Endocrine Abstracts (2018) 56 GP16 | DOI: 10.1530/endoabs.56.GP16

Pheochromocytoma associated with cutaneous and uterine leiomyomatosis and renal cancer in a patient with a germline mutation in the FH gene

Marta Morón Díaz, Mauro Boronat Cortés, Juan Luis Afonso Martín, Carolina Fernández-Trujillo Moujir, Ana María González Lleo, Adriana Ibarra González, Nuria Pérez Martín & Francisco Javier Nóvoa Mogollón

Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria, Las Palmas de Gran Canaria, Spain.

Introduction: Most of pheochromocytomas (PCC) and paragangliomas (PGL) are sporadic. However, up to 40% of them have an inherited origin due to germline mutations in at least 15 known PCC/PGL genes, being the VHL and SDHx genes the ones most frequently affected. The fumarate hydratase (FH) is a Kreb’s cycle enzyme encoded by the FH gene.Its inactivating mutations increase intracellular levels of fumarate, leading to tissular pseudohypoxia and transcription of genes involved in tumor growth, thus acting as a tumor-supressor gene. Germline heterozygous mutations in the FH gene have been associated with the hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC).More recently, FH mutations have been also related to rare cases of inherited PCC/PGL with an apparently high predisposition to malignant disease. However, none of the reported cases combined PCC/PGG and HLRCC.

Case report: In April 2007 a 44-year-old woman with a previous history of hysterectomy due to uterine myomatosis and with family background of uterine myomatosis in her mother, looked for medical attention because of frequent episodes of palpitations, headache, facial flushing and dizziness, associated with elevation of blood pressure. Laboratory tests showed increased levels of plasma and urine normetanephrine and norepinephrine.Abdominal CT scan revealed a 1.3×1.3×9.6 cm predominantly cystic mass in the left kidney and a 9 cm left adrenal tumor with peripheral enhancement after contrast administration and a central area of necrosis. After pre-surgical preparation, adrenalectomy and ipsilateral nephrectomy were done, with clinical improvement and normalization of urinary normetanephrine and norepinephrine. Pathological examination confirmed a 9.5 cm pheochromocytoma with foci of necrosis without vascular invasion and a 10 cm Fuhrman’s grade 4 renal carcinoma with extensive cystic degeneration and tubulo-papillary pattern. A preliminary genetic study was negative for RET, VHL and SHDB genes, but a further investigation with a genetic panel covering 14 PCC/PGG genes, showed a splice site mutation in the FH gene (c555+1G>A). This mutation had been previously reported in a Spanish family with uterine and cutaneous leiomyomatosis.Clinical reexamination of the patient revealed pink papules up to 2 cm of diameter on the forearms and trunk, whose biopsy confirmed to be cutaneous leiomyomas.Follow-up chest/abdomen CT scans and 123I-MIBG SPECT have ruled out local recurrence or metastases.

Conclusions: Subjects carrying germline pathogenic mutations of the FH gene are at risk of developing both PCC/PGG and HLRCC.Both conditions should be routinely screened once diagnosis has been established.