Oct. 24, 2017
Intraneural perineuriomas are benign peripheral nerve sheath tumors that cause progressive and debilitating focal extremity weakness. They occur most commonly in young patients, and no therapeutic options exist. The etiology of these tumors, which don't metastasize outside peripheral nerves, has remained largely unknown.
Typical histology and gene discovery in intraneural perineurioma
A-C. Typical histology and gene discovery in intraneural perineurioma. Illustrative case (A) epoxy section at similar level and magnification as shown in paraffin preparations with pseudo-onion bulb formations around occasionally seen thin myelinated fibers with (B) Schwann cell preparation (S-100) demonstrating sparse reactivity of the Schwann cells at the center and (C) prominent epithelial membrane antigen (EMA)-reactive staining of the leaflets of the pseudo-onion bulbs. D. Functional domains and location of recurrent TRAF7 mutations. The WD40 domain is the region with identified mutations in meningiomas. E. Rainbow cartoon representation of a model of TRAF7 WD40 domain structure. The three residues mutated in intraneural perineuriomas are highlighted as gray spheres and cluster together on the protein predicted to interfere with TRAF7 interaction with other proteins or to cause instability of the WD40 domain or both. F. TRAF7 immunoreactivity in perineurioma occurs in the same areas that reacted to EMA. Image reprinted with permission from Annals of Neurology.
Researchers at Mayo Clinic in Rochester, Minnesota, have identified a common cause for intraneural perineuriomas and an unexpected shared pathogenesis with intracranial meningiomas. As described in the February 2017 issue of Annals of Neurology, the researchers discovered three novel recurrent mutations in the WD40 domain of the TRAF7 protein TRAF7 mutations also frequently occur as a genetic cause of meningioma, the most common primary brain tumor.
"The fact that meningiomas and perineuriomas share the same mutation supports a hypothesis that both tumors originate from the same cell. The meninges are probably embryologically related to the lining of nerve fascicles," says Christopher J. Klein, M.D., a consultant in Neurology at Mayo Clinic's campus in Minnesota. "That is a true neuroscience breakthrough."
The discovery also indicates a pathway for potential treatments. "Understanding the pathogenesis of these tumors is critical to finding novel therapies," says Michelle L. Mauermann, M.D., a consultant in Neurology at Mayo Clinic's campus in Minnesota. "Intraneural perineuriomas can't be resected because they are entwined in the nerve. For patients, at this time, we use rehabilitation and bracing to try to preserve function, and consider tendon transfers when weakness progresses."
Rare and debilitating
Intraneural perineuriomas can be overlooked or mistaken for other conditions. "They are quite rare, so most neurologists and neurosurgeons will never see a case or, if they do, may not recognize it," Dr. Mauermann says.
Patients with intraneural perineuriomas might be diagnosed with other nerve sheath tumors, such as neurofibromas, schwannomas or malignancies — resulting in resection or repeated biopsies that further damage patients' nerves. Rarely, patients are diagnosed with autoimmune problems and given unnecessary immunotherapy. In very young patients, weakness might be attributed to birth trauma or a perinatal stroke.
Although the tumors are most common in childhood and early adulthood, Mayo Clinic neurologists have seen patients with disease onset occurring after age 50. Insidious, gradual onset of progressive mononeuropathy is typical; areas of nerves, such as the brachial plexus or lumbosacral plexus, are sometimes involved.
Feet demonstrating atrophy and inversion of the affected foot
Photograph of the feet of a 7-year-old boy demonstrating atrophy and inversion of the affected foot due to chronic sciatic neuropathy (arrow). B. Intraoperative photograph demonstrates focal fusion enlargement (arrow) of the tibial division (asterisk) of the sciatic nerve. Reprinted with permission from Brain.
The sciatic nerve is the most common tumor site. "Most patients have a foot drop, which requires them to wear an ankle foot orthosis that limits their ability to be active," Dr. Mauermann says. Patients might also have radial nerve involvement, resulting in wrist drop or finger drop that limits hand function.
"It often takes years for the patient to recognize the weakness. But it can progress to the point where it causes atrophy and disability," Dr. Mauermann says. "There is often sensory involvement, but it's overshadowed by the motor issues. This significantly affects the life of an active young person."
Serendipity and hard work
The identification of TRAF7 mutations in patients with intraneural perineuriomas required advances in technology and expertise from multiple Mayo Clinic specialists. As a major clinical, research and academic center, Mayo Clinic has the resources for this complex work.
Mayo Clinic radiologists and medical physicists worked together to develop novel 3-tesla MRI imaging techniques for imaging patients with suspected perineurioma. This led to elucidation of the condition's typical radiologic features. "Because of this we have been able to identify lesions that may have been overlooked in the past," Dr. Mauermann says.
Previous studies had linked intraneural perineuriomas to chromosome 22 mutations. Initially, the Mayo Clinic researchers used fluorescence in situ hybridization (FISH) to investigate that linkage. "But FISH just didn't have the sensitivity we needed," Dr. Klein says.
Eventually, the researchers were able to use whole-exome sequencing, a newly determined copy number algorithm developed at Mayo Clinic, and high-resolution whole-genome microarray. Those studies revealed large abnormalities in multiple chromosomes, including chromosome 22, in two of the 16 tumor cases studied. However, 10 of the 16 tumor cases (62.5 percent) had the TRAF7 mutations.
"Whole-exome sequencing allows us to see as few as 10 base-pair deletions. As a result, we found that the majority of these tumors are caused not by a large deletion but by a point mutation," Dr. Klein says. "We never expected that. It was serendipity and the result of a lot of hard work."
TRAF7 ubiquitinates the tumor-suppressing p53 protein. Dr. Klein suggests that TRAF7 mutations may result in abnormal p53 lingering in nerves. "That might explain the formation of benign tumors," he says. "The tumor exists because p53 is a little abnormal, but the tumor is benign because p53 remains present."
As a circulating protein, p53 might also provide an avenue for treatment. "If we could modify a protein circulating through the blood vessels of the nerves, then we might have a meaningful therapy," Dr. Klein says.
The seeds of Mayo Clinic's identification of a cause for intraneural perineuriomas were planted decades ago, when Peter J. Dyck, M.D., a consultant in Neurology at Mayo Clinic's campus in Minnesota, created a frozen nerve tissue bank. Samples from that tissue bank were used in the genomics study.
"Dr. Dyck had the vision to save a tiny portion of every nerve tissue biopsy under liquid nitrogen for research," Dr. Klein says. "Without this precious material we would not have been able to do this study."
"Mayo Clinic is unique. We bring to this work expertise in the neurosciences and radiology, the skill of neurosurgeons who can biopsy these tumors, and a strong patient base," Dr. Mauermann adds. "People here are driven to push the science forward."
For more information
Klein CJ, et al. Genomic analysis reveals frequent TRAF7 mutations in intraneural perineuromas. Annals of Neurology. 2017;81:316.
Mauermann ML, et al. Longitudinal study of intraneural perineurioma — A benign, focal hypertrophic neuropathy of youth. Brain. 2009;132:2265.