SUN-283 FH Variant in a Child with Family History of Early-Onset Pheochromocytoma

Pheochromocytoma (PCC) and paraganglioma (PGL) are rare neuroendocrine tumors associated with many genes. Recently, the fumarate hydratase gene (FH) has been implicated. We describe a case of a child evaluated for PCC who was found to have a variant in FH. A 7y5mo female was referred to our pediatric endocrinology clinic for evaluation of possible PCC. Family history included 3 relatives with reported early-onset PCC (ages 8-15), including mother (alive), maternal uncle and maternal grandfather (both deceased). There was reported thyroid disease in maternal grandmother, but no other family history of conditions seen with PCC-related syndromes. The patient was healthy aside from obesity until developing headaches 5 mo prior to visit with us. Given her family history, 24-hr urine collection for catecholamines was done which showed marked elevations in urine metanephrines, normetanephrines, norepinephrine, and dopamine compared to lab reference ranges. Contrast-enhanced abdominal CT was normal by report. At the time of her visit, headaches had improved. Exam was notable for high BP at >95th percentile for height (no prior hypertension diagnosis) and obesity; there were no mucosal neuromas and thyroid exam was normal. We arranged for plasma fractionated metanephrine and normetanephrine testing and checked prolactin, gastrin, calcitonin, calcium, phosphorus, and vitamin D levels. All labs were unremarkable. MIBG scan was normal. 24-hr urine free metanephrine testing was repeated and normal. She was seen in our genetics division and tested for PCC-associated genes. A heterozygous variant in FH, c.925C>T (p.Pro309Ser), was found. This variant was classified as of uncertain significance and is present in population databases but has not been described with FH-related disease. FH is associated with autosomal dominant hereditary leiomyomatosis and renal cell cancer (HLRCC), and has early evidence of correlation with hereditary PCC/PGL. We present a case of a child who was initially suspected to have PCC based on family history, headaches, and elevated urine catecholamines but who had normal results on confirmatory testing. She was found to have a FH variant, p.Pro309Ser, classified as uncertain in significance but which we believe may be disease-causing in this family; testing for the variant in her mother is being pursued. To our knowledge, only one case of a FH mutation associated with PCC in a child has been published. On a practical note, the patient’s fluctuating urine catecholamines may have been due to large volume on initial sample, which did not occur on the second sample; it is important to consider urine volume when interpreting urine catecholamine results. This case also highlights the impact on management that targeted genetic testing can have: knowledge of FH’s association with non-PCC conditions prompts consideration of additional screening that might not be performed for PCC alone.