Clinical Pearls & Morning Reports
Published June 15, 2022
When evaluating a patient with multiple fractures, obtaining a thorough history is critical. If the history and pattern of fractures are not suggestive of physical abuse or a genetic fragility disorder, one can turn to laboratory studies for additional information. Read the NEJM Case Records of the Massachusetts General Hospital here.
Q: What are some of the causes of hypophosphatemia?
A: There are many causes of hypophosphatemia. Acute hypophosphatemia is common among hospitalized patients and frequently results from carbohydrate refeeding or intracellular shifts, as is often seen in patients being treated for diabetic ketoacidosis. Causes of phosphate wasting in the kidney include hyperparathyroidism, hereditary hypophosphatemic rickets with hypocalciuria, and use of diuretic agents. Fanconi’s syndrome is a renal tubule disorder that causes hypophosphatemia.
Q: What does fibroblast growth factor 23 (FGF23) do?
A: FGF23, a hormone that is produced in bone, signals the kidney to excrete phosphate and decrease the production of 1,25-dihydroxyvitamin D. FGF23 plays an important role in normal phosphate and vitamin D homeostasis. Excessive FGF23 levels occur in association with certain disease states that can lead to hypophosphatemia. Genetic causes include X-linked hypophosphatemia, autosomal recessive hypophosphatemic rickets, and autosomal dominant hypophosphatemic rickets. These disorders typically manifest in childhood.
A: FGF23-mediated hypophosphatemia that manifests in adulthood is often caused by tumors that secrete FGF23. Although many types of tumors can secrete FGF23, the most common is referred to as a phosphaturic mesenchymal tumor of the mixed connective-tissue type (PMTMCT). Patients with a PMTMCT present with isolated hypophosphatemia, an inappropriately normal or low 1,25-dihydroxyvitamin D level, osteomalacia (and rickets in children), bone pain, and proximal muscle weakness. Unfortunately, diagnosis is often delayed, and patients may be wheelchair-bound or bedbound by the time of diagnosis. The tumor can be found almost anywhere in the body, is usually benign, and can be removed or ablated, although it can recur years later.
A: PMTMCTs are the most common cause of tumor-induced osteomalacia. Such tumors are rare, with approximately 500 affected patients reported to date. These tumors typically manifest in adulthood, with a wide age distribution. An overwhelming majority of PMTMCTs show increased FGF23 expression, which can be detected by a reverse-transcriptase–polymerase-chain-reaction assay, chromogenic in situ hybridization, or other methods. Genetically, approximately 70% of PMTMCTs harbor gene rearrangements involving FGFR1 or FGF1.