Generality
Neurofibromatosis type 1 is a genetic, sometimes inherited, disease that arises due to a mutation of the NF1 gene and leads to a completely characteristic symptomatology, including coffee-colored skin spots, benign skin tumors, benign tumors of the iris, benign brain tumors, physical-skeletal abnormalities, vision problems, hypertension, etc.
Brief review of neurofibromatosis
Neurofibromatosis is the name of a particular group of genetic conditions, sometimes even hereditary, that alter the normal processes of growth and development of nerve cells and determine the onset of tumors mostly benign at brain level, spinal cord, cranial nerves and peripheral nerves.
To be precise, in the neurofibromatosis group there are three diseases, different both in their causes and in their symptoms, whose names are: type 1 neurofibromatosis, type 2 neurofibromatosis and schwannomatosis.
What is neurofibromatosis type 1
Neurofibromatosis type 1 is neurofibromatosis resulting from a very precise mutation of the NF1 gene, located on chromosome 17 .
Also known as von Recklinghausen or NF1 disease, neurofibromatosis type 1 represents, among the three existing neurofibromatosis, the most common one .
Epidemiology
According to statistics, type 1 neurofibromatosis would affect a newborn every 3, 000 or so.
In 2015, new diagnoses of neurofibromatosis type 1 in the United States and the United Kingdom were 100, 000 and 15, 000 respectively.
Causes
As already mentioned, a specific mutation of the NF1 gene, located on chromosome 17, plays a crucial role on the onset of type 1 neurofibromatosis.
In an individual, the mutation in question may be hereditary - that is, transmitted by one of the parents - or acquired completely spontaneously during embryonic development - that is, after the spermatozoon fertilized the oocyte and embryogenesis began.
Neurofibromatosis type 1, therefore, is one of the genetic diseases sometimes also inherited.
What are the functions of NF1? What happens when it has changed?
Premise: the genes present on human chromosomes are DNA sequences that have the task of producing fundamental proteins in biologic processes indispensable to life, including cell growth and replication.
When it is healthy (that is, free of mutations), the NF1 gene produces a protein called neurofibromine, which is responsible for regulating the growth process of nerve cells.
The NF1 mutation that causes neurofibromatosis type 1 leads to the non-production of the neurofibromine and this results in the abnormal development of nerve cells (as it lacks a fundamental regulator of their correct growth). The appearance of benign neoplasms of type 1 neurofibromatosis depends on this abnormal development of nerve cells.
Is the hereditary form or the non-hereditary form more common?
According to statistics, about half of those with type 1 neurofibromatosis have a parent with the same disease; this means that the remaining part of the clinical cases are non-hereditary forms, due to spontaneous mutations occurring during embryonic development.
Inheritance of neurofibromatosis type 1
Type 1 neurofibromatosis is an autosomal dominant disease ; for an inexperienced reader of genetics, this means that:
- A parent carrying the mutation is sufficient to have the disease in question in part of the offspring;
- The disease and its symptoms are also manifested in the presence of only one mutated gene allele (no matter whether maternal or paternal), as this mutated allele is always dominant over the healthy one;
- The probability that a sick child will be born, from a couple where only one of the two components carries the mutation, is 50%.
Symptoms and complications
Normally, in an individual with type 1 neurofibromatosis, the symptoms and signs of the latter begin to appear a few years after birth.
The complete symptom picture of neurofibromatosis type 1 includes:
- Skin anomalies;
- Ocular anomalies;
- Visual problems;
- Physical-skeletal defects;
- Learning deficits and cognitive problems;
- Neurological problems;
- Hypertension.
Before going into the specifics of the symptomatology, it is necessary to clarify the following aspect: for some individuals the neurofibromatosis of type 1 is highly debilitating, while for others it is a condition only slightly symptomatic, which allows us to lead an almost normal life.
Skin anomalies
The skin abnormalities produced by type 1 neurofibromatosis consist of coffee-milk-colored spots, particular freckles on the axillae and groin, and finally neurofibromas .
- Milk coffee stains: these are probably the most characteristic signs of NF1; they are present from birth (with rare exceptions, in which they appear around the third year of life) and can reach, in terms of maximum width, no more than 5 millimeters.
Their number is not related to the severity of the disease; therefore, the presence of so many coffee-milk-colored stains is not the reflection of a very severe form of type 1 neurofibromatosis.
- Freckles on the axillae and groin: they are particular spots on the skin, which appear in the patients, on the above mentioned anatomical areas, around the age of 4-5 years.
- Neurofibromas: they are benign subcutaneous tumors, with extremely variable dimensions, which are harmless at least until they grow deeper and affect the nerves.
When neurofibromas involve the nerves they are called plexiform neurofibromas .
Ocular anomalies
The ocular anomalies are due to the appearance, on the iris, of small benign tumors, called Lisch nodules, which, despite what a reader might think, do not interfere with the patient's vision.
Visual problems
In the subject with type 1 neurofibromatosis, benign tumors of the optic nerve (a cranial nerve), called optical gliomas or optic pathway gliomas, cause visual problems.
The optical gliomas concern about 15% of patients, they appear from the age of 3 and end to form in adulthood.
Physical-skeletal defects
Generally, they consist of: scoliosis, bowed legs, short stature and head larger than normal .
The first three defects are almost certainly attributable to skeletal development abnormalities and a low bone mineral density; the precise causes of the last defect, however, remain a mystery.
Learning deficits and cognitive problems
Type 1 neurofibromatosis causes learning deficits and cognitive problems in about 60% of young patients.
Curiously, in many subjects with these disorders there is also the so-called attention deficit hyperactivity disorder ( ADHD ).
Neurological problems
The neurological problems consist of:
- Attacks of epilepsy,
- Hydrocephalus e
- Benign brain tumors, which are very often responsible for sudden changes in personality and momentary loss of balance and coordination.
Hypertension
In subjects with type 1 neurofibromatosis, hypertension appears to be due to benign adrenal tumors ( pheochromocytoma ), which impair the latter's functions.
Present in about 20% of patients, excessive blood pressure increases the risk of stroke and heart attacks.
Complications of type 1 neurofibromatosis
From neurofibromatosis type 1 different complications can arise, including:
- Serious skeletal problems related to scoliosis, for which surgery is required;
- Osteoporosis. Fruit of reduced bone mineral density over time, it is responsible for repeated fractures, especially in the lower limbs;
- Serious vision problems, due to a worsening or an increase in the number of optical gliomas;
- Cardiovascular problems dependent on hypertension;
- Respiratory problems related to the development of plexiform neurofibromas near the lungs;
- Inordinate numerical increase in neurofibromas. Neurofibromas grow in number following hormonal changes triggered by important events such as puberty, pregnancy or menopause;
- Malignant evolution of neurofibromas and plexiform neurofibromas. It is a phenomenon that occurs most commonly among adult patients (20-30 years).
According to statistics, the malignant evolution of neurofibromas and plexiform neurofibromas would affect 3-5% of clinical cases;
- Anxiety and depression. They are typical of adult patients, for whom skin abnormalities represent a serious aesthetic defect.
When should I go to the doctor?
All those newborns who have unusual coffee-colored spots on their skin are certainly subject to in-depth medical analysis.
Diagnosis
In general, for a correct diagnosis of type 1 neurofibromatosis, an accurate physical examination, an in-depth medical history and a detailed study of the patient's family history are sufficient.
To these investigations, however, doctors almost always tend to add other tests, which serve to clarify the precise consequences, on the patient, of neurofibromatosis type 1; these tests include:
- Radiological examinations, such as X-rays, CT and nuclear magnetic resonance, referring to various districts of the body (eyes, brain, spinal cord and peripheral nerves), to study the position and extent of tumors;
- The measurement of blood pressure, to identify a possible state of hypertension;
- A tumor biopsy, for the detection of possible malignant tumors;
- The electroencephalogram, for the study of epileptic phenomena (clearly in those who are subject to it);
- A genetic test for diagnostic confirmation.
Curiosity
Currently, there is the possibility of carrying out a genetic test, for the research of neurofibromatosis type 1, even in prenatal age; clearly, a similar genetic test is indicated only if there is a concrete risk of NF1 (eg: one of the two parents is the carrier of the disease in question).
When does an individual suffer from type 1 neurofibromatosis? The diagnostic criteria
According to the medical community, an individual suffers from type 1 neurofibromatosis, if he falls into at least two of the following situations:
- Presence of 6 or more coffee-milk-colored spots, which must be at least 5 millimeters, in young patients, and at least 15 millimeters in adult patients;
- Presence of at least two axillary or inguinal lentigines;
- Presence of at least two neurofibromas or a plexiform neurofibroma;
- Presence of optical glioma;
- Presence of at least two Lisch nodules;
- Presence of physical-skeletal anomalies (scoliosis, sphenoid dysplasia, arched legs, etc.);
- Family history of NF1.
Family history of the patient
Family history makes it possible to determine whether neurofibromatosis type 1 is a recurrent disease within the patient's family; an eventual recurrence would mean that the NF1 is of hereditary type.
Therapy
Type 1 neurofibromatosis is an incurable disease.
However, this aspect does not exclude that there are treatments aimed at alleviating the symptomatology ( symptomatic therapy ) and therapeutic approaches with preventive aims towards the numerous possible complications.
How to prevent the worst complications?
The prevention of the most serious complications of neurofibromatosis type 1 is based on periodic monitoring of neurofibromas, plexiform neurofibromas (if present), physical-skeletal defects (eg scoliosis), optical gliomas and brain tumors. In fact, periodic monitoring of the aforementioned problems makes it possible to identify early any deterioration, so as to remedy it, with an ad hoc treatment, before the situation has degenerated beyond all limits.
Among the carriers of neurofibromatosis type 1, the most critical moments of the disease - those to be monitored most carefully due to the ease with which new tumors appear or are aggravated by those already present - coincide with the years of early youth and adolescence.
Symptomatic therapy
Symptomatic therapy for neurofibromatosis type I includes:
- Surgical interventions aimed at removing the most dangerous tumors, including those that have undergone malignant evolution;
- Chemotherapy and radiotherapy against malignant tumors that cannot be surgically removed;
- Scoliosis surgery;
- Physiotherapy against possible coordination and balance problems;
- A hypotensive therapy aimed at preventing the most serious cardiovascular problems (stroke and heart attack);
- Psychotherapy against ADHD (if present);
- Attendance of support groups for people with the same disease, in order to overcome the consequences of aesthetic discomfort resulting from skin abnormalities.
Prognosis
Being an incurable disease and at risk of serious complications, neurofibromatosis type 1 can never have a positive prognosis.
Current symptomatic treatments and periodic monitoring of health status can be of considerable help, but not in all circumstances; in fact, for the most serious cases of NF1, their benefits are quite limited.
Prevention
Type I neurofibromatosis is an impossible condition to prevent.
