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Open access

Alyssa J Mancini, Amin Sabet, Gunnlaugur Petur Nielsen, J Anthony Parker, Joseph H Schwab, Ashley Ward, Jim S Wu, and Alan O Malabanan

Summary

Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia caused by fibroblast growth factor-23 (FGF23)-secreting tumors. Most of these tumors are phosphaturic mesenchymal tumors (PMTs) typically involving soft tissue in the extremities and bone of the appendicular skeleton and cranium. We report the case of a 60-year-old woman with about 3 years of persistent bone pain and multiple fractures, initially diagnosed as osteoporosis, who was found to have hypophosphatemia with low 1,25-dihydroxyvitamin D and elevated alkaline phosphatase and inappropriately normal FGF23 consistent with TIO. Her symptoms improved with phosphate supplementation, vitamin D and calcitriol. 68Ga-DOTATATE imaging revealed a T12 vertebral body lesion confirmed on biopsy to be a PMT. She underwent resection of the PMT with resolution of TIO and increased bone density. This rare case of TIO secondary to a PMT of the thoracic spine highlights some of the common features of PMT-associated TIO and draws attention to PMT-associated TIO as a possible cause of unexplained persistent bone pain, a disease entity that often goes undiagnosed and untreated for years.

Learning points

  • Tumor-induced osteomalacia (TIO) is typically caused by phosphaturic mesenchymal tumors (PMTs) that are usually found in the soft tissue of the extremities and bone of the appendicular skeleton/cranium and rarely in the spine.

  • TIO may be misdiagnosed as osteoporosis or spondyloarthritis, and the correct diagnosis is often delayed for years. However, osteoporosis, in the absence of fracture, is not associated with bone pain.

  • The hallmark of TIO is hypophosphatemia with inappropriately normal or low 1,25-dihydroxyvitamin D and elevated or inappropriately normal fibroblast growth factor-23 (FGF23) levels.

  • In patients with unexplained persistent bone pain, a serum phosphate should be measured. Consider PMT-associated TIO as a potential cause of unexplained persistent bone pain and hypophosphatemia.

  • PMTs express somatostatin receptors and may be identified with 68Ga-DOTATATE imaging.

  • Complete surgical resection is the preferred treatment for spinal PMTs associated with TIO.

Open access

Mike Lin and Kirtan Ganda

Summary

We present the case of a 60-year-old female who developed repeated atraumatic stress fractures. She was initially diagnosed with osteoporosis based on her dual-energy X-ray absorptiometry (DXA) scan bone mineral density (BMD) T-scores and started on denosumab therapy. Secondary osteoporosis screen revealed abnormal myeloma screen and low serum phosphate levels. It was thought that the patient had multiple myeloma with associated Fanconi-related tubular dysfunction. However, fibroblast growth factor-23 (FGF-23) levels were grossly elevated, making Fanconi syndrome unlikely. The patient was subsequently diagnosed with two separate conditions, namely cardiac amyloid light-chain (AL) amyloidosis and FGF-23-related hypophosphataemia, likely due to tumour-induced osteomalacia. This case highlights the importance of excluding osteomalacia as a cause of low BMD and checking FGF-23 levels in the workup for hypophosphataemia.

Learning Points

  • Tumour-induced osteomalacia is a difficult diagnosis as the tumour is often small and slow growing. Imaging may fail to identify a tumour, and treatment therefore consists of calcitriol and phosphate replacement.

  • Tumour-induced osteomalacia should be suspected in the adult presenting with new-onset hypophosphataemia, elevated FGF-23 levels and isolated renal phosphate wasting.

  • Serum phosphate is not part of the routine chemistry panels. Routinely checking phosphate levels prior to initiating antiresorptive therapy is warranted.

  • DXA cannot distinguish low bone mineral density due to osteoporosis from osteomalacia. Antiresorptive therapy should be avoided in osteomalacia due to the risk of clinical and radiographic deterioration.

Open access

Keerthana Haridas

Summary

Human T-cell lymphotropic virus-1 (HTLV-1) causes adult T-cell leukemia and lymphoma (ATLL) and is a rare but important cause of hypercalcemia. A 53-year-old male with HTLV-1-associated myelopathy presented with acute on chronic bilateral lower extremity weakness and numbness. Initial blood work revealed hypercalcemia with corrected calcium of 16.2 mg/dL (8.5–11.5) with normal levels of phosphorus and alkaline phosphatase. Workup for hypercalcemia revealed parathyroid hormone (PTH) of 14 pg/mL (10–65), 25 hydroxy vitamin D at 19.6 ng/mL (30–100), 1,25 dihydroxy vitamin D at 6.7 pg/mL (19.9–79.3), thyroid-stimulating hormone of 1.265 μIU/mL (0.5–5), undetectable PTH-related protein (PTHrP) and lactate dehydrogenase of 433 U/L (100–220). The urine calcium creatinine ratio was 0.388. Reverse transcriptase PCR was positive for HTLV-1 and negative for HTLV-2. Peripheral blood flow cytometry and lymph node biopsy confirmed ATLL. He received treatment with fluids, calcitonin and denosumab after which serum calcium levels fell (nadir: 7.7 mg/dL) and then normalized. Humoral hypercalcemia in this setting is mediated by receptor activator of nuclear factor-kappa B ligand (RANKL), PTHrP and other cytokines. PTHrP levels depend on levels of the TAX gene product, cell type and lymphocyte-specific factors. Thus, a low level, like in our patient, does not rule out HTLV-1 infection/ATLL as the cause of hypercalcemia. Hypercalcemia is known to be responsive to monoclonal antibodies against RANKL given the compound’s role in mediating hypercalcemia in these cases.

Learning points

  • Human T-cell lymphotropic virus-1 infection and adult T-cell leukemia and lymphoma are associated with high rates of hypercalcemia and hypercalcemic crises.

  • Hypercalcemia in these cases is mediated by osteoclastic bone resorption carried out by several agents including receptor activator of nuclear factor-kappa B ligand, parathyroid hormone-related protein (PTHrP), macrophage inflammatory protein 1 alpha, interleukins, etc. A normal PTHRrP does not rule out humoral hypercalcemia of malignancy in this setting, as indicated by this case.

  • Hypercalcemia in such settings is highly responsive to monoclonal antibodies against RANKL given the role the ligand plays in resorptive hypercalcemia.

Open access

Mohammed Anwar Hussain, Aneez Joseph, Vinoo Mathew Cherian, Alok Srivastava, Kripa Elizabeth Cherian, Nitin Kapoor, and Thomas Vizhalil Paul

Summary

Although bisphosphonates (BPs) are mainly used for the treatment of osteoporosis and are generally safe, long-term use and more dosage as utilised in malignant conditions may be associated with the rare adverse event of an atypical femoral fracture (AFF). Occasionally, the risk of developing an AFF persists long after BPs are withdrawn. A 39-year-old woman who underwent chemotherapy and an autologous stem cell transplantation for multiple myeloma presented to us with history of pain in the left thigh. She had received multiple doses of oral and parenteral BPs for about 10 years in view of the underlying myeloma with osteoporosis. Her investigations showed a suppressed CTX of 192 pg/mL, and radiograph of pelvis displayed thickened cortices with beaking of the left femoral shaft, which was suggestive of an AFF. Following discontinuation of BPs, she underwent prophylactic intra-medullary nailing with which her symptoms improved. Five years later, she presented with similar complaints on the right side. Investigations showed that her bone turnover continued to be suppressed with Cross linked C- Telopeptide of type 1 collagen (CTX) of 165 pg/mL and an X-ray done showed AFF on the right side despite being off BPs. A second intra-medullary nailing was done and on follow-up, she has been symptom-free and independent in her daily activities. Discontinuation of BPs may not prevent the incident second AFF and, therefore, thus warranting long-term follow-up.

Learning points

  • Regular screening and follow-up of patients who receive long-term bisphosphonate (BP) therapy should be done.

  • Discontinuation of BPs does not preclude the possibility of repeated occurrence of a second AFF.

  • Long-term BP therapy warrants regular monitoring and follow-up should an AFF occur

Open access

Caroline Schulmeister, Jason Lee, Farzana Perwad, Roger Long, and Shylaja Srinivasan

Summary

Skeletal abnormalities with delayed bone age and decreased linear bone growth are commonly found in children with prolonged juvenile hypothyroidism. However, rachitic bone abnormalities have not been previously reported in children with acquired hypothyroidism. Here, we present a case of newly found rickets in an 8-year-old female with untreated acquired hypothyroidism secondary to Hashimoto’s thyroiditis. Laboratory finding for abnormalities in calcium/phosphorus homeostasis and hormones that regulate skeletal health was normal. Her radiographic anomalies resolved with levothyroxine treatment alone, suggesting that hypothyroidism was the etiology of the rickets. To our knowledge, this is the first case report of rickets associated with long-standing severe acquired hypothyroidism that resolved exclusively with thyroid repletion.

Learning points

  • Thyroid hormone plays an important role in bone mineralization.

  • Prolonged hypothyroidism can result in rachitic bone abnormalities noted on radiographs.

  • Hypothyroidism should be considered in the evaluation of a child with rickets.

Open access

Sophie Bondje, Camilla Barnes, and Felicity Kaplan

Summary

Milk–alkali syndrome (MAS) is a triad of hypercalcaemia, metabolic alkalosis and renal insufficiency. In this study, we present a case of milk–alkali syndrome secondary to concurrent use of over-the-counter (OTC) calcium carbonate-containing antacid tablets (Rennie®) for dyspepsia and calcium carbonate with vitamin D3 (Adcal D3) for osteoporosis. A 72-year-old woman presented with a 2-day history of nausea, vomiting, epigastric pain, constipation, lethargy and mild delirium. Past medical history included osteoporosis treated with daily Adcal D3. Initial blood tests showed elevated serum-adjusted calcium of 3.77 mmol/L (normal range, 2.2–2.6) and creatinine of 292 µmol/L (45–84) from a baseline of 84. This was corrected with i.v. pamidronate and i.v. fluids. She developed asymptomatic hypocalcaemia and rebound hyperparathyroidism. Myeloma screen, vasculitis screen and serum angiotensin-converting enzyme (ACE) were normal, while the CT of the chest, abdomen and pelvis showed renal stones but no malignancy. A bone marrow biopsy showed no evidence of malignancy. Once the delirium resolved, we established that prior to admission, she had been excessively self-medicating with over-the-counter antacids (Rennie®) as required for epigastric pain. The increasing use of calcium preparations for the management of osteoporosis in addition to easily available OTC dyspepsia preparations has made MAS the third most common cause of hypercalcaemia hospitalisations. Educating patients and healthcare professionals on the risks associated with these seemingly safe medications is required. Appropriate warning labels on both calcium preparations used in the management of osteoporosis and OTC calcium-containing preparations would prevent further similar cases and unnecessary morbidity and hospital admission.

Learning points

What is known?

  • An association between high-dose calcium supplementation and hypercalcaemia crisis has been seen in case studies.

  • After as little as 1 week of excessive calcium carbonate ingestion, patients can present with symptomatic hypercalcemia, acute renal failure and metabolic alkalosis ().

  • Women aged 50 and younger need 1 g of calcium per day, while aged 51 and older need 1.2 g ().

  • Although the amount of calcium required for MAS is generally thought to be more than 4 g per day, there have been reports at intakes as low as 1.0–1.5 g per day in pre-existing risk factors including renal impairment ().

What this study adds?

  • The danger of excessive ingestion of antacid is not adequately highlighted to prescribers and patients.

  • Appropriate warning labels on OTC calcium-containing preparations could prevent unnecessary morbidity and hospital admission.

Open access

Leevi A Toivonen, Marko H Neva, Thanos Sioris, Pia Isomäki, and Saara Metso

Summary

Gorham–Stout disease (GSD) is a rare bone disease characterized by massive osteolysis and lymphatic proliferation. The origin of the condition is unknown, and no established treatment protocol exists. Massive pleural effusion is a frequent complication of GSD in the thoracic region. We present the case of a 23-year-old male with thoracic GSD, subsequent paraparesis, and life-threatening pleural effusion. The patient was managed by a multidisciplinary team with a good recovery. The pleural effusion was successfully treated with a pleuro-peritoneal shunt. This is the first report of the use of this mini-invasive technique in the management of pleural effusion related to GSD. Further, we present the potential role of interleukin-6 and bone resorption markers in the measurement of the disease activity.

Learning points

  • Multidisciplinary approach is important in the management of rare and severe disorders such as Gorham-Stout disease.

  • Pleuro-peritoneal shunting is a valuable option in the treatment of pleural effusion related to GSD.

  • Interleukin-6 and bone resorption markers appear useful in measuring the disease activity of GSD.

Open access

S D N De Silva, M Aravinthan, and P Katulanda

Summary

Long-term use of exogenous glucocorticoids leads to the suppression of the hypothalamic–pituitary–adrenal axis. Therefore, if the glucocorticoid is withdrawn abruptly, patients will develop adrenal insufficiency. Hypercalcaemia is a rare but well-known complication of adrenal insufficiency. However, hypercalcaemia is a rare presentation of glucocorticoid-induced adrenal insufficiency (GI-AI). A 62-year-old patient with a past history of diabetes mellitus, ischaemic heart disease, stroke, hypertension and dyslipidaemia presented with polyuria, loss of appetite, malaise and vomiting for a duration of 2 months. His ionized calcium level was high at 1.47 mmol/L. Intact parathyroid hormone was suppressed (4.3 pg/mL) and vitamin D was in the insufficient range (24.6 ng/mL). Extensive evaluation for solid organ or haematological malignancy including contrast-enhanced CT chest, abdomen, pelvis, multiple myeloma workup and multiple tumour markers were negative. His synacthan-stimulated cortisol was undetectable thus confirming adrenal insufficiency. His adrenocorticotrophic hormone level was 3.82 pg/mL (4.7–48.8) excluding primary adrenal insufficiency. His MRI brain and other pituitary hormones were normal. Further inquiry revealed that the patient had taken over-the-counter dexamethasone on a regular basis for allergic rhinitis for more than 2 years and had stopped 2 weeks prior to the onset of symptoms. Therefore, a diagnosis of GI-AI leading to hypercalcemia was made. The patient was resuscitated with intravenous fluids and replacement doses of oral hydrocortisone were started with a plan of prolonged tailing off to allow the endogenous adrenal function to recover. His calcium normalized and he made a complete recovery.

Learning points

  • Long-term use of glucocorticoids leads to the suppression of the hypothalamic–pituitary–adrenal axis.

  • If the glucocorticoid is withdrawn abruptly, patients will develop adrenal insufficiency which is known as glucocorticoid-induced adrenal insufficiency.

  • Adrenal insufficiency should be considered in the differential diagnosis of parathyroid hormone-independent hypercalcaemia.

  • A thorough clinical history is of paramount importance in arriving at the correct diagnosis.

Open access

E Nauwynck, J Vanbesien, J De Schepper, I Gies, A Van Leynseele, E De Wachter, B Hauser, and W Staels

Summary

Vitamin D intoxication in children is rare but its incidence is increasing as vitamin D is supplemented more often and in higher doses. Children with cystic fibrosis (CF) are at risk for vitamin D intoxication due to incorrect compounded preparations of liposoluble vitamins. Here, we report a severe vitamin D intoxication in a 4-year-old girl with CF, due to an error in the compounded vitamin A, D, E, and K preparation, presenting clinically with weight loss, constipation, polydipsia, polyuria, and nycturia. The administered compounded preparation contained 10 000-fold the prescribed vitamin D dose. The patient was treated with hyperhydration, loop diuretics, and bisphosphonates. Serum calcium levels normalized after 4 days but serum 25-hydroxyvitamin D levels remained elevated even up to 2 months after treatment.

Learning points

  • Vitamin D intoxication should be ruled out when patients with cystic fibrosis (CF) present with acute polyuria, constipation, and weight loss.

  • Prompt treatment is necessary to avert life-threatening complications.

  • Regularly measuring serum calcium and 25-hydroxyvitamin D concentrations in children with CF receiving vitamin A, D, E, and K supplements is important during their follow-up.

Open access

Annabelle M Warren, Peter R Ebeling, Vivian Grill, Ego Seeman, and Shoshana Sztal-Mazer

Summary

Hypophosphatasia (HPP) is a rare and under-recognised genetic defect in bone mineralisation. Patients presenting with fragility fractures may be mistakenly diagnosed as having osteoporosis and prescribed antiresorptive therapy, a treatment which may increase fracture risk. Adult-onset HPPhypophosphatasia was identified in a 40-year-old woman who presented with bilateral atypical femoral fractures after 4 years of denosumab therapy. A low serum alkaline phosphatase (ALP) and increased serum vitamin B6 level signalled the diagnosis, which was later confirmed by identification of two recessive mutations of the ALPL gene. The patient was treated with teriparatide given the unavailability of ALP enzyme-replacement therapy (asfotase alfa). Fracture healing occurred, but impaired mobility persisted. HPP predisposes to atypical femoral fracture (AFF) during antiresorptive therapy; hence, bisphosphonates and denosumab are contraindicated in this condition. Screening patients with fracture or ‘osteoporosis’ to identify a low ALP level is recommended.

Learning points

  • Hypophosphatasia (HPP) is a rare and under-recognised cause of bone fragility produced by impaired matrix mineralisation that can be misdiagnosed as a fragility fracture due to age-related bone loss.

  • Antiresorptive therapy is contraindicated in HPP.

  • Low serum alkaline phosphatase (ALP) provides a clue to the diagnosis.

  • Elevated serum vitamin B6 (an ALP substrate) is indicative of HPP, while identification of a mutation in the ALPL gene is confirmatory.

  • Enzyme therapy with recombinant ALP (asfotase alfa) is currently prohibitively costly.

  • Treatment with anabolic bone agents such as teriparatide has been reported, but whether normally mineralized bone is formed requires further study.