Hypophosphatemic Rickets 

Updated: May 02, 2018
Author: James CM Chan, MD; Chief Editor: Sasigarn A Bowden, MD 

Overview

Practice Essentials

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 term 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.[4] 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.[5, 6] 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 Etiology 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.[6]

Complications

An outstanding feature of familial hypophosphatemic rickets is short stature.[6, 7] The short stature associated with this condition is disproportionate, resulting from deformity and growth retardation of the lower extremities.

Diagnosis

Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range.

Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with that for adults (2.7-4.5 mg/dL).

Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range.

The renal tubular reabsorption of phosphate (TRP) in XLH is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration. The TRP is calculated with the following formula:

1 - [Phosphate Clearance (CPi) / Creatinine Clearance (Ccr)] X 100

Management

In April 2018, burosumab (Crysvita), a monoclonal immunoglobulin G1 (IgG1) antibody that binds excess fibroblast growth factor 23 (FGF23), became the first drug approved by the US Food and Drug Administration (FDA) for XLH. Clinical trials showed that the drug normalized phosphorus levels, improved bone mineralization, improved rickets in children, and helped to heal fractures in adults.[8, 9, 10]

The usual vitamin D preparations are not useful for treatment in hypophosphatemic rickets because they lack significant 1-alpha-hydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000-50,000 U/d (at the lower limit of toxic dosage), which placed the patient in jeopardy of frequent hypercalcemic episodes. Calcitriol is now more widely available and substantially diminishes, but does not eliminate, this risk. Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis.[11]

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.[12]  Spontaneous abscesses often require periodic dental procedures.

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.

Etiology

Several of the most vexing questions about the underlying mechanism that causes the clinical phenotype of X-linked hypophosphatemia (XLH) 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.[13, 14, 15]

PHEX gene

Nonetheless, great strides have been made in studying hypophosphatemic rickets, particularly with the cloning of the mutant gene known as PHEX.[16] 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.[16, 17, 18]

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.[17]

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.[18]

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.

Epidemiology

Although serum phosphate levels are similarly depressed in affected males and females, the degree of bone involvement is substantially less severe in heterozygous females.[19] All hemizygous males are clinically affected.[1, 5]

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.[20]

A study by Endo et al found the estimated incidence of X-linked hypophosphatemic rickets in Japan to be approximately 1 case in 20,000, with this condition being the most prevalent genetic FGF-23–related hypophosphatemic disease in the country.[21]  A study by Beck-Nielsen et al determined hereditary rickets to be the prevalent form of rickets in ethnic Danish children in southern Denmark, although among all young children in that region, nutritional rickets was found to be the most common type.[22]  A study by Rafaelsen et al reported that in Norwegian children, the prevalence of X-liked dominant hypophosphatemic rickets is about 1 in 60,000.[23]

Prognosis

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.[24] 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.[25] Nephrocalcinosis did not need to be present for hypertension to occur. Consequently, patients under treatment should be carefully monitored for laboratory signs of hyperparathyroidism.

 

Presentation

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, the patient's 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 Examination

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.

 

DDx

Diagnostic Considerations

Conditions to consider in the differential diagnosis of hypophosphatemic rickets include the following:

  • Renal tubular acidosis

  • Hereditary hypophosphatemic rickets with hypocalciuria

  • Fanconi syndrome (types I and II)

  • Vitamin D ̶ dependent rickets (types I and II)

  • Vitamin D ̶ deficient rickets

  • Pseudohypoparathyroidism

Differential Diagnoses

 

Workup

Approach Considerations

Begin clinical laboratory evaluation of rickets with assessment of serum calcium, phosphate, and alkaline phosphatase levels. In hypophosphatemic rickets, calcium levels may be within or slightly below the reference range; alkaline phosphatase levels will be significantly above the reference range.

Carefully evaluate serum phosphate levels in the first year of life, because the concentration reference range for infants (5.0-7.5 mg/dL) is high compared with that for adults (2.7-4.5 mg/dL). Hypophosphatemia can easily be missed in a baby.

Serum parathyroid hormone levels are within the reference range or slightly elevated, while calcitriol levels are low or within the lower reference range. Most importantly, urinary loss of phosphate is above the reference range.

Imaging studies

In all cases of rickets, the study of choice is radiography of the wrists, knees, ankles, and long bones. However, no pathognomonic sign on radiographs distinguishes hypophosphatemic rickets from any other etiology.

On the other hand, a study by Lempicki et al indicated that in hypophosphatemic rickets, magnetic resonance imaging (MRI) reveals characteristics of the knee—including maximum physial widening and transverse degree of widening—that correlate with alkaline phosphatase levels.[26]

Renal Tubular Phosphate Reabsorption

The renal tubular reabsorption of phosphate (TRP) is calculated with the following formula:

1 - [Phosphate Clearance (CPi) / Creatinine Clearance (Ccr)] X 100

The following formula calculates CPi:

[Urine Phosphate (mg/dL) X Volume (mL/min)] / Plasma Phosphate (mg/dL)

By substituting creatinine values for phosphate in the same formula, Ccr can also be calculated. A single early morning urine sample can be used, because CPi divided by Ccr causes units of urine volume to cancel each other.

The TRP in X-linked hypophosphatemia is 60%; normal TRP exceeds 90% at the same reduced plasma phosphate concentration.

 

Treatment

Approach Considerations

Treatment of hypophosphatemic rickets can be safely administered on an outpatient basis, although serum calcium concentrations must be periodically and carefully monitored. Conscientious follow-up is essential.[27]

In children receiving treatment, periodic renal ultrasonography studies are important to monitor for the development of nephrocalcinosis. Originally thought to be a sequela of the disease, this complication is now recognized as an iatrogenic result of therapy. Monitoring the ratio of calcium to creatinine in the urine is also important. A ratio of more than 0.25:1 requires reduction of the vitamin D dosage to avoid nephrocalcinosis. Consult a nephrologist for help treating any patient with possible kidney involvement.

Surgical care

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.[12]  Spontaneous abscesses often require periodic dental procedures.

A retrospective study by Gizard et al suggested that in patients with X-linked hypophosphatemic rickets, corrective surgery for leg bowing performed before puberty carries an increased risk that the limb deformity will recur. In the study, patients underwent osteotomy and bone alignment (with the exception of three transient hemiepiphysiodesis procedures). Fourteen out of 49 patients (29%) experienced recurrence, with the number of additional surgeries required being highest in individuals who underwent their first surgery before age 11 years and lowest in those whose first surgery was performed after age 15 years.[28]

Activity

If a patient is able, no activity restrictions are needed. Affected individuals obviously should not engage in contact sports until rickets is completely healed.

Pharmacologic Therapy

In April 2018, the FDA approved burosumab, the first drug for X-linked hypophosphatemia (XLH). Burosumab is a monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23). This action normalizes phosphorus levels, improves bone mineralization, improves rickets in children, and helps to heal fractures in adults.[8, 9, 10]

Approval for children followed a 64-week, randomized, open-label study in 52 patients aged 5 to 12 years, in which burosumab therapy was associated with an improvement in rickets, a rise in serum phosphorus levels, a reduction in serum alkaline phosphatase activity, and an increase in growth. Forty-week data from an open-label study in 13 patients aged 1 to 4 years also back up the indication, with burosomab showing similar benefits to the 64-week study.[8, 9, 10]

Approval in adults with XLH (n=134) was supported by a randomized, double-blind, placebo-controlled study. Compared with patients on placebo, a higher proportion of burosumab-treated adults attained serum phosphorus levels above the lower limit of normal. In addition, the rate of complete healing for active fractures and pseudofractures for burosumab treatment outpaced that of placebo therapy. A 48-week, open-label, single-arm bone biopsy study in 14 adults also bolstered the adult indication, with osteomalacia healing revealed by decreases in osteoid volume/bone volume, osteoid thickness, and mineralization lag time.[29, 30, 8, 9, 10]

The usual vitamin D preparations are not useful for treatment in this disorder because they lack significant 1-alpha-hydroxylase activity. Original treatment protocols advocated vitamin D at levels of 25,000-50,000 U/d (at the lower limit of toxic dosage), which placed the patient in jeopardy of frequent hypercalcemic episodes. Calcitriol is now more widely available and substantially diminishes, but does not eliminate, this risk. Amiloride and hydrochlorothiazide are administered to enhance calcium reabsorption and to reduce the risk of nephrocalcinosis.[11]

Healing of the rachitic changes typically occurs within 6-8 weeks of instituting treatment. During this time, maintain the calcitriol within the recommended dosage to maintain serum calcium and phosphate levels within reference ranges. Monitor these levels weekly over the first 2-3 months of treatment. Urinary calcium and phosphate excretion monitoring also are important.

The patient's requirements for calcium deposition and vitamin D to expedite the healing process diminish as healing progresses; thus, the patient with hypophosphatemic rickets becomes highly susceptible to hypercalcemia during this phase. Consider reducing the calcitriol dosage at this time, guided by the weekly calcium and phosphorus measurements, until a reduced and stable dosage is reached.

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.)[31, 32] Although GH therapy has been effective in promoting short-term growth, its high cost discourages widespread use.

A randomized, controlled, open-label study by Meyerhoff et al suggested that growth hormone (GH) therapy in short prepubertal children with X-linked hypophosphatemic rickets does not effectively increase adult height. In terms of exceeding baseline values, standard deviation scores (SDSs) for adult height, leg length, and arm length were not significant in patients who underwent 3 years of GH treatment (although the SDS for sitting height was). Body disproportion was not found to be exaggerated by GH.[33]

 

Medication

Medication Summary

Burosumab (Crysvita) is the first drug approved in the U.S. for X-linked hypophosphatemia (XLH). It is a monoclonal IgG1 antibody that binds excess fibroblast growth factor 23 (FGF23). This action normalizes phosphorus levels, improves bone mineralization, improves rickets in children, and helps to heal fractures in adults.[8, 9, 10]

Other treatment options include calcitriol, GH, phosphates, and anticalciurics to promote healthy bone growth and diminish mineral loss associated with hypophosphatemic rickets. As previously stated, acute hypercalcemia (with resulting irritability, confusion, and potential seizures) can occur during treatment. Nephrocalcinosis, the long-term result of overaggressive therapy,[11] may be more damaging.

Unless a concomitant GH deficiency is observed, administration of biosynthetic GH for growth promotion has not been approved. Only preliminary evidence of improved final height with GH therapy has been reported.[31]

Monoclonal Antibodies, Endocrine

Class Summary

The first targeted therapy directed toward correcting renal phosphate wasting, an underlying etiology of X-linked hypophosphatemia (XLH), has been approved in the United States.

Burosumab (Burosumab-twza, Crysvita)

Recombinant fully human monoclonal IgG1 antibody that binds fibroblast growth factor 23 (FGF23). This binding inhibits the biological activity of FGF23, thereby restoring renal phosphate reabsorption and increasing the serum concentration of 1,25 dihydroxy vitamin D. Burosumab is indicated for XLH in adults and children aged 1 year or older.

Vitamin D

Class Summary

Standard protocol for treatment of familial hypophosphatemic rickets includes the use of 1,25-dihydroxy-vitamin D (calcitriol). The use of calcitriol in place of standard vitamin D obviates near-toxic dosage of the latter, avoids fat storage of parent vitamin D, and diminishes the danger of hypercalcemia.

Calcitriol (Rocaltrol)

Calcitriol increases calcium levels by promoting calcium absorption in the intestines and retention in kidneys.

Phosphate replacement

Class Summary

Massive urinary phosphate loss is a problem intrinsic to the disorder, and the phosphate must be replaced.

Potassium phosphate/sodium acid phosphate (K-Phos Neutral, Phos-Nak)

This is a neutralized, buffered, oral phosphate-replacement solution containing 250 mg phosphorus, 280 mg potassium, 160 mg sodium . It is a combination of sodium and potassium phosphate.

Diuretics

Class Summary

Thiazides are anticalciuric, an effect that can assist in counteracting the tendency for bone calcium loss.

Hydrochlorothiazide (Microzide)

Hydrochlorothiazide is a well-known diuretic with antihypertensive action. It inhibits reabsorption of sodium in distal tubules, causing increased excretion of sodium and water, as well as of potassium and hydrogen ions. Hydrochlorothiazide is not metabolized and is rapidly excreted in the urine.

Amiloride

Hypokalemia is a hazard when kaliuretic-effect thiazides are used; this danger that can be counteracted with the use of a second diuretic. Amiloride has a well-characterized antikaliuretic effect. Often used together with thiazides for its synergistic antihypertensive effects, amiloride has the benefit of decreasing potassium loss. Thus, it is a useful adjunct in the treatment of patients with familial X-linked hypophosphatemia with thiazides, in whom hypokalemia is a risk.

 

Questions & Answers

Overview

What is hypophosphatemic rickets?

What are the complications of hypophosphatemic rickets?

How is hypophosphatemic rickets diagnosed?

How is hypophosphatemic rickets treated?

What is included in patient education about hypophosphatemic rickets?

What causes hypophosphatemic rickets?

What is the role of genetics in the etiology of hypophosphatemic rickets?

What is the role of low phosphate levels in the etiology of hypophosphatemic rickets?

What is the prevalence of hypophosphatemic rickets?

What is the prognosis of hypophosphatemic rickets?

Presentation

Which clinical history findings are characteristic of hypophosphatemic rickets?

Which physical findings are characteristic of hypophosphatemic rickets?

DDX

Which conditions should be included in the differential diagnoses of hypophosphatemic rickets?

What are the differential diagnoses for Hypophosphatemic Rickets?

Workup

What is the role of lab testing in the diagnosis of hypophosphatemic rickets?

What is the role of imaging studies in the diagnosis of hypophosphatemic rickets?

How is renal tubular reabsorption of phosphate (TRP) calculated during the workup of hypophosphatemic rickets?

Treatment

How are hypophosphatemic rickets treated?

What is the role of surgery in the treatment of hypophosphatemic rickets?

Which activity modifications are used in the treatment of hypophosphatemic rickets?

What is the role of pharmacologic therapy in the treatment of hypophosphatemic rickets?

Medications

Which medications are used in the treatment of hypophosphatemic rickets?

Which medications in the drug class Diuretics are used in the treatment of Hypophosphatemic Rickets?

Which medications in the drug class Phosphate replacement are used in the treatment of Hypophosphatemic Rickets?

Which medications in the drug class Vitamin D are used in the treatment of Hypophosphatemic Rickets?

Which medications in the drug class Monoclonal Antibodies, Endocrine are used in the treatment of Hypophosphatemic Rickets?