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Musculoskeletal disorders and connective tissue disorders
Published in Steve Hannigan, Inherited Metabolic Diseases: A Guide to 100 Conditions, 2018
A number of inherited conditions that cause low blood levels of phosphorus (hypophosphataemia) as a result of increased loss of this mineral in the urine can also cause rickets and osteomalacia. The commonest form of familial hypo-phosphataemic rickets is X-linked hypophosphataemic rickets (XLHR). An afected father will pass the disease on to all of his daughters, whereas an afected mother has a 50% chance of passing the disease on to her offspring of either sex. Most patients with XLHR have been shown to have mutations in the PHEX gene (a phosphateregulating gene with homologies to endopeptidases on the X chromosome). This gene has been localised to the Xp22.1 position on the short arm of the X chromosome. The product of the PHEX gene interacts with other factors, such as fibroblastic growth factor 23 (FGF23), to prevent loss of phosphorus in the urine, and also helps to maintain normal blood levels of the active form of vitamin D (1,25-dihydroxyvitamin D3). Other conditions that lead to hypophosphataemic rickets include autosomal-dominant hypophosphataemic rickets, hereditary hypophosphataemic rickets with hyper-calciuria, and tumour-induced rickets.
Paediatric orthopaedic disorders
Published in Brice Antao, S Irish Michael, Anthony Lander, S Rothenberg MD Steven, Succeeding in Paediatric Surgery Examinations, 2017
Loss of function mutation in a gene called PHEX results in reduced breakdown and clearance of fibroblast growth factor (FGF23), which acts on the kidney to cause increased phosphate excretion and decreased vitamin D activity leading to X-linked hypophosphataemic rickets. Delay in motor milestones in the early years and development of bony deformities with short stature over time are features of this condition.
Nutritional Regulation of the Growth Plate
Published in Crystal D. Karakochuk, Kyly C. Whitfield, Tim J. Green, Klaus Kraemer, The Biology of the First 1,000 Days, 2017
Genetic studies in mice have provided important insights into the molecular mechanisms by which vitamin D deficiency impairs childhood bone formation and growth. Targeted ablation of vitamin D receptor (Vdr) in mice leads to hypocalcemia, hyperparathyroidism, hypophosphatemia (due to hyperparathyroidism), and rickets [34]. However, prevention of abnormal mineral ion homeostasis in Vdr-null mice using a high-calcium and high-phosphorus diet has prevented the development of rickets, suggesting that impaired mineral ion homeostasis, rather than Vdr-mediated signaling itself, is the primary cause of impaired bone growth [35]. Importantly, mutations in PHEX in mice, which causes hypophosphatemia (but only slightly lower calcium), and mice fed with a low-phosphorus high-calcium diet, both developed rachitic bones [36]. Similarly, children with X-linked hypophosphatemia, which results from increased urinary phosphate excretion, have decreased phosphorus but normal levels of calcium and vitamin D in blood, but also developed rickets and short stature. Taken together, evidence from mouse models and human disease collectively suggest that impaired growth in rickets is primarily caused by phosphate deficiency, rather than the lack of vitamin D or calcium per se.
A novel method for observing proportional group awareness and consensus of items arising from list-generating questioning
Published in Current Medical Research and Opinion, 2020
Any process to obtain consensus from a group of experts would benefit from understanding awareness of items on which a later consensus is to be formed. The four case studies about X-linked hypophosphatemia (XLH) are reported to demonstrate the principle of group “awareness” of items and its relationship with consensus on items retention. XLH is a rare, hereditary and progressive disorder affecting around 1 in 20–25,000 individuals and is characterised by phosphate wasting mediated through elevated levels of circulating fibroblast growth factor (FGF) 23, resulting from mutations in the phosphate regulating endopeptidase homolog, X-linked (PHEX) gene5–8. Paediatric patients with XLH typically present with complications such as impaired and disproportional growth, progressive bowing of load bearing limbs and rickets, before developing issues such as osteomalacia, hearing deficits, musculoskeletal dysfunction and dental complications as adults9,10.
Cervical dural calcification and cervical myelopathy in X-linked hypophosphataemic rickets: a case report and review of the literature
Published in British Journal of Neurosurgery, 2019
Ali A. Najefi, Daniel B. Beder, Shiraz A. Sabah, Kia Rezajooi
Hypophosphatemic rickets is a group of disorders that result from a defect in renal tubular transport of phosphate, leading to phosphate wasting and hypophosphatemia. The more common form is genetic with dominant inheritance via the X-chromosome (XLHR) and has a prevalence of 1 in 20,000.1 This disorder is characterised by rickets, osteomalacia, short stature, and lower limb deformities, specifically genu varum.1 Unlike other forms of hypophosphatemia rickets, XLHR presents with normal vitamin D levels. This occurs despite the presence of low phosphate levels as abnormal regulation of vitamin D and increased resistance, compensate for this. As there is X-linked inheritance, the disorder is present in both males and females but males will experience the disease more severely as they are hemizygous whereas females have another X-chromosome which partly compensates for the deficiency. Control of phosphate and Vitamin D re-absorption at the renal tubules is achieved by Fibroblast Growth Factor 23 (FGF-23).1 This In turn is controlled by the phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX gene). A mutation in the PHEX gene results in XLHR from lack of regulation of FGF-23 resulting in phosphate wasting. XLHR may directly affect thickening of the vertebral laminae, because the PHEX protein is highly expressed in osteoblasts.2 Therefore, it may play a more important role in sustaining phosphate homeostasis than previously thought.
Value-based decision-making for orphan drugs with multiple criteria decision analysis: burosumab for the treatment of X-linked hypophosphatemia
Published in Current Medical Research and Opinion, 2021
Björn Vandewalle, Miguel Amorim, Diogo Ramos, Sofia Azevedo, Inês Alves, Telma Francisco, Helena Pinto, Sérgio Sousa
X-linked hypophosphatemia (XLH) is a rare genetic, progressive, lifelong disease characterized by a mutation in the PHEX gene, which causes the increase of fibroblast growth factor-23 (FGF-23) serum levels, leading to the inhibition of renal re-uptake of phosphate, calcium and vitamin D homeostasis abnormalities, and consequently poor bone mineralization leading to serious skeletal changes, namely rickets and osteomalacia1,2.