Could primary hyperparathyroidism develop in cases with neurofibromatosis type-1-associated pheochromocytoma: Two cases with pheochromocytoma gene panel analysis
Authors: Ozturk Beyza Olcay , Aggul Hunkar , Bilen Ogun , Elbuken Gulsah , Zuhur Sayid 
Published: January 2023

Introduction

Neurofibromatosis type-1 (NF-1) is an autosomal dominant genetic disorder. It is associated with the development of café-au-lait macules, axillary and/or inguinal frecklings, Lisch nodules, hypertension, osteoporosis, skeletal abnormalities, as well as benign and malignant tumors, such as optic gliomas, peripheral nerve sheet tumors, and rarely, pheochromocytomas. However, primary hyperparathyroidism is rarely documented in patients with bilateral pheochromocytomas associated with NF-1 and is typically linked to MEN-2 A syndrome. Here we present two cases of NF-1-associated bilateral pheochromocytomas who developed primary hyperparathyroidism during follow-up.

Clinical case

In 2010, diagnostic ultrasonography performed for abdominal pain in a 60-year-old female patient revealed an adrenal mass. Multiple neurofibromas, axillary freckling, café-au-lait macules, and lisch nodules were found on physical examination (Figure 1A, B, C, and D). A diagnosis of pheochromocytoma was confirmed by high urine metanephrines and a hyperintense, 35 x40 mm mass on T2 weighted MRI sequences. The patient underwent right adrenalectomy. One year later, a diagnosis of primary hyperparathyroidism was made based on the high serum levels of calcium and intact PTH, and low serum phosphorus levels (Table-1). Radiotracer uptake was seen on a parathyroid MIBI scan in the thyroid's right inferior area. During follow-up, a 50×51 mm mass, hyperintense on T2 weighted MRI sequences was discovered on the left adrenal gland (figure 1-E). A diagnosis of pheochromocytoma was confirmed by detecting high plasma metanephrine and normetanephrine levels. The patient underwent left adrenalectomy 5 years following the initial diagnosis.

Clinical case

A 64-year-old female patient was admitted due to recently developed hypercalcemia. She had previously undergone two successive adrenalectomies, 4 years apart in 1999 and 2003, and was confirmed to have bilateral pheochromocytomas by histopathological analysis. Multiple neurofibromas, axillary freckling, café-au-lait macules, and Lisch nodules were found on physical examination. A diagnosis of primary hyperparathyroidism was made by detecting high serum calcium, intact parathormone, and low serum phosphorus levels. The patient underwent a right parathyroidectomy in 2012.

In both cases, a panel analysis of pheochromocytoma gene mutations was carried out. In cases 1 and 2, a heterozygous nonsense mutation (17q11.2, C.2023G&gt;T (P.G675*) and a non-frameshift deletion (17q11.2 c.5036) in the NF-1 gene were respectively found. Both instances tested negative for genetic alterations for RET, FH, MAX, SDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM-127, and VHL.

Conclusion

The development of primary hyperparathyroidism in these two cases of pheochromocytomas associated with genetically confirmed NF-1 raises the possibility that primary hyperparathyroidism may develop in patients with NF-1-associated pheochromocytoma.