Tumours may develop in response to a genetic alteration occurring within an individual's cells. The cause of this change is not always identifiable but some are well known. When the change affects the genetic information transferred across generations it is known as a constituative or germline mutation. When it is found only within the cells of a tumour itself it is a somatic mutation.
Neurocutaneous Disorders
Neurocutaneous disorders or Phakomatoses is collective term sometimes conveniently applied to multi-system genetic disorders that are characterised by nervous system lesions as well as disorders of the skin, musculoskeletal or visceral systems. They are life-long conditions that are in how severely the gene abnormality is expressed between individuals (penetrance).
Neurofibromatosis Type 1
Neurofibromatosis type 1 (NF1) is a condition which results from a mutation in a gene on chromosome 17. It affects approximately 1 in 3000 people. The gene is called NF1 and codes for a protein called neurofibromin. It is a tumour supressor gene meaning that when it is not functioning the following can develop:
Cafe au Lait Spots- discolouration of the skin on the trunk.
Axillary Feckling- dense collections of freckles in the armpit.
Cutaneous Neurofibromas- benign peripheral nerve heath tumours on sensory nerves under the skin.
Peripheral Nerve Sheath Tumours- aising from nerves emerging form the spinal cord as well as running through the musculoskeletal system. While usually benign, in NF1 HERE IS AN 8-13% lifetime risk of malignant transformation. For this reason any painful mass should be considered fr excision or biopsy.
Lisch Nodules-Benign hamartomas in the iris of the eye.
Glioma- particularly of the anterior visual pathway in the brain.
Bone Dysplasia- resulting in misshapen vertebrae and longbones.
Peripheral Neuropathy- perpetuated by the spread of plexiform nerve sheath tumour along the nerve
Hypertension
Scoliosis- curvature of the spinal column.
Neurofibromatosis Type 2
Neurofibromatosis type 2 is a genetically and clinically quite distinct disease to the above. It is less common affecting aproximately 1:35000 individuals. All develop vestibular Schwannomas and in most cases these are bilateral. Other tumours assosciated with this condition include Schwannomas of other cranial nerves, meningioma and spinal cord ependymoma.
Schwann cells are support cells that insulate the peripheral nerve cells, assist with their nourishment and facilitate transmission of electrochemical signals along the nerve. Th benign overgrowth of Schwann cells produces a Schwannoma.
The gene mutation in NF2 is on chromosome 22 and its gene prodict is the Merlin protein. Juvenile cataracts may be the earliest detectable evidence of the disease
Schwannomatosis
Schwannomatosis is a related condition to the above with a predisposition to developing schwannomas on the spinal nerves but never on the vestibular nerves of the ear as in NF2. Schwannomatosis usually affects males in middle age and they are usually the only member of their family to be so affected. Meningiomas occur very rarely.
The gene abnormalities are distinct from the NF2 gene abnormality and at least two implicated genes have been identified on chromosome 22 close to the NF2 gene. (SMARCB1 and LZTR1)
Von-Hippel Lindau Disease
Approximately 20% of central nervous system haemangioblastomas occur in patients affected by Von Hippel-Lindau disease(VHL). This is a condition resulting from mutation of a gene on the shrt arm of chromosome 3. The mutation is inherited in 80% of cases but occurs de-novo in 20%. Someone with a parent harbouring the defective gene will have a 50% chance of inheriting the gene.The disease itself does not usually appear in childhood. Most patients will develop one of its manifestations by age 40. VHL causes tumours to develop in various locations throughout the body. For more infromation about VHL please click here.
Patients with VHL benefit from genetic counselling and from regular screening for the development of new tumours. New tumours developing within the nervous system do not always require immediate intervention. Growth in such haemangioblastomas is not always assosciated with the development of symptoms. Surgery is not indicated for asymptomatic growth although the development of oedema around the tumour foreshadowing the development of a cyst may indicate that intervention could be beneficial.
For some with VHL they will develop a large number of tumours within the spinal cord. This may mean it is difficult to work out which tumours are most biologically active and therefore potentially in need of treatment. Such decisions are best made with an experienced multidisciplinary team.
Tuberous Sclerosis Complex
Tuberous sclerosis is a rare genetic disorder that produces benign tumours called hamartomas in mny different parts o the body including the brain. Two gene mutations ave been identified (TSC1 and TSC2) . Malfunctions of these genes affect a signalling pathway called mTOR in particular the production of proteins called Hamartin and Tuberin the downstream result of which is the development of these tumours.
Most cases of TSC result from the inheritance of a malfunctioning gene from one parent (constitutive or germline mutation). There are cases that develop without parents being affected either as result of the mutation developing de-novo in the affected individuals cells (somatic mutation) or mosaicism where only a fraction of gremlin or somatic cells acquire the mutation.
TSC is associated with autism, epilepsy, learning difficulties and kidney problems. The degree to which apersons life is impacted by the condition varies considerably. Management is ideally within multidisciplinary setting and a summary of what might be required is available here.
Sturge-Weber Syndrome
Sturge-Weber Syndrome (SWS) is another rare inherited disorder due to mutation of the GNAQ gene which is characterised by malformation of the capillary networks in the skin, eyes and brain. This may result in:
Port-Wine Birthmark- a purple or red area on the face most often around the eye and forehead.
Seizures
Capillary haemangioma of the brain- which may be mistaken for an arteriovenous malformation on imaging but has a different morphology and the clinic context usually should indicate the diagnosis. While associated with seizures and focal deficits it is not particularly associated with brain haemorrhage.
Neurodevelopmental difficulty
Focal Neurological Deficit- for example arm and leg weakness on the opposite side to the birthmark.
