Posted December 1, 2020

Neurofibromatosis (NF) is a group of hereditary cancer syndromes where different gene mutations result in tumors developing in the central and peripheral nervous systems [1]. There are three different types of neurofibromatosis (NF1, NF2, and schwannomatosis), and each NF type has its own diagnostic criteria and clinical manifestations [1].

One important neurofibromatosis clinical manifestation is pain. For the past several years, the Neurofibromatosis Research Program (NFRP) has listed pain as an area of emphasis in its program funding opportunities, encouraging research applications aimed at addressing this critical need in the NF community.

Clinical presentation of pain is mainly associated with schwannomatosis. The predominant characteristic of both NF2 and schwannomatosis is the development of schwannomas, tumors in the Schwann cells wrapped around peripheral nerves. However, NF2 schwannomas are more commonly associated with neurological deficits. One retrospective study found that schwannomatosis patients’ most common symptom was chronic pain [1,2]. In addition, the 2011 International Schwannomatosis Workshop identified uncovering the mechanism of pain in schwannomatosis as a top research priority [3].

In fiscal year 2014 (FY14), the NRFP awarded funding to Dr. Larry Sherman at the Oregon Health and Science University to examine what role the SMARCB1 (also known as Snf5) gene plays in developing pain. Mutations in the SMARCB1 gene are linked to schwannomatosis [1]. Dr. Sherman’s research found that disrupting SMARCB1 in Schwann cells caused secretion of factors that increased expression of pain receptors, suggesting a mechanism for the prevalent pain found in schwannomatosis [4]. In FY09 and FY17, the NFRP awarded funds to Dr. Jeremie Vitte and Dr. Marco Giovannini at the University of California, Los Angeles to examine the role that SMARCB1, LZTR1, and NF2 genes play in the development of Schwann cell tumors. Mutations in the SMARCB1 and LZTR1 genes cause schwannomatosis, while mutations in the NF2 gene result in NF2. However, schwannomas developed in both conditions carry somatic NF2 mutations, thus underlying its crucial role in Schwann cell tumorigenesis [9]. Dr. Giovannini’s research is examining what roles SMARCB1, LZTR1, and NF2 genes play in the development of schwannomas and why mutations in SMARCB1 and LZTR1 possibly lead to painful schwannomas in schwannomatosis compared to NF2 mutation-driven schwannomas that are more likely to result in neurological deficits. This research is also developing novel model systems to examine what pain behaviors are associated with these gene disruptions and development of these tumors.

While chronic pain is a hallmark symptom of schwannomatosis, pain is found across all types of neurofibromatosis. However, its role has been understudied in NF1 [5]. Questionnaires have shown that NF1 patients across the world identify pain as majorly affecting their quality of life. At the 2017 International Neurofibromatosis Conference, Dr. Wolkenstein from Hôpital Henri‐Mondor in France commented on the significant impact that pain and itching from cutaneous neurofibromas have had on NF1 patients [5,4]. One recent study of the Washington University NF1 Patient Registry reported a higher incidence of pain interference and severity in NF1 patients than had been previously reported, emphasizing the need for the study of pain in this neurofibromatosis type [6]. Pain has also been shown to be a main interfering factor on quality of life in NF2 patients [7].

Pain is believed to be caused by the developing tumors within the peripheral and central nervous system, but the relationship is not always clear-cut, and the presence and intensity of pain does not always correlate with number, location, and size of tumors [3]. In fact, one study showed that 46% of a patient cohort had pain unassociated with a mass [2]. Treatment to help neurofibromatosis-related pain is primarily surgical resection of the painful tumor, but this can result in complications as tumors are near nerve tissues and vital structures. Patients’ have reported that chronic pain has persisted despite surgical intervention, and, in some cases, surgery has actually worsened their global pain symptoms [2,3]. Pain medication (i.e., opioids, over-the-counter medications) have not been shown to be highly effective at treating neurofibromatosis-associated pain [5,6]. Therefore, information collected from studies like those conducted by Dr. Sherman and Dr. Giovannini to uncover the unique mechanisms of neurofibromatosis pain is critical for development of alternative pain management therapies.

There are pain management options other than surgery or drug treatments. Behavioral therapy has been shown to help decrease pain severity and interference and reduce depression and anxiety in individuals. One study showed that complementary treatments (i.e., therapy, mindfulness, yoga, etc.) had a significant effect on pain ratings in NF1 patients [6]. In another study, a cohort of NF1/NF2 patients who reported high levels of pain interference in their quality of life also reported high levels of anxiety and depression, indicating that this type of approach could help [8,7]. In FY18, the NFRP awarded funding to Dr. Buono at Yale University to see if a complementary mind-body approach could help NF1 patients self-manage their pain. Using the iCanCope mobile application, Dr. Buono hopes to help NF1 patients better understand and identify their pain, which will help patients better communicate with their medical providers and advocate for themselves. Also, the mobile application will instruct the patient in pain self-management.

These are just some of the examples of the pain research being supported within the NFRP research portfolio. The NRFP continues to strongly encourage researchers to address this important topic and looks forward to receiving future novel applications aimed at mechanisms and treatment of all types of neurofibromatosis pain.

Links to the abstracts of the abovementioned awards:

Dr. Sherman (NF140064) https://cdmrp.health.mil/search.aspx?LOG_NO=NF140064 

Dr. Vitte (NF093091) https://cdmrp.health.mil/search.aspx?LOG_NO=NF093091 

Dr. Giovannini (NF170084) https://cdmrp.health.mil/search.aspx?LOG_NO=NF170084 

Dr. Buono (NF180073) https://cdmrp.health.mil/search.aspx?LOG_NO=NF180073 

References:

1. Walsh M and Kresak J. 2016. Neurofibromatosis: A review of NF1, NF2, and schwannomatosis. Journal of Pediatric Genetics 05(02):098–104.https://doi.org/10.1055/s-0036-1579766 

2. Merker VL, Esparza S, Smith MJ, et al. 2012. Clinical features of schwannomatosis: A retrospective analysis of 87 patients. The Oncologist 17(10):1317–1322.https://doi.org/10.1634/theoncologist.2012-0162 

3. Plotkin SR, Blakeley JO, Evans DG, Hanemann CO, Hulsebos TJM, Hunter-Schaedle K, Kalpana GV, Korf B, Messiaen L, Papi L, Ratner N, Sherman LS, Smith MJ, Stemmer-Rachamimov AO, Vitte J, and Giovannini M. 2013. Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. American Journal of Medical Genetics Part A 161(3): 405–416. https://doi.org/10.1002/ajmg.a.35760 

4. Ferner RE, Bakker A, Elgersma Y, Evans DGR, Giovannini M, Legius E, Lloyd, A, Messiaen LM, Plotkin S, Reilly KM, Schindeler A, Smith MJ, Ullrich NJ, Widemann B, and Sherman LS. 2019. From process to progress—2017 International Conference on Neurofibromatosis 1, Neurofibromatosis 2 and Schwannomatosis. American Journal of Medical Genetics Part A 179(6):1098–1106. https://doi.org/10.1002/ajmg.a.61112 

5. Bellampalli SS and Khanna R. 2019. Towards a neurobiological understanding of pain in neurofibromatosis type 1. PAIN 160(5):1007–1018. https://doi.org/10.1097/j.pain.0000000000001486 

6. Buono FD, Grau LE, Sprong ME, Morford KL, Johnson KJ, and Gutmann DH. 2019. Pain symptomology, functional impact, and treatment of people with Neurofibromatosis type 1. Journal of Pain Research 12: 2555–2561. https://doi.org/10.2147/jpr.s209540 

7. Hamoy-Jimenez G, Kim R, Suppiah S, Zadeh G, Bril V, and Barnett C. 2020. Quality of life in patients with neurofibromatosis type 1 and 2 in Canada. Neuro-Oncology Advances 2(Supplement_1):i141–i149. https://doi.org/10.1093/noajnl/vdaa003 

8. Mochari‐Greenberger H, Andreopoulos E, Peters A, and Pande RL. 2020. Clinical and workplace outcomes from a virtually delivered cognitive behavioral therapy program for pain. Pain Practice 20(4):387–395. https://doi.org/10.1111/papr.12867 

9. Vitte J, Gao F, Coppola G, Judkins AR, and Giovannini M. 2017. Timing of Smarcb1 and Nf2 inactivation determines schwannoma versus rhabdoid tumor development. Nature Communications 8(1):300. https://doi.org/10.1038/s41467-017-00346-5 

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