eMedicine Specialties > Pediatrics: General Medicine > Endocrinology

Hypophosphatemic Rickets

Author: Karl S Roth, MD, Professor and Chair, Department of Pediatrics, Creighton University School of Medicine
Coauthor(s): James CM Chan, MD, Professor of Pediatrics, University of Vermont College of Medicine; Director of Research, The Barbara Bush Children's Hospital, Maine Medical Center
Contributor Information and Disclosures

Updated: Feb 6, 2009

Introduction

Background

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 has 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.

In 1958, the definitive study of familial hypophosphatemic rickets gave legitimacy to the formal name of X-linked hypophosphatemic rickets.¹ This amply detailed and large pedigree study defined hypophosphatemia as a highly reliable disease marker.

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 (T_max) of phosphate in both sexes, pointing to an additional factor in the creation of the bone disease in affected males. Although clinical response to different analogues of cholecalciferol suggests that the deficient factor may be 1-alpha-hydroxylation of the 25-hydroxycholecalciferol metabolite released from the liver; however, no direct evidence has been reported.

Pathophysiology

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 T_max in both sexes juxtaposed against the significant difference in clinical disease between the sexes. Another question involves the relationship between the reduced tubular T_max and the reduced 1-alpha-hydroxylation of 25-hydroxycholecalciferol.

Great strides have been made in recent years, particularly with the cloning of the mutant gene known as PHEX. The change created in the gene is a loss-of-function mutation and results in reduced breakdown; hence, circulatory clearance of a substance known as fibroblast growth factor (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.

The PHEX gene, found on the X chromosome, is thought to protect an extracellular matrix glycoprotein (MEPES) from proteolysis through formation of a Zn-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.

The pathogenesis of this disorder 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 a,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.

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 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. Recent data suggest that hyperparathyroidism may be a part of the clinical disorder preceding any therapy.

Although much has been learned about the pathophysiology of this fascinating disorder in the 4 decades since its original definition, a great deal more remains undiscovered.

Frequency

United States

The frequency is unknown.

Mortality/Morbidity

The nomenclature alone indicates that 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.

Sex

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.

Age

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.

Clinical

History

• The earliest clinical sign of hypophosphatemic rickets is usually a somewhat slowed growth rate in the first year of life. The next clinical sign is the patient's reluctance to bear weight when beginning to stand or walk.
• Oddly, affected individuals do not have seizures and other systemic signs related to muscle function or oxidative metabolism.
• To the degree that heterozygous females are affected, patients' maternal family history is likely to include short stature and rickets. Short stature in men is also expected.
• Older children may have a history of late dentition or multiple dental abscesses.

Physical

• Affected newborns have normal weight, but infants may show growth retardation. Intellectual development is unaffected.
• Widened joint spaces and flaring at the knees may become apparent in children by their first birthday, particularly in boys. When a child begins to stand and walk, bowing of the weight-bearing long bones quickly becomes clinically evident.
• Dentition may be absent or delayed in very young children; older children may experience multiple dental abscesses.

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