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Neurofibromatosis Type 2

Neurofibromatosis type 2 Type 2 Spinal Muscular Atrophy is a neurocutaneous disorder that can arise from mutations in the NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics located in chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22 and may be inherited in an autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance fashion or occur from de novo mutations. The main clinical features are bilateral vestibular schwannomas, intracranial/spinal meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma, and intramedullary and extramedullary spinal tumors. Other features can include eye lesions such as cataracts, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions, and peripheral neuropathy Neuropathy Leprosy. Diagnosis is made clinically from history and examination and confirmed with MRI, molecular testing, and histopathology. Tumor Tumor Inflammation surveillance Surveillance Developmental Milestones and Normal Growth and follow-up with screening Screening Preoperative Care of at-risk family members is recommended. Management includes surgical interventions, radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy, and/or monoclonal antibody therapy with bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy.

Last updated: 20 Jun, 2022

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Overview

Epidemiology

  • The incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency of neurofibromatosis type 2 Type 2 Spinal Muscular Atrophy (NF2) is 1 in 25,000.
  • Bilateral vestibular schwannomas are present in 90%–95% of affected individuals.
  • Meningiomas are present in 50% of affected individuals.
  • De novo mutations that occur in the absence of a positive family history Family History Adult Health Maintenance are present in > 50% of affected individuals.
  • NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutations are detected in > 93% of families, with multiple members affected with NF2.

Etiology

  • Caused by NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations located in chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22
  • The abnormal gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics:
    • May be passed down from 1 parent ( autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance)
    • May occur via de novo mutations 
  • Risk of gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics transmission from parent to offspring is 50%.

Pathogenesis

  • Mutations occur in NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics, located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22.
  • NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics codes for merlin (schwannomin):
    • Cell-membrane–related protein 
    • Acts as a tumor Tumor Inflammation suppressor 
    • Found on Schwann cells
  • Mutations lead to loss of merlin expression, allowing tumor Tumor Inflammation eruption in the central and peripheral nervous systems.
  • 2-hit hypothesis Hypothesis A hypothesis is a preliminary answer to a research question (i.e., a “guess” about what the results will be). There are 2 types of hypotheses: the null hypothesis and the alternative hypothesis. Statistical Tests and Data Representation:
    • Schwannomas and other tumors occur only after inactivation of both NF2 alleles:
      • Affected individuals are born with 1 abnormal allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics.
      • Abnormalities of the 2nd allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics are acquired.
    • Acquired loss of function Loss of Function Inflammation in the entire NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics or in chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22 is most common.
    • Point mutations of the wild-type allele Allele Variant forms of the same gene, occupying the same locus on homologous chromosomes, and governing the variants in production of the same gene product. Basic Terms of Genetics occur less commonly.

Clinical Presentation

The clinical presentation of NF2 may vary widely between individuals with de novo mutations and families carrying genetic mutations Genetic Mutations Carcinogenesis. Younger ages at onset are often associated with an atypical presentation with more severe symptoms.

Clinical manifestations of nf2

Clinical manifestations of NF2

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Age at onset

  • Childhood onset:
    • Visual/ocular manifestations
    • Pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
    • Weakness
    • Mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy
    • Cutaneous tumors
    • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Adult onset (most commonly at about age 20):
    • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
    • Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies

Neurologic lesions

  • Vestibular schwannomas (cranial nerve (CN) VIII):
    • Present in approximately 95% of NF2-affected individuals
    • Develop by 30 years of age
    • Typically bilateral
    • Typically benign Benign Fibroadenoma
    • Symptoms:
      • Tinnitus Tinnitus A nonspecific symptom of hearing disorder characterized by the sensation of buzzing, ringing, clicking, pulsations, and other noises in the ear. Objective tinnitus refers to noises generated from within the ear or adjacent structures that can be heard by other individuals. The term subjective tinnitus is used when the sound is audible only to the affected individual. Tinnitus may occur as a manifestation of cochlear diseases; vestibulocochlear nerve diseases; intracranial hypertension; craniocerebral trauma; and other conditions. Cranial Nerve Palsies
      • Hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
      • Loss of balance/ equilibrium Equilibrium Occurs when tumor cells survive the initial elimination attempt These cells are not able to progress, being maintained in a state of dormancy by the adaptive immune system. In this phase, tumor immunogenicity is edited, where T cells keep selectively attacking highly immunogenic tumor cells.This attack leaves other cells with less immunogenicity to potentially develop resistance to the immune response. Cancer Immunotherapy
  • Schwannomas of other cranial nerves Cranial nerves There are 12 pairs of cranial nerves (CNs), which run from the brain to various parts of the head, neck, and trunk. The CNs can be sensory or motor or both. The CNs are named and numbered in Roman numerals according to their location, from the front to the back of the brain. The 12 Cranial Nerves: Overview and Functions:
    • Present in 25%–50% of NF2-affected individuals
    • Not observed in CN I or CN II (absence of Schwann cells)
    • Cause compressive cranial nerve palsies Cranial Nerve Palsies Cranial nerve palsy is a congenital or acquired dysfunction of 1 or more cranial nerves that will, in turn, lead to focal neurologic abnormalities in movement or autonomic dysfunction of its territory. Head/neck trauma, mass effect, infectious processes, and ischemia/infarction are among the many etiologies for these dysfunctions. Diagnosis is initially clinical and supported by diagnostic aids. Management includes both symptomatic measures and interventions aimed at correcting the underlying cause. Cranial Nerve Palsies
    • Most commonly observed in:
      • CN III (oculomotor)
      • CN V (trigeminal)
      • CN VII (facial)
  • Intracranial meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma:
    • Present in 45%–60% of NF2-affected individuals
    • Often multiple
    • Develops in NF2 at a younger age than in sporadic Sporadic Selective IgA Deficiency cases
    • Symptoms depend on location and size:
      • Focal neurologic deficits Neurologic Deficits High-Risk Headaches
      • CSF flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure obstruction
      • Seizures Seizures A seizure is abnormal electrical activity of the neurons in the cerebral cortex that can manifest in numerous ways depending on the region of the brain affected. Seizures consist of a sudden imbalance that occurs between the excitatory and inhibitory signals in cortical neurons, creating a net excitation. The 2 major classes of seizures are focal and generalized. Seizures
  • Spinal meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma:
    • Present in approximately 20% of NF2-affected individuals
    • Arise from extramedullary space
    • Symptoms depend on location and size:
      • Back pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
      • Nerve root pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways/paresthesia
      • Muscle weakness/paralysis
      • CSF flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure obstruction
  • Spinal ependymomas:
    • Present in 20%–50% of NF2-affected individuals
    • Typically arise from intramedullary space
    • Symptoms depend on location and size:
      • Back pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways
      • Nerve root pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways/paresthesia
      • Muscle weakness/paralysis
      • CSF flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure obstruction
  • Peripheral neuropathy Neuropathy Leprosy:
    • Present in > 65% of NF2-affected individuals
    • May present as a compression Compression Blunt Chest Trauma neuropathy Neuropathy Leprosy ( mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy)
    • May present as a mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy multiplex
    • May present as a systemic (nonfocal) sensorimotor neuropathy Neuropathy Leprosy
    • Symptoms of mononeuropathy Mononeuropathy Disease or trauma involving a single peripheral nerve in isolation, or out of proportion to evidence of diffuse peripheral nerve dysfunction. Mononeuropathy multiplex refers to a condition characterized by multiple isolated nerve injuries. Mononeuropathies may result from a wide variety of causes, including ischemia; traumatic injury; compression; connective tissue diseases; cumulative trauma disorders; and other conditions. Mononeuropathy and Plexopathy dependent on the affected nerve(s).
    • Symptoms of systemic polyneuropathy Polyneuropathy Polyneuropathy is any disease process affecting the function of or causing damage to multiple nerves of the peripheral nervous system. There are numerous etiologies of polyneuropathy, most of which are systemic and the most common of which is diabetic neuropathy. Polyneuropathy:

Eye lesions

  • Cataracts:
    • Present in 60%–80% of NF2-affected individuals
    • Present with visual loss, lens Lens A transparent, biconvex structure of the eye, enclosed in a capsule and situated behind the iris and in front of the vitreous humor (vitreous body). It is slightly overlapped at its margin by the ciliary processes. Adaptation by the ciliary body is crucial for ocular accommodation. Eye: Anatomy opacity Opacity Imaging of the Lungs and Pleura
  • Epiretinal membranes:
    • Present in approximately 80% of NF2-affected individuals
    • White/gray membranes with distinct white edges
    • May be translucent or semitranslucent
    • Do not typically interfere with vision Vision Ophthalmic Exam
  • Retinal hamartomas:
    • Present in 5%–20% of NF2-affected individuals
    • Affect Affect The feeling-tone accompaniment of an idea or mental representation. It is the most direct psychic derivative of instinct and the psychic representative of the various bodily changes by means of which instincts manifest themselves. Psychiatric Assessment the macula Macula An oval area in the retina, 3 to 5 mm in diameter, usually located temporal to the posterior pole of the eye and slightly below the level of the optic disk. It is characterized by the presence of a yellow pigment diffusely permeating the inner layers, contains the fovea centralis in its center, and provides the best phototropic visual acuity. It is devoid of retinal blood vessels, except in its periphery, and receives nourishment from the choriocapillaris of the choroid. Eye: Anatomy 
    • Present with visual loss

Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions lesions

  • May occur anywhere, no particular area of predilection 
  • Most commonly skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions tumours are schwannomas, though neurofibromas or mixed histology may be observed.
  • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions plaques:
    • Present in 40%–50% of NF2-affected individuals
    • Circumscribed, slightly raised, slightly hyperpigmented, scaly, rough lesions
    • Typically < 2 cm in diameter
  • Subcutaneous tumors:
    • Present in 40%–50% of NF2-affected individuals
    • Develop as swellings along peripheral nerves Peripheral Nerves The nerves outside of the brain and spinal cord, including the autonomic, cranial, and spinal nerves. Peripheral nerves contain non-neuronal cells and connective tissue as well as axons. The connective tissue layers include, from the outside to the inside, the epineurium, the perineurium, and the endoneurium. Nervous System: Histology
    • May be palpated as fusiform or nodular swellings 
    • Tenderness to palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination may be noted.
  • Intradermal tumors:
    • Present in 60%–70% of NF2-affected individuals
    • Well-demarcated, superficial lesions with blue/purple coloration
    • Soft to palpation Palpation Application of fingers with light pressure to the surface of the body to determine consistency of parts beneath in physical diagnosis; includes palpation for determining the outlines of organs. Dermatologic Examination

Diagnosis

Clinical criteria for neurofibromatosis type 2 Type 2 Spinal Muscular Atrophy (revised Manchester criteria)

  • Any 1 of the following:
    • Bilateral vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma at < 70 years of age
    • Unilateral vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma at < 70 years and 1st-degree relative (not a sibling alone) with NF2
  • Any 2 of the following:
    • Meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma, nonvestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma, ependymoma Ependymoma Ependymomas are glial cell tumors arising from CSF-producing ependymal cells lining the ventricular system. Ependymomas most commonly occur within the posterior fossa in contact with the 4th ventricle, or within the intramedullary spinal cord. Ependymoma, cataract; and 
    • 1st-degree relative with NF2 or unilateral vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma and negative LZTR1 testing (if ≥ 2 non-intradermal schwannomas)
  • Other criteria:
    • Multiple meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma and:
      • Unilateral vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma or
      • Any 2 of the following: nonvestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma, ependymoma Ependymoma Ependymomas are glial cell tumors arising from CSF-producing ependymal cells lining the ventricular system. Ependymomas most commonly occur within the posterior fossa in contact with the 4th ventricle, or within the intramedullary spinal cord. Ependymoma, cataract
    • Constitutional or mosaic pathogenic NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations from the blood or by the identification Identification Defense Mechanisms of an identical mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations from 2 separate tumors in the same individual 

Clinical diagnosis

  • Detailed clinical and family history Family History Adult Health Maintenance
  • Physical examination:
    • Auditory evaluation
    • Ophthalmic evaluation
    • Neurologic examination
    • Skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions examination

Molecular testing

  • Indications:
    • 1st-degree relative with NF2 
    • Presence of multiple spinal tumors 
    • Presence of cutaneous schwannomas
    • Presence of vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma at < 30 years of age
    • Presence of meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma or schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma (nonvestibular) at < 25 years of age
  • Begin with analysis of tumor Tumor Inflammation DNA DNA A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine). DNA Types and Structure with sequencing for NF2 abnormalities, followed by analysis of blood lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology for the same NF2 abnormality.
Vestibular schwannoma histopathology

Vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma histopathology

Image: “Vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma” by Pećina-Slaus N, Zeljko M, Pećina HI, Nikuseva Martić T, Bacić N, Tomas D, Hrasćan R. License: CC BY 2.5

Imaging

  • MRI with contrast is the method of choice.
  • Scans of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification and entire spine Spine The human spine, or vertebral column, is the most important anatomical and functional axis of the human body. It consists of 7 cervical vertebrae, 12 thoracic vertebrae, and 5 lumbar vertebrae and is limited cranially by the skull and caudally by the sacrum. Vertebral Column: Anatomy are recommended to evaluate for intracranial/spinal tumors.

Management

Management of NF2 is multidisciplinary and often involves contributions from multiple specialists.

  • Consultations with the following specialties:
    • Oncology
    • Neurology
    • Neuroradiology
    • Ophthalmology
    • Dermatology
    • Audiology
    • Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics/ genetic counseling Genetic Counseling An educational process that provides information and advice to individuals or families about a genetic condition that may affect them. The purpose is to help individuals make informed decisions about marriage, reproduction, and other health management issues based on information about the genetic disease, the available diagnostic tests, and management programs. Psychosocial support is usually offered. Myotonic Dystrophies
    • Neurosurgery Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. Neurosurgery/skull-base surgery 
  • Tumor Tumor Inflammation surveillance Surveillance Developmental Milestones and Normal Growth and follow-up:
    • Annual history and physical exam (audiology, ophthalmic evaluation, neurologic, and cutaneous examination)
    • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification MRI every 12 months beginning at 10 years of age
    • Spinal MRI Spinal MRI Imaging of the Spine and Spinal Cord every 24–36 months beginning at 10 years of age
  • Vestibular schwannoma Schwannoma Schwannomas (also known as neurilemmomas) are benign nerve sheath tumors in the peripheral nervous system (PNS), arising from Schwann cells that encase the peripheral nerves. Schwannomas are the most common tumors in the PNS. Schwannoma(s): 
    • Surgery:
      • Neurosurgery Neurosurgery Neurosurgery is a specialized field focused on the surgical management of pathologies of the brain, spine, spinal cord, and peripheral nerves. General neurosurgery includes cases of trauma and emergencies. There are a number of specialized neurosurgical practices, including oncologic neurosurgery, spinal neurosurgery, and pediatric neurosurgery. Neurosurgery or skull-base surgery consultation
      • Surgery may be complex and high risk depending on size, location, and multifocality.
    • Bevacizumab Bevacizumab An anti-vegf humanized murine monoclonal antibody. It inhibits vegf receptors and helps to prevent pathologic angiogenesis. Targeted and Other Nontraditional Antineoplastic Therapy
      • Monoclonal antibody against vascular endothelial growth factor Vascular endothelial growth factor A family of angiogenic proteins that are closely-related to vascular endothelial growth factor a. They play an important role in the growth and differentiation of vascular as well as lymphatic endothelial cells. Wound Healing
      • Induces tumor Tumor Inflammation shrinkage and hearing improvement
    • Other targeted therapies:
      • Everolimus Everolimus A derivative of sirolimus and an inhibitor of tor serine-threonine kinases. It is used to prevent graft rejection in heart and kidney transplant patients by blocking cell proliferation signals. It is also an antineoplastic agent. Immunosuppressants: chemotherapeutic kinase inhibitor that decreases tumor Tumor Inflammation blood supply.
      • Lapatinib Lapatinib A quinazoline derivative that inhibits epidermal growth factor receptor and HER2 tyrosine kinases. It is used for the treatment of advanced or metastatic breast cancer, where tumors overexpress HER2. Targeted and Other Nontraditional Antineoplastic Therapy: chemotherapeutic tyrosine Tyrosine A non-essential amino acid. In animals it is synthesized from phenylalanine. It is also the precursor of epinephrine; thyroid hormones; and melanin. Synthesis of Nonessential Amino Acids kinase inhibitor interrupts epidermal growth factor receptor Receptor Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors (EGFR) pathways.
    • Hearing impairment Hearing impairment Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss
      • Cochlear implants
      • Brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification stem implants 
  • Meningioma Meningioma Meningiomas are slow-growing tumors that arise from the meninges of the brain and spinal cord. The vast majority are benign. These tumors commonly occur in individuals with a history of high doses of skull radiation, head trauma, and neurofibromatosis 2. Meningioma
    • Surgery: 
      • Rapidly growing tumors
      • Tumors threatening functional loss
    • Radiation Radiation Emission or propagation of acoustic waves (sound), electromagnetic energy waves (such as light; radio waves; gamma rays; or x-rays), or a stream of subatomic particles (such as electrons; neutrons; protons; or alpha particles). Osteosarcoma therapy:
      • Tumors that are surgically inaccessible or for which only partial resection is possible
      • Concern for development of secondary neoplasms Neoplasms New abnormal growth of tissue. Malignant neoplasms show a greater degree of anaplasia and have the properties of invasion and metastasis, compared to benign neoplasms. Benign Bone Tumors
    • Targeted therapy Targeted Therapy Targeted therapy exerts antineoplastic activity against cancer cells by interfering with unique properties found in tumors or malignancies. The types of drugs can be small molecules, which are able to enter cells, or monoclonal antibodies, which have targets outside of or on the surface of cells. Targeted and Other Nontraditional Antineoplastic Therapy with lapatinib Lapatinib A quinazoline derivative that inhibits epidermal growth factor receptor and HER2 tyrosine kinases. It is used for the treatment of advanced or metastatic breast cancer, where tumors overexpress HER2. Targeted and Other Nontraditional Antineoplastic Therapy is being investigated.
  • Intramedullary spinal tumors: 
  • Genetic evaluation:
    • Identification Identification Defense Mechanisms of specific NF2 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations
    • Screening Screening Preoperative Care of at-risk family members

Differential Diagnosis

  • Sporadic Sporadic Selective IgA Deficiency vestibular schwannomas: also known as acoustic neuromas. In the general population, sporadic Sporadic Selective IgA Deficiency vestibular schwannomas are relatively common. In contrast to NF2, sporadic Sporadic Selective IgA Deficiency vestibular schwannomas are typically unilateral and present at > 30 years of age. Presentation is with hearing loss Hearing loss Hearing loss, also known as hearing impairment, is any degree of impairment in the ability to apprehend sound as determined by audiometry to be below normal hearing thresholds. Clinical presentation may occur at birth or as a gradual loss of hearing with age, including a short-term or sudden loss at any point. Hearing Loss and equilibrium Equilibrium Occurs when tumor cells survive the initial elimination attempt These cells are not able to progress, being maintained in a state of dormancy by the adaptive immune system. In this phase, tumor immunogenicity is edited, where T cells keep selectively attacking highly immunogenic tumor cells.This attack leaves other cells with less immunogenicity to potentially develop resistance to the immune response. Cancer Immunotherapy problems. These lesions are diagnosed on clinical suspicion and confirmed with neuroimaging Neuroimaging Non-invasive methods of visualizing the central nervous system, especially the brain, by various imaging modalities. Febrile Infant. Conservative and surgical options are similar to those outlined for NF2. 
  • Schwannomatosis: rare sporadic Sporadic Selective IgA Deficiency or familial form of neurofibromatosis associated with mutations in the SMARCB1 and LZTR1 genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure located on chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 22. Schwannomatosis is characterized by multiple noncutaneous peripheral and intracranial schwannomas in the absence of bilateral vestibular schwannomas. Diagnosis is made with clinical evaluation and confirmed with biopsy Biopsy Removal and pathologic examination of specimens from the living body. Ewing Sarcoma. Management is symptomatic, treating the chronic pain Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways that occurs in roughly half of all patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with schwannomatosis. 
  • Neurofibromatosis type 1 Neurofibromatosis type 1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder caused by mutations in the NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1 gene Gene A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. Basic Terms of Genetics located in chromosome Chromosome In a prokaryotic cell or in the nucleus of a eukaryotic cell, a structure consisting of or containing DNA which carries the genetic information essential to the cell. Basic Terms of Genetics 17q11.2. Clinical manifestations can overlap with NF2, but the key differences include that Lisch nodules Lisch Nodules Neurofibromatosis Type 1 are seen in few numbers in NF2, schwannomas rarely undergo malignant transformation Transformation Change brought about to an organism’s genetic composition by unidirectional transfer (transfection; transduction, genetic; conjugation, genetic, etc.) and incorporation of foreign DNA into prokaryotic or eukaryotic cells by recombination of part or all of that DNA into the cell’s genome. Bacteriology to a neurofibrosarcoma, the “dumbbell” spinal root tumors that are seen in both NF2 and NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1 are schwannomas in NF2 and neurofibromas in NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1, and NF2 is not associated with the cognitive impairment seen in NF1 NF1 Neurofibromatosis type 1 (NF1), also known as phakomatosis, is a neurocutaneous disorder that is most commonly of autosomal dominant inheritance due to mutations in the NF1 gene. Neurofibromatosis type 1 presents a range of clinical manifestations with the most prominent features being various pigmented skin lesions called café au lait macules (CALMs), neurofibromas, freckling of the inguinal and axillary regions, and iris hamartomas. Neurofibromatosis Type 1. Management is based on the clinical features and may vary from surgical removal to chemotherapy Chemotherapy Osteosarcoma/radiotherapy for tumors, occupational and physical therapy Physical Therapy Becker Muscular Dystrophy for motor Motor Neurons which send impulses peripherally to activate muscles or secretory cells. Nervous System: Histology impairments, and treatment with growth hormone and bracing in bone Bone Bone is a compact type of hardened connective tissue composed of bone cells, membranes, an extracellular mineralized matrix, and central bone marrow. The 2 primary types of bone are compact and spongy. Bones: Structure and Types abnormalities. 
  • Tuberous sclerosis Sclerosis A pathological process consisting of hardening or fibrosis of an anatomical structure, often a vessel or a nerve. Wilms Tumor: autosomal dominant Autosomal dominant Autosomal inheritance, both dominant and recessive, refers to the transmission of genes from the 22 autosomal chromosomes. Autosomal dominant diseases are expressed when only 1 copy of the dominant allele is inherited. Autosomal Recessive and Autosomal Dominant Inheritance disorder with mainly neurocutaneous symptoms. Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations in the TSC TSC Tuberous sclerosis or tuberous sclerosis complex (TSC) is an autosomal dominant disorder with mainly neurocutaneous symptoms. Mutation in the tsc genes causes excessive tumor-like growths in the brain, eyes, heart, kidney, and lungs. Cutaneous manifestations include hypopigmentation (i.e., ash leaf spots, confetti lesions) or excessive growth (i.e., angiofibroma, shagreen patch). Tuberous Sclerosis genes Genes A category of nucleic acid sequences that function as units of heredity and which code for the basic instructions for the development, reproduction, and maintenance of organisms. DNA Types and Structure causes excessive tumor-like growths in the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification, eyes, heart, kidneys Kidneys The kidneys are a pair of bean-shaped organs located retroperitoneally against the posterior wall of the abdomen on either side of the spine. As part of the urinary tract, the kidneys are responsible for blood filtration and excretion of water-soluble waste in the urine. Kidneys: Anatomy, and lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy. Cutaneous manifestations include hypopigmentation Hypopigmentation A condition caused by a deficiency or a loss of melanin pigmentation in the epidermis, also known as hypomelanosis. Hypopigmentation can be localized or generalized, and may result from genetic defects, trauma, inflammation, or infections. Malassezia Fungi (i.e., ash-leaf spots Ash-Leaf Spots Physical Examination of the Newborn, confetti lesions Confetti Lesions Tuberous Sclerosis) or excessive growth (i.e., angiofibroma Angiofibroma A benign neoplasm of fibrous tissue in which there are numerous small and large, frequently dilated, vascular channels. Tuberous Sclerosis, shagreen patch Patch Nonpalpable lesion > 1 cm in diameter Generalized and Localized Rashes). The diagnosis is made on clinical suspicion and confirmed by genetic testing Genetic Testing Detection of a mutation; genotype; karyotype; or specific alleles associated with genetic traits, heritable diseases, or predisposition to a disease, or that may lead to the disease in descendants. It includes prenatal genetic testing. Myotonic Dystrophies. Management entails a multidisciplinary approach that targets monitoring and treatment of the various manifestations of the disorder.

References

  1. Evans, D.G. (2021). Neurofibromatosis type 2. UpToDate. Retrieved August 30, 2021, from https://www.uptodate.com/contents/neurofibromatosis-type-2
  2. Park, J.K. et al. (2020). Vestibular schwannoma (acoustic neuroma). UpToDate. Retrieved August 30, 2021, from https://www.uptodate.com/contents/vestibular-schwannoma-acoustic-neuroma
  3. Victorio, M.C. (2021). Neurofibromatosis. MSD Manual Professional Version. Retrieved August 28, 2021, from https://www.msdmanuals.com/professional/pediatrics/neurocutaneous-syndromes/neurofibromatosis
  4. Hsieh, D.T. (2018). Neurofibromatosis type 2. Medscape. Retrieved August 28, 2021, from https://emedicine.medscape.com/article/1178283
  5. Tiwari, R., Singh, A.K. (2021). Neurofibromatosis Type 2. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK470350/
  6. Asthagiri, A.R., et al. (2009). Neurofibromatosis type 2. Lancet 373:1974–1986. https://doi.org/10.1016/S0140-6736(09)60259-2

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