Neurofibromatosis type 1 is a systemic disorder primarily affecting the skin, bones, and central nervous system, with an estimated prevalence ranging from 1 to 10 in 10,000.1–4 It is inherited in an autosomal dominant fashion with high penetrance and variable expressivity. The NF1 gene, located on chromosome 17, encodes the protein neurofibromin, which acts as a negative regulator of the Ras proto-oncogene with a role in tumor suppression.5 A diagnosis of neurofibromatosis type 1 is made, based on the National Institutes of Health (NIH) diagnostic criteria,6 when an individual has two of the following clinical features: (1) café-au-lait spots; (2) intertriginous freckling; (3) Lisch nodules; (4) neurofibromas; (5) optic pathway gliomas; (6) distinctive bony lesions; and (7) a first-degree relative with neurofibromatosis type 1.
Although the ocular and non-ocular manifestations of neurofibromatosis type 1 are well known, epidemiologic reports are rare. The goals of this study were to identify the incidence and de novo mutation rate of neurofibromatosis type 1 and to describe the ocular and non-ocular findings in a population-based cohort of patients diagnosed over a 30-year period.
Patients and Methods
The medical records of all patients diagnosed as having neurofibromatosis type 1 from January 1, 1980, through December 31, 2009, while residing in Olmsted County, Minnesota, were retrospectively reviewed. Institutional review board approval was obtained from the Mayo Clinic and Olmsted Medical Group, and all data were collected in a manner compliant with the Health Insurance Portability and Accountability Act. Potential cases were identified by the use of the resources of the Rochester Epidemiology Project, a medical linkage system designed to capture data in any patient–physician encounter in Olmsted County. The population of Olmsted County is relatively isolated from other urban areas, and almost all medical care is provided to its residents by the Mayo Clinic, Olmsted Medical Group, and their affiliated hospitals.
A list of potential cases from both institutions generated by a comprehensive diagnostic code search identified 217 cases. The codes searched included ICD-9 diagnosis code range of 237.70 to 237.79 where available, along with a Mayo Clinic–specific coding system (HIDA) for the earlier period when ICD-9 was not available. Each record was meticulously reviewed by an ophthalmologist to confirm the diagnosis based on the NIH diagnostic criteria.6 Patients were excluded if they were diagnosed outside the study period, were diagnosed while not residing in Olmsted County, or did not meet the NIH diagnostic criteria. Patients who met NIH diagnostic criteria but had negative genetic testing were included unless they had features more consistent with Legius syndrome.
Data from the medical records were reviewed through December 31, 2015, to allow 5 years or more of follow-up. To determine the incidence of neurofibromatosis type 1 in Olmsted County, annual age- and sex-specific incidence rates were constructed using the age- and sex-specific population figures for this county from the U.S. Census. The de novo mutation rate was calculated using the number of individuals who did not have a parent diagnosed as having neurofibromatosis type 1.
A total of 50 residents of Olmsted County were diagnosed as having neurofibromatosis type 1 during the 30-year study period, yielding an annual incidence of 1.2 per 100,000 individuals (95% confidence interval [CI]: 0.8 to 1.5). The estimated prevalence rate of neurofibromatosis type 1 in this population was 0.10% over the 30-year period. The mean age at diagnosis was 11.7 years (range: 0.2 to 47 years), with 36 (72.0%) diagnosed before the age of 18 years. Twenty-six (52%) of the study patients were male. Twenty-two (44%) had a positive family history of neurofibromatosis type 1 in either parent, yielding a de novo mutation rate of 56%. Only 8 patients underwent genetic testing, which was positive in 6 (12%) and negative in 2 (4%).
The initial and final features of neurofibromatosis type 1 observed in this cohort of 50 patients are shown in Table 1. The patients were observed for a mean duration of 9.8 years (range: 3 weeks to 32 years) to a mean age of 21.6 years (range: 0.3 to 66.2 years). Café-au-lait macules were ultimately observed in all but 1 (98%) patient, and 37 (74.0%) had freckling of the axillary and inguinal regions. Skeletal anomalies were present in 15 (30%) patients and neurofibromas in 23 (46%) patients, the most common type of which were discrete cutaneous neurofibromas in 17 (34%) patients. Plexiform neurofibromas were present in only 8 (16%) patients.
Initial and Final Clinical Features Observed in 50 Patients With Neurofibromatosis Type 1 From 1980 Through 2009 in Olmsted County, Minnesota
Forty-seven (94%) patients underwent an ophthalmic examination at a mean age of 12.3 years (range: 3 months to 54 years). The most common ophthalmic feature was Lisch nodules observed in 26 (52.0%) patients, of which 22 occurred bilaterally. Only 1 (2%) patient (95% CI: 0.1% to 10.7%) developed an optic nerve glioma, diagnosed at the age of 26 years. None of the patients were found to have an eyelid neurofibroma, other orbital tumors, retinal astrocytoma, choroidal nevus, or melanoma. Other reported ophthalmic features included strabismus in 2 patients, amblyopia in 1 patient, and congenital hypertrophy of the retinal pigment epithelium in 1 patient.
Central nervous system gliomas were diagnosed in 3 (6%) patients: 1 patient had a brainstem glioma diagnosed at the age of 8 years, which was 7 years following her diagnosis of neurofibromatosis type 1; a second had an optic nerve glioma diagnosed at the age of 26 years, which was 5 years following her diagnosis of neurofibromatosis type 1; and a third patient had a cerebellar glioma diagnosed at the age of 5 years, which was 4 years following the diagnosis of neurofibromatosis type 1, in addition to an intracranial fibromyxosarcoma diagnosed at the age of 17 years. Only 1 (2%) patient developed malignant nerve sheath tumors, located in both his abdomen and axilla at the age of 18 years. Among all 50 patients, 1 patient developed leukemia and died at the age of 3 years.
Neurofibromatosis type 1 was diagnosed in 50 patients during the 30-year period, yielding an incidence rate of 1.2 per 100,000 individuals. Approximately half of the patients in this cohort were de novo mutations. Most patients were diagnosed in childhood and café-au-lait macules and axillary and inguinal freckling were the most prevalent presenting features. During a mean follow-up of approximately 10 years, 6 patients developed different forms of malignancy, including 1 (2%) patient with an optic nerve glioma and 2 patients with gliomas elsewhere in the brain, 1 patient with malignant nerve sheath tumor, and 1 patient with leukemia.
Neurofibromatosis type 1 is a dominantly inherited disease with high penetrance and variable expression that is caused by a germline mutation of the NF1 gene, which encodes the protein neurofibromin, a regulator of the Ras proto-oncogene.5,7 Approximately half of affected individuals in this cohort developed de novo mutations, consistent with one prior report.8 Although 2 of the 8 genetically tested individuals were negative for neurofibromatosis type 1, they were included in this cohort because current multistep mutation detection protocols can identify more than 95% of pathogenic neurofibromatosis type 1 mutations in individuals fulfilling the NIH diagnostic criteria.9 The estimated prevalence of neurofibromatosis type 1 in this population of 1 in 1,000 is consistent with prior reports, which range from 1 to 10 in 10,000.1–3
Patients with neurofibromatosis are at increased risk of various benign and malignant neoplasms.10,11 The most common benign tumor is cutaneous neurofibroma, which typically occurs in late childhood or early adolescence.12 Approximately one-third of the patients in this study developed cutaneous neurofibromas by a mean age of 21.5 years at their last follow-up examination. Plexiform neurofibromas are reported to occur in 30% of patients, and first appear either at birth or in early childhood.13 In this study, they occurred in only 1 in 5 patients. The second most prevalent tumors in individuals with neurofibromatosis type 1 are low-grade glial neoplasms or gliomas. The lifetime risk of developing a glioma in an individual with neurofibromatosis type 1 is estimated to be 15% to 20%.14 They typically occur in young children and are often asymptomatic.15 They more commonly develop in the optic pathway, but can also develop along the brainstem and rarely in the cerebellum, cortex, and subcortical regions. Three (6%) patients in this cohort had a documented low-grade glioma, only 1 (2%) of which occurred in the optic pathway. The low rate of optic nerve gliomas in this cohort, although markedly lower than in the previous reports, appears sound given the study design, isolated population, and a mean follow-up of 10 years. Prior studies with higher rates of optic nerve gliomas may be, in part, due to referral biases of tertiary care referral centers.16,17 However, the rate in this cohort may be an underestimate if some affected individuals remained asymptomatic and avoided central nervous system imaging or sought their diagnosis and care elsewhere.
Malignant nerve sheath tumors are the most common malignant tumors observed in neurofibromatosis.18–20 Their prevalence in patients with neurofibromatosis type 1 is estimated to occur in 2% to 29% in contrast to 0.001% in the general population.21,22 They commonly arise from preexisting plexiform neurofibromas, and typically occur in adults in the third to fourth decade of life, a decade or more earlier than sporadic cases.21 Consistent with prior reports,21,23 only 1 (2%) patient in this cohort had a documented malignant nerve sheath tumor even though the mean age at the last follow-up was only 21.8 years. Other malignancies, such as breast adenocarcinoma24 and leukemia,25 were not as common in this cohort as they were in previous studies.
There are several limitations to the findings of this study. Its retrospective design is limited by incomplete data and an evolving understanding of neurofibromatosis and its clinical manifestations. This experience is reflected in the fact that some patients went undiagnosed until an older age even though they possessed enough diagnostic criteria to be diagnosed at a much younger age. Some of the patients may have sought care outside Olmsted County, thereby decreasing the true incidence in this population. The de novo mutation rate might also be an underestimate given the variable expressivity of the disease and the fact that the majority of parents were not genetically tested to confirm whether or not they have the disease. Furthermore, the rate of optic nerve glioma may have been underestimated because there is not enough data on which of those received surveillance in the form of brain imaging. Finally, this cohort is also limited by occurring in a relatively homogenous white population, making extrapolation to other populations problematic.
Although the estimated prevalence and de novo mutation rate of neurofibromatosis type 1 in this population-based study are similar to previous reports, the prevalence of optic nerve gliomas was much lower.
- Samuelsson B, Axelsson R. Neurofibromatosis: a clinical and genetic study of 96 cases in Gothenburg, Sweden. Acta Derm Venereol Suppl (Stockh). 1981;95:67–71.
- Huson SM, Compston DA, Clark P, Harper PS. A genetic study of von Recklinghausen neurofibromatosis in south east Wales: I. Prevalence, fitness, mutation rate, and effect of parental transmission on severity. J Med Genet. 1989;26:704–711. doi:10.1136/jmg.26.11.704 [CrossRef]
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- Friedman JM. Epidemiology of neurofibromatosis type 1. Am J Med Genet. 1999;89:1–6. doi:10.1002/(SICI)1096-8628(19990326)89:1<1::AID-AJMG3>3.0.CO;2-8 [CrossRef]
- Brems H, Beert E, de Ravel T, Legius E. Mechanisms in the pathogenesis of malignant tumours in neurofibromatosis type 1. Lancet Oncol. 2009;10:508–515. doi:10.1016/S1470-2045(09)70033-6 [CrossRef]
- National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. . Bethesda, Md., USA. , July 13–15, 1987. . Neurofibromatosis. 1988;1:172–178.
- Dilworth JT, Kraniak JM, Wojtkowiak JW, et al. Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochem Pharmacol. 2006;72:1485–1492. doi:10.1016/j.bcp.2006.04.010 [CrossRef]
- Friedman JM. Neurofibromatosis 1. In: Pagon RA, Adam MP, Ardinger HH, , eds. GeneReviews. Seattle, WA: University of Washington, Seattle; 1993–2019. http://www.ncbi.nlm.nih.gov/books/NBK1109/.
- Wimmer K, Yao S, Claes K, et al. Spectrum of single- and multi-exon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006;45:265–276. doi:10.1002/gcc.20289 [CrossRef]
- Walker L, Thompson D, Easton D, et al. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. 2006;95:233–238. doi:10.1038/sj.bjc.6603227 [CrossRef]
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- Listernick R, Louis DN, Packer RJ, Gutmann DH. Optic pathway gliomas in children with neurofibromatosis 1: consensus statement from the NF1 Optic Pathway Glioma Task Force. Ann Neurol. 1997;41:143–149. doi:10.1002/ana.410410204 [CrossRef]
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Initial and Final Clinical Features Observed in 50 Patients With Neurofibromatosis Type 1 From 1980 Through 2009 in Olmsted County, Minnesota
|Feature||Initial No. (%)||Final No. (%)||Mean Age at Diagnosis (y), (Range)|
|Café-au-lait macules||48 (96%)||49 (98%)||10.5 (0.1 to 50.4)|
|Freckling of axillary or inguinal regions||32 (64%)||37 (74%)||12.4 (0.3 to 50.4)|
|Neurofibromas||15 (28%)||26 (52%)||21.3 (0.5 to 50.4)|
| Cutaneous||9 (18%)||17 (34%)||22.7 (1.8 to 43.6)|
| Plexiform||4 (8%)||8 (16%)||16.2 (0.5 to 35.2)|
| Not specified||4 (8%)||6 (12%)||24.1 (10.3 to 50.4)|
|Skeletal anomalies||6 (12%)||14 (28%)||13.6 (0.6 to 50.4)|
| Short stature||2 (4%)||4 (8%)||15.5 (1.7 to 50.4)|
| Macrocephaly||2 (4%)||4 (8%)||3.6 (1.6 to 4.6)|
| Scoliosis||2 (4%)||7 (14%)||16.8 (1.5 to 40.8)|
| Thinning of long bone cortex||1 (2%)||1 (2%)||0.6|
|CNS gliomas||0||3 (6%)||(4.9 to 26.0)|
| Optic pathway||0||1 (2%)||26.0|
| Others||0||2 (4%)||6.6 (4.9 to 8.2)|
|Lisch nodules||7 (14%)||26 (52%)||18 (1.4 to 54.2)|
|Seizure disorder||0||2 (4%)||–|
|Other tumors (breast Ca, leukemia)||0||2 (4%)||–|
|Coarctation of aorta||0||2 (4%)||–|