The genetics of vestibular schwannoma
Vestibular schwannoma(acoustic neuroma) is a rare benign tumour that occurs at an incidence of between 4-5/100 000 of the population in one year. It is more common in older people but can rarely occur in children (1). Vestibular schwannoma (VS) occurs equally between men and women. VS usually presents with hearing loss, tinnitus, disequilibrium, vertigo, headache, and numerous other neurological symptoms, depending on the size. However, it may also be asymptomatic.
In 95% of cases, it occurs as a solitary lesion with the exact cause unknown. In less than 5% of cases, it may be genetically predisposed, meaning it is possible to inherit it from a parent and transmit it to your children.
DNA, genes and chromosomes
Genes are segments of Deoxyribonucleic acid (DNA) that serve as the instructions for building and maintaining an organism. These instructions are used to produce proteins, which ultimately determine an organism’s characteristics and functions. Genes are located on chromosomes, which are long strands of DNA housed in the nucleus of a cell.
The function of genes is to control the production of proteins through a process called gene expression. This process involves the transcription of a gene into a messenger RNA molecule, which is then translated into a protein. The proteins produced by genes play a critical role in almost all biological processes, including growth, development, and metabolism.
Chromosomes are the structures that carry genes, which are organized into specific regions on each chromosome. The number and arrangement of chromosomes in an organism’s cells determine its genetic information and ultimately its characteristics. For example, humans have 23 pairs of chromosomes, with each pair containing one chromosome inherited from each parent.
Vestibular schwannoma, chromosome 22 and merlin
Vestibular schwannom is commonly associated with a mutation on chromosome 22. This mutation leads to the loss of function of the tumor suppressor gene NF2, also known as merlin. Merlin plays a critical role in controlling cell growth and division, and its inactivation can result in the development of vestibular schwannoma. Understanding the link between this gene and tumor formation is crucial for developing targeted therapies for this condition.
Genetic testing
Genetic testing is a medical test that looks for changes in an individual’s genes, chromosomes, or proteins. It can be used to identify genetic disorders, assess the risk of developing certain diseases, determine an individual’s response to certain medications, and provide information about ancestry. This test usually involves taking a sample of blood, saliva, or tissue and analyzing it in a laboratory to detect any genetic abnormalities. Results can help individuals make informed decisions about their health and medical care.
Inheritance patterns
Inheritance patterns refer to how genetic traits are passed down from one generation to the next. There are several patterns of inheritance including dominant, recessive, codominant, and sex-linked. Dominant traits are expressed when at least one copy of the gene is present, while recessive traits are only expressed when both copies of the gene are present. Codominant traits show both alleles and sex-linked traits are associated with the X or Y chromosomes.
Family testing for vestibular schwannoma
Should a patient with a VS pursue genetic testing? Patients may like to know whether their VS is genetically inherited and whether they can pass it on to their children. Sometimes, siblings of patients with VS would like to know their chances of developing it. Patients that may consider genetic testing are those with a personal or family history of:
- Vestibular schwannomas, especially if bilateral
- Multiple meningiomas
- Neurofibromas
- Gliomas
- Cataracts
- Posterior subcapsular lenticular opacities
The genetic conditions that may lead to the development of vestibular schwannomas.
Neurofibromatosis type2 (NF2) and schwannomatosis are the two primary known genetic conditions that may lead to vestibular schwannoma.
Neurofibromatosis type 2 (NF2)
Neurofibromatosis type 2 (NF2) is a genetic disorder in which patients develop numerous benign brain and spinal cord tumours, typically before 30 years. (2). The prevalence is estimated at 1 in 33,000 to 1 in 45,000 individuals (3). Many of these patients may die at a younger age, and some only develop symptoms late. Therefore, the annual adult incidence rate in the UK is estimated to be 1 in 2 355 000 people per year; thus, it is not that common. VS is inherited in an autosomal dominant way, with one abnormal gene needed from only one parent to develop the condition. 50% of cases are inherited from an affected parent, and 50% result from a spontaneous mutation.
Bilateral VS are a common finding. Other tumours include meningiomas, ependymomas, neurofibromas and gliomas. Different results include cataracts at a young age and posterior subcapsular lenticular opacities that impair vision.
Then, the symptoms will depend on the affected nerve. More than one nerve can be affected (polyneuropathy). It may already be present in early childhood. Patients with VS may have hearing loss, tinnitus, vertigo, disequilibrium and facial nerve weakness. The face may lose sensation on one side with larger tumours, and headaches can occur. Involvement of the lower cranial nerves leads to swallowing disorders, hoarseness, throat numbness, and shoulder and tongue weakness. Larger tumours may lead to increased intracranial pressure and become life-threatening.
Schwannomatosis
Schwannomatosis patients develop multiple schwannomas throughout their bodies (4). Patients usually present with pain, tingling, weakness and numbness of the area supplied by the affected nerve.
It may be difficult to distinguish between NF2 and schwannomatosis on the clinical grounds alone. The two disorders’ genetics, histories, management, and mortality differ. Patients with NF2 develop VS at an earlier stage, typically before 30, whereas patients with schwannomatosis develop VS later in life, typically after 30 years. NF2 carries a poorer prognosis.
Genetic testing for Neurofibromatosis type 2 and schwannomatosis in South Africa.
Genetic tests can be requested, and some genetic laboratories, such as Invitae in San Fransisco in the USA, will add the schwannomatosis gene for free when testing for NF2 (5). According to Invitae, the mutations picked up in the NF2 gene occur in greater than 92% of familial cases and approximately 70% of simplex cases (i.e., a single occurrence in a family).
The turnaround time to get the results is about three weeks. Unfortunately, genetic testing for these conditions is unavailable in South Africa, and specimens must be sent overseas for testing. Testing can be arranged through local pathology firms such as Ampath, Lancet and Pathcare.
The genetic testing for VS can be conducted on blood, saliva, sputum or other DNA samples. Consult with a geneticist before requesting a test. Counselling geneticists specialising in genetic disorders will help interpret and explain the findings, give specific advice on hereditary issues, and help plan future management.
If you have any questions or require a referral to a geneticist, kindly contact the rooms of Dr Hofmeyr for further information