Oncogenic osteomalacia (OOM) is characterised by tumour production of fibroblast growth factor 23 (FGF23) that results in hypophosphataemia and renal phosphate wasting, reduced 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) synthesis and osteomalacia. Here, we demonstrate the roles of serum FGF23 and 1,25(OH)2D3, together with the lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), as biomarkers for OOM. A previously well 52-year-old man presented with a 2-year history of generalised musculoskeletal pain and proximal myopathy. He had hypophosphataemia, elevated serum alkaline phosphatase activity, low serum 1,25(OH)2D3 and a reduced tubular maximum of phosphate/glomerular filtration rate. These findings indicated a diagnosis of OOM, but magnetic resonance imaging (MRI) and octreotide scintigraphy did not identify any tumours. Treatment with oral phosphate and calcitriol resolved the symptoms and biochemical abnormalities within 6 months. Four years later, he relapsed whilst on treatment with oral phosphate and calcitriol. Serum FGF23 concentration was elevated and MRI identified a 2 cm tumour within Hoffa's fat pad of the left knee. Removal of the tumour resulted in a complete resolution of symptoms and normalisation of the serum biochemical abnormalities including serum FGF23. Histology demonstrated a phosphaturic mesenchymal tumour, mixed connective tissue variant (PMTMCT), which revealed immunostaining with anti-LYVE-1 antibody and hence the presence of lymphatic vessels. Serum FGF23 and 1,25(OH)2D3 were found to be reliable biomarkers for OOM. In addition, the demonstration of lymphatics in the PMTMCT helps to distinguish this tumour from most typical benign haemangiomas.
Fadil M Hannan, Nicholas A Athanasou, James Teh, Christopher L M H Gibbons, Brian Shine and Rajesh V Thakker
Dharshini Karuppiah, Gaya Thanabalasingham, Brian Shine, Lai Mun Wang, Gregory P Sadler, Niki Karavitaki and Ashley B Grossman
Hypercalcaemia is an important cause of increased morbidity and mortality in patients with parathyroid carcinoma. Surgical resection is the mainstay of treatment but, equally, managing hypercalcaemia is of paramount importance. At present, few therapies have been shown to be effective in the most severe cases. This report describes the efficacy of denosumab in a patient with parathyroid carcinoma when conventional therapies had been shown to be relatively ineffective.
Subject, methods and results
A 50-year-old man presented with symptomatic hypercalcaemia 1 year after the surgery for his parathyroid carcinoma. Investigations revealed raised serum calcium and parathyroid hormone concentrations consistent with the recurrence of the disease. Imaging failed to localise any surgically remediable foci. Medical management with loop diuretics, calcimimetics and bisphosphonates failed to provide a sustained response. Denosumab, as a monthly injection, led to a gradual decrement in his peak calcium concentrations with the values now persistently below 3 mmol/l.
Denosumab, a fully human MAB that binds to the ‘receptor activator of nuclear factor κB ligand (RANKL)’, was shown to have a profound effect in modulating malignant hypercalcaemia. This medication should be considered as an effective option in patients with refractory hypercalcaemia secondary to parathyroid carcinoma.
Emilia Sbardella, Zoe Maunsell, Christine J H May, Michael Tadman, Tim James, Bahram Jafar-Mohammadi, Andrea M Isidori, Ashley B Grossman and Brian Shine
In patients with phaeochromocytomas or paragangliomas (PPGLs), 24-h urine collections for metanephrines (uMNs) are cumbersome.
To evaluate the diagnostic utility of ratios to creatinine of ‘spot’ uMNs.
Concentrations of uMNs and plasma metanephrines (pMNs) were measured by HPLC-mass-spectrometry. We retrospectively compared correlations of 24-h-urine output and ratio to creatinine in historical specimens and prospectively assessed 24-h and contemporaneous spot urines and, where possible, pMNs. Using trimmed log-transformed values, we derived reference intervals based on age and sex for spot urines. We used multiples of upper limit of normal (ULNs) to compare areas under curves (AUCs) for receiver-operator characteristic curves of individual, and sum and product of, components.
In 3143 24-h-urine specimens on 2416 patients, the correlation coefficients between the ratios and outputs of metanephrine, normetanephrine and 3-methoxytyramine in 24-h urines were 0.983, 0.905 and 0.875, respectively. In 96 patients, the correlations between plasma concentrations, urine output and ratios in spot specimens were similar to those for raw output or ratios in 24-h specimens. Of the 160 patients with PPGLs, the CIs for AUCs for individual metabolites overlapped for all four types of measurement, as did those for the sum of the multiple ULNs although these were slightly higher (AUC for spot urine: 0.838 (0.529–1), plasma: 0.929 (0.874–0.984) and output: 0.858 (0.764–0.952)).
Ratios of fractionated metanephrines to creatinine in spot urine samples appear to have a similar diagnostic power to other measurements. The ease of spot urine collection may facilitate diagnosis and follow-up of PPGLs through improved patient compliance.