Context X-linked hypophosphatemia (XLH) is characterized by excess FGF23, hypophosphatemia, skeletal abnormalities, and growth impairment. We aimed to understand the burden of disease of XLH across the life span. Methods Responses were collected from adults with XLH and parents/caregivers of a child with XLH in an online survey, including multiple-choice and open-ended questions on demographics, disease manifestations, treatment history, assistive device use, and age-specific patient-reported outcomes (PROs). Results Data was collected from 232 adults with XLH (mean age 45.6 years, 76% female), and 90 parents/caregivers of a child with XLH (mean age 9.1 years, 56% female). Mean age recalled for symptom onset was 3.2 years for adults and 1.3 years for children. When surveyed, nearly all children (99%) and 64% of adults were receiving oral phosphate, active vitamin D, or both. Prior participation in a trial investigating burosumab, a fully human monoclonal antibody against FGF23, was reported in 3% of children and 10% of adults; of these respondents, only one child reported current treatment with burosumab at the time of the survey. Both children and adults reported typical features of XLH including abnormal gait (84% and 86%, respectively), bowing of the tibia/fibula (72% and 77%), and short stature (80% and 86%). Nearly all adults (97%) and children (80%) reported bone or joint pain/stiffness. Adults reported a history of fractures (n/N = 102/232; 44%), with a mean (SD) age at first fracture of 26 (16) years. Adults reported osteophytes (46%), enthesopathy (27%), and spinal stenosis (19%). Mean scores for PROs evaluating pain, stiffness, and physical function were worse than population norms. Analgesics were taken at least once a week by 67% of adults. Conclusions Despite the common use of oral phosphate and active vitamin D established in the 1980s, children with XLH demonstrate a substantial disease burden, including pain and impaired physical functioning that persists, as demonstrated by similar responses reported in adults with XLH.

Context: X-Linked hypophosphatemia (XLH) is a lifelong metabolic disease with musculoskeletal comorbidities that dominate the adult clinical presentation. Objective: The adult XLH disorder has yet to be quantified on the basis of the physical and functional limitations that can affect activities of daily living. Our goal was to report the impact of the musculoskeletal manifestations on physical function. Design and setting: Musculoskeletal function was evaluated by validated questionnaires and in an interdisciplinary clinical space where participants underwent full-body radiologic imaging, goniometric range of motion (ROM) measurements, general performance tests, and kinematic gait analysis. Patients: Nine adults younger than 60 years with a diagnosis of XLH and self-reported musculoskeletal disability, but able to independently ambulate, were selected to participate. Passive ROM and gait analysis were also performed on age-approximated controls to account for differences between individual laboratory instrumentation. Results: Enthesophytes, degenerative arthritis, and osteophytes were found to be consistently bilateral and diffusely present at the spine and synovial joints across participants, with predominance at weight-bearing joints. Passive ROM in adults with XLH was decreased at the cervical spine, hip, knee, and ankle compared to controls. Gait analysis relative to controls revealed increased step width, markedly increased lateral trunk sway, and physical restriction at the hip, knees, and ankle joints that translated into limitations through the gait cycle. Conclusions: The functional impact of XLH musculoskeletal comorbidities supports the necessity for creating an interprofessional health-care team with the goal of establishing a longitudinal plan of care that considers the manifestations of XLH across the lifespan.

Background: X-linked hypophosphatemia (XLH) is the most common form of familial phosphate-wasting disorders, due to an inactivating mutation in the phosphate-regulating neutral endopeptidase, X-linked gene. Persistent osteomalacia, enthesophytes, osteophytes, degenerative arthritis and dental abscesses/periodontal disease dominate the adult disorder. However, the impact of insufficient phosphate on hydroxyapatite composition, the major inorganic component of bone and teeth, is unknown in individuals with XLH. Methods: Using Raman spectroscopy, the carbonate (CO₃²⁻) to phosphate (PO₄³⁻) ion ratio was measured in HYP and wild-type mice and in primary and permanent teeth from XLH individuals and unaffected controls. Results: There was a significant difference in carbonate ion substitution between the HYP and wild-type femoral cortical bone (0.36 ± 0.08 versus 0.24 ± 0.04; p < 0.001). Carbonate ion substitution levels were also higher in permanent XLH teeth compared with unaffected individuals (0.39 ± 0.12 versus 0.23 ± 0.04; p < 0.001), but not in primary teeth (0.29 ± 0.11 versus 0.26 ± 0.02; p = 0.29). Complementary Fourier transform infrared analyses demonstrated higher relative intensities of the four major vibrational bands originating from the carbonate anion in XLH teeth compared with unaffected controls. Conclusion: Ionic substitution within the crystal lattice is a common feature of hydroxyapatite and one that confers the physiological properties of bone that impact mechanical strength and the process of bone remodeling. Our data demonstrating anionic substitution in human dentin from individuals with XLH validate the use of dentin as a proxy for bone and to better understand the molecular adaptations that occur in the biochemical milieu of XLH.

Background: Muscarinic agonists are indicated for the treatment of many conditions including ileus, urinary retention, glaucoma, and Sjögren’s syndrome. Due to their lack of tissue specificity, these drugs can lead to undesirable side effects at off-target sites and may be potentiated by supplements that impact the half-life of these drugs. Case presentation: A 58-year-old Caucasian female with history of Sjögren’s syndrome, who was being managed with cevimeline, presented to the primary care office with reported hyperhidrosis, malaise, nausea, and tachycardia. She reported taking an herbal supplement containing B. monnieri and phosphatidylserine the previous night. It has been previously demonstrated that B. monnieri alters cytochrome P450 enzymes. Electrocardiogram showed no acute ST–T changes. Clinical improvement occurred with hydration and discontinuation of the supplement. Conclusions: To our knowledge, there has only been one other documented cevimeline overdose, and it was not associated with an herbal supplementation interaction. Physicians should actively elicit herbal supplement information from patients to anticipate possible drug–herb interactions. An additional consideration of clinical relevance is the known genetic variability that may affect drug responsiveness due to differences in metabolism and half-life of drugs that arise from common genetic variants of cytochrome P450 genes.