Inside and Out

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Posted by Carla Rothaus

What are some of the features of the vasculopathy that can occur in patients with neurofibromatosis type 1?

A diagnosis of neurofibromatosis type 1 can be established purely on clinical grounds, with high specificity, when at least two conditions of National Institutes of Health consensus criteria are met. Read the NEJM Clinical Problem-Solving Article here.

Clinical Pearls

Q: How prevalent is neurofibromatosis type 1?

A: Neurofibromatosis type 1 is a common autosomal dominant disorder, with a prevalence of 1 in 3000 persons, that arises from a heterozygous germline deletion or loss-of-function mutation in the tumor-suppressor gene NF1, followed by a loss of heterozygosity or a second-hit somatic mutation in the remaining wild-type allele. Although cutaneous features typically appear in childhood and adolescence, penetrance even within a family can vary considerably; neurofibromas may be absent entirely. In some patients, neurofibromatosis type 1 is diagnosed in adulthood only when a complication of the disorder manifests. 

Q: Patients with neurofibromatosis type 1 have a heightened risk of what complications?

A: As with other inherited diseases of tumor-suppressor genes, neurofibromatosis type 1 is associated with increased susceptibility to the development of benign and malignant tumors, particularly nerve-sheath tumors. Affected persons also have a heightened risk of vascular abnormalities and valvular heart disease. Neurofibromin, the protein encoded by NF1, acts as a Ras guanosine triphosphatase (GTPase)–activating protein and inactivates the proto-oncogene Ras by accelerating conversion into its inactive form. Several lines of evidence support a link between neurofibromin function and vasculopathy.


Morning Report Questions

Q: What are some of the features of the vasculopathy that can occur in patients with neurofibromatosis type 1?

A: Neurofibromatosis type 1 vasculopathy can manifest as stenosis, spontaneous dissection, vasospasm, thrombosis, or aneurysms. It commonly involves the medium and large elastic arteries with proliferation of fusiform vascular smooth-muscle cells, and may affect the aorta and the renal, mesenteric, carotid, vertebral, and coronary arteries. Although the cardiac manifestations are not widely recognized, more than a dozen reports describe coronary-artery aneurysms in association with neurofibromatosis type 1, in some cases leading to myocardial infarction or sudden cardiac death. The average life expectancy of patients with neurofibromatosis type 1 is reduced by 8 to 15 years owing to the development of cancer or cardiovascular complications.

Q: What screening tests are recommended for adults with neurofibromatosis type 1?

A: Professional guidelines provide recommendations for imaging for cancers or high-risk lesions in adults with neurofibromatosis type 1. Malignant peripheral nerve-sheath tumors frequently arise from preexisting plexiform neurofibromas, metastasize early, and are associated with high mortality. Imaging is recommended when there is clinical suspicion of such tumors (e.g., new or worsening pain), but consensus is lacking regarding the screening of asymptomatic persons with whole-body MRI. Given that neurofibromatosis type 1 is associated with an increased risk of breast cancer, the National Comprehensive Cancer Network recommends annual mammography starting at 30 years of age, with consideration of contrast-enhanced MRI between 30 and 50 years of age. Blood-pressure monitoring is recommended; new hypertension warrants evaluation for renal-artery stenosis and pheochromocytoma. It is important that genetic counseling be offered to patients with neurofibromatosis type 1 and their relatives. Genetic testing is particularly useful for persons with an unusual or incomplete clinical phenotype and can be used in prenatal screening or in preimplantation genetic diagnosis.

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