Author: Zhang Li
Unit: Department of Clinical Laboratory, Zhongshan Hospital, Fudan University
A 13-year-old boy came to our neurology department for poor control of epilepsy, and the boy's facial skin condition attracted the attention of the doctor at the same time, mainly in the bilateral cheeks and nasal wing areas, there are many small pimples (papule-like lesions). This skin alteration is often clinically referred to as an angiofibroma (figure 1), and angiofibroma often suggests that the patient may have inherited neurodermatotaneous syndrome. Based on these symptoms in boys, doctors believe that the simultaneous occurrence of epilepsy and cutaneous angiofibromas may not be a coincidence, but like a rare disease - tuberous sclerosis, so what is tuberous sclerosis? How is this disease treated?
Fig. 1 Angiofibroma (papular lesions) on the patient's face
Tuberous Sclerosis Complex (TSC) is an autosomal dominant neurocutaneous syndrome with an incidence of about 1/10 000 to 1/5 000, and was included in the First Catalogue of Rare Diseases in 2018. The disease can affect multiple systems and organs in the human body [1], and patients often have different symptoms and manifestations, making it complicated to confirm the clinical diagnosis of the disease. Doctors suspected the boy might have TSC, and to confirm the diagnosis, the patient was advised to undergo genetic testing.
Tuberous sclerosis
Next, let's look at how genetic testing can help boys find the culprit behind the recurrent seizures:
Genetic diagnosis of tuberous sclerosis
The main pathogenic genes of TSC are TSC1 and TSC2. TSC1 and TSC2 genes encode an important protein complex in the human body - Hamartin-Tuberin (hamartin-potato protein) complex, genetic mutations will make the protein complex function missing, resulting in abnormal activation of mTOR signaling pathways in the body, excessive proliferation of cells, skin, brain, eyes, mouth, heart, lungs, kidneys, liver and bone and other multi-system and organ benign hamartomas. Patients present with epilepsy, intellectual disability, leukoplakia, and facial angiofibroma, and about one in three adult female patients develop Lymphangioleiomyomatosis (LAM) [1].
In patients with TSC, the detection rate of pathogenic/suspected causative mutations in the TSC1 and TSC2 genes (see Table 1 for mutation types) is as high as 75% to 90%.
Table 1 Pathogenic/suspected pathogenic mutation types of TSC1 and TSC2 genes
The International TSC Consensus Conference proposes that TSC can be independently diagnosed if a disease-causing/suspected pathogenic mutation of the TSC1 or TSC2 gene is found in non-diseased tissues. International TSC guidelines also recommend genetic testing (see figure 2) for suspected/indeterminate TSC patients who do not meet clinical criteria for confirming the diagnosis [2].
Figure 2 International TSC guidelines recommend genetic testing for suspected/indeterminate TSC patients who do not meet clinical criteria for confirming the diagnosis
Full exome detection
Whole Exome Sequencing (WES) is the sequencing of exon regions in the human genome, covering all exons of about 25,000 genes. Detection ranges include single nucleotide variants (SNV), small insertion deletions (Indels) within 50 bp, large fragment deletions and replicates within the full exome range. Although the exon region accounts for only about 1% of the length of the whole genome sequence, about 80% of the genetic disease-related variants are in this region.
Figure 3 Genetic testing process
Through the whole exome test (WES), mutations in the TSC1 or TSC2 gene can be accurately detected, providing a basis for genetic diagnosis of TSC. The test can also help other at-risk relatives in the family line, such as the patient's parents or siblings, screen for mutations in the TSC1 or TSC2 gene. In addition, if the confirmed patient meets the appropriate indications, eugenic guidance can also be performed through prenatal diagnosis or pre-transfer genetic testing (PGT) techniques to avoid vertical transmission of the causative variant in the family [1].
In the end, the "culprit" behind the recurrent seizures in the boy in this case was identified through the whole exome test (WES) - the pathogenic mutation of the TSC2 gene. This mutation causes TSC, which in turn triggers epilepsy. Based on this, the neurologist of our hospital gave him the etiology treatment of mTOR inhibitors, supplemented by anti-seizure drugs, and the boy's epilepsy was effectively controlled, and the facial hemangiofibromas also subsided. The boy's parents and relatives also did the above-mentioned verification test for the TSC2 pathogenic variant, and none of them carried the mutation, that is, the causative variant detected by the boy was a new mutation, which reduced the panic of family members about the disease. We also recommend that in his adult life, considering that blocking of this causative variant can be performed through prenatal diagnosis or PGT when giving birth.
Detection advantages
Convenient materials: only peripheral blood samples need to be taken.
Early screening and early diagnosis: For patients with TSC who are clinically atypical or suspected of TSC, genetic testing can help with early screening and early diagnosis of this population.
Accurate detection: Genetic test results can provide a reliable basis for the precise treatment of TSC patients.
High-risk groups
1. If the following symptoms require vigilance, the test is recommended for people who are suspected of TSC by the doctor's judgment [1-2].
Figure 4 Common clinical manifestations of TSC
Seizures: Epilepsy is a common neurologic manifestation in patients with tuberous sclerosis, with seizures in >75% of patients with TSC. Infantion may present with repeated spasms of the head and legs, seizures called infantile spasms.
Skin abnormalities: characteristic light brown or slight brown facial angiofibromas in a "butterfly-like" distribution, or facial comedogenic hyperplasia beginning in childhood, or subparagraphic fibromas, hypopigmentation spots on the trunk, shark spots on the waist.
Cognitive and behavioral disorders: People with tuberous sclerosis may have symptoms of developmental delay, sometimes with intellectual disability or learning disability, and may also develop autism or hyperactivity.
Renal hamartomas: Most patients with tuberous sclerosis have hamartomas in the kidneys, which can affect renal function in severe cases.
Other manifestations: cardiac (ventricular) rhabdomyomas, or lesions in the lungs causing vesicle changes, pulmonary hamartomas (which can cause coughing or shortness of breath, more pronounced during physical activity or exercise, more common in women than men), or hamartomas or white plaques on the back of the eye (retina), which may be accompanied by vision loss.
2. People with a family history of TSC are recommended for this test [1-2].
The Department of Laboratory Medicine, Zhongshan Hospital, Fudan University, has carried out whole exome detection (WES) for genetic diseases, which can provide accurate molecular diagnosis basis for TSC patients, which is of great significance for patients to clearly diagnose the cause and receive accurate treatment. At the same time, our department can also assist clinicians to provide genetic consulting services for patients before, during and after the test of the project.
At present, total exome detection (WES) has been widely used in the field of adjuvant diagnosis and treatment of a variety of genetic diseases. In the future, we will continue to share the diagnosis and treatment application of this detection technology.
【Reference】
1. Professional Committee of Nodular Sclerosis of Chinese Anti-Epilepsy Association. Consensus of Chinese experts on the surgical treatment of epilepsy associated with tuberous sclerosis. CJCP.2019,21(8):735-742.
2.Northrup H,et al. Updated International Tuberous Sclerosis Complex Diagnostic Criteria and Surveillance and Management Recommendations. Pediatr Neurol. 2021,123:50-66.
The case of this article is quoted from "Zhongshan Shennei Brain Intelligence Platform"
Editor: Ren Mileage Reviewer: Xiao Ran