Neurofibromatosis type 1

OVERVIEW: What every practitioner needs to know

Are you sure your patient has neurofibromatosis type 1? What are the typical findings for this disease?

Neurofibromatosis type 1 (NF1) is a common autosomal dominant genetic disorder that affects approximately 1 in 3,500 people and may be inherited or arise spontaneously. It is caused by a mutation in the NF1 gene located on the long arm of chromosome 17; specifically 17q11.2. NF1 is typically characterized by prominent cutaneous features (café-au-lait macules, freckling and cutaneous and subcutaneous neurofibromas) though many other organ systems may be affected. The clinical phenotype is highly variable. NF1 most commonly presents during childhood with the development of cutaneous manifestations.

Diagnostic Criteria

The diagnosis of NF1 is made on the basis of presence of specific physical findings. Some of the physical features of NF1 are not obvious until a child is older than 5 years of age. Practically all (97%) of those affected with NF1 will have enough clinical manifestations of the disorder to make the diagnosis by 8 years of age. The National Institutes of Health has set criteria to make the diagnosis of NF1. According to these criteria, NF1 is present in a person who has 2 or more of the following signs:

1) Six or more café-au-lait spots (5mm in greatest diameter in prepubertal individuals or 15mm in greatest diameter after puberty)

2) Two or more neurofibromas of any type or one plexiform neurofibroma

3) Freckling in the axillary or inguinal regions

4) A tumor of the optic pathway

5) Two or more Lisch nodules

6) A distinctive bone lesion, such as sphenoid wing dysplasia, or thinning of the cortex of the long bones (with or without pseudarthrosis)

7) An affected first degree relative by the above criteria

Clinical features

Cutaneous Manifestations:

Café-au-lait macules are usually the first clinical manifestation of NF1, and are present in essentially all NF1 patients by the age of 1 year. Café-au-lait spots are flat, hyperpigmented skin macules, typically ovoid in shape, about 10-40mm in diameter with relatively smooth borders, that usually appear during first year of life but are often already present at birth. They may increase in number and size with age but often fade later in life. Café-au-lait spots are commonly seen in the general population. 25% of the general population has between 1 and 3 café au lait macules. For the purpose of diagnosing NF1, there must be a minimum of 6 café-au-lait spots that are greater than 5mm in diameter in children or greater than 15mm in diameter in adolescents and adults.

A distinctive pattern of freckling is a common feature of NF1, seen in about 90% of patients. The freckles tend to appear after Café-au-lait macules are evident, most commonly during childhood. They appear in the axillary and inguinal regions, but can develop in any intertriginous region. Some patients with NF1 develop more diffuse freckling and/or skin hyperpigmentation.

Nerve Sheath Tumors:

Neurofibromas are benign nerve sheath tumors commonly seen in NF1. Neurofibromas consist of a mixture of proliferated Schwann cells, as well as fibroblasts and mast cells. There are several types of neurofibromas: cutaneous, subcutaneous and plexiform.

Cutaneous neurofibromas are soft fleshy tumors arising from the peripheral nerve sheath, often appearing in late childhood or young adulthood. They can become cosmetically significant and can cause itching or discomfort but do not become cancerous.

Subcutaneous neurofibromas are firm, tender nodules along the course of peripheral nerves beneath the skin that most commonly appear during adolescence or young adulthood.

Nodular plexiform neurofibromas are discrete tumors that arise in nerves frequently clustering around proximal nerve roots. The clinical impact of these lesions depends on location and size. When these neurofibromas arise from the proximal nerve root they may extend through foramina, expanding within the spinal canal, potentially causing cord compression, and exterior to the spine, potentially compressing other organs. In addition, they can cause vertebral erosion, and scoliosis. These tumors often take on a typical “dumbbell” appearance on neuroimaging.

Diffuse plexiform neurofibromas can involve long portions of nerves or bundles of nerves. They can be deep or they can be superficial and involve the skin, torso, extremities, head or neck. When they occur they are typically present at birth though may not be apparent initially. They most commonly appear as a soft mass under the skin. Sometimes the skin overlying plexiform neurofibromas may be darker than the surrounding skin and/or thickened.

Plexiform neurofibromas tend to grow with age and can sometimes become disfiguring and depending on location may limit function (such as limitation of range of motion of a limb or obstruction of sight) or impair organ function. Plexiform neurofibromas are often highly vascular and have extensive nerve involvement, often making complete surgical excision difficult or impossible.

Plexiform neurofibromas may undergo malignant transformation, to become malignant peripheral nerve sheath tumors (MPNSTs). These tumors are highly aggressive, often fatal sarcomas. The lifetime risk of development of an MPNST in a patient with NF1 is about 10%. Malignant transformation often is heralded by new onset of rapid or asymmetric growth of the mass or new onset of significant pain. magnetic resonance imaging (MRI) and PET imaging may be helpful in determining malignant transformation, though biopsy is often required.

Central Nervous System Manifestations:

CNS gliomas are the second most common tumor type in NF1 after neurofibromas. Though they are most commonly low grade pilocytic astrocytomas and tend to behave more indolently than their sporadic counterparts, high grade tumors may also develop. Most gliomas associated with NF1 arise within the optic pathways and occur in up to 15% of children affected with NF1. They can appear anywhere along the optic pathways. They are typically slow growing and benign.

Only about 1/3 of optic gliomas are symptomatic. In patients who do have symptoms they may develop vision loss or proptosis. They may also present with premature onset of puberty if the tumor involves the suprasellar region. The tumors that are destined to become symptomatic or progress typically do so during the first decade of life, so yearly ophthalmologic evaluation is particularly important in children with NF1.

Brainstem tumors associated with NF1 behave more indolently than their sporadic counterparts, with a majority never requiring treatment. They are estimated to occur in up to 4% of the NF1 population. Brainstem tumors in patients with NF1 are often asymptomatic or may present with headache, signs of increased intracranial pressure, cranial neuropathies, hemiplegia or ataxia. Hydrocephalus can occur and shunting may be required.

Cognitive deficits in NF1, particularly learning disabilities (LD) and attention deficit disorder (ADHD) are common. The incidence of mental retardation (Full Scale IQ<70) is only slightly higher than that of the general population. However, IQ tends to be 5-10 points lower in comparison to unaffected siblings, and learning disabilities are quite common, seen in about half of patients.

Unidentified Bright Objects (UBOs) are a characteristic radiographic feature of NF1. They appear as focal areas of T2 bright signal on MRI of the brain. These lesions do not enhance and do not cause mass effect. They most commonly occur in the cerebellum, brainstem, basal ganglia and subcortical white matter. UBOs may represent areas of increased fluid within myelin in areas of dysplastic glial proliferation. They are not thought to be malignant or premalignant. They are not associated with focal neurologic deficits. UBO burden may correlate with the degree of cognitive and behavioral dysfunction, though results of studies to date have been mixed.

Seizures are not very common in NF1 though incidence is increased with a lifetime risk approximately twice that of the general population. They can begin at any age and can be focal or generalized.

Ophthalmologic Manifestations:

Visual impairment in NF1 is not common though there may be deterioration of vision with the growth of OPGs. Congenital glaucoma is occasionally seen in NF1. The most common ophthalmologic sign in NF1 is the development of iris hamartomas called Lisch nodules. Lisch Nodules are raised, usually pigmented bumps (hamartomas) on the iris of the eye that are best seen with a slit lamp examination by an ophthalmologist. They rarely cause any problems. Lisch nodules are most commonly seen in late childhood. By adulthood, 80% of NF1 patients have two or more Lisch nodules.

Orthopedic Manifestations:

Bone abnormalities sometimes seen in NF1 include tibial bowing/pseudarthrosis, sphenoid wing dysplasia, vertebral dysplasias, and scoliosis.

Pseudarthrosis results from thinning of long bone cortex followed by pathologic fracture and impaired healing. It usually presents as bowing of the tibia. Half of cases occur by 2 years of age. Pseudarthrosis occurs in up to 5% of patients affected with NF1. Most cases occur before 2 years of age. Treatment for pseudarthrosis may include bracing, surgical correction or amputation.

Dysplasia of the sphenoid bone results in deformation of the orbit and can be a disfiguring complication with proptosis or displacement of the globe. It may occur with or without an associated plexiform neurofibroma. It is uncommon, with an incidence of about 5% of patients with NF1. When it does occur it is typically present at birth.

Scoliosis is a relatively common feature of NF1, with an incidence reported of up to half of patients with NF1. Cervical or upper thoracic kyphosis is most common. Scoliosis can occur as a result of either deformation of the vertebral bodies by neurofibromas in the vertebral foramina or from vertebral dysplasia. Scoliosis in NF1 is divided into dystrophic and non-dystrophic types. Dystrophic scoliosis can be accompanied by scalloping of the vertebrae, rib spindling, paravertebral soft tissue masses, foraminal enlargement, a short curve with severe apical rotation, or subluxation of a vertebral body.

Dystrophic curves are more likely to progress rapidly and, therefore, need early and aggressive surgical management. Non-dystrophic scoliosis is managed similarly to idiopathic scoliosis, with observation, bracing and eventually surgical fusion if indicated.

Cardiovascular Manifestations:

Patients with NF1 are at increased risk of cardiovascular abnormalities including vasculopathy, hypertension and congenital heart defects.

Symptomatic vasculopathy may involve small or large vessels resulting in stenosis, occlusion, aneurysm formation or arteriovenous malformations. The most common lesion is renal artery stenosis causing hypertension. Cerebrovascular abnormalities are also seen, particularly stenosis or occlusion of the internal carotid arteries or the intracranial circulation. These lesions are sometimes accompanied by Moyamoya disease and may present with signs and symptoms of stroke, hypoperfusion, cognitive decline or seizures.

Hypertension in adults with NF1 may be seen as a result of pheochromocytoma, primary hypertension or renal artery stenosis. Hypertension in children with NF1 is most likely to be a result of renal artery stenosis. Renal artery angiography should be considered for children, young adults and pregnant women with persistent blood pressure elevation. 24-hour collection of urine for catecholamines should be considered in adults with refractory hypertension.

Malignancy:

The most common malignancies associated with NF1 are glial neoplasms and MPNSTs but patients are at risk for other malignancies as well. Children with NF1 have an up to 500-fold increase in risk for developing myeloid disorders, especially juvenile myelomonocytic leukemia (JMML). Juvenile xanthogranulomas are seen with increased incidence in NF1, and their presence may be associated with an increased risk of JMML. Other benign and malignant tumors associated with NF1 include pheochromocytoma, leukemia, gastro-intestinal stromal tumors (GIST) and rhabdomyosarcoma. Other tumors including breast cancer, melanoma, carcinoid and Wilms tumor may have increased incidences in NF1, but the data is conflicting.

Other Manifestations:

The incidence of gastrointestinal manifestations of NF1 is not well described but they are at increased risk of chronic constipation, gastrointestinal bleeding, and failure to thrive.

Macrocephaly, or large head size, occurs in up to half of children with NF1. It is usually due to increased brain size, the cause of which is unclear.

Short stature is common in persons with NF1. About 13% of patients with NF1 are two standard deviations below the mean for height.

Precocious or delayed puberty can be seen in children with NF1.

Vitamin D deficiency is common in individuals with NF1 and there may be an increased incidence of osteopenia and fractures in adults with NF1.

What other disease/condition shares some of these symptoms?

There are a number of disorders that may present with café au lait macules. In the absence of other features of NF1, these alternative diagnoses must be considered. Some of these include McCune-Albright syndrome, ataxia-telangiectasia, tuberous sclerosis complex, Leopard syndrome, constitutional mismatch repair deficiency syndrome, Legius syndrome and others.

Children with Legius syndrome may meet clinical criteria for NF1 with multiple café au lait macules and characteristic freckling. Additionally they may have some degree of cognitive impairment. They do not develop other manifestations of NF1 such as Lisch nodules, optic glioma, or neurofibromas. Patients with Legius Syndrome may be differentiated from those with NF1 with genetic testing. Legius Syndrome is associated with a mutation in the SPRED1 gene.

There is some clinical overlap with NF2 and schwannomatosis. Schwannomas may be indistinguishable from neurofibromas radiographically, however, cutaneous manifestations such as café au lait macules and freckling are typically not present in persons with NF2 or schwannomatosis.

What caused this disease to develop at this time?

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Currently, the diagnosis of NF1 is made based on clinical grounds as previously discussed. Genetic testing is available though its clinical utility is limited. NF1 testing is currently about 95% sensitive and essentially 100% specific. For those who proceed with genetic testing, if no gene mutation is identified, NF1 remains a possible diagnosis. If a gene mutation is identified the diagnosis is confirmed, however knowing the genetic status of the NF1 gene is unlikely to change how children and adults are cared for or monitored or provide prognostic information.

There are a few exceptions. Children with microdeletions of the NF1 gene may have a Noonan’s like phenotype and tend to have a more severe phenotype. For children with only café au lait spots and/or characteristic freckling, genetic testing for NF1 and SPRED1 may be helpful in differentiating persons with Legius Syndrome which tends to have a very mild phenotype. Additionally, genetic testing may be indicated for family planning purposes for persons with NF1 considering pre-implantation genetic testing.

Would imaging studies be helpful? If so, which ones?

For patients with NF1, screening examinations such as MRI, EEG and X-rays are not necessary unless specifically indicated by history or examination. The decision to image should be based on the presence of clinical features suggestive of involvement of the nervous system, such as vision impairment, focal neurologic signs or symptoms, severe cognitive impairment, progressive headaches, proptosis, precocious or delayed puberty, a plexiform neurofibroma of the head or face, rapid change in head circumference and/or seizures. MRI of the brain with thin cuts through the orbits with and without gadolinium should be considered for individuals with NF1 and any evidence of orbital or optic nerve involvement.

Baseline imaging of neurofibromas is not necessary, though MRI and FDG PET should be obtained if there is any concern of malignant transformation of a benign plexiform neurofibroma to an MPNST. Symptoms of concern would include new rapid or asymmetric growth, new significant pain associated and/or new neurologic deficit.

If you are able to confirm the patient has neurofibromatosis type 1, what treatment should be initiated?

Due to the complexities of the manifestations of NF1 and the need for access to multiple medical disciplines, patients are best served by evaluation and management through a multidisciplinary clinic with familiarity and expertise in the care of patients with neurofibromatosis. Coordinated multidisciplinary care should include specialists from genetics, neurology, neurosurgery, radiology, ophthalmology, orthopedics, dermatology, plastic surgery, neuropsychology, oncology and radiation oncology.

Most patients with NF1 should undergo biannual physical examinations through childhood and then yearly thereafter. In index cases, other undiagnosed first degree relatives should be examined for stigmata of the disorder. Because of the risk of hypertension secondary to pheochromocytoma and renal arterial abnormalities, blood pressure should be checked twice yearly at a minimum.

In children and adolescents with NF1 special attention should be paid to examination of the spine for early detection of scoliosis, and limbs for evidence of bowing or pseudarthrosis. The skin should be examined for the presence of or change in the cutaneous manifestations and signs of precocious or delayed puberty. In the first 3 years of life head circumference should be checked regularly for signs of rapid growth. Behavior and development should be evaluated for signs of learning disability and ADHD. Formal neuropsychiatric evaluation should be offered if there are any concerns. Patients with NF1 should generally undergo yearly neurologic and ophthalmologic examinations.

Additionally, because of the increased incidence of low Vitamin D levels and increased risk of osteopenia, we recommend daily Vitamin D supplementation.

What are the adverse effects associated with each treatment option?

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What are the possible outcomes of neurofibromatosis type 1?

There is extreme phenotypic variability in symptom severity in persons with NF1. Data on the morbidity and mortality of NF1 are scant and studies are prone to sampling bias but it is estimated that approximately 2/3 of persons with NF1 never have a serious medical complication of the disorder. Lifespan is probably reduced by 10 to 15 years in comparison to the general population, with malignancy as the most common cause of death.

What causes this disease and how frequent is it?

NF1 is an autosomal dominant genetic disease without specific racial or gender predilection. The locus for NF1 is 17q11.2. The NF1 gene has a very high rate of spontaneous mutation, resulting in 50% of cases arising de novo. There is essentially 100% penetrance but wide phenotypic variability. The factors modulating phenotypic variability are not well understood but likely represent both genetic and environmental factors. There is poor genotype-phenotype correlation. NF1 is fairly common with an incidence of about 1 in 3500. Genetic mosaicism can occur.

How do these pathogens/genes/exposures cause the disease?

Mutations in the NF1 gene result in loss of function of neurofibromin, a GTPase-activating protein (GAP) that helps maintain the proto-oncogene ras in an inactive form. Loss of neurofibromin results in increased ras activity leading to increased cell proliferation and tumorigenesis.

Other clinical manifestations that might help with diagnosis and management

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What complications might you expect from the disease or treatment of the disease?

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Are additional laboratory studies available; even some that are not widely available?

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How can neurofibromatosis type 1 be prevented?

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What is the evidence?

DeBella, K, Szudek, J, Friedman, JM. “Use of the National Institutes of Health Criteria for diagnosis of neurofibromatosis 1 in children”. Pediatrics. vol. 105. 2000. pp. 608-614. (The authors retrospectively analyzed clinical data of 1803 NF1 patients under 21 to assess the value of the NIH Diagnostic Criteria for NF1 in early childhood, to determine the age at which diagnosis can confidently be made, and to clarify the age at onset of the cardinal clinical features used in the NIH Diagnostic Criteria.)

Listernick, R, Ferner, RE, Liu, GT, Gutmann, DH. “Optic pathway gliomas in neurofibromatosis-1: Controversies and recommendations”. Annals of Neurology. vol. 61. 2007. pp. 189-198. (Reviews epidemiology, pathogenesis and clinical features of OPG in children with NF1, and reviews current evidence for OPG screening, monitoring and management.)

Hersh, JH. “Health supervision for children with neurofibromatosis”. Pediatrics. vol. 121. 2008 Mar. pp. 633-42. (In addition to reviewing diagnostic criteria and clinical manifestations of NF1, delineates current surveillance and management guidelines for health supervision of individuals with NF1.)

Shah, KN. “The diagnostic and clinical significance of café-au-lait macules”. Pediatr Clin North Am. vol. 57. 2010 Oct. pp. 1131-53. (A review of disorders that should be considered in the differential diagnosis of patients with CALs, including NF1.)

Brems, H, Beert, E, de Ravel, T, Legius, E. “Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1”. Lancet Oncol. vol. 10. 2009 May. pp. 508-15.

Ongoing controversies regarding etiology, diagnosis, treatment

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