PP1001 - Neurofibromatosis Type 1: A Red Flag for Diagnosing Paragangliomas (Glomus Tumors)

Paragangliomas are benign neuroendocrine tumors from paraganglia cells. Neurofibromatosis 1 and 2 (NF1 & NF2) are a cluster of benign neurocutaneous tumors. Approximately, a third to half of paragangliomas are associated with NF1. Clinical and genetic characteristics of both conditions will be presented. Patients with NF1 are at a greater risk of paragangliomas during childhood; paragangliomas are probably an integral part of the tumor spectrum of NF1. Neurofibromatosis 1 is a red flag that should be incorporated in the diagnostic criteria for paragangliomas, which can allow for early diagnosis, better patient management and health outcomes.

Summary:

This poster proposal will address the comorbidity of the benign tumors paraganglioma and neurofibromatosis type 1 (NF1). The clinical value of understanding this association will be discussed.

Paragangliomas are neuroendocrine tumors that arise from paraganglia cells; small, oval, highly vascular bodies, connected with ganglia of the sympathetic nervous system. They were incorrectly called glomus tumors because it was believed they originated from true glomus (arteriovenous) complexes. Paragangliomas are the most common soft tissue tumor of the middle ear and second most common tumor of the temporal bone. Tumors involve areas of the skull base/neck and are named for structures they arise from, i.e., the carotid body (chemodectoma), jugular bulb (glomus jugulare), middle ear (glomus tympanicum), and vagus nerve (glomus vagale). Glomus jugulare and tympanicum tumors can present with pulsatile tinnitus, hearing loss, and otalgia.

Paragangliomas can be sporadic or show autosomal dominant inheritance with 100% penetrance. Mutation of the gene SDHD mapped to 11q23 is identified in these tumors. Genomic imprinting may be involved (Baysa, 2013). Patients usually present after the 5th decade and diagnosed ~ 4-10 years after initial occurrence.

Neurofibromatosis 1 and 2 are a cluster of neurocutaneous tumors. About a third to half of paragangliomas are associated with NF1. This association was first reported by Klaber (1938). Mutations on both NF1 alleles found within glomus tumor cells were discovered in a molecular genetic study, confirming the association between the two (Brems et al., 2009). This association between NF1 and paragangliomas is, however, still relatively unknown to audiologists and often missed.

About half the cases of neurofibromatosis 1 and 2 are sporadic while half are inherited through autosomal dominant transmission, demonstrating 100% penetrance and variable expressivity. Both conditions are progressive with no known cure. Neurofibromatosis 1 affects the peripheral nervous system. The defective tumor suppressor NF1 gene is on chromosome 17 (17q11.2), resulting in abnormal protein neurofibromin that causes increased proliferation and tumorigenesis. Age of onset for NF1 is between 10-15 years. Neurofibromatosis 2 is a condition of the CNS typically resulting in bilateral vestibular schwannomas. The defective NF2 gene is on chromosome 22 (22q12), which provides instructions for the production of the protein merlin (schwannomin). Age of onset for NF2 is between 18-24 years.

Most individuals with NF1 have normal/near normal hearing sensitivity, yet studies revealed that 1 in 3 patients with NF1 have significant auditory pathway abnormalities and perceptual deficits (Rance et al., 2021). Individuals with NF1 often exhibit ADHD and complex cognitive symptoms (Shilyansky, et al, 2010). Patients with NF1, which is considered a tumor predisposition syndrome, are at a greater risk of multifocal paragangliomas during childhood; paragangliomas are probably an integral part of the tumor spectrum of NF1 (Hilde et al, 2009).

Diagnosis of paragangliomas in childhood requires a complete medical/surgical, family history, and targeted review of systems for NF1 (Lipner et al, 2021). Increased awareness of the association of these tumors can allow for early diagnosis and better health outcomes. Management of these conditions will be discussed.