Neurofibromatosis type 1 | |
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Other names |
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Main symptoms of neurofibromatosis type I. [1] | |
Specialty | Neurosurgery, dermatology, ophthalmology |
Usual onset | At birth |
Neurofibromatosis type I (NF-1), or von Recklinghausen syndrome, is a complex multi-system human disorder caused by the mutation of neurofibromin 1 (NF-1), a gene on chromosome 17 that is responsible for production of a protein (neurofibromin) which is needed for normal function in many human cell types. NF-1 causes tumors along the nervous system which can grow anywhere on the body. NF-1 is one of the most common genetic disorders and is not limited to any person's race or sex. NF-1 is an autosomal dominant disorder, which means that mutation or deletion of one copy (or allele) of the NF-1 gene is sufficient for the development of NF-1, although presentation varies widely and is often different even between relatives affected by NF-1. [2]
As of 2015 [update] , there are at least 100,000 people in the U.S. and about 25,000 people in the UK who have been diagnosed with NF. Common symptoms of NF-1 include brownish-red spots in the colored part of the eye called Lisch nodules, benign skin tumors called neurofibromas, and larger benign tumors of nerves called plexiform neurofibromas, scoliosis (curvature of the spine), learning disabilities, vision disorders, mental disabilities, multiple café au lait spots and epilepsy. While some people have major complications, others with the condition can lead productive and full lives.
NF-1 is a developmental syndrome caused by germline mutations in neurofibromin, a gene that is involved in the RAS pathway (RASopathy). Due to its rarity, and to the fact that genetic diagnosis has been used only in recent years, in the past NF-1 was in some cases confused with Legius syndrome, another syndrome with vaguely similar symptoms, including cafe-au-lait spots. [3]
NF-1 is an age-specific disease; most signs of NF-1 are visible after birth (during infancy), but many symptoms of NF-1 occur as the person ages and has hormonal changes. NF-1 was formerly known as von Recklinghausen disease, after the researcher who first documented the disorder, Friedrich Daniel von Recklinghausen. [4]
The severity of NF-1 varies widely, and little is known about what causes a person to have more severe or less severe symptoms. Even within the same family (as there is a 50% chance that a parent will pass their condition to their offspring), levels of severity can vary enormously. [2] However, 60% of people with NF-1 have mild cases, with few symptoms that have very little effect in their day-to-day lives. About 20% of NF-1 patients have moderate cases, with several symptoms that have little more than cosmetic effects. The other 20% have severe cases, with several symptoms that affect the person's quality of life. Even in this last group, symptoms are rarely life-threatening. [5]
The following is a list of conditions and complications associated with NF-1, and, where available, age range of onset and progressive development, occurrence percentage of NF-1 population, method of earliest diagnosis, and treatments and related medical specialties. [7] [8] The progression of the condition is roughly as follows:
Musculoskeletal abnormalities affecting the skull include sphenoid bone dysplasia, congenital hydrocephalus and associated neurologic impairment.
Disorders affecting the spine include:
Skeletal muscle weakness and motor control deficits
Deficits in motor function in NF-1 have been long recognised and have been historically attributed to nerve dysfunction. In recent years however, studies suggest NF-1 is associated with a primary problem in muscle function (myopathy). [11]
Clinical findings in people with NF-1 include:
Studies in genetically modified mice have thus far confirmed that the NF1 gene is vital for normal muscle development and metabolism. Knockout of the NF1 gene in muscle results in deregulated lipid metabolism and muscle weakness. [11] [13]
NF-1 is a disease in the RASopathy family of diseases, which include Costello Syndrome, Noonan Syndrome, and Cardiofaciocutaneous syndrome. The RASopathies also present with skeletal muscle weakness. [14] It is likely that impaired muscle function in these disorders is linked to altered Ras/MAPK signalling, however, the precise molecular mechanisms remain unknown. [11]
The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 90% of children and adults with NF-1 and have significant effects on their schooling and everyday life. [19] These cognitive problems have been shown to be stable into adulthood mainly in the mid 20s to early 30s and do not get worse unlike some of the other physical symptoms of NF-1. [20] The most common cognitive problems are with perception, executive functioning and attention. Disorders include:
The primary neurologic involvement in NF-1 is of the peripheral nervous system, and secondarily of the central nervous system. Schwannomatosis is a rare condition defined by the presence of multiple benign tumors of nerves that are frequently very painful. In addition to pain, weakness is a common problem. Symptoms usually begin in young or mid-adult years.[ citation needed ]
A neurofibroma is a lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1.
Neurofibroma conditions are progressive and include:
Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system, primarily optic nerve gliomas and associated blindness. [25]
Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain. These UBOs are typically found in the Cerebral peduncle, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin.[ citation needed ]
Within the CNS, NF-1 manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement due to chronic exposure to the pressures of CSF pulsation, and typically presents as paraesthesia or loss of motor or sensory function. [10] It has been shown that dural ectasia occur near plexiform neurofibromas which may be infiltrative leading to weakening of the dura. [26]
Acetazolamide has shown promise as a treatment for this condition, and in very few cases do dural ectasia require surgery. [26]
People with NF1 are at increased risk for experiencing social and emotional difficulties such as; anxiety, depression, low self-esteem and/or body image, social withdrawal, difficulty forming interpersonal relationships, behavioural problems, and difficulties in school. [27] People with NF1 are much more likely to experience suicidal thoughts than the general population. One study found that 45% of people with NF had suicidal thoughts compared to 10% of a healthy control group. [28] Another study found that 46.5% were of people with NF1 were found to have at least one psychiatric comorbid diagnosis. [29]
Children and adults with NF-1 often have Autism and/or ADHD.
Children diagnosed with NF-1 may experience delayed or precocious puberty. Recent studies have correlated precocious puberty in individuals with NF-1 with the presence of optic pathway tumours. [32] Furthermore, the heights of children affected by NF-1 have been shown to increase normally until puberty, after which increases in height lessen when compared to healthy counterparts. [32] This eventually causes a shorter stature than expected in individuals with NF-1.
Cancer can arise in the form of malignant peripheral nerve sheath tumor resulting from malignant degeneration of a plexiform neurofibroma. [33] [34]
People assigned female at birth with NF also have a five-fold increased risk of breast cancer and may have an increased breast cancer related mortality. The median survival for breast cancer in people with NF was 5 years vs. the reported median survival of over 20 years in the general population using the SEER database. [36] [37]
NF-1 is a microdeletion syndrome caused by a mutation of a gene located on chromosomal segment 17q11.2 on the long arm of chromosome 17 which encodes a protein known as neurofibromin [38] (not to be confused with the disorder itself) which plays a role in cell signaling. [39] [40] The Neurofibromin 1 gene is a negative regulator of the Ras oncogene signal transduction pathway. It stimulates the GTPase activity of Ras.
In 1989, through linkage and cross over analyses, neurofibromin was localized to chromosome 17. [41] It was localized to the long arm of chromosome 17 by chance when researchers discovered chromosome exchanges between chromosome 17 with chromosome 1 and 22. [41] This exchange of genetic material presumably caused a mutation in the neurofibromin gene, leading to the NF1 phenotype. Two recurrent microdeletion types with microdeletion breakpoints located in paralogous regions flanking NF1 (proximal NF1-REP-a and distal NF1-REP-c for the 1.4 Mb type-1 microdeletion, and SUZ12 and SUZ12P for the 1.2 Mb type-2 microdeletion), are found in most cases. [42]
The neurofibromin gene was soon sequenced and found to be 350,000 base pairs in length. [43] However, the protein is 2818 amino acids long leading to the concept of splice variants. [44] For example, exon 9a, 23a and 48a are expressed in the neurons of the forebrain, muscle tissues and adult neurons respectively. [44]
Homology studies have shown that neurofibromin is 30% similar to proteins in the GTPase activating protein (GAP) family. [43] This homologous sequence is in the central portion of neurofibromin and being similar to the GAP family is recognized as a negative regulator of the Ras kinase. [45]
Additionally, being such a large protein, more active domains of the protein have been identified. One such domain interacts with the protein adenylyl cyclase, [46] and a second with collapsin response mediator protein. [47] Together, likely with domains yet to be discovered, neurofibromin regulates many of the pathways responsible for overactive cell proliferation, learning impairments, skeletal defects and plays a role in neuronal development. [48]
The mutant gene is transmitted with an autosomal dominant pattern of inheritance, but up to 50% of NF-1 cases arise due to spontaneous mutation. The incidence of NF-1 is about 1 in 3500 live births. [49]
Prenatal testing may be used to identify the existence of NF-1 in the fetus. For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis to screen for NF-1. [50]
While the presence of NF-1 can be identified through prenatal testing the severity with which the condition will be expressed is impossible to determine. [51]
People with NF-1 have a 50% percent chance of passing the disorder to their offspring, but people can have a child born with NF-1 when they themselves do not have the condition. This is caused by a spontaneous mutation.
The National Institutes of Health (NIH) has created specific criteria for the diagnosis of NF-1. Two of these seven "Cardinal Clinical Features" are required for positive diagnosis. [52] [53] There is practical flowchart to distinguish between NF1, NF2 and schwannomatosis. [54]
Treatment for NF1 is limited, there is currently no cure. Pain meds can be prescribed to help with pain. In some cases, growths may be removed surgically or reduced with radiation therapy. Treatment options are limited, given the tumours tendency to regrow following surgery and their propensity to transform into malignant tumours following radiation. [55] Although surgery in these areas can cause further injury to nerves and additional neurological problems. The benefits of surgery should always be considered against its risks. Some NF tumours are inoperable.
Selumetinib, is a drug produced by Astra Zeneca sold under the brand name Koselugo, and was approved by the FDA in April 2020 [56] for the treatment of NF-1 in the pediatric population who are two or more years of age. It is a mitogen-activated protein kinase inhibitor (MEKi) and is indicated for use in pediatric patients who are symptomatic and have inoperable plexiform neurofibromas. [57] However, this medication is not curative and is not suitable for all patients.
Side effects of Selumetinib include headache, nausea/vomiting, abdominal pain and other problems of the gastrointestinal tract, fatigue, muscle pain, Constipation, Paronychia as well as dry skin and other skin and hair problems. [58] The side effects can have a significant impact on a patient's life and may lead to someone having to discontinue treatment.
In an open-label, phase 2 trial of selumetinib with 50 children:
NF-1 is a progressive and diverse condition, making the prognosis difficult to predict. The NF-1 gene mutations manifest the disorder differently even amongst people of the same family. This phenomenon is called variable expressivity. For example, some individuals have almost no symptoms, while others may have a manifestation that is rapidly more progressive and can lead to significant disability and death.
For many NF-1 patients, a primary concern is the disfigurement caused by cutaneous/dermal neurofibromas, pigmented lesions, and the occasional limb abnormalities. However, there are many more severe complications caused by NF-1 like increased cancer risk, a plexiform neurofibroma has a 10-15% chance of developing into a MPNST (Malignant Peripheral Nerve Sheath Tumour) Epidemiology NF-1 is estimated to affect around 25,000 people in the UK. [59]
In the novel "The Covenant of Water" by Abraham Verghese, Von Recklinghausen disease (referred to as "The Condition") is a key element of the plot.
For many years it was thought Joseph Merrick, known as the Elephant Man, had suffered from neurofibromatosis type 1 (NF1). In 1986, geneticists Tibbles and Cohen demonstrated that Merrick was actually afflicted with Proteus syndrome, a much rarer condition. [60]
Charcot–Marie–Tooth disease (CMT) is a hereditary motor and sensory neuropathy of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. This disease is the most commonly inherited neurological disorder, affecting about one in 2,500 people. It is named after those who classically described it: the Frenchman Jean-Martin Charcot (1825–1893), his pupil Pierre Marie (1853–1940), and the Briton Howard Henry Tooth (1856–1925).
Neurofibromatosis (NF) refers to a group of three distinct genetic conditions in which tumors grow in the nervous system. The tumors are non-cancerous (benign) and often involve the skin or surrounding bone. Although symptoms are often mild, each condition presents differently. Neurofibromatosis type I (NF1) is typically characterized by café au lait spots, neurofibromas, scoliosis, and headaches. Neurofibromatosis type II (NF2), on the other hand, may present with early-onset hearing loss, cataracts, tinnitus, difficulty walking or maintain balance, and muscle atrophy. The third type is called schwannomatosis and often presents in early adulthood with widespread pain, numbness, or tingling due to nerve compression.
A vestibular schwannoma (VS), also called acoustic neuroma, is a benign tumor that develops on the vestibulocochlear nerve that passes from the inner ear to the brain. The tumor originates when Schwann cells that form the insulating myelin sheath on the nerve malfunction. Normally, Schwann cells function beneficially to protect the nerves which transmit balance and sound information to the brain. However, sometimes a mutation in the tumor suppressor gene, NF2, located on chromosome 22, results in abnormal production of the cell protein named Merlin, and Schwann cells multiply to form a tumor. The tumor originates mostly on the vestibular division of the nerve rather than the cochlear division, but hearing as well as balance will be affected as the tumor enlarges.
Spinal tumors are neoplasms located in either the vertebral column or the spinal cord. There are three main types of spinal tumors classified based on their location: extradural and intradural. Extradural tumors are located outside the dura mater lining and are most commonly metastatic. Intradural tumors are located inside the dura mater lining and are further subdivided into intramedullary and extramedullary tumors. Intradural-intramedullary tumors are located within the dura and spinal cord parenchyma, while intradural-extramedullary tumors are located within the dura but outside the spinal cord parenchyma. The most common presenting symptom of spinal tumors is nocturnal back pain. Other common symptoms include muscle weakness, sensory loss, and difficulty walking. Loss of bowel and bladder control may occur during the later stages of the disease.
Facial nerve paralysis is a common problem that involves the paralysis of any structures innervated by the facial nerve. The pathway of the facial nerve is long and relatively convoluted, so there are a number of causes that may result in facial nerve paralysis. The most common is Bell's palsy, a disease of unknown cause that may only be diagnosed by exclusion of identifiable serious causes.
A malignant peripheral nerve sheath tumor (MPNST) is a form of cancer of the connective tissue surrounding nerves. Given its origin and behavior it is classified as a sarcoma. About half the cases are diagnosed in people with neurofibromatosis; the lifetime risk for an MPNST in patients with neurofibromatosis type 1 is 8–13%. MPNST with rhabdomyoblastomatous component are called malignant triton tumors.
Neurofibromatosis type II is a genetic condition that may be inherited or may arise spontaneously, and causes benign tumors of the brain, spinal cord, and peripheral nerves. The types of tumors frequently associated with NF2 include vestibular schwannomas, meningiomas, and ependymomas. The main manifestation of the condition is the development of bilateral benign brain tumors in the nerve sheath of the cranial nerve VIII, which is the "auditory-vestibular nerve" that transmits sensory information from the inner ear to the brain. Besides, other benign brain and spinal tumors occur. Symptoms depend on the presence, localisation and growth of the tumor(s). Many people with this condition also experience vision problems. Neurofibromatosis type II is caused by mutations of the "Merlin" gene, which seems to influence the form and movement of cells. The principal treatments consist of neurosurgical removal of the tumors and surgical treatment of the eye lesions. Historically the underlying disorder has not had any therapy due to the cell function caused by the genetic mutation.
A neurofibroma is a benign nerve-sheath tumor in the peripheral nervous system. In 90% of cases, they are found as stand-alone tumors, while the remainder are found in persons with neurofibromatosis type I (NF1), an autosomal-dominant genetically inherited disease. They can result in a range of symptoms from physical disfiguration and pain to cognitive disability.
Phakomatoses, also known as neurocutaneous syndromes, are a group of multisystemic diseases that most prominently affect structures primarily derived from the ectoderm such as the central nervous system, skin and eyes. The majority of phakomatoses are single-gene disorders that may be inherited in an autosomal dominant, autosomal recessive or X-linked pattern. Presentations may vary dramatically between patients with the same particular syndrome due to mosaicism, variable expressivity, and penetrance.
Schwannomatosis is an extremely rare genetic disorder closely related to the more-common disorder neurofibromatosis (NF). Originally described in Japanese patients, it consists of multiple cutaneous schwannomas, central nervous system tumors, and other neurological complications, excluding hallmark signs of NF. The exact frequency of schwannomatosis cases is unknown, although some populations have noted frequencies as few as 1 case per 1.7 million people.
A schwannoma is a usually benign nerve sheath tumor composed of Schwann cells, which normally produce the insulating myelin sheath covering peripheral nerves.
Neurofibromin 1 (NF1) is a gene in humans that is located on chromosome 17. NF1 codes for neurofibromin, a GTPase-activating protein that negatively regulates RAS/MAPK pathway activity by accelerating the hydrolysis of Ras-bound GTP. NF1 has a high mutation rate and mutations in NF1 can alter cellular growth control, and neural development, resulting in neurofibromatosis type 1. Symptoms of NF1 include disfiguring cutaneous neurofibromas (CNF), café au lait pigment spots, plexiform neurofibromas (PN), skeletal defects, optic nerve gliomas, life-threatening malignant peripheral nerve sheath tumors (MPNST), pheochromocytoma, attention deficits, learning deficits and other cognitive disabilities.
Juvenile myelomonocytic leukemia (JMML) is a rare form of chronic leukemia that affects children, commonly those aged four and younger. The name JMML now encompasses all diagnoses formerly referred to as juvenile chronic myeloid leukemia (JCML), chronic myelomonocytic leukemia of infancy, and infantile monosomy 7 syndrome. The average age of patients at diagnosis is two (2) years old. The World Health Organization has included JMML as a subcategory of myelodysplastic and myeloproliferative disorders.
Spinal disease refers to a condition impairing the backbone. These include various diseases of the back or spine ("dorso-"), such as kyphosis. Dorsalgia refers to back pain. Some other spinal diseases include spinal muscular atrophy, ankylosing spondylitis, scoliosis, lumbar spinal stenosis, spina bifida, spinal tumors, osteoporosis and cauda equina syndrome.
Bonnet–Dechaume–Blanc syndrome, also known as Wyburn-Mason syndrome, is a rare congenital disorder characterized by arteriovenous malformations of the brain, retina or facial nevi. The syndrome has a number of possible symptoms and can, more rarely, affect the skin, bones, kidneys, muscles, and gastrointestinal tract. When the syndrome affects the brain, people can experience severe headaches, seizures, acute stroke, meningism, and progressive neurological deficits due to acute or chronic ischaemia caused by arteriovenous shunting.
Legius syndrome (LS) is an autosomal dominant condition characterized by cafe au lait spots. It was first described in 2007 and is often mistaken for neurofibromatosis type I. It is caused by mutations in the SPRED1 gene. It is also known as neurofibromatosis type 1-like syndrome.
Selumetinib (INN), sold under the brand name Koselugo, is a medication for the treatment of children, two years of age and older, with neurofibromatosis type I (NF-1), a genetic disorder of the nervous system causing tumors to grow on nerves. It is taken by mouth.
Within medical ophthalmology, Intraocular schwannoma, also termed uveal schwannoma, is a type of schwannoma found in the eye. These tumors are almost always benign in nature and while malignant forms have been documented in other areas of the body, this has not been reported in the uveal region. Composed of Schwann cells, these masses are generally slow growing and can be found in the peripheral nerve tract, often around the head and neck.
Brigitte C. Widemann is German-American pediatric oncologist. She is chief of the pediatric oncology branch and clinical deputy director of the center for cancer research at the National Cancer Institute. She is also the special advisor to the NCI director for childhood cancer.
Congenital Pseudarthrosis of the Tibia (CPT) is a rare paediatric disease presenting with a bowing deformity of the tibia at birth or within the first decade of life. It is most commonly associated with Neurofibromatosis type 1 (NF-1). For children with CPT, pathological fracture of the tibia eventually occurs, resulting in persistent nonunion of the fracture site. If left untreated, leg deformities, joint stiffness, leg-length discrepancy and pain will persist. Diagnosis is done clinically and through X-ray imaging, with numerous classifications based on the severity of bowing and presence of fracture or intraosseous lesion.