Welcome to the Endocrine Society's fellow training series, Rare Bone Disease Module. In this section, we'll be talking about hypophosphatemic disorders. The objectives are for you to be able to describe FGF23, manage hypophosphatemic rickets, and identify the most common genetic mutation. FGF23 comes primarily from osteocytes in the setting of an elevated serum phosphate, 125 vitamin D, and PTH levels. It binds to cloth FGF receptor complexes in the kidney tubules, leading to reduced expression of sodium phosphate transporters, thus causing increased urinary excretion of phosphorus. Furthermore, elevated FGF23 inhibits the 1-alpha hydroxylation of 25 vitamin D that leads to a reduction in 125 vitamin D levels in the kidney, which results in reduced phosphate absorption in the gut. The resultant hypophosphatemia leads to osteomalacia, bone pain, fractures, and muscle weakness. Overall, if you can remember anything from this slide, remember that FGF23 wastes phosphorus into the urine. Question, what is the primary problem in hereditary hypophosphatemic rickets? Is it A, vitamin D resistance, B, vitamin D deficiency, or C, phosphate wasting? Please pause the video if you need more time. The best answer is C, because FGF23 causes phosphate wasting from the serum into the urine for hereditary hypophosphatemic rickets. This is a case that summarizes one of my actual patients. She is a 61-year-old woman who presents for a medication refill. She received a diagnosis of hereditary hypophosphatemic rickets when she was five years old. Her other medical problems include fractures that required 11 osteotomies over a 10-year period, fibromyalgia, osteoarthritis, hypertension, and surgery to remove a calcium deposit from her ankle. Her medications include hydrochlorothiazide and supplements. This is the patient's pedigree. Circles are women, squares are men, black are affected family members, and white are unaffected family members. The patient's paternal grandmother had bowed legs, so it is likely that she had rickets. The patient's father, children, and grandchildren have confirmed hypophosphatemic rickets. Physical exam and labs are significant for hypertension, obesity, elevated parathyroid hormone, and hypophosphatemia. Please think about how you would manage her. The phenotype of hereditary hypophosphatemic rickets consists of osteomalacia, poor bone growth, especially in the legs, leg deformity, bone pain, and fractures. Tooth abscesses occur more often in the X-linked type. Enthesopathy is a disorder involving attachments of tendons or ligaments to bone. You can see this at the white arrows in the picture on the right. It occurs in both the X-linked and autosomal dominant types. Patients have hypophosphatemia and high urinary phosphorus levels. Serum calcium is normal, which contrasts with a low calcium in osteomalacia from vitamin D resistance. Serum, 125 vitamin D, and urinary calcium are typically low or inappropriately normal. PTH is typically high or inappropriately normal. There are many genetic mutations that alter FGF23. The most common is of the FEX gene and is X-linked. Question, which lab is most consistent with hereditary hypophosphatemic rickets? Is it A, a high serum phosphorus, B, a low urinary phosphorus, C, a high PTH, or D, a low FGF23? Please pause the video if you need more time. The best answer is C, because the labs typically show a low serum phosphorus, high urinary phosphorus, high or normal PTH, and high FGF23. Question, what gene defect causes most X-linked hereditary hypophosphatemic rickets? Is it A, COL1A1 gene mutation, B, a postzygotic activating mutation of GNAS, C, an inactivating mutation of FEX, or D, an inactivating mutation of BNP1? Please pause the video if you need more time. The best answer is C. A leads to osteogenesis imperfecta, B leads to McCune-Albright syndrome, and D leads to autosomal recessive hypophosphatemic rickets. Not the X-linked form. It is standard of care to teach children with high doses of calcitriol and phosphate. Osteomalacia recurs when stopping these supplements. However, adults have fewer skeletal problems, so treatment is controversial in this age group. Treating adults may help their teeth. It is important to treat pseudofractures, which are a form of osteomalacia. You can see an example in the picture at the red arrow. Consider treatment prior to orthopedic procedures because it can speed recovery and avoid loosening of joint prostheses. In 2018, the FDA approved Baruzumab to treat X-linked hypophosphatemic rickets in children and adults. It is an FGF23 neutralizing antibody that improves function, pain, and the biochemical profile. It is currently expensive at close to $200,000 a year, so it may be challenging to get. Patients who are refractory or intolerant to calcitriol and phosphorus may have the most benefit from it. Here's another question. What is the treatment goal for hereditary hypophosphatemic rickets? Is it A, normalized serum phosphorus, B, slow growth, C, increase alkaline phosphatase, D, minimize osteomalacia, or E, promote hypercalceria? Please pause the video if you need more time. The best answer is D because patients want strong bones. It is possible to see epithelial healing on X-rays. A is incorrect because it would promote nephrocalcinosis and secondary hyperparathyroidism. B is incorrect because patients actually experience catch-up growth with therapy frequently. C is incorrect because the aim is to normalize alkaline phosphatase. E is incorrect because this can also promote nephrocalcinosis. A complication of calcitriol and phosphate treatment is nephrocalcinosis, especially with therapy early in the disease course and with higher phosphate doses. The ultrasound on the left shows a normal kidney and the ultrasound on the right shows nephrocalcinosis. It is associated with renal tubular acidosis. Adding thiazides and or amelioride may arrest progression. There is currently no long-term data on burzumab about nephrocalcinosis or cardiac complications. Phosphorus supplements may complex with calcium, lowering the serum calcium and raising PTH. This results in secondary hyperparathyroidism that can progress to tertiary hyperparathyroidism and may require surgery. Sinocalcet reduces the chance of developing secondary hyperparathyroidism. Here's another question. What is the most common inheritance pattern of hereditary hypophosphatemic rickets? Is it A, autosomal dominant, B, autosomal recessive, or C, X-linked dominant? Please pause the video if you need more time. The best answer is C because 80 to 90% of cases are X-linked dominant. The other patterns are possible but less common. This is in contrast to osteogenesis imperfecta where 90% of cases are autosomal dominant. Question. What is the first-line therapy for hereditary hypophosphatemic rickets? Is it A, calcitriol, B, sinocalcet, C, growth hormone, D, telescoping intramedullary rods, or E, bisphosphonates? Please pause the video if you need more time. The correct answer is A. Calcitriol and beruzumab are the first-line therapies for hereditary hypophosphatemic rickets. Sinocalcet and growth hormone are possible second-line agents. Telescoping rods are a treatment option for children with osteogenesis imperfecta and bisphosphonates are treatment options for osteoporosis, osteogenesis imperfecta, or McCune-Albright syndrome. A condition that is similar to hereditary hypophosphatemic rickets is tumor-induced osteomalacia. People with these tumors also have osteomalacia, renal phosphate wasting, low 125 vitamin D, and elevated FDF-23 levels. The patient in the gown has tumor-induced osteomalacia. He used to be taller than his father who was standing next to him, but the bone deformities changed his stature. Tumor-induced osteomalacia is a rare acquired perineoplastic condition. Tumors produce excess FDF-23 leading to hypophosphatemia and osteomalacia. These tumors are typically small, slow-growing, and of mesenchymal origin. They present in unusual anatomic locations, about half or more in the pelvis and legs, about 20 to 30% in the head and neck, and only about 5 to 17% in the thorac, abdomen, or arms. Patients present with profound myopathy, bone pain, and fractures. The biochemical hallmark are low serum phosphorus, low or inappropriately normal 125 vitamin D, and elevated FDF-23. 24-hour urine phosphate levels are inappropriately high for the serum phosphate level. Serum FDF-23 levels can be measured and in the fitting clinical scenario, confirm the diagnosis. Imaging modalities for tumor-induced osteomalacia include a DOTATATE scan, PET-CT, or Octreotide scan. DOTATATE has the greatest sensitivity and specificity to diagnosing an FDF-23-producing mesenchymal tumor. If imaging does not localize the tumor, selective venous sampling for FDF-23 is a diagnostic option. In this patient, Octreotide scan was negative in localizing the tumor, but the FDG PET and DOTATATE scans were positive. In panel A1 through 4, Octreotide scan did not reveal abnormal uptake in the acetabulum. However, FDG PET and DOTATATE demonstrated increased activity in the right acetabulum, which is visible in panels B1 through 4 and C1 through 4, respectively. Question, a 66-year-old man presents for osteomalacia. He went through puberty normally and did not break a bone until he was 63 years old. For the past five years, he has had myopathy and bone pain. Labs show low serum phosphate and 125 vitamin D, but high FDF-23, as well as phosphaturia. What is the most likely diagnosis? Is it A, tumor-induced osteomalacia, B, hereditary hypophosphatemic rickets, or C, pageant disease of the bone? Please pause the video if you need more time. The correct answer is A, tumor-induced osteomalacia, because phosphate wasting presented in adulthood, not childhood. Medical therapy with calcitriol at approximately one to three micrograms daily and phosphorus at about two grams daily helps skeletal symptoms and myopathy until imaging can localize a tumor. Definitive treatment involves surgical remover of the FDF-23-producing tumor, if it can be localized. Serum FDF-23 levels return to normal after successful resection. Biochemical abnormalities and osteomalacia recover over a period of about six to 12 weeks. Buruzumab is approved by the USDA for use in tumor-induced osteomalacia when tumors cannot be curatively resected. Buruzumab is a monoclonal antibody directed towards FDF-23, and in doing so, reverses the phosphaturic effect of FDF-23. It is administered as a subcutaneous injection every four weeks. In summary, FDF-23 wastes phosphate into the urine. The most common gene mutation for hypophosphatemic rickets is FEX. Treat hypophosphatemic rickets with phosphate and calcitriol or buruzumab. Treatment complications include nephrocalcinosis and hyperparathyroidism. Tumor-induced osteomalacia results from an FDF-producing tumor. DOTATATE scan is the best localizing study. Medical treatment is similar to hypophosphatemic rickets. However, tumor-induced osteomalacia is potentially curable with surgery.

FGF23

hypophosphatemic rickets

genetic mutation

osteomalacia

tumor-induced osteomalacia