Hereditary Paragangliomas of the Head and Neck

ABSTRACT

• Paragangliomas are mostly benign, slow growing tumors in the head and neck region originating from the parasympathetic paraganglion system.

• Between 10 and 50 percent of the cases are caused by an inherited gene-defect. The inheritance pattern seen in most families displays a parent-of-origin effect. In these families, children of affected mothers never develop the disease; only paternal transmission of the gene-defect confers susceptibility.

• Mutations in SDHD gene are the major cause of this inherited tumor. SDHD is a subunit of the mitochondrial respiratory chain complex II. Two families have been identified in which the disease mutation resides in other genes, namely in SDHC in a family of German origin, and in an as yet unidentified gene (PGL2) in a Dutch family. Mutations in SDHB have been found in a small number of families with adrenal pheochromocytoma, with or without head and neck paraganglioma. SDHB and SDHC are two other subunits of the mitochondrial complex II.

• Tumors developing in carriers of an SDHC or SDHD mutation have invariably lost the wild-type allele, suggesting that both genes function as a tumor-suppressor gene in parasympathetic paraganglion tissues.

• SDHC and SDHD are the first tumor suppressor genes whose normal cellular function are exerted in the mitochondria.

INTRODUCTION

Head and neck (HN-) paragangliomas are rare, predominantly benign tumors that arise from extra-adrenal paraganglion tissue associated with the parasympathetic nervous system. Most frequently, these hypervascular tumors originate from the carotid body at the carotid bifurcation.¹ Less common are paragangliomas originating from the glomus bodies of the jugular bulb, the tympanic plexus of Jacobson's nerve, and the vagal nerve. The average age at which a tumor is diagnosed is approximately 45 years in most studies, and the tumors characteristically progress extremely slowly. Histories spanning several decades are not uncommon. At present, surgery is considered to be the optimal method of treatment.

CLINICAL ASPECTS

Diagnostic Criteria and Site of Origin

The clinical symptoms associated with paragangliomas depend on their site of origin. Jugulotympanic paragangliomas are confined to the middle ear cavity and usually cause pulsatile tinnitus and hearing loss. Local extension may lead to palsies of cranial nerves VII to XII. Eventually, intracranial growth can lead to compression of the brainstem and death. Carotid and vagal body tumors usually present as a firm, painless, lateral neck mass (Fig. 52–1A) and may lead to impairment of cranial nerves X and XII. In a very small proportion of patients (∼1 percent), the tumors are vasoactive in that they produce large amounts of catecholamines.² For this reason, and to distinguish them from the excreting phaeochromocytomas originating from the sympathetic paraganglion system, HN paragangliomas are sometimes also referred to as nonchromaffin paragangliomas. Yet the normal function of carotid bodies, i.e., chemo- and oxygen-sensing, is exerted by excretion of physiological levels of a neurotransmitter (most probably catecholamines).³ Negation ...