The term neurofibromatosis refers to a group of rare genetic diseases included in the larger group of so-called neurocutaneous syndromes, that is to say those genetic conditions characterized mainly by an involvement of the skin and nervous system.
To date, neurofibromatosis includes Neurofibromatosis 1 (NF1), Neurofibromatosis 2 (NF2) and schwannomatosis (SCHWN1 and SCHWN2). The schwannomatosis 1 and 2, recently identified, are both characterized by the presence of multiple tumors of the outer sheath of the peripheral nerves and / or more rarely of the cranial nerves (schwannomas) in the absence of other clinical manifestations. On the other hand, neurofibromatosis 1 and 2 bear little resemblance from a clinical point of view, despite being indicated by the same name.
Among the various forms of neurofibromatosis, NF1 is the most common disease, with a prevalence of approximately 1 in 3,000 cases. The gene responsible for NF1 is located on the long arm of chromosome 17 and controls the production of a protein, the neurofibromin, whose abnormal functioning is responsible for the manifestations of the disease.
There is a certain variability in the presentation of the disease: some people are mildly affected and have a good quality of life, others have the severe form and may develop various types of tumors or complications during their life; this can also happen within a single family group.
Neurofibromatosis 2 (NF2) is much rarer, 1 in 33,000 is estimated. The clinical picture (manifestations and disorders) is very different from NF1 (in fact, there are almost exclusively multiple tumors of the central and / or peripheral nervous system) and is caused by mutations in the NF2 gene, located on chromosome 22.
In Italy, neurofibromatosis is included in the "list of rare diseases exempt from the cost of the ticket (DPCM January 12, 2017 - attachment 7) with the code RBG010.
For information on the disease, on how to obtain the exemption, on the clinical centers for the assessment (diagnosis) and treatment of the National Network for Rare Diseases and on patient associations, it is possible to contact the Rare Disease Toll-Free Telephone (TVMR) of the "Istituto Superiore di Sanità. The number 800.89.69.49 - free throughout the national territory - is active from Monday to Friday from 9.00 to 13.00.
Clinically, Neurofibromatosis 1 (NF1) is characterized by three types of manifestations:
- main clinical signs, are the disorders and symptoms that are present in the vast majority of sick individuals and are part of the diagnostic criteria along with some of the typical complications of the disease
- minor clinical signs, are present only in a certain percentage of sick individuals and do not yet fall within the criteria for ascertaining the disease
- complications, are variable and infrequent but often serious and disabling
Main clinical signs of type 1 neurofibromatosis
The main clinical signs of neurofibromatosis type 1 (NF1) include:
- coffee-milk colored skin spots, constitute the most common sign, being present in 95% of people with NF1. The spots almost always develop at birth or occur within the first year of age. During infancy, most children with NF1 have at least six milky-coffee-colored spots of about 5 millimeters in size, which typically increase by size with age. The number of spots is not associated with the severity of the disease; moreover, having a few spots of this type does not necessarily mean developing the disease: in fact, they are normally present in 1 in 10 healthy people
- freckled, another common sign is the presence of small café au lait spots (similar to freckles) in certain areas of the body, such as the armpits, groin and under the breasts
- neurofibromas, the most common are cutaneous ones, are nodular formations detected, appear around puberty and are almost always present in adults with NF1. They are benign tumors that develop from the nerve lining cells (Schwann cells) and alter the structure of the nerve itself by subverting it from the inside. They can vary in size, from light bumps on the skin to the size of a pea. or even more (pendulous) and have a purplish color. Their number can vary and they can cover more parts of the body. Almost all skin nodules do not cause discomfort or pain. The nodules, however, may appear unsightly, cause skin irritation skin by rubbing on clothes or causing itching (because they release a substance, histamine, which dilates small blood vessels). A variety of neurofibromas affect the larger peripheral nerves (neurofibromas nodular or subcutaneous) and can cause pain or cause difficulties in the perception of sensations or in movement (sensory and / or motor deficits).In the event that neurofibromas are located along the nerve and its branches, they are defined as "plexiform" and usually cause pain, weakness, numbness or compression effects on nearby parts and / or internal organs such as, for example, the bladder or the "intestine
- Lisch nodules, small accumulations of cells that appear around puberty in the iris (the part of the eye that surrounds the pupil and determines the color of the eye). They are visible by the ophthalmologist with the slit lamp or, very rarely, at naked eye (in people with light colored iris). They appear as rounded, raised, yellow-brown nodules. They do not cause any visual disturbance, usually appear around 8 years of age and are present in a very large proportion of adults with NF1
Minor clinical signs
THE minor clinical signs to date, they are not part of the criteria for ascertaining (diagnosing) the disease but when present they can contribute to the suspicion of NF1. These include:
- macrocephaly, in other words, the head circumference above average
- slightly shorter than average stature
- chest malformations (for example, faired / protruding or sunken chest)
- hypertelorism (increased distance between the two eyes)
- small angiomas of the skin mainly located in the trunk or thigh
Complications of the disease are present in a minority of sick people; they occur mainly within the first years of life and, in any case, in certain periods of life.
Among the first complications to be visible are:
- orthopedic manifestations which mainly concern the spine (scoliosis due to growth and position anomalies of some vertebrae; 10-20% of children)
- dysplasia with pseudarthrosis of the long bones, which affects approximately 2% of children with NF1.As a result of abnormal bone growth, small, thinner, more curved and structurally weaker bone areas are formed that can more easily undergo fractures: the latter, following an abnormal bone repair process, do not form a normal bone callus. . Consequently, the union of the bone fragments does not occur and alterations in the length and shape of the bone occur
- lack of vitamin D., some people with NF1 have very low levels of vitamin D, which is needed by bone tissue to form its structure well. It is produced by the body when it is exposed to sunlight and is found in certain foods such as milk, yogurt and fatty fish.
Other complications include:
- learning and behavioral disorders, some children with NF1 develop learning and behavioral problems caused by the alteration of the protein produced by the NF1 gene (neurofibromin). It is of vital importance in some processes that take place within the cells of the central nervous system responsible to learning, memory and behavior. About 60% of children (and later of adults) have learning difficulties of varying degrees. Children with NF1 and learning difficulties may have a normal intelligence quotient (IQ) (mean value 100) or slightly below normal. school or attending pre-school programs, and partly treatable with specific supportive school therapies. They can result in lower academic performance, with poorer performance in reading and spelling (ie the act of pronouncing a word slowly distinguishing and pronouncing individual letters or syllables separately) than in mathematics.There may also be disturbances in the articulation of speech (phonation), especially in the pronunciation of nasal sounds. In about 40% of cases, there are difficulties in coordinating movements. Regarding behavior, about half of all children with NF1 also has an attention deficit, often isolated and only sometimes with hyperactivity, which leads to problems with attention span, concentration and impulse control often associated with short-term memory disorders
- plexiform neurofibroma, it is the most frequent complication after learning disorders. It is characterized by the appearance of multiple neurofibromas of soft consistency and variable size. The overlying skin often appears darker and thicker. Usually the most serious lesions, very extensive and disfiguring, usually appear within the first two years of life and are mainly located in the neck and, sometimes, on the face or they can develop inside the abdomen or pelvic area (lower abdomen).
At a later age they can affect other sites causing minor aesthetic and functional damage. Plexiform neurofibroma is an extensive lesion that affects a large tract of nerve deforming it to the point of forming the typical vermiform appearance with numerous nodules called a rosary crown inside a tortuous mass. Sometimes, plexiform neurofibromas can develop into malignant tumors of the nerve sheaths of peripheral nerves
Other organs and systems may be affected by the complications of NF1:
- nervous system, some people with NF1 experience headaches, although it is not a specific disorder for NF1. It is very important to rule out that the headache is a sign of a nervous system tumor
- convulsions, they are very rarely related to NF1. They have a frequency of about 3-4% (ie a little higher than the general population).The course and response to therapy are similar to that of seizures in the general population
- brain tumors, are more frequently gliomas. They can appear most often in the optic pathways, brain stem and cerebellum. About 5% of people with NF1 develop cancer, which may or may not cause ailment (asymptomatic). Some cancers, related to the part of the nervous system in which they develop, can cause symptoms such as personality changes, weakness in only one part of the body, and difficulty with balance and coordination.
- optic pathway tumors, about 15% of children with NF1 develop optic nerve cancer. The optic nerve is located at the back of each eye and has the function of sending visual information from the eye to the brain (occipital lobes). This type of tumor is called optic glioma (OPG). Children of school age are at greatest risk for this type of cancer. Many OPGs are small tumors that grow slowly and cause no noticeable disturbances (symptoms). Other OPGs are fast growing and can cause vision problems including: decreased vision, impaired color perception, narrowed field of vision, squinting or bulging one eye over the other. Younger children may be unable to report problems. to the sight, therefore parents will have to pay attention to small indirect signals. The best way to verify the possible appearance of a optic glioma, is to have the child undergo an eye examination at least once a year
- brain stem gliomas And cerebellar, present greater difficulties for a possible removal neurosurgical intervention but, in almost all cases, they do not cause disturbances and do not evolve over time. However, they need to be monitored very continuously
- malignant peripheral nerve sheath tumor (MPNST), is one of the most serious problems that can occur in people with NF1. It is estimated that there is a 5-10% probability that this complication can occur over the course of the life of a person with NF1; in most cases this can happen between 20 and 30 years of age, more rarely in other age groups (including pediatric or more adult age). The malignant tumor usually develops from a Plexiform neurofibroma pre-existing, but it can also manifest itself from the beginning as a malignant lesion.
Disorders (symptoms) and / or signs of MPNST that should arouse the attention of people with NF1, or family members, and prompt them to seek specialist advice, include:
- change in appearance and texture of neurofibroma, from soft to hard
- sudden growth in a pre-existing neurofibroma
- persistent pain, which lasts for several days / weeks and which also appears during the night
- sudden and previously not present disturbances (symptoms), weakness, numbness, tingling in the arms and legs
- loss of urinary and intestinal control
- difficulty in breathing and swallowing
- hypertension, is present in 6% of people with NF1, more frequently it is caused by stenosis of the renal artery (ie a progressive narrowing of the artery that supplies the kidney with consequent development, by the kidney, of substances that increase blood flow towards the kidney itself); from a tumor of the adrenal gland (pheochromocytoma), that is the endocrine gland that is placed above the kidney and normally produces substances that increase blood pressure; from severe narrowing of the aorta artery. Rarely, dilations (aneurysms) or external compressions (tumors) of the renal artery have been found. If the higher blood pressure is not treated pharmacologically, it could cause serious complications in the people who suffer from it.For this reason, regular blood pressure checks are recommended for children and adults with NF1
- NF1 and pregnancy, most women with NF1 have normal pregnancies. In some cases, the number of neurofibromas may increase due to hormonal changes. It is therefore necessary to be followed by specialists who know the disease well, or to contact the specialist doctor for NF1 where you are being treated.
Neurofibromatosis type 1 (NF1) is caused by mutations in the gene called NF1. Genes contain the information that determines all the characteristics of the human being. A genetic mutation is a permanent change in the DNA sequence that makes up the gene itself. The NF1 gene is responsible for the production of a protein, called neurofibromin, which under normal conditions controls and inhibits cell growth and is important in various intracellular metabolic pathways of various tissues (for example, bone tissue, nervous tissue). The defect of the NF1 gene causes a malfunction of the neurofibromin which, being no longer able to effectively control the growth of some types of cells, causes an abnormal growth (for example, benign tumors, tissue dysplasia) or, being no longer able to intervening normally in the intracellular circuits, alters their function (for example, learning difficulties) and causes the manifestations of the disease.
NF1 follows a so-called inheritance model autosomal dominant, in other words, it is sufficient for one of the two parents to possess only one defective gene (ie a single defective copy of the gene present in one of the two chromosomes 17 normally present in human cells) to transmit the disease to their children. In about half of NF1 cases, the mutated gene is passed from parent to child. Males and females are equally likely to develop the disease.However, gravity isn't always hereditary. For example, a child may have a mild form of NF1, even if she has inherited the disease from one of the parents who has more severe disorders (symptoms).
In the other half of NF1 cases, the mutation of the gene responsible for the disease is not inherited from either parent but occurs spontaneously, in spermatocytes or eggs, just before conception (sporadic mutation). It is not clear what the cause is. or whether there are factors that increase the risk of the mutation. If the child has developed NF1 as a result of a spontaneous mutation, it is highly unlikely that further children of the couple will develop the disease. A person with sporadic NF1 can transmit the disease to their children with the same probability as those with the hereditary form.
Neurofibromatosis type 1 (NF1) is usually ascertained (diagnosed) on the basis of fairly typical signs and disorders (symptoms). To diagnose it, it is useful to refer to the presence of two or more of the following signs / symptoms:
- six or more coffee-milk stains, larger than 5 millimeters in children or 15 millimeters in adults
- freckles in the armpit area or around the groin
- two or more neurofibromas (lumps on or under the skin), or a plexiform neurofibroma (i.e. that develops along the branches of the nerves)
- an optic nerve tumor (optic glioma), which can cause visual disturbances
- two or more small brown spots in the iris (the colored part of the eye), known as Lisch nodules
- bone abnormalities, such as bowing of the lower leg
- family members sick with NF1 (family history)
Usually, it is easier to ascertain (diagnose) NF1 in adults and older children and more difficult to detect in young children, due to the absence of clinical signs that appear later in life.
To check (monitor) the disease over time, it is advisable to carry out the following investigations, with a frequency to be defined with the reference specialist:
- blood pressure measurement
- ultrasound of the abdominal-pelvic organs
- electrocardiogram (ECG) and echocardiogram
- eye examination
- electroencephalogram (EEG), indicated in case of evaluation of seizure events
- magnetic resonance, allows to obtain detailed images of the soft tissues of the body and the nervous system
The genetic test is performed, in the context of genetic counseling, with a simple blood sample. In almost all cases it allows to identify the mutation of the NF1 gene responsible for the disease.
Before and during pregnancy
It would be advisable for couples with NF1 sick family members who wish to have a child to contact a geneticist to receive information on the characteristics of the NF1 gene, on the risk of recurrence within the family unit and on the possibility of ascertaining the disease before birth ( prenatal diagnosis) by:
- Chorionic villus cell sampling (CVS), usually performed from the 10th week of pregnancy
- amniocentesis, performed during the 15th to 20th weeks of pregnancy
The tests cannot predict the severity of the disease, in fact, even if the parent has a severe form of NF1, the child could develop a mild form.
Pre-implantation genetic diagnosis (PDG)
For couples at risk of having a child with NF1, pre-implantation genetic diagnosis may be an option to consider. The PDG is performed following the in vitro fertilization (IVF), a technique by which the eggs are taken from the woman's ovaries to fertilize them in the laboratory using the partner's sperm.After a few days, the developing embryos are analyzed for the NF1 gene and those that do not have the NF1 gene mutation are transferred to the uterus.
People with NF1 need to be cared for by a team of disease specialists.
Most children with NF1 will need to have checks once a year which include:
- careful examination of the skin, to evaluate the appearance of new neurofibromas or modifications of existing ones
- eye exam, in both eyes
- examination of bone development, to check for the presence of scoliosis or badly healed bone fractures
- blood pressure measurement
- measurement of the child's level of physical development
- assessment of the child's academic progress, such as reading, writing, problem solving and comprehension skills
As your child grows up, he or she should continue to have annual checkups but, over time, they will learn to monitor their health so much that they know when to ask for help. However, should complex health problems appear between one check-up and the next, you should immediately contact the referral specialist.
Latte coffee stains
There is usually no need for treatment. Sometimes the spots fade as we age. Laser treatment is useless if the spots are numerous. If the child is stressed by the presence of the spots, a choice may be to hide them with make-up. Special camouflage make-ups are sold in pharmacies to cover skin blemishes.
Small neurofibromas do not require treatment. However, you can choose to treat them if they are particularly unpleasant to the eye and cause emotional distress, or if they cause irritation, itching, or pain. In most cases, plastic surgery is required.The surgeon first removes the neurofibroma and then repairs the skin.
Small neurofibromas, on the other hand, can be eliminated with laser surgery. The results of these surgical treatments are usually good and most people are satisfied although the procedure may leave scars or there may occasionally be delays in wound healing.
Surgery for painful neurofibromas, which develop in the nerve branches, can become complicated because this type of tumor often spreads to adjacent tissue by exerting pressure on important bony structures.
Sometimes, following surgery, nerve damage can occur that can cause loss of sensation or an inability to move a part of the body. A study on a small sample of 120 people who underwent surgery to remove plexiform neurofibroma showed that 5% of them reported nerve damage.
It is therefore necessary to consult the NF1 specialist to be informed about the risks of surgical removal of plexiform neurofibromas.
Difficulty in learning
If the child has a learning disability, it is necessary to contact the competent authorities in the area that will have to deal with the elaboration of the Individual Educational Project (IEP) based on the assessment of the specific needs of the child with NF1. The IEP, for example, sets the number of support teacher hours per week allotted to the child. The IEP will be audited annually. Likewise, the need for additional support from other professionals, such as a health care therapist, should be established. language, an educational psychologist, an occupational therapist.
Behavioral disorders, such as attention deficit hyperactivity syndrome (ADHD), can be treated both with drugs (for example methylphenidate), which help improve attention and concentration times, and through behavioral therapy, which teaches the child to use strategies to improve their behavior.
If the child has a social communication disorder, it may also be necessary to consult a specialist psychologist for proper evaluation.
High blood pressure
Some people are able to control high blood pressure by changing their lifestyle, for example:
- reducing salt in the diet
- doing regular exercise
- keeping the weight in the norm
- not smoking and moderating alcohol consumption (for adults)
However, if the pressure remains very high despite following healthy lifestyles, it is necessary to consult a specialist doctor to start a drug treatment.
Optic nerve tumors
If the child develops a tumor in the nerve that connects the eye with the brain, said optic glioma (OPG), but has no complaints (asymptomatic), immediate treatment is not required. In fact, this type of tumor is usually very small and grows slowly.
However, if your child has an OPG, he or she will have to undergo regular tests to check for the tumor, and in the event of symptoms (symptoms), chemotherapy should be used to shrink the tumor.
If the child develops a curved spine (scoliosis), treatment will depend on the severity of the curvature. In fact, mild cases do not necessarily require treatment, as the baby's spine may improve on its own over time. Moderate cases, on the other hand, can be treated by having the child wear an orthopedic corset designed to correct the position of the spine over time.Surgery can be used for more severe cases of scoliosis, in order to correct the position of the bones of the spine.
Surgery can also be used to treat poorly healed bone fractures that prevent normal movement (pseudarthrosis). Possible surgery options are: rejoining the two pieces of bone using screws and metal rods or having a bone graft. Bone transplantation consists of repairing one part of the bone by taking a small section of bone from another part of the body. The portion of the transplanted bone will grow into the bone where it is placed.
In a small number of cases, where the limbs are involved, it is not possible to repair the bone, but it is necessary to amputate a section of the limb in order to recover its normal function. People with pseudarthrosis should always be referred to the specialist orthopedic for the treatment of complications.
Nervous system problems
Tumors that develop in the brain or nervous system do not always cause disturbances (symptoms), but they can prevent normal body functions. The treatments needed include surgery, medications, or, in some cases, radiation therapy (high-energy waves used to kill cancer cells). However, radiation therapy may increase the risk of developing cancer. Therefore this treatment should only be used if necessary and after consultation with the NF1 specialist.
Epilepsy can be treated with the use of drugs that help reduce the frequency of attacks.
Malignant tumor of the peripheral nerve sheath
If a malignant tumor develops from a neurofibroma covering the nerve (called a peripheral nerve sheath malignancy or MPNST), surgical removal is usually recommended.Radiotherapy and chemotherapy, performed after surgery, can reduce the risk of the cancer coming back, although there is uncertainty about their effectiveness.
Glomus tumors are benign and form around the nail bed of the fingers or toes, sometimes causing a purplish discoloration. They could cause severe pain in the finger from bumps, changes in temperature, or pressure on the nail. This tumor is sometimes identified on MRI and can be removed surgically.
NHS. Neurofibromatosys type 1 (English)
Neuro Fibromatosis Association Onlus (ANF)
ANANAS ONLUS - National Association of Aid for Neurofibromatosis, friendship and solidarity