to further research to see if we start treatment before seizures present, whether we can prevent them from happening and ultimately improve developmental outcomes. We don’t know the answer yet, but it’s an ongoing study where we are enrolling and randomizing children to either early treatment or standard-of-care treatment to see if the outcomes are different.

One of our goals is to determine which kids are at high risk for developing neurological complications and which are not. If we could make that differentiation early in life, we could treat the high-risk kids differently from those at low risk. For example, we might prescribe a pharmacological treatment for high-risk kids before symptoms arise, while providing low-risk kids with physical therapy, occupational therapy or other therapies that might be sufficient for optimal growth.

What should pediatricians keep in mind in terms of diagnosing tuberous sclerosis?

Boston Children’s and other specialized centers are attuned to looking for these signs, but they may be easy to miss in general practice. If children in your practice are diagnosed with epilepsy or autism, it’s important to have a skin exam to check for abnormalities related to tuberous sclerosis. Or if they have skin manifestations and a family history of kidney tumors or brain tumors, that could also be a reason to look deeper.

There are now about 30 clinics around the country associated with the Tuberous Sclerosis Alliance. We have many ongoing clinical treatment trials, and pediatricians may be able to refer patients to one of the specialty sites to take part in a trial.

Mustafa SahinAbout our expert: Mustafa Sahin, MD, PhD, is director of the Translational Neuroscience Center at Boston Children’s Hospital and professor of neurology at Harvard Medical School.




Learn more about our Tuberous Sclerosis Program.