Introduction
Background
Neurofibromatosis (NF) is an autosomal dominant disorder, probably of neural crest origin, that affects all 3 germinal layers; therefore, it can involve any organ system. NF is not a single entity but a group of heterogeneous multisystemic neurocutaneous disorders involving both neuroectodermal and mesenchymal derivatives. Although 8 subtypes have been proposed to date, the National Institutes of Health (NIH) Consensus Development Conference has defined 2 distinct types: neurofibromatosis type 1 (NF1), or von Recklinghausen disease, which affects 85% of patients, and neurofibromatosis type 2 (NF2), or bilateral acoustic neuromas/vestibular schwannomas, which affects 10% of patients.1,2,3,4,5,6,7,8,9,10
Neurofibromas may affect any organ in the body. Discrete cutaneous and subcutaneous neurofibromas may develop at any time in life, but they occur infrequently before puberty. The total number of neurofibromas seen in adults with NF1 varies from a few to hundreds or even thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year.
Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Although the course of the pregnancy is normal in most women with NF1, serious complications can occur. Hypertension may first become symptomatic or, if preexisting, may become greatly exacerbated during pregnancy. Large pelvic or genital neurofibromas can complicate delivery, and cesarean delivery appears to be necessary more often in women with NF1 than in other women.11
Hypertension is frequent in patients with NF1 and may develop at any age. In most patients, the hypertension is essential, but vascular dysplasia can occur in association with NF1 and may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with severe hypertension in adult patients with NF1.1,9,12,13 Pheochromocytoma can cause severe hypertension in patients with NF1. Malignant neoplasms can occur in patients with NF1 at any age.
Intracranial manifestations of NF1 include development of optic pathway gliomas, cerebral gliomas, hydrocephalus, schwannomas of the cranial nerves, vascular dysplasias, hamartomas, craniofacial plexiform neurofibromas, and spongiotic myelinopathy. NF1 can involve the spine, musculoskeletal system, and the gastrointestinal (GI) tract,14,15,16 and NF1 is associated with neural crest tumors.17
Multisystemic involvement is common, and a variety of problems may present in childhood,18 including seizures and intellectual compromise, optic and acoustic involvement, intracranial and spinal tumors, and an increased incidence of malignancies, osseous defects and congenital dislocations, oral pathology, endocrine disorders, autonomic involvement, GI tract involvement, hypertension, and vascular anomalies.
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Pathophysiology
The NIH has developed criteria for the diagnosis of NF1 and NF2.5 The criteriafor the diagnosis of NF1 are met in an individual if 2 or more of the following signs are found:
- Six or more café au lait macules larger than 5 mm in the greatest diameter in prepubertal children and larger than 1.5 cm in postpubertal individuals
- Two or more neurofibromas of any type or 1 plexiform neurofibroma
- Multiple freckles (Crowe sign) in the axillary or inguinal region
- A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long bone cortex, with or without pseudoarthrosis
- Optic glioma
- Two or more iris hamartomas (Lisch nodules) seen on slitlamp or biomicroscopy examination
- A first-degree relative (parent, sibling, offspring) with NF1, as diagnosed by using the above criteria.
However, the NIH criteria are often insufficient for diagnosis of NF1 in young children who have multiple café au lait spots, no other NF1 features, and no family history of NF1. The overwhelming majority of these children later are diagnosed with NF1 because many of the features are rare in infancy but increase in frequency with age.
Children who have inherited NF1 from an affected parent can usually be identified within the first year of life because the diagnostic criteria require just 1 feature in addition to a family history for NF1. This feature is usually multiple café au lait spots, which are present in infancy in more than 95% of patients with NF1. Development of multiple café au lait spots in a child with no family history without NF1 is insufficient to establish a diagnosis of NF1 if no other signs of the disease are present, although NF1 should be strongly suspected in these children, and they should receive clinical follow-up monitoring.19
A definite diagnosis of NF1 can be made in most children by age 4 years by using the NIH criteria. Various manifestations of NF1 appear at different characteristic times. For example, bone manifestations, such as cortical thinning, are congenital. Café au lait spots are often present at birth and increase in number during the first few years of life. Diffuse plexiform neurofibromas of the face and neck rarely appear after age 1 year, and plexiform neurofibromas of other parts of the body rarely develop after adolescence.
Optic gliomas develop during the first 4 years of life. Optic glioma is the most common intracranial tumor associated with NF1. It occurs in 12% of patients and is bilateral in 4%; 75% of optic gliomas occur in the first decade of life. The tumor spreads to the optic chiasm (in 25% of patients), optic tracts, and optic radiation. Malignant peripheral nerve sheath tumors (neurofibrosarcomas) usually occur in adolescents and adults.20
Abdominal involvement in patients with NF1 has been described, including neurofibromas within the liver, mesentery, retroperitoneum, and GI tract. Large-bowel intussusception has been reported. Small-bowel leiomyomas, adenocarcinomas with neuroendocrine function, GI tract vasculopathy, GI tract bleeding, pseudo-obstruction, and protein-losing enteropathy also may occur.8,14,15,16,21
Neurofibromas arise within or are attached to nerve trunks anywhere in the skin, as well as any conceivable internal site, including intracranial and intraspinal locations. Histologically, neurofibromas comprise all the components of the peripheral nerves, including fibroblasts, Schwann cells, and neurites. These cells are distributed in a loose myxoid stroma in which Schwann cells predominate with their elongated serpentine structure and their slender spindle-shaped nuclei. Neurofibromas in NF1 may undergo malignant degeneration in 3% of patients. Schwannomas are composed entirely of Schwann cells, and malignant transformation is extremely rare; however, when it occurs, it is associated with von Recklinghausen disease in 75% of patients.22
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Frequency
United States
NF1 is one of the most common autosomal dominant genetic disorders, with an incidence of 1 case per 3000-4000 people. One half of cases are caused by new mutations. The mutation rate in the NF1 gene (1 case per 10,000 population) is among the highest known for any human gene. The cause of the unusually high mutation rate in NF1 is unknown. In familial cases, expressivity of the disorder is variable, but the penetrance is 100%.20
International
International frequency of NF1 appears to be the same as in the United States.
Mortality/Morbidity
Mean and median ages at death in patients with NF1 are 54.4 and 59 years, respectively, as compared with 70.1 and 74 years in the general US population. Results of proportionate mortality ratio analysis show that persons with NF1 are 34 times more likely to have a malignant connective or other soft-tissue neoplasm listed on the death certificate. Similarly, vascular disease is recorded more often on the death certificates of patients younger than 30 years with NF1 as compared with the general population. Malignant transformation of neurofibromas and schwannomas occurs in 3-15% of patients with NF1.23
Age
Children who have inherited the NF1 gene from an affected parent can usually be identified within the first year of life because the diagnosis requires the presence of only 1 feature in addition to a family history for NF1. The manifestations of NF1 appear at characteristic times. Bone manifestations (eg, cortical thinning) are congenital. Café au lait spots often are present at birth and increase in number during the first few years of life. Diffuse plexiform neurofibromas of the face and neck rarely appear in children older than 1 year, and plexiform neurofibromas of other parts of the body rarely develop after adolescence. Optic gliomas develop in children as old as 4 years. Other malignant tumors may develop at any point in life.
Presentation
NF1 is a multisystemic disorder that may affect any organ in the body. Clinical presentation depends on the body system involved.
Skin
Discrete cutaneous and subcutaneous neurofibromas may develop at any time but are infrequent before puberty. Total numbers of cutaneous and subcutaneous neurofibromas seen in adults vary from a few to thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy. Other cutaneous lesions include café au lait spots, elephantoid overgrowth of skin and subcutaneous tissue, breast enlargement, and other cutaneous lesions, such as hemangiomas, xanthogranulomas, red-blue macules, giant hairy nevi, and depigmented macules.24
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GI tract
GI tract involvement includes neurofibromas within the liver, mesentery, retroperitoneum, large bowel (with possible intussusception), rectum, and jejunum, as well as small-bowel leiomyomas, small-bowel adenocarcinoma with neuroendocrine function, GI tract vasculopathy and bleeding, pseudo-obstruction, and protein-losing enteropathy. Patients may present with abdominal pain, nausea, abdominal distention, diarrhea, constipation, bowel perforation, or GI tract bleeding.14,15,16,21,25
Cardiovascular system
Hypertension is frequent in NF1 and may develop at any age. In most patients, the hypertension is essential, but vascular dysplasia can occur in NF1, which may produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with hypertension. Pheochromocytoma can cause severe hypertension in adult patients with NF1. Other cardiovascular abnormalities that have been reported in patients with NF1 include congenital heart defects (with a 10-fold increase in pulmonary valve stenosis, atrial septal defect, and ventricular septal defect).9,12,13
Further abnormalities reported include complete heart block, aortic coarctation, regressive cardiomyopathy in infancy, idiopathic hypertrophic subaortic stenosis, coronary heart disease associated with myocardial infarction or coronary artery spasm, and intestinal angina due to compression of GI blood supply by a neurofibroma.
Musculoskeletal system
Spinal rotational anomalies can include kyphoscoliosis, bowed legs, skull defects and anomalies of skull shape, pulsating or nonpulsating exophthalmos, orbital displacement, edema of the eyelids, ptosis, macrodactyly, postaxial polydactyly, and thoracic cage deformities, such as pectus excavatum and pseudoarthrosis of bones.
Endocrine and metabolic functions
Hyperparathyroidism, multiple endocrine adenomatosis type 2B (also termed multiple endocrine neoplasia type 2B [MEN 2B], pheochromocytoma, medullary carcinoma of the thyroid and multiple neuromas, sexual precocity, gigantism, osteomalacia/rickets, hypoglycemia, hypertrophy of the clitoris or labia or penis, irregular menses, infertility, ovarian cysts, early menopause, or hyperprolactinemia may occur.
Central nervous system, eye, and otologic functions
Learning disabilities, behavioral disorders, seizures, mental retardation, hyperactivity, moyamoya phenomenon, childhood hypertensive strokes, eyelid neurofibromas, congenital glaucoma, buphthalmos, retinal detachment, retinal phakoma,26 hypertelorism, abnormal hearing, and neurofibromas of the external and middle ears may occur.
Associated neoplasms
MEN 2B, optic pathway glioma, cerebral glioma, CNS hamartomas, small-bowel leiomyoma/leiomyosarcoma, meningiomas (intracranial and spinal), sarcomas, various types of carcinomas, leukemia, lymphoma, melanoma, pheochromocytoma, neuroblastoma, nonossifying fibromas, adrenal cortical adenomas, and sarcomatous changes in a neurofibroma may occur.
Preferred Examination
The preferred examination depends on the clinical problem to be investigated and the organ involved. Although plain radiographs may be sufficient for evaluating skeletal lesions, sonography and MRI may be the investigation of choice for peripheral nerve tumors and tumors of solid intra-abdominal organs or for associated renal artery stenosis. CT and MRI are preferred with spinal or intracranial lesions. Radionuclide scans are useful when functional imaging is needed in associated tumors such as a pheochromocytoma.16,27,28,29,30
Limitations of Techniques
Limitations depend on the organ being investigated and the suspected pathology. Plain radiographs are excellent at showing skeletal abnormalities of both the axial and appendicular skeleton. Similarly, chest radiography remains a useful technique for demonstrating thoracic cage abnormalities and pulmonary fibrosis. For intracranial, intrathoracic, or intra-abdominal pathology, cross-sectional imaging is more appropriate, and the modality chosen is tailored to the problem.
Differential Diagnoses
Other Problems to Be Considered
Neurofibromatosis type 2 - Bilateral acoustic neuromas, first-degree relatives with unilateral acoustic neuroma, neurofibroma, meningioma, and glioma, schwannoma, and juvenile posterior subcapsular lenticular opacity
Neurofibromatosis–Noonan syndrome - NF1 with some associated features of Noonan syndrome
Proteus syndrome - Congenital neurocutaneous disorder associated with thickening of palms and soles, hyperkeratosis, lipomas (subcutaneous and abdominal), hamartomas, hemangiomas, and lymphangiomas
Jaffe-Campanacci syndrome - Café au lait spots, mental retardation, hypogonadism, precocious puberty, disseminated nonossifying fibromas, fractures, and kyphoscoliosis
Multiple endocrine neoplasia 2B - Multiple mucosal neuromas, pheochromocytoma, and ganglioneuromatosis
Klippel-Trenaunay syndrome - Port-wine stains, elongation and widening of the bones of a limb (with limb hemihypertrophy), cortical thickening, and various vascular anomalies
Bannayan-Riley-Ruvalcaba syndrome - Macrocephaly, mesodermal and hamartomatous tumors (subcutaneous, intracranial, visceral, intestinal, skeletal thoracic)
McCune-Albright syndrome - Patchy cutaneous pigmentation, sexual precocity, and polyostotic fibrous dysplasia
Hemihypertrophy - Range of asymmetry from enlargement of 1 digit to an entire half of the body associated with skin abnormalities and hamartomatous lesions
Autosomal dominant familial angiolipomatosis - Large subcutaneous angiolipomata
Watson syndrome - Characteristic facies, extensive skeletal abnormalities, congenital heart disease, liver and biliary tree anomalies, and renal function anomalies
Elephant man - Definite diagnosis not yet established for this patient, but NF1 and Proteus syndrome are possibilities
Hip dislocations
Moyamoya disease
Polyostotic fibrous dysplasia (PFD)- Café-au-lait spots occur in 50% of patients, particularly in those patients who also have endocrinopathy. The café-au-lait spots in PFD typically have irregular borders ("coast of Main" lesions), whereas the café-au-lait spots in NF1 have smooth, well-defined borders ("coast of California" lesions). Café-au-lait spots in PFD are also darker and fewer in number.31
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Further Reading
Keywords
NF, NF1, NF-1, von Recklinghausen disease, von Recklinghausen syndrome, von Recklinghausen's disease, von Recklinghausen's syndrome, elephant man, nerve sheath tumor, neurofibromas
