TIO Associated with Hyperparathyroidism: A Rarity, a Rule, or a Novel HPT-PMT Syndrome—A Case Study with Literature Review

Abstract

Objective. Association of primary hyperparathyroidism (pHPT) with phosphaturic mesenchymal tumors (PMT) is rarely reported. This report entertains the hypothesis of the causal association of HPT with tumor-induced osteomalacia (TIO) and of the existence of HPT-PMT syndrome. Case Presentation. A 49-year-old man presented with fragility rib fractures, generalized bone pain, and muscle weakness worsening over the past 3 years. Initial tests demonstrated hypophosphatemia and high PTH. The diagnosis of pHPT was entertained, but parathyroid scan was negative. During a 2-year follow-up, the patient reported minimal improvement of symptoms after intermittent treatment with calcitriol and phosphate. Biochemical evaluation showed persistent hypophosphatemia with renal phosphate wasting, elevated FGF23, and osteopenia on DXA scan. TIO was suspected. Multiple MRIs and whole-body FDG-PET scans were inconclusive. The patient subsequently underwent 68Ga-DOTATATE PET-CT, which revealed a somatostatin receptor-positive lesion in the lung. The resected mass was confirmed as PMT. The patient had dramatically improved symptoms, normal phosphate, calcium, and FGF23. During follow-up over 3 years postsurgery, the patient had slowly rising calcium and persistently elevated PTH. Conclusion. The debate whether the patient had pHPT or tertiary HPT prompted literature review showing that aberrant genes including FGFR1, FGF1, fibronectin 1, and Klotho were mechanistically involved in the HPT-PMT association. This case highlights the pitfalls contributing to delayed diagnosis and treatment of TIO and hypothesizes the association between pHPT and PMT.

Phosphaturic Mesenchymal Tumors with or without Phosphate Metabolism Derangements

“…Both drugs are administered in multiple daily doses, i.e., phosphate at 1–2 g/day and calcitriol at 1–3 mcg/day. Because of their mechanism and due to the underlying disease, patients may develop secondary or tertiary hyperparathyroidism in the long term [ 51 ]. This is presumably due to reduced calcitriol levels, or because of the mechanism by which phosphate supplements intermittently reduce ionized calcium.…”

Phosphate Metabolism and Pathophysiology in Parathyroid Disorders and Endocrine Tumors

“…Until the tumor is not localized, oral phosphate and calcitriol should be given to aid mineralization in the bone and alleviate patient symptoms, and to increase serum phosphate levels. Phosphate (1–2 g/day) and calcitriol (1–3 mcg/day) are given in multiple daily doses, and, with long-term exposure, patients may develop secondary or tertiary hyperparathyroidism [ 44 ]. The presumed mechanism is likely due to both deficient 1,25(OH) 2 vitamin D production and phosphate supplementation, which lowers ionized calcium, thereby continuously triggering PTH release.…”