Overview Of Hypophosphatemic Rickets Biology Essay


The term rickets came from the old English word wrick, which means "to twist." This twisting of the bones which has been known to physicians since the early part of the century, was gradually found to be made of more than one etiology. Albright and colleagues made one of the first descriptions of the hypophosphatemic rickets in 1937. These authors described a clinical case of rickets, with hypophosphatemia and hyperphosphaturia resistant to normal doses of vitamin D, and classified this metabolic condition as inheritable

 X-linked hypophosphatemic rickets (XLHR). Since the beginning 20th century, ultraviolet radiation or vitamin D ingestion has been recognized as a cure for nutritional rickets, although certain forms of rachitic disease have remained refractory to this therapy. Study of these refractory cases has shown low serum phosphate concentration as a common factor. The occurrence of this condition in different families led to the diagnosis of familial hypophosphatemic rickets. Treatment of this condition with vitamin D produced no change in the rachitic state of these patients, even at rather high doses, leading to the term vitamin D-resistant rickets (Roth, Chan, 2009). Hypophosphatemic rickets which was previously known as vitamin D-resistant rickets is a condition that causes the bones to become painfully soft and bend easily because of the low levels of phosphate in the blood. This very rare disorder is almost always hereditary, and it is passed on, on the X chromosome carried as a dominant gene. This genetic abnormality makes the kidney to function defectively allowing an abnormally high amount of phosphate to be excreted into the urine, resulting in low levels of phosphate in the blood. Because phosphates are essential component for bone growth and strength, this lack of phosphates causes defective bones growth and bone weakness. Females with hypophosphatemic rickets have less severe bone disease than male partly because females have two X-chromosomes. In rare cases, the disorder develops as a result of certain cancers, such as giant cell tumors of bone, sarcomas, prostate cancer, and breast cancer. Hypophosphatemic rickets is different from the rickets caused by vitamin D deficiency (Brazy, 2006).

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Case Study

A 7-year-old girl is brought to the emergency department by her father and aunt with a chief complaint of ongoing weight loss. She recently moved from Mexico, where she had been living with her mother and two siblings, to receive further medical attention. She was in her usual state of normal health until she was 3 years, at which time she began having difficulty walking, with worsening deformities of her arms and legs. This progressed to complete inability to walk or bear weight. One year before presentation, she was seen in a clinic in Mexico and had routine blood work, as well as an electromyography (EMG) study, and was given the diagnosis of Duchenne muscular dystrophy. Her developmental history is significant for loss of fine motor skills, with normal expressive and receptive language. She eats all types of foods with no specific restrictions; however, she has always had a poor appetite. Birth and past surgical history are unremarkable. Her family history is significant for a 10-year-old brother who has decreased range of motion of all extremities, but with normal gait and weight gain. She has a 5-year-old sister with no medical issues (Zipkin, 2010).

Genetic of Hypophosphatemic Rickets

This condition is caused by a mutation on the X chromosome. The PHEX gene, found on the X chromosome, is thought to protect an extracellular matrix glycoprotein (MEPES) from proteolysis through formation of a Zinc-dependent protein-protein interaction. A mutated PHEX gene could result in failure to form this interaction, leading to proteolysis and release of the C-terminal ASARM peptide, which possesses phosphaturic and mineralization-inhibiting properties. These two mechanisms acting in synergy could account for the massive hyperphosphaturia in this disorder (Roth, Chan, 2009).

Pedigree for X - linked dominant Hypophosphatemic Rickets


Hypophosphatemic rickets which is an inherited form of rickets is caused by a mutation in the X chromosome-linked PHEX gene or the chromosome 12-linked FGF23 gene. Hypophosphatemic rickets is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Hypophosphatemic rickets, or a subtype of Hypophosphatemic rickets, affects less than 200,000 people in the US population. Even though it is relatively rare, X-linked hypophosphatemic rickets is still the most common form of familial rickets. It affects about 1 in 20,000 newborns. Each of the other forms of hereditary hypophosphatemic rickets has been identified in only a few families. In this condition, phosphate wasting at the proximal tubule level is the basis of the affected individual's inability to establish normal ossification. This phenomenon is secondary to defective regulation of the sodium-phosphate co-transporter in the epithelial cell brush border. Normal phosphate re-absorption in response to calcitriol provides clear evidence that the sodium-phosphate co-transporter is capable of proper function and is not intrinsically defective. Inadequate levels of inorganic phosphate impair the function of mature osteoblasts which helps with bone matrix ossification, because formation of mature bone involves the precipitation of hydroxyapatite [3-Ca3 (PO4)2: Ca(OH)2] crystals. Although much has been learned about the pathophysiology of this fascinating disorder in the past four decades since its original definition, a great deal more remains undiscovered (Roth, Chan, 2009).

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The diagnosis of X-linked hypophosphatemic rickets relies on several pieces of information, like taking a detailed family history, performing a physical examination, and some basic blood tests such as phosphorus, calcium, and alkaline phosphatase levels. X-rays of the bones may also be helpful. Hypophosphatemic rickets usually manifest itself in the form of bone growth abnormality in the first year of life. Abnormalities may be so mild that they produce no noticeable symptoms or so severe that they produce bowing of the legs and other bone deformities, bone pain, and a short stature. Joints movement can be limited when there is bony out growth where muscles attach to bones. The space between a baby's skull bones may close too soon, leading to seizures. Once a diagnosis of X-linked hypophosphatemic rickets has been established, genetic testing to identify the DNA sequence of the gene that causes this condition may be carried out by a geneticist. Currently, individuals with X-linked hypophosphatemic rickets are usually placed under the care of a geneticist and/or endocrinologist (Single, 2010).


Treatment of hypophosphatemic rickets can be safely administered on an outpatient basis, although serum calcium concentrations must be periodically and carefully monitored. The purpose of treatment is to increase phosphate levels in the blood, which will facilitate normal bone formation. Phosphate can be taken by mouth and should be combined with calcitriol; the activated form of vitamin D because vitamin D enhances the absorption of the phosphates. It should be noted that taking vitamin D alone is not enough to correct the problem. The amounts of phosphate and calcitriol must be adjusted carefully because this treatment can leads to high levels of calcium in the blood, the accumulation of calcium in kidney tissue, or kidney stones. These effects can harm the kidneys and other tissues. In some adults, hypophosphatemic rickets resulting from cancer improves greatly after the cancer is removed. Calcitriol is now more widely available and substantially diminishes, but does not eliminate the risk of the disease. Amiloride and hydrochlorothiazide are administered to enhance calcium re-absorption and to reduce the risk of nephrocalcinosis. Osteotomy to realign extremely distorted leg curvatures may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate. Skull deformity may require treatment for synostosis. (DiMeglio, 2001).