A single term to indicate a set of genetic diseases that predispose to develop tumors of the nervous system.
When we talk about neurofibromatosis we do not refer to a single genetic disease, but to more than one pathology, with some characteristics in common. There are basically two of the best known, namely neurofibromatosis type NF1 and NF2.
NF1, also known as von Recklinghausen disease, is the most frequent form, affecting about one in every 3,500 people. NF2 neurofibromatosis, on the other hand, is rarer and affects about one in 40,000 people, but it is also more severe. Let’s find out together.
They are hereditary genetic diseases
Both forms of neurofibromatosis mentioned are genetic diseases, i.e. linked to alterations of specific genes. Each gene consists of a small sequence of DNA encoding a specific protein, and its alteration corresponds to an error within that sequence, due to which the resulting protein is defective or absent.
In this specific case, von Recklinghausen disease is due to the mutation of the NF1 gene (identified in 1990) located on chromosome 17, while NF2 to a mutation of the homonymous gene (identified in 1993) located on chromosome 22. The two genes code respectively for the proteins neurofibromin 1 and neurofibromin 2 (also called merlin or schwannomina) that function as tumor suppressors, that is, they counteract the proliferation of cancer cells. As a result, the genetic defect results in the predisposition to develop tumors that, in this case, affect the nervous system.
They are both inherited diseases with autosomal dominant inheritance: autosomal because both genes involved are located on one of the 22 pairs of chromosomes that do not contain genetic information specific to the sexual characterization of the individual (called autosomes for this); dominant because a single copy of the allele (each gene has two alleles, one coming from the genetic information of the father, the other from that of the mother) defective is enough to ensure that the pathological character (therefore the disease) is expressed.
It follows that in a couple, it is enough that only one parent has a mutation of the gene to have a 50% probability, at each pregnancy, of transmitting the mutation to the child, regardless of sex.
However, the alteration of the gene can also develop without having been inherited from one of the two parents: and in fact in about half of the cases the diagnosis of neurofibromatosis occurs in the absence of a family history for this disease.
NF1 neurofibromatosis: symptoms
The manifestations of neurofibromatosis 1 are extremely variable. Somesymptoms more than others tend to be present in most sick subjects and these are:
- café au lait spots, flat skin lesions, with defined contours but variable shape and size, which usually appear on the trunk and limbs, sometimes already at birth or in any case in the first months of life, increasing in number and size during childhood (up to 5-6 years). They often represent the first sign of the disease
- freckles, very small spots located in particular in the armpits, groin and base of the neck, on both sides, which usually appear from 5 years of age, possibly increasing in number until puberty
- Lisch nodules, also known as iris hamartomas, a sort of small raised yellow-brown eye spots that tend to appear shortly before puberty and can only be detected with a specialist eye examination
- neurofibromas (which give the disease its name), i.e. benign tumors that originate from the sheath of peripheral nerves, cutaneous and / or subcutaneous. They generally develop gradually, but the number and location are very variable from person to person. Cutaneous neurofibromas look like small bumps of soft consistency that form along the course of nerves at the level of the skin surface, tend to manifest themselves with growth and are present in almost all adult patients. Subcutaneous neurofibromas are less frequent than cutaneous, generally affect the nerve roots or trunks of the main peripheral nerves, and are generally harder in consistency.
Instead, they concern only about 30% of patients, even if they may be present since childhood, the so-called plexiform neurofibromas, which form along the main nerves, and, unlike the previous ones, develop in width, with poorly defined contour, so much so that to the touch they look like a bundle of nodules, even reaching dimensions such as to have aesthetic and / or functional consequences. They can also be painful and there is a rare possibility that, over time, they can evolve into malignancies (such as soft tissue sarcomas).
In a fair portion of patients there are also:
- short stature
- macrocephaly (abnormal growth of head volume)
- malformations of the chest.
Other symptoms are often considered complications of the disease:
- learning disabilities (found in 40-60% of cases)
- attention deficit hyperactivity disorder
- glioma (brain tumor affecting the optic nerve, present in 15-20% of cases, with onset during early childhood)
- bone abnormalities, such as dysplasia of the sphenoid (a bone of the base of the skull), dysplasia of the long bones, especially of the tibia, pseudoarthrosis of the tibia, and scoliosis
- headache
- hypertension
- Seizures
- cerebrovascular diseases
- stenosis of the cerebral aqueduct (rare complication leading to hydrocephalus).
There are cases in which multiple sclerosis can be diagnosed together with NF1 neurofibromatosis: this happens as a result of a particular mutation involving a segment of the NF1 gene, called intron, on which a protein is located that is involved in myelination, the process of formation of the myelin sheath of the central nervous system (multiple sclerosis is characterized precisely by areas where the myelin sheath is destroyed).
Individuals with NF1 neurofibromatosis also have a higher risk than the general population of developing a malignant tumor (e.g. tumors of the central nervous system, but also breast cancer).
NF1 in childhood
According to the National Institute of Health, the diagnosis of NF1 neurofibromatosis requires a complete clinical examination, also associated with fundus examination, and is placed with certainty only when at least two clinical signs are present between:
- six or more café au lait spots (larger than 5 mm in childhood, greater than 15 mm after puberty)
- freckles
- two or more Lisch nodules
- two or more cutaneous/subcutaneous neurofibromas or at least one plexiform neurofibroma
- optic nerve glioma
- Typical bone lesions
- first-degree relative with NF1.
Typically, the disease manifests itself within six years of life, although the various clinical signs appear at different ages. For this reason, in children with only one clinical sign, the diagnosis can be confirmed by genetic testing (molecular DNA analysis test to search for mutation of the specific gene).
The diagnosis is followed by genetic counseling aimed at the patient and family members, to explain the disease and its impact. It also follows a periodic monitoring (generally annual, at least in the early years) of the patient, with a multidisciplinary team of experts, to search for and control any complications, depending on age. In general, monitoring also involves a clinical examination and only in case of suspicion of complications can the use of further instrumental investigations be evaluated.
In at-risk families with an identified genetic mutation, prenatal diagnosis can be made (through amniocentesis or chorionic villus sampling).
NF2 neurofibromatosis: symptoms
NF2 neurofibromatosis is characterized by the development of tumors of the central and peripheral nervous system belonging to the group of:
- schwannomas or neuromas (benign tumors originating from Schwann cells)
- meningiomas (almost always benign tumors that originate from the outermost membrane that surrounds the brain and spinal cord)
- astrocytomas
- ependymomas (brain tumors that originate in ependymal cells).
These tumors are mostly benign, but still able, given their location, to determine serious disabilities and neurological deficits, with even fatal outcomes at a young age.
In particular, in about 85-90% of cases, a vestibular schwannoma occurs to the auditory nerve, sometimes on one side only but more often bilateral, which generally involves hearing impairment (up to deafness), dizziness, tinnitus, balance disorders (with also obstacles to walking).
In a high percentage of cases (around 80%) the presence of congenital cataracts is also found.
Also in this form of neurofibromatosis, moreover, tumors are often found at the skin and subcutaneous level, but these are more frequently schwannomas (very rare neurofibromas). Coffee-lait spots may also be present, but in less than half of the patients and in numbers generally lower than those found in NF1.
Diagnosis of NF2
The diagnosis of NF2 neurofibromatosis requires a clinical examination, associated with eye examination, auditory control (audiometry and evoked potentials of the brainstem) and brain and spinal magnetic resonance imaging. To make the diagnosis, the presence of a “major criterion” plus any “additional criteria” is required.
Higher criteria | Additional policies |
---|---|
Bilateral vestibular schwannoma | |
A first-degree relative with NF2 | Unilateral vestibular schwannoma |
A first-degree relative with NF2 | At least two between: meningioma, glioma, schwannoma, posterior subcapsular opacities of the lens |
Bilateral vestibular schwannoma | At least two of: meningioma, glioma, neurofibroma, schwannoma, posterior subcapsular opacities of the lens |
Multiple meningiomas | Unilateral vestibular schwannoma |
Multiple meningiomas | At least two lesions between: glioma, schwannoma, neurofibroma, juvenile cataract |
Those who have a family history of NF2 should undergo an eye check already in the first two years of life and then a series of checks in the presence or absence of symptoms of the disease. Also in this case, in at-risk families with identified genetic mutation it is possible to make a prenatal diagnosis.
Once the diagnosis has been made, in addition to genetic counseling for patients and family members, it is necessary to plan periodic monitoring (usually annually, involving a multidisciplinary team composed of neurologists and neurosurgeons, geneticists, otolaryngology, ophthalmologist, psychologist, physiotherapist, speech therapist, etc.) which includes:
- neurological examination
- eye and auditory control
- cerebrospinal magnetic resonance imaging.
Therapies for neurofibromatosis
For both forms of neurofibromatosis there is currently no specific and decisive cure, but we intervene to manage the problems related to the symptoms and prevent (when possible) or otherwise treat complications (which are the main causes of morbidity of the disease).
In NF1 the correction can be carried out, even surgical, of bone lesions (for example of some forms of scoliosis), as well as surgical or laser treatment of cutaneous neurofibromas (in subcutaneous and plexiform ones the removal must instead be carefully evaluated and limited to specific cases). In cases of gliomas that progress rapidly or are large, chemotherapy and possibly surgery can be used. Medical therapies can be used against problems such as hypertension, headaches etc. Psychological and rehabilitative support is also necessary (especially in the presence of learning disabilities).
In NF2, surgery of brain and bone marrow tumors is very complex and risky and therefore limited to cases in which the neoplasms grow excessively and / or determine important neurological deficits. It is also possible, for example, to intervene surgically on cataracts and counteract hearing impairments with ad hoc interventions (for example with cochlear implants). Even more valuable in these cases is the multidisciplinary psychological and rehabilitation support.
Joycelyn Elders is the author and creator of EmpowerEssence, a health and wellness blog. Elders is a respected public health advocate and pediatrician dedicated to promoting general health and well-being.
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