Hereditary endocrine tumour syndromes

Endocrine tumour predisposition syndromes are inherited disorders affecting multiple endocrine organ systems. They typically present at a younger age than their sporadic counterparts and often exhibit a familial pattern of disease. Commonly affected tissues include the parathyroid glands, anterior pituitary, thyroid C-cells, adrenal cortex and medulla, paraganglia, and pancreatic islet cells. Hereditary endocrine tumours are more likely to occur bilaterally, multifocally, and as synchronous or metachronous lesions, making early genetic diagnosis essential for personalised surveillance and management.

The most important syndromes include , characterised by parathyroid, duodenopancreatic, and pituitary tumours; , characterised by medullary thyroid carcinoma, pheochromocytoma, and, in MEN2A, primary hyperparathyroidism; ; and hereditary pheochromocytoma–paraganglioma syndromes, in which neural crest-derived tumours arise along the sympathetic and parasympathetic paraganglial system. Age at presentation is highly variable, ranging from early childhood in MEN2B to late adulthood in other hereditary endocrine tumour syndromes.

The estimated prevalence is approximately 1 in 20,000 individuals for , 1 in 40,000 for and between 1 in 36,000 and 1 in 91,000 for . Furthermore, approximately 35% to 40% of phaeochromocytomas and paragangliomas are attributable to an underlying hereditary predisposition syndrome.

A large number of genes have been implicated in hereditary endocrine tumour predisposition syndromes. The most clinically relevant entities include multi-organ tumour syndromes, such as and , as well as hereditary pheochromocytoma–paraganglioma syndrome. Among the latter, pathogenic variants in SDHx genes represent the most common genetic causes.

MEN1 is characterised by parathyroid, pituitary, and duodenopancreatic neuroendocrine tumours, whereas von Hippel–Lindau disease is associated with pheochromocytoma and pancreatic neuroendocrine tumours in addition to non-endocrine manifestations. Examples of hereditary pheochromocytoma–paraganglioma syndromes include SDHB-related disease, which is characterised by extra-adrenal sympathetic paragangliomas and an increased risk of metastatic spread.

The genetic conditions associated with endocrine tumour predisposition syndromes predominantly follow autosomal dominant inheritance. Within the hereditary paraganglioma-phaeochromocytoma syndrome, pathogenic variants in SDHD and SDHAF2 demonstrate a well-established parent-of origin effect, with tumour development occurring predominantly after paternal transmission. A similar effect has been proposed or MAX-associated disease. Less common alternative inheritance patterns have been reported for selected tumour predisposition syndromes.

• Where an endocrine tumour predisposition syndrome is suspected to have a genetic cause, molecular genetic testing can identify the underlying condition and confirm a clinical suspicion.
• The identified entity guides further clinical management and is a prerequisite for targeted medical care; therapeutic options are evaluated individually by the treating physicians.
• Identification of the underlying pathogenic germline variant enables predictive testing of at-risk family members and provides information relevant to family planning.

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