The Neurofibromatosis (NS) is a type of neurocutaneous disease (Rubio-González and Álvarez Valiente) and constitutes one of the most frequent genetic diseases (Ministry of Health, Social Services and Equality, 2016).
At the clinical level, neurofibromatosis is a multisystem disorder that essentially affects the nervous system, skin and bone structure through the development of tumor formations (Woodrow, Clarke and Amirfeyz, 2015).
On the other hand, in the medical literature more than eight different types have been described (Rubio-Gonzáles and Álvarez Valiente), among which:
- Type I (NF1) or von Recklinghausen disease (accounting for approximately 95% of all cases).
- Type II (NFII).
- Schwanosis.
When the diagnosis is made, the medical examination requires a specific physical and neurological examination, fundamentally through different neuroimaging tests accompanied by the genetic study (Mayo Clinic, 2015).
Although there is no cure for neurofibromatosis because of its etiological origin, different therapeutic approaches have been designed for symptomatic treatment, among which surgical or pharmacological approaches. These may vary depending on the type of neurofibromatosis (Mayo Clinic, 2015).
Characteristics of neurofibromatosis
Neurofibromatosis (NF) is a genetic pathology that causes the development of tumor formations and other types of lesions in different areas of the body. Although it presents a multisystemic course, it affects fundamentally the nervous system, the skin or the corporal bone structure (Association of Affected of Neurofibromatosis, 2010).
Pathologies classified under the term neurofibromatosis also belong to neurocutaneous diseases, generally defined as a group of disorders that occur with the progressive development of cutaneous and tumor lesions in different body areas (Singht, Traboulsi and Schoenfield, 2009).
Around the different types of neurofibromatosis, there have been many clinical classifications in which reference is made from a set of three different pathologies up to 8.
However, currently, medical classifications usually refer to three fundamental types (National Institute of Neurological disorders and Stroke, 2016):
- Neurofibromatosis Type 1
- Neurofibromatosis Type 2
- Schwannomatosis
Although the clinical signs and symptoms may vary depending on the specific subtype of neurofibromatosis that the affected person suffers, in general, this set of pathologies is characterized essentially by the affectation of the nervous system (SN) (National Institute of Neurological Disorders and Stroke, 2016).
In general, the presence of different genetic abnormalities causes tumor cells to proliferate in the affected person, so that abnormal and pathological formations begin to appear in areas surrounding nerve terminals and other areas of the body (Neurofibromatosis Network, 2011).
Typically, this type of tumors begins to form in the fibers that surround the nerve terminals, that is, the Myelin , Causing its progressive destruction. In addition, they have to expand into surrounding areas (National Institute of Neurological Disorders and Stroke, 2016).
Although the typology of tumor formation may vary depending on the body location or the cells involved, neurofibromas (National Institute of Neurological disorders and Stroke, 2016) are among the most frequent.
Neurofibromas constitute a type of benign tumor formation, usually composed of Schwann cells , Neurite and connective tissue. In general, they usually appear in the peripheral nerves, bone or cutaneous structure and soft tissues (UCLA Neurosurgery, 2016).
Although the medical complications associated with neurofibromatosis can vary considerably among the different subtypes, they usually produce neurological, sensory, musculoskeletal, growth, etc. alterations.
In this sense, although clinical descriptions have been identified compatible with this pathology in the thirteenth century (Woodrow, Clarke and Amirfeyz, 2015), neurofibromatosis was initially described by a German researcher, Friedrich Daniel Von Recklinghausen , In the year 1882 (Spanish Association of Neurofibromatosis, 2001).
Thus, Von Recklinghausen, interested especially in the study of the pathologies associated to the presence of alterations in the nervous system, was able to describe an association between the cutaneous and tumor lesions with the Neurofibromatosis (Woodrow, Clarke and Amirfeyz, 2015).
Frequency
The Spanish Association of Neurofibromatosis (2001), points out that neurofibromatosis is the dominant genetic pathology of dominant hereditary character in the general population.
Although, as a whole, few statistical data are identified, it has been estimated that in the United States approximately 100,000 suffer from this type of pathology (National Institute of Neurological disorders and Stroke, 2016).
On the other hand, in relation to the sociodemographic characteristics of those affected, it has not been possible to identify a greater number of cases associated with sex, geographical origin or membership of particular ethnic and / or racial groups (National Institute of Neurological disorders and Stroke , 2016).
Thus, in reference to other characteristics, it has been identified that more than half of the people affected by neurofibromatosis have a family history of it, while the remaining percentage has some type of genetic mutation Again (Neurofibromatosis Network, 2016).
Signs and symptoms
Different authors point out that neurofibromatosis may present a course and clinical characterization widely heterogeneous, mainly due to The different etiologies that cause each of the subtypes of this disorder.
Although some of the clinical signs of neurofibromatosis can be identified from the moment of birth, it is more common than symptoms Are evident around the end of early childhood or at the beginning of puberty (Heredia-García, 2012).
Thus, the most common alterations are related to:
- Cutaneous manifestations (spots, neurofibromas, erythema, diffuse pigmentation, etc.).
- Neurological manifestations (headache, paresthesia, paralysis and muscle weakness, convulsive episodes, etc.).
- Ocular manifestations Pigmentosa, macules, alterations of vision, etc.) (Heredia-García, 2012).
Types
The different types of neurofibromatosis are classified according to the genetic base and the own clinical characteristics. The categorization Classical and more used at hospital and experimental level, refers fundamentally to three different types:
1- Neurofibromatosis Type I (NF1): von Recklinghausen disease
Type I neurofibromatosis represents one of the most frequent neurological disorders in the general population, in addition it represents approximately 95% Of all cases of neurofibromatosis (Jhons Hopkins Medicine, 2016).
At the clinical level, this pathology presents a variable course characterized by the appearance of alterations in the skin, the nervous system and the eyes, Evident around 10 years of age (Jhons Hopkins Medicine, 2016).
Thus, some of the most frequent symptoms are skin blemishes, nodules or the development of neurofibromas (Jhons Hopkins Medicine, 2016).
Regarding the etymological origin of neurofibromatosis type I, it is related to the genetic factors, specifically with a mutation of the gene ND1, located on chromosome 17 (Genetics Home Reference, 2016).
The diagnosis of this pathology is based fundamentally on the criteria proposed by the National Institute of Heath (1987), identified Around physical, neurological and ophthalmological exploration (Puig Sanz, 2007).
On the other hand, in terms of treatment, this mainly focuses on the elimination of tumor formations through procedures Surgical procedures. In addition, pharmacological treatments for the treatment of symptomatology and medical complications are also used (National Institute of Neurological Disorders and Stroke, 2016).
Definition
Type I neurofibromatosis is also called Von Reclinckhausen's disease, in honor of its discoverer (National Organization for Rare Disorders, 2016).
As we have pointed out above, it is essentially characterized by the growth of multiple tumors, usually of a benign nature, in the Nerve terminals, skin, or tissues such as the eyes (National Organization for Rare Disorders, 2016).
Unlike other subtypes, the cardinal trait of neurofibromatosis type is the appearance of wide, with a coloration similar to coffee with milk In multiple areas of the body, along with the involvement of the nervous system, which can lead to the development of Neurological symptoms (Association of Affected by Neurofibromatosis, 2010).
In addition, the most common is that, clinical manifestations appear in the infantile stage, being evident around the age of 10 years (Mayo Clinic, 2016).
Frequency
Neurofibromatosis type I is considered one of the most common subtypes. Thus, the different epidemiological analyzes indicate that it presents a prevalence Of approximately 1 case per 3,000 in the general population (Jhons Hopkins Medicine, 2016).
In this way, it is possible that around the world there are about 2 million cases diagnosed, of which 20,000 have been identified in Great Britain and Another 13,000 in the Spanish medical services (Spanish Association of Neurofibromatosis, 2001).
In addition, it affects men and women similarly, it appears in parallel in all population groups (Spanish Association of Neurofibromatosis, 2001).
Symptomatology
In general, neurofibromatosis type I is distinguished by three fundamental clinical features: skin patches, neurofibromas and nodules of Lishc (Spanish Neurofibromatosis Association, 2001, Children's Tumor Foundation, 2016, National Organization for Rare Disorders, 2016):
- Spots on the skin
The most common skin manifestations in this pathology are skin blemishes. In this case, they have a characteristic appearance defined by A light brown color, simulating the color of coffee with milk.
These manifestations are the result of an abnormal increase in skin pigmentation, that is, the substances responsible for coloring the skin. Skin, such as melanin .
Thus, the most common is that they are numerous, around six or more and with an extension of approximately 5 mm. However, they tend to Expand around puberty, reaching even 15 mm.
In addition, it is also common to observe the exponential appearance of freckles (or ephelides) in different areas, especially in the armpits or areas Inguinal.
- Neurofibromas
As we have pointed out previously, neurofibromas constitute the most frequent tumor formation thymus in neurofibromatosis.
They are tumors of benign nature and in this case, they have to grow around the nerve terminals or below the surface of the skin, but also May appear in other deeper areas.
In general, neurofibromas will cause significant musculoskeletal malformations and neurological symptoms.
- Nodes of Lishc
Nodes of Lishc
With the term Lish nodule, we refer to an abnormal accumulation of pigment in the iris of the eye, ie in the color part of the globe ocular.
Although it is not usually associated with visual impairment, this alteration is one of the Neurofibromatosis type I, is identified in more than 97% of the cases.
Medical Complications
Although medical complications can range from mild to severe, some of the most common are related to growth deficits, Scoliosis, craniofacial malformations, Convulsive episodes , Alterations of the visual capacity, Recurrent headaches , Learning problems , Cognitive impairment , etc. (Association of Affected Neurofibromatosis, 2010).
Generally, symptoms and complications tend to worsen exponentially, since neurofibromatosis type I is considered a Progressive disease.
However, the symptoms do not usually endanger the survival of the person, so the life expectancy is not different from that of the population generate.
Causes
Von Recklinghausen disease is due to the presence of alterations in chromosome 17 (Mayo Clinic, 2015), specifically in the NF1 gene (National Organization for Rare Disorders, 2016).
The ND1 gene is especially involved in the production of biochemical instructions for the manufacture of a protein involved in suppression Tumor, that is, this protein is primarily responsible for controlling cell growth and division (Genetics Home Reference, 2016).
Diagnosis
Neurofibromatosis type I is diagnosed from the identification of various clinical findings, through the physical, neurological and Ophthalmologic.
Thus, to confirm this pathology it is necessary to identify the following medical characteristics:
- 6 or more brown spots on the skin with an approximate extension of 1.5 cm after adolescence or 0.5 before this.
- 2 or more tumor formations compatible with neurofibromas.
- Presence of freckles or ephelides in English and armpits.
- 2 or more Lish nodules.
- A significant bone lesion: dysplasia of the sphenoid or long bones.
- Presence of family history of this pathology.
Treatment
The treatment focuses mainly on the control of neurofibromas, since the growth of a tumor in nerve areas can give rise to Development of important medical complications.
Although no approaches have been identified that are capable of slowing down their growth, surgical resection is usually used for their elimination. (National Institute of Neurological Disorders and Stroke, 2016).
However, there are cases in which access to them carries important risks for the survival of the patients, so that others are used Approaches such as radiotherapy wave chemotherapy (National Institute of Neurological Disorders and Stroke, 2016).
In addition, some drugs, such as analgesics and anticonvulsant drugs, are also used for symptomatic treatment (National Institute of Neurological disorders and Stroke, 2016).
2- Neurofibromatosis Type II (NF2)
Neurofibromatosis Type II is another type of neurofibromatosis, together with Type I and Schwanosis, being scarcely common In the general population and especially in the pediatric age.
At the clinical level, this pathology presents a variable course characterized by the growth of neoplasias or tumors in the central nervous system and Peripheral, and especially in the auditory nerves (Heredia García, 2012).
Generally, the signs of neurofibromatosis Type II are usually evident around 20 years of age (Spanish Association of Neurofibromatosis, 2001), some of the most frequent medical complications being hearing loss or the development of other neurological alterations, Such as impaired balance, muscle paralysis, etc. (Neurofibromatosis Network, 2016).
Regarding the etymological origin of neurofibromatosis type II, this is related to genetic factors, specifically with a mutation of the gene NF2, located on chromosome 22 (Genetics Home Reference, 2016).
Definition
Neurofibromatosis type II, also known as bilateral acupuncture neurofibromatosis (NAB) or central neurofibromatosis (National Organization for Rare Disorders, 2015), whose genetic characteristics were not identified until 1993 (Spanish Association of Neurofibromatosis, 2001).
As noted above, this subtype is essentially characterized by the growth of tumor masses. They are usually benign and Are located in the central or peripheral nervous system (National Institute of Neurological Disorders and Stroke, 2016).
Unlike other subtypes, the cardinal trait of neurofibromatosis type II is the affectation of the auditory and vestibular nerves, that is to say, Those who are responsible for transmitting information related to sound and balance, from the inner ear to the brain centers (National Organization for Rare Disorders, 2016).
In addition, in neurofibromatosis type 2, the most common is that clinical manifestations begin to manifest around puberty or adolescence (National Organization for Rare Disorders, 2016).
However, the characteristics of this pathology are usually fully evident in adulthood, around 20 or 30 years (Heredia García, 2012).
Frequency
Neurofibromatosis type II is considered one of the less frequent subtypes in the general population. The different statistical studies have shown Which has an estimated prevalence of 1 case per 33,000 people worldwide (Genetics Home Reference, 2016).
On the other hand, this disorder has an annual incidence of approximately 1 case per 40,000 births (Asociación Española de Neurofibromatosis, 2001).
In addition, neurofibromatosis type II can suffer any type of person, ie, affects similarly to men and women, appears in a way Parallel in all population groups (Genetics Home Reference, 2016).
Symptomatology
As we have pointed out previously, neurofibromatosis is characterized by the development of non-cancerous tumors in the nervous system (Neurofibromatosis Network, 2016).
Therefore, the appearance of neoplasias can be very varied (Ministry of Health, Social Services and Equality, 2016):
- Intracranial tumors : In the case of the growth of brain tumors, the most frequent are the Schwannomas Of pairs Cranial and Meningiomas . They usually cover around 98% and 55%, respectively, of the total cases.
- Tumors of the spinal cord : In the case of growth of tumor formations at the spinal level, the most frequent are schwannomas Radicular, intramedullary ependiomas and meningiomas. They usually appear in around 70-90% of patients.
- Peripheral and cutaneous tumors: In general, tumors that appear on the skin, such as plexiform schwannomas and tumors Peripherals are rare, they usually develop around 65% of cases.
Apart from each tumor variety, in this pathology the most common are acoustic neuromas or vestibular schwannomas (Neurofibromatosis Network, 2016).
Acoustic neuromas constitute a type of benign tumor formation with a slow and progressive formation (National Institutes of Health, 2016).
Thus, they are located in the auditory nerve, responsible for transmitting information related to hearing and balance towards brain (Genetics Home Reference, 2016).
Specifically, these tumors are located in the Schwann cells of the nerve terminals, ie those that make up the myelin sheath that Protects the nerves of the extracellular environment (National Institute of Neurological Disorders and Stroke, 2016).
In general, they often damage both the area in which they are located and the adjacent ones due to the mechanical pressure they can exert (National Institute of Neurological Disorders and Stroke, 2016).
Medical Complications
The medical complications present in people affected by Neurofibromatosis type II, will depend mainly on the type, location and Severity of tumor formations.
Some of the most frequent manifestations are related to (Mayo Clinic, 2015):
- Loss of acuity and hearing.
- Auditory tinnitus, Tinnitus .
- Partial or total loss of vision.
- Facial paralysis, partial or total.
- Muscle weakness, numbness and / or paralysis of the lower and upper limbs.
- Motor discoordination and gait alteration,
- Dizziness and balance problems.
- Recurrent headache.
- Convulsive episodes.
Causes
Neurofibromatosis type II has a genetic etiological origin, related to a specific mutation of the NF2 gene, located in chromosome 22 (Neurofibromatosis Network, 2016).
At a specific level, the FN2 gene has the essential function of providing different biochemical instructions for the manufacture of a protein Known as merlin (Genetics Home Reference, 2016).
In particular, this type of protein is generated essentially in the nervous system and acts as a tumor suppressor, that is, it has the function of preventing That cells grow and divide uncontrollably (Genetics Home Reference, 2016).
Although the specific functions are still not known with exactness, the most current experimental investigations suggest that the loss or Alteration of this protein, allows the cells and in particular those of Schwann to multiply giving rise to the growth of tumors (Genetics Home Reference, 2016).
Diagnosis
In the diagnosis of neurofibromatosis type II, different factors must be considered, both from the results of physical examination and Clinical criteria, such as laboratory observations.
Therefore, this type of pathology requires an exhaustive evaluation focused mainly on different tests, such as Computed tomography (CT) or the nuclear magnetic resonance (NMR) (Neurofibromatosis Network, 2016).
On the other hand, the diagnostic criteria most used in the clinical area refer to the following aspects (Association of Affected Neurofibromatosis, 2016):
- Presence of one or more acoustic neuromas.
- Direct family history (parents or siblings) of NF2 or unilateral acoustic tumors.
- Direct family history (parents or siblings) of any of the following medical conditions:
or Glioma
O Meningioma
The Neurofiborma the Schwannoma
O Juvenile Falls
Treatment
In this case, the treatment is mainly focused on the removal and control of acoustic tumors. Depending on the severity and accessibility Of training, surgical approaches are often used for complete resection (National Organization for Rare Disorders, 2015).
However, in a large number of cases major surgery is not recommended because of the large side effects that It entails. In addition, tumors are often resistant to pharmacological treatment (Heredia García, 2012).
3- Schwannomatosis
Schwannomatosis is another subtype of neurofibromatosis. This medical condition is fundamentally related to the characteristic signs of Subtypes NF1 and NF2 (Ministry of Health, Social Services and Equality, 2016).
Thus, Schwannomas are a type of neoplastic or tumor formation that have to affect the Schwann cells of different areas of the nervous system, Especially in non-intracranial areas.
At the clinical level, this pathology can present very varied signs and symptoms, since its characteristics and locations are largely heterogeneous (Ministry of Health, Social Services and Equality, 2016).
However, the signs and symptoms of Schwannomas are mainly related to the presence of abnormalities and neurological abnormalities, and with The episodes of intense and localized pain (Ministry of Health, Social Services and Equality, 2016).
As for the etiological cause of Schwannomas, they appear to be related to genetic modifications compatible with the INI1 gene (Genetics Home Reference, 2016).
The diagnosis of Schwannomas is based mainly on neuroimaging tests and clinical suspicion on the symptoms and complications (Neurofibromatosis Network, 2016).
On the other hand, in terms of treatment, procedures are usually used for surgical resection or pharmacological reduction of tumor formations (Heredia García, 2012).
Definition
Schwannomatosis is another type of neurofibromatosis, which has been recently discovered and presents several clinical differences with respect to Subtypes NF1 and NF2 (Neurofibromatosis Network, 2016).
As we have pointed out previously, schwannomatosis is characterized mainly by the development of tumor formations in different areas With the exception of the vestibular nerve (National Institute of Neurological Disorders and Stroke, 2016).
In general, the clinical course of this pathology is characterized by the localized development of Neoplasms And the presence of pain and symptoms (National Organization for Rare Disorders, 2016).
Frequency
Statistical studies indicate that Schwannomatosis is a rare disease, an incidence has been observed around one case for every 40,000 Births in the general population (Neurofibromatosis Network, 2016).
In addition, it is estimated that the mean age of appearance of the first obvious symptoms of this pathology is around the first stage of age Adult (Neurofibromatosis Network, 2016).
Symptomatology
Schwannomatosis is characterized by the growth of Shwannomas, that is, benign tumors that develop in nerve areas, affecting Mainly to Schwann cells (Neurofibromatosis Network, 2016).
Generally, its appearance is limited to the peripheral nerve branches and the spinal areas, so the vestibular affectation is usually absent in the Most cases diagnosed (Ministry of Health, Social Services and Equality, 2016).
Medical Complications
Although the medical complications secondary to the growth of the Schwannomas will vary in the different cases, depending on their location And severity, the most common medical conditions are associated with (Neurofibromatosis Network, 2016):
- Presence of episodes of intense and recurrent pain.
- Neurological manifestations, related to sensation of tingling, numbness or paralysis in the upper and lower extremities, Especially hands and feet.
Causes
At present, experimental studies have not been able to know precisely all the genetic factors that can contribute to the Development of Schwannomatosis. However, its causes seem to be related to the presence of genetic alterations in the INI gene (Ministry Of Health, Social Services and Equality, 2016).
Specifically, the mutations in this genetic component are related to an increase in the biological predisposition to develop neoplasms in Non-intracranial areas (Ministry of Health, Social Services and Equality, 2016).
Diagnosis
Like the other pathologies described above, the diagnosis of Schwannomatosis is based on the clinical findings and the results of Neuroimaging, especially nuclear magnetic resonance (NMR) (Neurofibromatosis Network, 2016):
- Age equal or superior to 30 years.
- Presence of two or more Schwannomas, confirmed through tissue histological analysis.
- Absence of vestibular tumors, confirmed by magnetic resonance.
Absence of genetic mutations compatible with the NF2 subtype.
Treatment
Generally, the initial treatment of choice are analgesics. The essential goal is to reduce episodes of pain that can The daily and work activities of the affected persons (National Institute of Neurological Disorders and Stroke, 2016).
On the other hand, surgical resections are usually used for the removal of the tumors, although it is not possible in all cases. Thus, when Completely eliminate episodes of pain refer progressively (National Institute of Neurological Disorders and Stroke, 2016).
References
- AAAF. (2010). What are Neurofibromatosis?
- Diagnosis of NF1 . (2016). Obtained from Children's Tumor Foundation
- Johns Hopkins Medicine. (2016). Neurofibromatosis Type 1 (NF1) . Obtained from Johns Hopkins Medicine
- Mayo Clinic. (2016). Neurofibromatosis .
- MD. (2016). Neurofibromatosis .
- NF. (2016). What is NF 1? Obtained from Neurofibromatosis Network: 1
- NIH. (2016). Neurofibromatosis . Retrieved from National Institute of Neurological Disorders and Stroke
- NIH. (2016). Neurofibromatosis type 1 . Genetics Home References
- NIH. (2016). Neurofibromatosis Type 1 and Cancer . Obtained from National Cancer Institute
- NORD. (2016). Neurofibromatosis Type 1 (NF1) . Obtained from National Organization for Rare Disorders
- UCLA. (2016). UCLA Multidisciplinary NF2 (Neurofibromatosis Type 2) Clinic .