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Hypophosphatemic Rickets

  • Author: James CM Chan, MD; Chief Editor: Stephen Kemp, MD, PhD  more...
Updated: Dec 02, 2015


Hypophosphatemic rickets is a form of rickets that is characterized by low serum phosphate levels and resistance to treatment with ultraviolet radiation or vitamin D ingestion. The term rickets evolved from the old English word wrick, which means "to twist." This twisting or bending of the bones has been known to physicians since antiquity and, as with many diseases, was gradually found to encompass more than a single etiology.

Since the early 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 revealed low serum phosphate concentration as a common factor. Familial occurrence of this condition led to the diagnosis of familial hypophosphatemic rickets. Treatment 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. (See Etiology and Treatment.)

With recent advances in the understanding of the genetic basis of familial hypophosphatemic rickets, the name of X-linked hypophosphatemic rickets has become more commonly used.[1] X-linked hypophosphatemia (XLH) is a dominant disorder and accounts for more than 80% of all familial hypophosphatemia. XLH is considered to be a systemic disorder, from mutation of the phosphate-regulating gene homologous to endopeptidases on the X chromosome (PHEX). PHEX stimulates fibroblast growth factor-23 (FGF-23), expressed in bone.[2, 3] FGF-23 requires heparin and Klotho for binding to the proximal tubule to stimulate phosphaturia. Circulating FGF-23 concentrations have been shown to be 5 times higher in XLH patients, resulting in significant phosphaturia. Finally, XLH patients demonstrate a normal or low serum concentration of 1,25-dihydroxyvitamin D3, suggestive of inadequate formation of this vitamin D metabolite.

The remaining 20% of familial hypophosphatemia patients have autosomal dominant hypophosphatemic rickets from gain-of-function autosomal recessive hypophosphatemic rickets and hereditary hypophosphatemic rickets with hypercalciuria.[1]

Impaired growth and rickets of the femur/tibia are characteristics of XLH. Delayed dentition; dental abscesses; deafness; Chiari malformation; extraskeletal calcification of the tendons, ligaments, and joint capsules; and craniosynostosis are occasionally encountered.

Serum phosphate reduction in relation to normal levels was equal for male and female subjects. Females generally had markedly less bone disease than males, suggesting the random inactivation of the affected X chromosome in females, as might be expected from the Lyon hypothesis. However, lowered serum phosphate levels correlated with an equal degree of renal tubular reduction of tubular time of maximal concentration (Tmax) of phosphate in both sexes, pointing to an additional factor in the creation of the bone disease in affected males. (See E tiology and Workup.)

In XLH patients, the severe hypophosphatemia (< 2.5 mg/dL) is associated with elevated serum alkaline phosphatase. However, despite the severe hypophosphatemia, the serum calcium, PTH, andf 25-hydroxyvitamin D concentrations are normal. Even the serum concentration of 1,25 dihydroxyvitamin D is inappropriately normal or low in XLH patients. Bone radiographs show short, squat long bones and coarse, axial skeleton trabeculation, especially in boys. More severe rachitic knees than wrists are also characteristic findings.

Filtered phosphate, not reabsorbed in the proximal tubule, becomes concentrated in the thick descending limb of loop of Henle, due to water retrieval. The thick descending limb becomes rich in mucopolysaccharides, which attracts calcium phosphate. Such crystals, on migration to the papilla get precipitated as stones.[4]


An outstanding feature of familial hypophosphatemic rickets is short stature.[5] The short stature associated with this condition is disproportionate, resulting from deformity and growth retardation of the lower extremities. Attempts have been made in clinical trials to address patient stature by adding growth hormone (GH) to the usual treatment protocol to stimulate growth plates in the long bones. At least one study reported a mild degree of disproportionate truncal growth, which requires further evaluation. (See Medication.)[6, 7]

Although GH therapy has been effective in promoting short-term growth, its high cost discourages widespread use. As a result, many properly treated children ultimately achieve less-than-average height.

Patient education

Provide genetic counseling following initial diagnosis to help an affected child's parents understand the hereditary basis of the condition. Counseling must be provided with sensitivity to avoid family conflict. In addition, the patient and family need to know the importance of close follow-up to avoid complications.



Several of the most vexing questions about the underlying mechanism that causes the clinical phenotype of X-linked hypophosphatemia remain unanswered. A key question awaiting explication concerns the equal degree of reduction in tubular Tmax in both sexes juxtaposed against the significant difference in clinical disease between the sexes. Another question involves the relationship between the reduced tubular Tmax and the reduced 1-alpha-hydroxylation of 25-hydroxycholecalciferol.[8, 9, 10]

PHEX gene

Nonetheless, great strides have been made in studying hypophosphatemic rickets, particularly with the cloning of the mutant gene known as PHEX.[11] The change created in the gene is a loss-of-function mutation, resulting in reduced breakdown and leading to circulatory clearance of a substance known as fibroblast growth factor-23 (FGF23). FGF23 acts on the kidney to cause increased phosphate excretion and decreased alpha-1 hydroxylase activity. The gene product is now known to be a zinc-metallopeptidase.[12, 4]

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 2 mechanisms acting in synergy could account for the massive hyperphosphaturia in this disorder.[13]

Effect of low phosphate levels on bone metabolism

The pathogenesis of hypophosphatemic rickets is clear; 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 cotransporter in the epithelial cell brush border.

Normal phosphate reabsorption in response to 1 α,25-dihydroxycholecalciferol (calcitriol) provides clear evidence that the sodium-phosphate cotransporter is capable of proper function and is not intrinsically defective. This evidence also bolsters the hypothesis advanced above, which implicates an additional factor in the pathogenesis of the phosphaturia.[14]

Inadequate levels of inorganic phosphate impair the function of mature osteoblasts (ie, bone matrix ossification), because formation of mature bone involves the precipitation of hydroxyapatite [3-Ca3 (PO4)2: Ca(OH)2] crystals. Although treatment with oral phosphate supplements should remedy the defect, all such attempts have failed. This failure could be due to the enhanced mineralization-inhibiting presence of the ASARM peptide secondary to the mutated PHEX gene in bone.

The advantages of improved technology and hindsight now confirm that phosphate supplementation elicits a parathyroid hormone (PTH) response to the fall in serum calcium from the temporary surge in bone mineralization induced by phosphate ingestion. Following this surge is an immediate return to the initial status quo, because PTH depresses phosphate reabsorption at the renal tubule. Data suggest that hyperparathyroidism may be a part of the clinical disorder preceding any therapy.

Although much has been learned about the etiology of hypophosphatemic rickets, a great deal more remains undiscovered.



Although serum phosphate levels are similarly depressed in affected males and females, the degree of bone involvement is substantially less severe in heterozygous females. All hemizygous males are clinically affected.[15]

As in all genetic disorders, hypophosphatemic rickets is present from conception. Infant birth weight is generally normal, but early growth may be slower than normal. The author's experience indicates abnormalities are common at birth, including cranial synostosis and increased bone density.



Apart from the short stature of most affected adults, the prognosis for a normal lifespan and normal health is good.

The chief aspects of morbidity in X-linked hypophosphatemia are the metabolic processes linked to phosphate. Clinically, the most obvious of these aspects is the effect on bone formation and growth that causes very severe rickets, especially in affected males. The early development of rickets indicates alterations in the orderly processes of bone growth and remodeling that cause bone deformation. Abnormal dentine formation causes late dentition and spontaneous abscess formation.

Hypercalcemia, nephrocalcinosis, and hypertension

Acute hypercalcemia (with resulting irritability, confusion, and potential seizures) can occur during treatment. Nephrocalcinosis, the long-term result of overaggressive therapy, may be more damaging. Aside from hypercalcemia from vitamin D supplementations, the phosphate supplementations need to be approached with caution. A long-term study in XLH patients treated with combination therapy demonstrated a distinct relationship between mean phosphate dose and the grade of nephrocalcinosis; if the phosphate supplementations are kept to below 60 mg/kg body weight per day, the risk of nephrocalcinosis is minimized.[16] Although ultrasonography reveals that 47% of properly treated patients show evidence of nephrocalcinosis, this condition in X-linked hypophosphatemia apparently does not usually progress to renal failure.

Hypertension has been reported in older children under treatment as a consequence of persistent hyperparathyroidism.[17] Nephrocalcinosis did not need to be present for hypertension to occur. Consequently, patients under treatment should be carefully monitored for laboratory signs of hyperparathyroidism.

Contributor Information and Disclosures

James CM Chan, MD Professor of Pediatrics, Tufts University School of Medicine; Director of Research, The Barbara Bush Children's Hospital, Maine Medical Center

James CM Chan, MD is a member of the following medical societies: American Pediatric Society, Alpha Omega Alpha, American Academy of Pediatrics, American Physiological Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology

Disclosure: Nothing to disclose.


Karl S Roth, MD Retired Professor and Chair, Department of Pediatrics, Creighton University School of Medicine

Karl S Roth, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American College of Nutrition, American Pediatric Society, American Society for Nutrition, American Society of Nephrology, Association of American Medical Colleges, Medical Society of Virginia, New York Academy of Sciences, Sigma Xi, Society for Pediatric Research, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Stephen Kemp, MD, PhD Former Professor, Department of Pediatrics, Section of Pediatric Endocrinology, University of Arkansas for Medical Sciences College of Medicine, Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics, American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi Beta Kappa, Southern Medical Association, Southern Society for Pediatric Research

Disclosure: Nothing to disclose.

Additional Contributors

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for Pediatric and Adolescent Diabetes

Disclosure: Nothing to disclose.

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