Tumor-induced osteomalacia: An overview.

Tumor-induced osteomalacia (TIO) is rare paraneoplastic syndrome of hypophosphatemic osteomalacia, caused by phosphaturic factors secreted by small mesenchymal origin tumors with distinct pathological features, called 'phosphaturic mesenchymal tumors'. FGF23 is the most well-characterized of the phosphaturic factors. Tumors are often small and located anywhere in the body from head to toe, which makes the localisation challenging. Functional imaging by somatostatin receptor-based PET imaging is the first line investigation, which should be followed with CT or MRI based anatomical imaging. Once localised, complete surgical excision is the treatment of choice, which brings dramatic resolution of symptoms. Medical management in the form of phosphate and active vitamin D supplements is given as a bridge to surgical management or in inoperable/non-localised patients. This review provides an overview of the epidemiology, pathophysiology, pathology, clinical features, diagnosis, and treatment of TIO, including the recent advances and directions for future research in this field.

Genotypic Spectrum and its Correlation with Alopecia and Clinical Response in Hereditary Vitamin D Resistant Rickets: Our Experience and Systematic Review.

Alopecia in hereditary vitamin D resistant rickets (HVDRR) has some correlation with severe rickets and poor overall response. However, these observations are based on small series. Hence, we aim to assess the genotypic spectrum of HVDRR and its correlation with alopecia and clinical response. Seven genetically-proven HVDDR patients from five unrelated families and 119 probands from systematic review were analysed retrospectively for phenotypic and genotypic data and overall response to therapy. In our cohort mean age at rickets onset was 12 (± 3.4) months. Alopecia was present in all patients but one. All patients had poor overall response to oral high-dose calcium and calcitriol and most required intravenous calcium. Genetic analyses revealed four novel variants. On systematic review, alopecia was present in majority (81.5%) and preceded the onset of rickets. Patients with alopecia had higher serum calcium (7.6 vs.6.9 mg/dl, p = 0.008), lower 1, 25(OH)2 D (200 vs.320 pg/ml, p = 0.03) and similar overall response to oral therapy (28.7% vs. 35.3%, p = 0.56). Alopecia was present in 51.4% of non-truncating (NT) ligand-binding domain (LBD) variants, whereas it was universal in truncating LBD and all DNA binding-domain (DBD) variants. Overall response to oral therapy was highest in LBD-NT (46.4%) as compared to 7.6% in LBD-truncating and 19% in DBD-NT variants. Among LBD-NT variants, those affecting RXR heterodimerization, but not those affecting ligand affinity, were associated with alopecia. Both alopecia and overall response have genotypic correlation. Age at diagnosis and overall response to oral therapy were similar between patients with and without alopecia in genetically proven HVDRR.

68 Ga-DOTATATE PET/CT imaging in endogenous hyperinsulinemic hypoglycemia: A tertiary endocrine centre experience.

OBJECTIVE: Literature regarding utility of 68 Ga-DOTATATE PET/CT in insulinoma localization across various subgroups [benign/malignant/multiple endocrine neoplasia-1 (MEN-1) syndrome associated] remains scarce. In this study, the performance of 68 Ga-DOTATATE PET/CT was compared with contrast-enhanced computed tomography (CECT) and 68 Ga-NODAGA-Exendin-4 PET/CT (whenever available) in an endogenous hyperinsulinemic hypoglycemia (EHH) cohort. DESIGN: Retrospective audit. PATIENTS: EHH patients [N = 36, lesions (n) = 49, final diagnosis: benign sporadic insulinoma (BSI) (N = 20), malignant insulinoma (N = 4, n = 14), MEN-1 syndrome associated insulinoma (N = 9, n = 15), Munchausen syndrome (N = 2) and drug-induced hypoglycemia (N = 1)] having both preoperative imaging modalities (CECT and 68 Ga-DOTATATE PET/CT). MEASUREMENTS: Per-lesion sensitivity (Sn) and positive predictive value (PPV) for histopathological diagnosis of insulinoma. RESULTS: Sn and PPV of 68 Ga-DOTATATE PET/CT were 67.3% and 89.2%; 55% and 100%; 85.7% and 100%; and 66.7% and 77% for overall EHH, BSI, malignant, and MEN-1 syndrome associated insulinoma cohorts respectively. Despite having comparatively lower sensitivity in BSI cohort, 68 Ga-DOTATATE PET/CT localized a pancreatic tail lesion missed by other modalities. 68 Ga-DOTATATE PET/CT had comparatively higher sensitivity in malignant insulinoma than BSI cohort. 68 Ga-DOTATATE PET/CT also paved the way for successful response to 177 Lu-based peptide receptor radionuclide therapy (PRRT). In MEN-1 cases, lower PPV as compared with BSI was due to uptake in non-insulinoma pancreatic neuroendocrine tumours (Pan-NET). CONCLUSIONS: 68 Ga-DOTATATE PET/CT has supplemental role in selected cases of BSI with negative and/or discordant results with CECT and 68 Ga-NODAGA-Exendin-4 PET/CT. In malignant insulinoma, 68 Ga-DOTATATE-PET/CT has an additional theranostic potential. Interference due to uptake in non-insulinoma Pan-NET in MEN-1 syndrome may hinder insulinoma localization with 68 Ga-DOTATATE-PET/CT.

Tumor-induced rickets-osteomalacia: an enigma.

Objective We report a case of pediatric thoracic tumor-induced osteomalacia (TIO) causing severe hypophosphatemic rickets with delayed diagnosis and emphasize on timely management of this rare entity. Case presentation A young boy presented with rickets since five years of age. Biochemical evaluation revealed hypophosphatemia, hyperphosphaturia, elevated alkaline phosphatase and normal calcium levels. Initially managed as hereditary hypophosphatemic rickets, he was given phosphorus supplements and calcitriol. Despite the therapy, skeletal deformities worsened requiring surgical corrections. Subsequently, he developed iatrogenic tertiary hyperparathyroidism for which he underwent total parathyroidectomy. Later on, he was found to have fibroblast growth factor-23 secreting thoracic mass (10.5 cm in largest dimension) which was excised with significant post operative improvement. Histopathology showed phosphaturic mesenchymal tumor-mixed connective tissue variant, confirming the diagnosis of TIO. Conclusion TIO, a correctable cause of hypophosphatemic rickets, should be considered in children presenting with hypophosphatemic rickets with evident mass on examination/imaging and in refractory cases.