SINGAPORE – Madam Chua Siew Tin, 49, had bleeding in her kidneys in 1997. Three years later, her lungs collapsed and she nearly died. Both conditions were caused by the same disease – tuberous sclerosis complex (TSC).

But her doctors did not know this at the time – separately, they treated her to stabilise each condition instead of the underlying cause of her problems. As a result, both conditions recurred.

It was only after her first child, born in 2002, started having fits at the age of four months and was diagnosed with this genetic condition that the housewife’s own condition was also diagnosed.

TSC is a rare genetic disease, affecting one in 8,000 people, that causes benign tumours to grow in various parts of the body, such as the brain, spinal cord, nerves, eyes, lungs, heart, kidneys, bones and skin. They are the result of uncontrolled cell growth and division.

The effects of the disease range from being so mild that they hardly affect a person’s life to being life-changing and even fatal. But patients whose condition is mild can pass the genetic defect to their children, who might get it as a severe condition.

About 700 people in Singapore most likely have TSC. About 30 per cent of TSC patients would have inherited it from a parent. For the rest, it is caused by a spontaneous mutation of their DNA.

Around a dozen TSC patients here are under the care of Dr Loh Ne-Ron, a neurologist at KK Women’s and Children’s Hospital (KKH). The Singaporean had worked in Britain over the past 30 years and headed a TSC clinic in Bath for the last eight years. When he returned to Singapore in 2023, he set up a TSC clinic at KKH in October that year.

“TSC is my sub-speciality. I’ve been training in it for 14 years, but I was only involved in the TSC Centre in Bath for the last eight years. I saw around 300 patients a year, both adults and children,” he said.

“A lot of patients come from far away. Their child has been diagnosed, but parents might want a second opinion or they want to know what’s the latest thing for TSC. So what we do is after we see them, we provide advice to their local physician. When the physicians run into a complication, they call us and ask, ‘What’s your advice on this?’”

Among his TSC patients are two of Madam Chua’s four children, while Madam Chua is under the care of specialists at Singapore General Hospital (SGH). Her other two children do not have the genetic condition.

As a population, TSC patients have a somewhat lower intelligence quotient (IQ) than the general population, although Dr Loh said there are also some TSC patients with high IQ. About half of them have a mild to severe learning disorder, while the rest have normal IQ.

For more than 80 per cent of people with the condition, TSC manifests before the age of two years as epileptic fits, intellectual disability or autism spectrum disorder. It shows up in more than 90 per cent of patients by the age of 18.

For the rest, it could manifest at any time, as it did for Madam Chua in her early 20s, making it more difficult to diagnose.

Further confounding some doctors, genetic testing for TSC may be negative in some cases because not all cells have the mutation. About 20 per cent of TSC patients have this mosaic form of the disease.

Most very young children with TSC have tumours in the brain – some of them can have as many as 100 tiny ones scattered throughout the brain. While the tumours are usually benign, some can result in bad seizures, depending on their location in the brain. Surgery might be an option if there is a large tumour in a critical location.

For the lucky ones, the tumours do not grow and cause no ill effects.

In 2010, everolimus, a drug used for certain cancers, was licensed for use in the US to treat TSC as it is able to shrink the tumours. In 2013, a second drug, sirolimus, which is given to kidney transplant patients to prevent rejection, was found to work the same way on benign tumours and was also licensed for TSC.

In large doses, the drugs can be fairly toxic. Dr Loh said the dosage is adjusted to treat specific tumours, so a low dosage can be given, with fewer side effects. Generally, lower doses are needed to control tumours in the brain, and higher doses for those in the kidneys and lungs.

But he always tells patients whom he puts on either of the drugs to stop taking them for a day or two if they have a fever, until they know what caused the fever. This is because high doses of the drugs are known to cause sepsis, when a person’s immune system’s extreme response to an infection can damage tissues and organs, and cause death.

“Most of the time, stopping the drug is unnecessary, but it’s better to be safe. A day or two without the drug will not reduce the benefits,” Dr Loh said.

The drugs’ potential toxicity is one reason doctors who rarely see TSC cases are reluctant to prescribe them to their patients, he added.

Other side effects include mouth ulcers, diarrhoea, acne, swollen legs, delayed wound healing and higher cholesterol levels. But these can be reduced or even avoided at lower doses, which may be all that the patients need, he said.

Madam Chua is now on medication, so her risk of suffering another lung collapse is low, Dr Loh said. Without it, the risk of having her lungs collapse again is 40 per cent within two years.

Doctors estimate that a cystic condition in the lungs occurs in 70 per cent of women with TSC. If left untreated, one in five will suffer a lung collapse at some point due to the growth of cysts in the lungs.

The lungs collapse when these cysts burst, causing air to leak, resulting in insufficient oxygen to the body. A trigger for this condition is oestrogen, so it is extremely rare in men with TSC.

The lung collapse can happen multiple times. This is why when it happens, doctors scar the outer layer of the lungs to give them a protective layer to keep the air in should the condition recur in future.

When Madam Chua’s lungs collapsed a second time in 2021, she was rushed to the National University Hospital. The doctors there did not know she had TSC until treatment was over and she was conscious, so they did not initiate the scarring of the outer layer of the lungs.

Her specialists at SGH have since started her on the TSC medication.

Dr Loh said that as doctors know more about the disease, TSC patients can have a better quality of life with early diagnosis and treatment or intervention.

To prevent them passing the defective gene to their children, those with TSC are counselled to have children through in-vitro fertilisation (IVF) to genetically test the embryos and choose the ones that do not have the defect.

IVF treatment usually results in about eight embryos. As there is a 50 per cent chance of the defect being passed on, there should be some embryos free of TSC.

More about tuberous sclerosis complex

What is it?

It is a genetic condition that causes benign tumours to grow in various parts of the body, such as the brain, spinal cord, nerves, eyes, lungs, heart, kidneys, bones and skin.

The name tuberous sclerosis comes from the characteristic tuber- or potato-like nodules in the brain, which are affected by calcium with age and become hard or sclerotic, says the National Institutes of Health (NIH) in the United States.

TSC is caused by genetic mutations on either the TSC1 or TSC2 gene. A mutation of either of these genes leads to abnormal development and exponential growth of cells within the body.

The TSC1 gene produces a protein called hamartin. The TSC2 gene produces the protein tuberin. Scientists believe these proteins act as growth suppressors by silencing or interfering with the activation of a protein called mTOR, said NIH. Loss of regulation of mTOR occurs in cells lacking either hamartin or tuberin, and this leads to abnormal cell changes and development, and enlarged cells.

How common is it?

It is a rare disease that occurs in one out of 8,000 people. If one parent has the disease, there is a 50 per cent chance of his children getting it. However, only about 30 per cent of cases are hereditary.

How serious is it?

Depending on where the tumours are in the brain, the condition can be harmless, or can cause learning disability, seizures and autism. In women, tumours in the lungs can cause the lungs to collapse. Tumours on the skin, especially if they are on the face, can be disfiguring.

Is there a cure?

There is no cure, but there is now medication used to treat TSC patients that can shrink the tumours. Doctors may also surgically remove tumours that may cause problems.