Clinical
HNPGL (parasympathetic- derived paragangliomas) are most common in the fourth and fifth decades and are more frequent in females than males. More than 50% of HNPGL arise in the carotid body (known as carotid body paraganglioma or chemodectoma) and, in contrast to sympathetic paragangliomas, metastatic disease is infrequent (<5%). Carotid body HNPGL usually present with a slowly enlarging neck mass and only rarely secrete catecholamines. Glomus jugulare or glomus tympanicum tumours may be associated with partial or complete hearing loss and pulsatile tinnitus. HNPGL may be familial or bilateral (in which case a genetic cause should be suspected) and/ or there may be a previous history of PPGL, wild- type gastrointestinal stromal tumour (wtGIST) or renal cell carcinoma (which are each associated with germline mutations in SDHX genes. In patients with sporadic HNPGL, about 20% of patients may have a genetic cause.
Genetics
Familial and/ or multicentric HNPGL most often results from germline mutations in the SDH complex genes (SDHA, SDHB, SDHC, SDHD, and SDHAF2). Which SDHX gene harbours a mutation is critical for determining the risk to other family members. The most commonly mutated gene in HNPGL, SDHD, displays a parent- of- origin effect in penetrance such that individuals who inherit a SDHD mutation from their father are at high risk of HNPGL (and also PPGL) whereas if the mutation is inherited from their mother the risk of disease is very low (see Chapter 6.12). Inherited SDHAF2 mutations show similar parent- of- origin effects on tumour risk. Mutations in SDHB, SDHC, and SDHA do not demonstrate any parent- of- origin effects and are inherited in a conventional autosomal dominant manner. Though each of these genes encodes an SDH complex protein the tumour- specific risks vary (e.g. for SDHD and SDHC the risks of HNPGL are higher than those for PPGL whereas the reverse is true for SDHB mutations). While SDHA mutations are infrequent in patients with HNPGL and PPGL it is the most commonly mutated gene in wtGIST. Individuals presenting with a HNPGL who are found to harbour a SDHX gene mutation are at risk of further HNPGL and other SDHX- related tumours and re quire lifelong surveillance and their relatives should be offered gen etic investigations/ surveillance also. Occasionally HNPGL may be associated with other inherited causes of PPGL (e.g. VHL, TMEM127, MAX).
Management
Symptomatic HNPGL are usually treated by surgery but in some locations (e.g. carotid body tumours, vagal, and jugular paragangliomas) resection of more advanced tumours can be associated with a significant risk of vascular/ cranial nerve damage and external beam radiotherapy may be preferable. Small asymptomatic HNPGL may be detected in hereditary mutation carriers and, if multiple, may be kept under surveillance though the risk of malignancy in SDHB mutation carriers should be considered.
