Tuberous sclerosis complex is a genetic disease, and prenatal diagnosis is beneficial to the family!

Author: Xie Han, deputy chief physician, Peking University First Hospital

Reviewer: Jiang Yuwu, Chief Physician, Peking University First Hospital

What is tuberous sclerosis complex?

There is a very special disease, which is a systemic disease related to genetics and conforms to the autosomal dominant inheritance mode. The patient's brain, skin, heart, lungs, kidneys and other organs may be affected. This disease is called tuberous sclerosis.

The cause of this disease is mainly due to mutations in the TSC1 or TSC2 gene, which leads to abnormal cell proliferation and differentiation, thus forming some chronic tumor-like changes, which eventually affect the functions of various organs and cause various clinical manifestations. Severe patients may become disabled or die.

The onset of tuberous sclerosis is generally early, and even in the fetal neonatal period, there will be symptoms. This disease may show different manifestations at different ages, and parents need to pay attention to observation. For example, in the neonatal or fetal period, monitoring ultrasound can detect the presence of cardiac myxoma in patients; epilepsy is prone to occur in infancy, and the epilepsy of patients with tuberous sclerosis often manifests as infantile epileptic spasm syndrome, a drug-resistant epilepsy that often seriously affects the patient's cognitive function; kidney damage is prone to occur in adolescence; respiratory system damage may become a prominent manifestation in adulthood. In short, it is a disease that changes with age. In addition, parents should pay attention to their children's skin. These characteristic skin changes of tuberous sclerosis are easy for us to observe. If a child has these skin changes, it is recommended to see a doctor as soon as possible and let the doctor determine whether the child may have tuberous sclerosis. The characteristic skin changes of patients with tuberous sclerosis include depigmented spots, forehead plaques, shark skin-like spots, and fibroma around the nails.

Common causes of death from tuberous sclerosis include severe kidney damage, severe status epilepticus, giant cardiac rhabdomyosarcoma in the neonatal period, obstructive hydrocephalus caused by enlarged subependymal giant cell astrocytoma, severe respiratory failure, etc. It can be seen that tuberous sclerosis is a very harmful disease that can affect multiple organs. Parents need to be vigilant. Whether they find characteristic skin manifestations, or infants have epileptic convulsions, or hospital examinations reveal multiple organ lesions, they need to consider the possibility of tuberous sclerosis.

How is tuberous sclerosis complex diagnosed?

At present, the diagnosis of tuberous sclerosis complex includes clinical diagnosis and genetic diagnosis. Clinical diagnosis requires that the patient must meet sufficient major and minor characteristics, which include clinical manifestations and imaging examinations. The specific content of the clinical diagnostic criteria is shown in Figure 1 (for parents' reference). Because tuberous sclerosis complex is currently believed to be mainly caused by TSC1 or TSC2 gene mutations, genetic diagnosis can be made if genetic testing finds that the patient has a clear pathogenic TSC1 or TSC2 gene mutation. Now there is neonatal genetic screening to help us detect children with tuberous sclerosis complex early, so that early intervention can be carried out to obtain a better prognosis for the child and obtain a higher quality of life. About 75%-90% of patients with tuberous sclerosis complex can be found to have clear TSC1 or TSC2 pathogenic gene mutations. If pathogenic TSC1 or TSC2 gene mutations are found in the family, it is strongly recommended that other family members go to the genetic disease specialist clinic for genetic counseling and, if necessary, to test for the gene mutation.

Note: Clinical diagnostic criteria for tuberous sclerosis complex (modified from the 2021 international expert consensus on the diagnostic criteria for tuberous sclerosis complex). A confirmed diagnosis requires the fulfillment of 2 major criteria or 1 major criterion plus 2 minor criteria (Note: If the patient only has LAM and angiomyolipoma without other characteristic manifestations, it does not meet the conditions for a confirmed diagnosis of 2 major criteria). A suspected diagnosis requires the fulfillment of 1 major criterion or ≥ 2 minor criteria.

Figure 1 Original copyright image, no permission to reprint

How much do you know about prenatal diagnosis and genetic counseling for tuberous sclerosis complex?

Tuberous sclerosis is an autosomal dominant genetic disease. If one of the parents is ill, the theoretical probability of the child being ill is 50%; if both parents are patients with tuberous sclerosis, the theoretical probability of the child being ill is 75%. In addition, we need to pay attention to some special genetic situations, such as when the fertilized egg undergoes a genetic mutation during development, resulting in the child having a new pathogenic mutation in the TSC1 or TSC2 gene when both parents are normal, and thus the child becomes a patient with tuberous sclerosis; or when either the father or the mother has germ cell mosaic pathogenic mutations in the TSC1 or TSC2 gene, the DNA test of the parents' peripheral tissue cells cannot detect the mutation, but the child may become ill due to mutations in the sperm or egg that formed the fertilized egg.

If parents are willing to undergo genetic counseling and prenatal diagnosis, it is recommended that they go to a hospital with prenatal diagnosis qualifications for relevant consultation and examination when planning to have a child. At present, genetic counseling and prenatal diagnosis of tuberous sclerosis mainly include: 1. Routine regular pregnancy ultrasound, mainly through the discovery of cardiac rhabdomyomas to indicate that the child may have tuberous sclerosis; 2. Prenatal genetic testing, such as fetal gene sequencing through chorionic villus tissue or amniotic fluid after 12 weeks of pregnancy. If a clear pathogenic variant of the TSC1 or TSC2 gene is found, a clear diagnosis can be made. After the diagnosis, the parents will choose whether to continue the pregnancy and retain the fetus according to their wishes.

How is tuberous sclerosis complex treated?

There is no radical treatment for this disease, but there are still many advances in treatment. It should be emphasized that tuberous sclerosis may affect multiple organ systems throughout the course of the disease. Regardless of whether it is a child or an adult patient, once tuberous sclerosis is diagnosed, it is recommended that a doctor familiar with tuberous sclerosis conduct a comprehensive evaluation, develop a long-term follow-up treatment strategy, strive to identify treatable clinical manifestations as early as possible, adopt targeted comprehensive treatment, and provide anticipatory guidance (for example, for children with tuberous sclerosis, doctors should not only treat current epileptic seizures, but also remind parents to follow up long-term and pay attention to monitoring the kidneys and respiratory system, etc.) and genetic counseling. The main treatment methods include: 1. Mechanism-based treatment. The mTOR pathway inhibitor Everolimus has been approved by the FDA for the treatment of progressive subependymal giant cell astrocytoma and renal angiomyolipoma with good results. It has recently been approved for the treatment of drug-resistant epilepsy. 2. Symptomatic treatment, such as anti-epileptic seizure drug treatment for epilepsy (such as vigabatrin, which is particularly effective in treating infantile spasms in patients with tuberous sclerosis, but this drug may have adverse reactions such as narrowing of the visual field), surgical treatment (for epilepsy that is not well controlled by drugs, if the main responsible lesion can be determined, epilepsy lesion resection surgery can be used to control or reduce epilepsy), and neuromodulation therapy (such as reducing epilepsy through vagus nerve stimulation therapy). More precise and effective treatments, including gene therapy, are also under study.

Although some children with tuberous sclerosis complex have serious illnesses and are at risk of disability or even death, some children with tuberous sclerosis complex, if discovered early, with active and correct long-term treatment and comprehensive management, can achieve good results, have normal intellectual and motor development, and can live a completely normal life, go to school, get married and have children.