A Branching Algorithm

After the diagnosis was made, the patient’s family recalled that a maternal uncle had been diagnosed with a paraganglioma of the carotid body. Genetic testing of the patient identified a succinate dehydrogenase complex subunit B (SDHB) pathogenic variant and confirmed hereditary paraganglioma syndrome (HPGL). One year after the diagnosis, liver and lung metastases developed. He was treated with lanreotide (somatostatin analogue), capecitabine, and temozolomide, as well as a craniotomy and radiotherapy for palliation of bony metastases. The patient died less than two years after diagnosis.

Most patients with hypertension (defined as blood pressure >130/80 mm Hg¹) do not have an identifiable etiology (primary hypertension). Many components of this patient’s history, however, including his young age of onset, a teenage sibling with hypertension, lack of obesity, hypertension refractory to multiple medications, and LVH suggested secondary hypertension. Hypertension onset at an age less than 30 years, resistance to three or more medications,^1,2 and/or acute onset hypertension at any age should prompt an evaluation for secondary causes.¹ The prevalence of secondary hypertension is approximately 30% in hypertensive patients ages 18 to 40 years compared with 5%-10% in the overall adult population with hypertension.³ Among children and adolescents ages 0 to 19 years with hypertension, the prevalence of secondary hypertension may be as high as 57%.⁴

The most common etiology of secondary hypertension is primary aldosteronism.^5,6 However, in young adults (ages 19 to 39 years), common etiologies also include renovascular disease and renal parenchymal disease.⁷ Other causes include obstructive sleep apnea, medications, stimulants (cocaine and amphetamines),⁸ and endocrinopathies such as thyrotoxicosis, Cushing syndrome, and catecholamine-secreting tumors.⁷ Less than 1% of secondary hypertension in all adults is due to catecholamine-secreting tumors, and the minority of those catecholamine-secreting tumors are paragangliomas.⁹

Paragangliomas are tumors of the peripheral autonomic nervous system. These neoplasms arise in the sympathetic and parasympathetic chains along the paravertebral and paraaortic axes. They are closely related to pheochromocytomas, which arise in the adrenal medulla.⁹ Most head and neck paragangliomas are biochemically silent and are generally discovered due to mass effect.¹⁰ The subset of paragangliomas that secrete catecholamines most often arise in the abdomen and pelvis, and their clinical presentation mimics that of pheochromocytomas, including episodic hypertension, palpitations, pallor, and diaphoresis.

This patient had persistent, nonepisodic hypertension, while palpitations and diaphoresis only manifested following micturition. Other cases of urinary bladder paragangliomas have described micturition-associated symptoms and hypertensive crises. Three-fold increases of catecholamine secretion after micturition have been observed in these patients, likely due to muscle contraction and pressure changes in the bladder leading to the systemic release of catecholamines.¹¹

Epinephrine and norepinephrine are monoamine neurotransmitters that activate alpha-adrenergic and beta-adrenergic receptors. Adrenergic receptors are present in all tissues of the body but have prominent effects on the smooth muscle in the vasculature, gastrointestinal tract, urinary tract, and airways.¹² Alpha-adrenergic vasoconstriction causes hypertension, which is commonly observed in patients with catecholamine-secreting tumors.¹⁰ Catecholamine excess due to secretion from these tumors causes headache in 60%-80% of patients, tachycardia/palpitations in 50%-70%, anxiety in 20%-40%, and nausea in 20%-25%.¹⁰ Other symptoms include sweating, pallor, dyspnea, and vertigo.^9,10 This patient’s chronic nausea, which was attributed to gastroesophageal reflux, and his anxiety, attributed to generalized anxiety disorder, were likely symptoms of catecholamine excess.¹³

The best test for the diagnosis of paragangliomas and pheochromocytomas is the measurement of plasma free or 24-hour urinary fractionated metanephrines (test sensitivity of >90% and >90%, respectively).¹⁴ Screening for pheochromocytoma should be considered in hypertensive patients who have symptoms of catecholamine excess, refractory or paroxysmal hypertension, and/or familial pheochromocytoma/paraganglioma syndromes.¹⁵ Screening for pheochromocytoma should also be performed in children and adolescents with systolic or diastolic blood pressure that is greater than the 95th percentile for their age plus 5 mm Hg.¹⁶

While a typical tumor location and elevated metanephrine levels are sufficient to make the diagnosis of a pheochromocytoma or catecholamine-secreting paraganglioma, functional imaging with FDG-PET, Ga-DOTATATE-PET, or 123I-meta-iodobenzylguanidine (123I-MIBG) can further confirm the diagnosis and detect distant metastases. However, imaging has low sensitivity for these tumors and thus should only be considered for patients in whom metastatic disease is suspected.¹⁴ Biopsy is rarely needed and should be reserved for unusual metastatic locations. Treatment with an alpha-adrenergic receptor antagonist often reduces symptoms and lowers blood pressure. Definitive management typically involves surgical resection for benign disease. Surgery, radionuclide therapy, or chemotherapy is used for malignant disease.

While most pheochromocytomas are sporadic, up to 40% of paragangliomas are due to germline pathogenic variants.¹⁷ Mutations in the succinate dehydrogenase (SDH) group of genes are the most common germline pathogenic variants in the autosomal dominant hereditary paraganglioma syndrome (HPGL). Most paragangliomas and pheochromocytomas are localized and benign, but 10%-15% are metastatic.¹⁸ SDHB mutations are associated with a high risk of metastasis.¹⁹ Thus, genetic testing for patients and subsequent cascade testing to identify at-risk family members is advised in all patients with pheochromocytomas or paragangliomas.²⁰ This patient’s younger brother and mother were both found to carry the same pathogenic SDHB variant, but neither was found to have paragangliomas. Annual metanephrine levels (urine or plasma) and every other year whole-body magnetic resonance imaging (MRI) scans were recommended for tumor surveillance.

The clinician team followed a logical branching algorithm for the diagnosis of severe hypertension with biochemical testing, advanced imaging, histology, and genetic testing to arrive at the final diagnosis of hereditary paraganglioma syndrome. Although this patient presented for urgent care because of the acute effects of catecholamine excess, he suffered from chronic effects (nausea, anxiety, and hypertension) for years. Each symptom had been diagnosed and treated in isolation, but the combination and severity in a young patient suggested a unifying diagnosis. The family history of hypertension (brother and father) suggested an inherited diagnosis from the father’s family, but the final answer rested on the other branch (maternal uncle) of the family tree.