An individual with 2 or more of the following signs is considered to have NF1:
1. 6 or more café-au-lait macules (must be greater than 5 mm in greatest diameter in prepubertal children and greater than 15 mm in greatest diameter after puberty)
2. 2 or more neurofibromas of any type or 1 plexiform neurofibroma
3. Freckling in the axillary or inguinal regions
4. A tumor of the optic pathway (optic glioma)
5. 2 or more Lisch nodules (iris hamartomas)
6. A distinctive osseous lesion, such as sphenoid wing dysplasia or thinning of the cortex of long bones (with or without pseudoarthrosis)
7. A first-degree relative (parent, sibling, child) diagnosed with NF1 by the above criteria
Currently, the diagnosis of NF1 is based on clinical grounds alone. Additional diagnostic testing with NF1 genetic testing is available, but of limited clinical utility. The current genetic tests are over 95 % sensitive and essentially 100 % specific. There are some exceptions where genetic testing can be helpful. For instance, in children with café-au-lait macules and characteristic freckling only, genetic testing for NF1 and SPRED1 can be useful to differentiate Legius syndrome from NF1. Genetic tests can also be useful for family planning purposes for persons with NF1 considering pre-implantation genetic diagnosis (PGD).
Clinical Manifestations
Cutaneous
Café-au-lait macules are typically the first manifestation of NF1. Nearly all patients with NF1 tend to have enough café-au-lait macules for diagnosis (99 %) by the age of 1 year. These flat, well circumscribed, evenly hyperpigmented macules are usually oval in shape with smooth borders and measure between 10 and 40 mm in diameter (see Fig. 7.1). Café-au-lait macules can be present at birth and in individuals with NF1 they tend to appear predominantly on the torso, buttocks, and legs, but can appear almost anywhere. They can increase in number and size with age, but may fade later in life. In the general population, as many as 25 % of people will have one or more café-au-lait macules without any associated disorder. Several other disorders, including neurofibromatosis type 2 (NF2), McCune-Albright syndrome , and Legius syndrome , are also known to be associated with the presence of café-au-lait spots. In particular, Legius syndrome may meet clinical criteria for NF1 with multiple café-au-lait macules and characteristic freckling. However, they do not develop other manifestations of NF1 and there is an association with a mutation in the SPRED1 gene.
Fig. 7.1
Axillary freckling and a café-au-lait macule in a patient with NF1
Freckling is also a common cutaneous finding in NF1 with about 90 % of patients exhibiting this feature by age 7. Freckles tend to appear later than café-au-lait macules and are most commonly are found in the axillary, inguinal, or other intertriginous regions (see Fig. 7.1).
Nerve Sheath Tumors
Neurofibromas are benign nerve sheath tumors primarily composed of Schwann cells, fibroblasts, perineural cells, and mast cells. They can be classified as cutaneous, subcutaneous, or plexiform. Neurofibromas are present in about half of individuals with NF1 by 10 years of age and >80 % of people with NF1 by the age of 20. Cutaneous neurofibromas are soft, flesh-like, exophytic papules and nodules in the skin that usually present during childhood and adolescence. They can cause cosmetic disfigurement or pruritis, but are usually otherwise asymptomatic and are not known to have malignant potential. Subcutaneous neurofibromas are firm, rubbery subcutaneous nodules that can be painful or tender. Both cutaneous and subcutaneous neurofibromas are rarely present at birth and tend to appear in mid or late childhood with an increase in number and, slowly in size, as individuals age.
Plexiform neurofibromas are typically present at birth, but often do not manifest symptomatically until later in childhood or adulthood. This type of neurofibroma can be classified as either nodular or diffuse. Nodular neurofibromas can present along any peripheral nerve, including the brachial or sacral plexus and spinal nerve roots. They are typically asymptomatic, but can be painful and have the potential to cause symptoms of spinal cord compression when they involve proximal nerve roots via extension through foramina into the spinal canal. Most often they are discovered in adulthood and on neuroimaging have a typical “dumbbell” appearance. Diffuse plexiform neurofibromas tend to be found earlier in childhood. They most often appear as a soft mass under the skin and can give the overlying skin a dark or thickened appearance. These neurofibromas tend to grow with age and can become disfiguring, limit range of motion, or impair organ function. Unlike other neurofibromas, they are not limited by perineurium and can have projections into surrounding normal tissues. This, in addition to the fact that they are often highly vascular and have extensive nerve involvement, makes complete surgical resection impossible without sacrificing adjacent healthy tissue or resulting in significant loss of function.
Unlike cutaneous and subcutaneous neurofibromas, plexiform neurofibromas may undergo transformation to become malignant peripheral nerve sheath tumors (MPNSTs) . MPNSTs are aggressive sarcomas that are reported to occur in around 10 % of individuals with NF1. They carry a poor prognosis and are often fatal. Malignant transformation is seen more often in deep nodular or diffuse plexiform neurofibromas. The transformation to a MPNST is often heralded by new onset of rapid or asymmetric growth of the mass or new onset of severe pain. Malignant transformation can be determined in part with MRI and PET imaging, though biopsy is often required (see Fig. 7.2a, b).
Fig. 7.2
NF1 patient with a malignant peripheral nerve sheath tumor of the left arm (a) with accompanying MRI (b)
Currently, there are no proven medical therapies for nerve sheath tumors, and generally, surgical excision is the only treatment option despite carrying a high risk of nerve injury, bleeding, and recurrence of tumor.
Central Nervous System (CNS ) Tumors
CNS gliomas are the second most common tumor seen in NF1 after neurofibromas. In contrast to sporadically occurring CNS gliomas, the gliomas seen in NF1 often behave more indolently. While most gliomas in NF1 are low-grade pilocytic astrocytomas, some people will develop high-grade tumors. Most of the CNS gliomas seen occur in the optic pathway and can be present in about 15 % of individuals with NF1 (see Fig. 7.3a, b). These optic gliomas are usually asymptomatic (roughly 2/3). This benign behavior differs from optic gliomas that are unrelated to NF1. They tend to arise prior to age 4, usually in the intraorbital portion of the optic nerve, and often bilaterally. These tumors can also involve the optic chiasm and can cause precocious puberty due to their proximity to the suprasellar region. Symptomatically, optic gliomas in NF1 can cause vision loss or proptosis.
Fig. 7.3
MRI with optic glioma shown in axial (a) and sagittal (b) views
Since optic gliomas in NF1 tend to cause symptoms or progress in the first decade of life, the current recommendation is for annual ophthalmologic examination until age 6, as well as serial neuroimaging. Surgery is considered in instances of significant proptosis or visual loss, particularly in unilateral gliomas anterior to the chiasm. Chemotherapy has been effective and is most commonly used in symptomatic optic gliomas.
Brainstem tumors associated with NF1 are similarly more indolent than sporadic equivalents and often do not require any treatment. Most often they are asymptomatic, but can cause headache, ataxia, cranial neuropathies, and increased intracranial pressure that may require shunting.
Other CNS Manifestations
Unidentified bright objects (UBOs) are focal areas of T2 hyperintensity on MRI that are characteristic radiographic findings in NF1. They are not contrast enhancing and not associated with any edema or mass effect. Likewise, they are not known to be associated with any neurologic deficits. Most often they are noted in the brainstem, cerebellum, basal ganglia, or subcortical white matter. It is thought that they represent increased fluid within myelin in areas of dysplastic glial proliferation.
It has also been recognized that many people with NF1 (30–60 %) have mild cognitive deficits, particularly attention deficit hyperactivity disorder (ADHD) and learning disabilities. IQ in patients with NF1 tends to be 5–10 points lower when compared to the general population or unaffected siblings. While seizures are not a common finding in NF1, the lifetime risk of seizure is approximately twice that of the general population with an overall prevalence of 4 %. The onset of seizures varies and they can be focal or generalized. Macrocephaly also occurs in up to half of children with NF1. On occasion, it is the result of hydrocephalus from aqueductal stenosis, but more commonly it is caused by increased brain size and cerebral white matter volume.
Other Malignancies
In addition to intracranial gliomas and astrocytomas and the potential for transformation of plexiform neurofibromas to MPNSTs, there are some other malignancies associated with NF1. These include pheochromocytomas, rhabdomyosarcomas, gastrointestinal stromal tumors, and juvenile myelomonocytic leukemia (JMML). Children with NF1 have an up to 500-fold increased risk of JMML in particular.
Ophthalmologic
Lisch nodules are benign, asymptomatic iris hamartomas that present in greater than >70 % of people with NF1 by age 10. Typically, they are only visualized under slit lamp examination as raised, usually pigmented bumps on the iris. Another rare ophthalmologic complication of NF1 is congenital glaucoma.
Skeletal
NF1 has several characteristic osseous lesions that are usually apparent within the first year of life and are found in about 14 % of patients. Around 5 % of people with NF1 will have sphenoid wing dysplasia that is most commonly found incidentally on imaging of the skull with computed tomography (CT) or X-ray. Sphenoid wing dysplasia in NF1 tends to be unilateral, may or may not be associated with an overlying neurofibroma, and can be associated with compromised integrity of the bony orbit leading to proptosis or globe displacement.
Pseudoarthrosis can also be seen as a result of cortical thinning of long bone, most often causing tibial bowing (see Fig. 7.4). This occurs in up to 5 % of individuals with NF1 with most cases occurring before 2 years of age. Depending on the severity, treatment can involve bracing, surgical correction, or amputation.
Fig. 7.4
Tibial bowing in a patient with NF1 (a) with accompanying radiograph (b)
Scoliosis is seen up to 50 % of individuals with NF1. Cervical or upper thoracic kyphosis is most commonly seen. Most often, scoliosis is caused by distortion of vertebral bodies by neurofibromas in neural foramina or from vertebral dysplasia. Generally, scoliosis in NF1 is divided into dystrophic and non-dystrophic forms. The less common dystrophic form can be accompanied by scalloping of vertebrae, rib spindling, paravertebral soft tissue masses, foraminal enlargement, a short curve with severe apical rotation, or subluxation of a vertebral body. Dystrophic scoliosis is more likely to progress rapidly and can produce spinal cord compression causing chronic or acute neurologic symptoms. Therefore, early and aggressive surgical management is often needed. Non-dystrophic scoliosis requires management similar to idiopathic scoliosis, with close observation, bracing, and surgical fusion when indicated.
Another skeletal manifestation seen in around 30 % of NF1 patients is short stature. Children with NF1 are often vitamin D deficient and can have precocious or delayed puberty.
Cardiovascular
Patients with NF1 are at increased risk of cardiovascular abnormalities , including vasculopathy, hypertension, and congenital heart defects. Symptomatic vasculopathy is fairly uncommon, but can involve large or small vessels and result in stenosis, occlusion, aneurysm formation, or arteriovenous fistulae. The most common vascular dysplasia is renal artery stenosis, often with resultant hypertension. Renal angiography should be considered in any child with NF1 who has persistently elevated blood pressure. In adults with NF1, hypertension can also be caused by pheochromocytoma or primary hypertension. Cerebrovascular abnormalities can also be seen, especially stenosis of the internal carotid arteries and the middle or anterior cerebral arteries. This can sometimes be accompanied by Moyamoya disease and present with signs and symptoms of stroke, hypoperfusion, or seizures.
Management Considerations
Due to the complex array of manifestations in NF1, it is important that patients are evaluated and managed at a center with familiarity and expertise in neurofibromatosis. Effective care requires a multidisciplinary approach that includes genetics, neurology, neurosurgery, radiology, ophthalmology, orthopedics, dermatology, plastic surgery, neuropsychology, oncology, and radiation oncology. Current recommendations for screening include biannual physicals through childhood. These exams should pay special attention to screening for hypertension, macrocephaly, scoliosis, evidence of orthopedic abnormalities, and new or changing cutaneous lesions. They should also undergo yearly neurologic and ophthalmologic examinations. Close monitoring for neuro-developmental problems is warranted and a referral should be made for formal neuropsychiatric evaluation if there are any concerns. Routine screening with imaging is not indicated and should only be performed for specific indications on history or exam. This includes focal neurologic signs or symptoms, progressive or severe headaches, visual changes, proptosis, precocious or delayed puberty, new onset of seizures, and plexiform neurofibromas of the neck or face. Baseline imaging of neurofibromas is not necessary, though MRI or PET scans should be obtained if there is any concern for transformation to an MPNST. Additionally, because of the high incidence of Vitamin D deficiency and increased risk of osteopenia, daily Vitamin D supplementation may be considered.
Neurofibromatosis Type 2
Overview
NF2 is far less common than NF1 with a prevalence of about 1:40,000. Unlike NF1, NF2 usually presents in young adults and is restricted almost entirely to tumors of the central and peripheral nervous systems (see Table 7.2). The average age of symptom onset in NF2 is around 20 years, while the average age of diagnosis is about 28. Most people present with hearing loss secondary to vestibular schwannomas or with other symptoms caused by meningiomas or spinal schwannomas. Patients presenting in childhood tend to present with signs or symptoms from tumors other than vestibular schwannomas (cranial meningiomas or spinal tumors) and tend to have a more severe phenotype.
Table 7.2
Features of NF1 and NF2
NF1 | NF2 | |
|---|---|---|
Inheritance | Autosomal dominant | Autosomal dominant |
Spontaneous mutations | 50 % | 50 % |
Incidence | 1:3000 | 1:40,000 |
Chromosome | 17q11.2 | 22q12.2 |
Gene Product | Neurofibromin | Merlin |
Typical presentation | Café-au-lait macules during infancy or early childhood | Hearing loss or vestibular dysfunction in young adulthood or cataracts |
Nerve sheath tumors | Neurofibroma, plexiform neurofibroma, MPNSTs | Schwannoma |
Intracranial tumors | Optic pathway gliomas, other astrocytomas/gliomas | Vestibular schwannomas, meningiomas |
Spinal tumors | Nodular plexiform neurofibromas (roots) | Schwannomas (roots), ependymomas (intramedullary) |
Cutaneous features | Café-au-lait macules, axillary/inguinal freckling, cutaneous neurofibromas, subcutaneous neurofibromas | Cutaneous schwannomas |
Cognitive | LD and ADHD common, IQ mildly decreased | Normal |
Skeletal | Scoliosis, short stature, pseudoarthrosis, sphenoid dysplasia | None |
Ophthalmologic | Lisch nodules, congenital glaucoma | Juvenile subcapsular lenticular opacities, cataracts, corneal scarring, retinal hamartomas |
Other tumors | CML, pheochromocytoma | None |
Other neuro manifestations | UBOs, macroencephaly | Neuropathy, areflexia |
Other | Vascular abnormalities, GI bleeding, constipation |
The hallmark feature of NF2 is the development of bilateral vestibular schwannomas, often leading to deafness. Other features include meningiomas, schwannomas of cranial, spinal, or peripheral nerves, café-au-lait macules, lens opacities, and peripheral neuropathy. NF2 is also inherited in an autosomal dominant genetic pattern due to a mutation encoding the protein merlin on the long arm of chromosome 22 (22q11.2), which is thought to act as a tumor suppressor. Like NF1, as many as 50 % of individuals present with NF2 as the result of a sporadic mutation. It also has nearly 100 % penetrance with high phenotypic variability.
Data on the morbidity and mortality in NF2 is limited and studies are prone to sampling bias. Most patients eventually lose hearing and a third will have some degree of visual impairment. Many develop facial weakness due to tumor growth or complications of treatment and some patients also develop weakness or sensory dysfunction secondary to myelopathy, neuropathy, or brain tumor growth.
Diagnosis
The diagnosis of NF2 is made using a set diagnostic guidelines based on specific clinical findings (see Table 7.3).
Table 7.3
Diagnostic criteria for neurofibromatosis type 2
NF2 can be diagnosed in individuals with one of the following: |
1. Bilateral vestibular schwannomas |
OR |
2. First-degree relative (parent, sibling, child) with NF2 AND |
(a) A unilateral vestibular schwannoma before age 30 OR |
(b) Any 2 of the following: meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacity |
Presumptive or probable NF2 is diagnosed in individuals with the following: |
1. Unilateral vestibular schwannomas before age 30 AND at least 1 of the following: meningioma, schwannoma, glioma, posterior subcapsular lenticular opacity |
OR |
2. Multiple meningiomas (2 or more) AND unilateral vestibular schwannoma before the age of 30 OR 1 of the following: schwannoma, glioma, posterior subcapsular lenticular opacity |
Current testing of lymphocyte DNA from non-founder (familial) NF2 patients is about 92 % sensitive, but only about 70 % sensitive in founder (sporadic) NF2 patients. The lack of sensitivity in nonfamilial cases is likely due to the high prevalence of genetic mosaicism. As such, a positive genetic test can be helpful in confirming the diagnosis, screening family members, and possibly for PGD. A negative test result does not rule out NF2 and the diagnosis must be made on the basis of the above clinical diagnostic criteria.
Clinical Manifestations
Cutaneous
While café-au-lait macules can be seen in 30–40 % of people with NF2, they are usually fewer in number compared to NF1. Additional cutaneous findings in NF2 are usually associated with underlying superficial schwannomas or cutaneous schwannomas and, less commonly, neurofibromas.
Schwannomas
Schwannomas are the cardinal feature of NF2. They are benign, encapsulated tumors that arise from Schwann cells of cranial nerves III–XII, spinal nerves, or peripheral nerves. Malignant transformation is rare for a schwannoma. While they can arise from any cranial nerve, they most commonly arise from the vestibular portion of cranial nerve VIII and are referred to as vestibular schwannomas (VS). VS can be bilateral and are present in essentially all individuals with NF2 They arise at the cerebellopontine angle and are typically slow growing, causing gradual loss of hearing (see Fig. 7.5a, b). Balance and other cranial nerve functions may become impaired and brainstem compression and obstructive hydrocephalus can occur as well.
Fig. 7.5
Bilateral vestibular schwannomas in a patient with NF2 shown on MRI in axial (a) and coronal (b) views
Schwannomas arising from the dorsal spinal roots (spinal schwannomas) are present in more than 80 % of patients with NF2. Spinal schwannomas are typically small and asymptomatic, though they can become large and cause compression of the spinal cord or adjacent organs. These tumors are radiographically indistinguishable from neurofibromas arising from spinal roots in NF1 patients, frequently taking on the same “dumbbell” appearance.
Peripheral schwannomas can arise from any nerve, superficial or deep, and can cause pain or impaired motor or sensory function. Superficial peripheral schwannomas can manifest as subcutaneous nodules or as raised, well-circumscribed cutaneous lesions, often with some associated skin and hair changes. Though cutaneous schwannomas are seen in up to half of NF2 patients, they are generally a relatively minor component of the disorder.
Other Nervous System Tumors
Approximately half of patients with NF2 develop meningiomas . They are typically slow growing and can occur in the meninges of the brain, spine, or optic nerve. Many of these meningiomas are asymptomatic, though pain and neurologic dysfunction may occur based on tumor size, location, and extent of associated edema. Ependymomas and other low-grade gliomas, including astrocytomas, are also more prevalent in patients with NF2, with an estimated incidence as high as one in three patients. The vast majority of glial neoplasms seen in NF2 patients are ependymomas. These are most often intramedullary spinal or cauda equina tumors but rarely can be intracranial.
Ophthalmologic
Visual impairment is common in the NF2 population. Juvenile posterior subcapsular lenticular opacities are common (60–80 %), though are not always symptomatic. Retinal abnormalities, particularly hamartomas are also frequently seen. Corneal injury may occur in patients with facial weakness. Optic nerve and/or orbital meningiomas are also seen in some patients with NF2 and can cause visual impairment.
Other Nervous System Manifestations
Patients with NF2 develop few neurologic manifestations other than the direct result of their tumor burden. Patients with NF2 may develop a peripheral neuropathy and hyporeflexia that is not necessarily directly related to the growth of schwannomas. Foot drop is one of the most common findings.
Management Considerations
The initial evaluation of a person with NF2 should include thorough neurologic and ophthalmologic examinations, and audiologic testing, in addition to a gadolinium-enhanced MRI of the brain with thin cuts through the internal auditory canals for most patients. Individuals with any signs or symptoms that are concerning for myelopathy should also have a spinal MRI. Genetic counseling covering genetic and/or radiologic screening for any at risk relatives should be provided. Follow-up evaluation should be done yearly with a thorough clinical/neurologic exam, audiologic testing, and brain MRI. Serial spinal MRI is only needed for patients with known symptomatic or large spinal tumors.
Treatment decisions for VS in NF2 should be made on an individual basis, taking into consideration degree of hearing loss, size and growth of the tumor, contralateral hearing function, impact on other cranial nerves and the brainstem. The primary treatment for VS is surgical resection and it carries a high risk of nerve injury, bleeding, and tumor recurrence. VS in NF2 tend to be more difficult to treat than sporadic VS because they are often multifocal along the vestibular nerve and can be associated with facial nerve schwannomas. Small (less than 1.5 cm) VS can often be resected without loss of hearing or other cranial nerve function. However, larger tumors are usually monitored and resected or debulked only with evidence of progression (clinically or radiographically) due to the higher risk of functional loss (hearing loss and facial weakness). Many centers offer cochlear implantation and auditory brainstem implants, as well as auditory rehabilitation with instruction in lip reading and signing. Stereotactic radiosurgery may be used in some cases; however, there have been mixed outcomes and concern that people with NF2 have increased risk of secondary malignancies following radiation. There has been some recent interest in using molecularly targeted therapies to treat people with NF2. A retrospective analysis of ten NF2 patients treated with bevacizumab showed that the majority of these patients showed radiographic and symptomatic improvement, and additional clinical trials are ongoing.
The treatment of other tumors in NF2 (peripheral/spinal schwannomas, ependymomas, meningiomas) is limited to progressive or symptomatic tumors. Treatment of these tumors also includes surgical resection or debulking.
Tuberous Sclerosis Complex
Overview
Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disorder that affects multiple organ systems and is primarily characterized by the development of benign neoplasms of the brain, skin, and kidneys. The incidence of TSC has been reported to be as high as 1 in 5800. TSC is only inherited in 30 % of cases and results from a spontaneous mutation in the remaining 70 %. Two distinct genes have been identified as causative of TSC: TSC1 located on chromosome 9q34 and TSC2 located on chromosome 16p33.3. TSC1 encodes for a protein called hamartin while TSC2 encodes for a protein called tuberin. These two proteins interact to form a complex that has been shown to be integral in multiple intracellular signaling pathways. TSC has near 100 % penetrance but with wide phenotypic variability. Patients with mutations in TSC1 may have a milder phenotype compared to those with mutations in TSC2. Neurologic disease, particularly subependymal giant cell tumors (SGCTs), status epilepticus, and renal disease including renal cell carcinoma and hemorrhage into angiomyolipomas, are the most common causes of premature death in TSC.
Diagnosis
TSC is generally diagnosed based on clinical findings (see Table 7.4). While genetic testing is available, it has a limited clinical utility due to poor sensitivity.
Table 7.4
Clinical criteria for diagnosing tuberous sclerosis complex
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