Hypophosphatemic rickets
Hypophosphatemic rickets is a rare genetic disorder characterized by impaired bone formation, leading to rickets in children and osteomalacia in adults. It is primarily caused by genetic mutations that disrupt the reabsorption of phosphorus in the kidneys, resulting in low levels of phosphorus necessary for healthy bone mineralization. Several genetic factors are involved, including mutations in the PHEX and FGF23 genes, with X-linked hypophosphatemic rickets (XLH) accounting for the majority of cases.
Symptoms typically manifest in children as bowing of the lower limbs, short stature, and dental issues, while adults may experience bone pain and muscle weakness. Diagnosis is achieved through blood tests showing low phosphorus levels, normal calcium levels, and genetic testing for specific mutations. Treatment generally involves oral calcitriol and phosphate supplements, with newer therapies like the monoclonal antibody burosumab being approved for certain cases.
Early intervention is crucial to prevent severe deformities and complications. As awareness of nutritional deficiencies linked to socioeconomic factors grows, especially in certain regions, public health initiatives are encouraged to ensure children receive an adequate diet and necessary supplements to prevent conditions like hypophosphatemic rickets.
Hypophosphatemic rickets
ALSO KNOWN AS: X-linked hypophosphatemic rickets; XLH; autosomal dominant hypophosphatemic rickets; autosomal recessive hypophosphatemic rickets; hereditary hypophosphatemic rickets with hypercalciuria; tumor-induced osteomalacia; oncogenic osteomalacia; oncogenic hypophosphatemic osteomalacia
DEFINITION Hypophosphatemic rickets is a disorder of bone formation leading to rickets in children or osteomalacia in adults. The disorder is caused by genetic defects that result in inadequate phosphorus reabsorption by the kidneys and subsequent inadequate phosphorus supply for bone formation, or by a reduction in bone matrix proteins needed for mineralization.
Risk Factors
Several defective genes have been shown to lead to hypophosphatemic rickets, including PHEX, FGF23, DMP1, and SLC34A3. Since hypophosphatemic rickets is a rare disease, affecting only one in 20,000 persons, it is not feasible to screen the general population for the disorder. However, parents known to be affected should be tested.
X-linked hypophosphatemia (XLH) is a dominant disorder of the X sex chromosome. A father with the disorder will pass on XLH to all of his daughters but none of his sons. A mother with the disorder has the probability of passing on XLH to fifty percent of her sons and daughters. Males with defective genes exhibit more severe bone disorders than affected females.
Etiology and Genetics
Parathyroid hormone and vitamin D3 play key roles in phosphorus homeostasis (balance) in the body, responding to dietary phosphorus absorption through the intestine and phosphorus reabsorption through the kidneys. In order for vitamin D3 to exert its physiological effects, it must be converted to the hormone form, 1,25-dihydroxy vitamin D3 (1,25 (OH)2D), in the body. Researchers have proposed that the effects of hypophosphatemic rickets are mediated through hormone-like peptides called phosphatonins, and a bone mineralization inhibitor called minhibin. The phosphatonins may include PHEX and FGF23, while MEPE may be the postulated minhibin. These substances are described in the following text.
There are five known genetic causes of hypophosphatemic rickets. The metabolic defects associated with these genetic abnormalities are interrelated and complex and many questions remain.
X-linked hypophosphatemic rickets, accounting for about 80 percent of all cases, is caused by loss-of-function mutations in the PHEX gene located on the X chromosome. This gene codes for a PHEX enzyme that is membrane bound in cells of bone and teeth. A defective PHEX gene, through a yet-to-be-identified substrate intermediate, results in buildup of full-length FGF23 and instability of a compound called matrix extracellular phosphoglycoprotein(MEPE). Normal PHEX inhibits breakdown of MEPE by cathepsin B protease enzymes. Defective PHEX permits breakdown to occur, releasing a peptide group known as ASARM which inhibits bone mineralization. ASARM may also inhibit renal phosphate reabsorption through reduced activity of sodium-phosphate cotransporter (NPT-2). This leads to low blood phosphorus (hyphosphatemia).
Autosomal dominant hypophosphatemic rickets are a result of missense mutations in fibroblast growth factor 23 (FGF23) gene, which makes the resultant protein resistant to breakdown by protease enzymes. Full-length FGF23 inhibits phosphate reabsorption by the kidney due to reduced activity of NPT-2 and inhibits proteins required for mineralization of bone. Mutations in either PHEX or FGF23 result in decreased 1,25(OH)2D levels, while the normal response to hyphosphatemia is to increase 1,25(OH)2D levels.
Tumors that induce osteomalacia have been shown to overproduce FGF23 that overpowers the body’s mechanism for its degradation.
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is caused by mutations on the sodium-phosphate cotransporter gene, SLC34A3, resulting in reduced reabsorption of phosphorus from the kidneys. Contrary to other causes of hypophosphatemic rickets, HHRH shows increased levels of 1,25(OH)2D, resulting in increased intestinal absorption of calcium, and hypercalcemia.
Autosomal recessive hypophosphatemic rickets (ARHR) can be caused by inactivating mutations in dentin matrix protein-1 gene. ARHR results in metabolic abnormalities similar to other genetic causes of hypophosphatemic rickets.
Symptoms
All causes of hypophosphatemic rickets lead to the same symptoms. Children exhibit bowing of the lower limbs, short stature, enlargement of wrists and knees, late dentition and tooth abscesses. Adults show signs of osteomalacia including bone pain and muscle weakness.
Screening and Diagnosis
Hypophosphatemic rickets demonstrates low serum phosphorus, normal serum calcium, inappropriately normal 1,25(OH)2D, and greater urinary loss of phosphorus. Radiography of bone deformities is definitive for rickets, but does not distinguish hypophosphatemic rickets from other causes. Genetic testing for deformities in PHEX or FGF23 can allow differential diagnosis from other causes of rickets.
Treatment and Therapy
Calcitrol (1,25 dihydroxy vitamin D3) given orally is the standard treatment for familial hypophosphatemic rickets. Standard vitamin D3 should not be used, since near toxic levels would be needed for effectiveness. Phosphate salts are given as capsules or pills to replenish loss of phosphorus. In 2018, the US Food and Drug Administration approved the injectable monoclonal antibody burosumab for use in some cases. Surgery may be necessary to correct limb deformities, reducing pain and restoring function. In 2023, researchers working at Children’s Hospital Los Angeles discovered that in addition to surgery, providing metabolic control following surgical treatment ensured better outcomes. Metabolic control monitors and supplements the nutrients that lead to rickets; researchers found that this type of treatment improved outcomes more than metabolic control measures undertaken before surgery.
Prevention and Outcomes
Early treatment is essential to minimize limb and growth deformities. There is a critical balance between adequate phosphate and calcitrol treatments to cure the clinical picture, but not to give rise to hypercalcemia.
In 2019, physicians in the United Kingdom raised concerns about rising cases of rickets, among other diseases not commonly seen in developed nations since the nineteenth century. They attributed this poor nutrition sparked by childhood poverty as well as the frequently cloudy weather conditions in the UK. They emphasized the need for programs to ensure proper nutrition along with the use of nutritional supplements to ensure children have adequate nutrients to prevent rickets.
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