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. Clinical laboratory evaluation of rickets begins with assessment of serum calcium, phosphate, and alkaline phosphatase levels. Osteotomy to realign extremely distorted leg curvatures may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate.
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.
A retrospective study by Hanna et al indicated that hereditary hypophosphatemic rickets with hypercalciuria (HHRH) may be strongly associated with the development of kidney cysts, finding them in nine of 12 study patients (75%) with the disease. The investigators suggested that elevated active vitamin D and hypercalciuria may be related to cystogenesis in HHRH, since HHRH has biochemical similarities to CYP24A1 deficiency, a condition which research also indicates is associated with kidney cysts. [8]
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. [9, 10, 11]
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. [12]
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. [13] 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. [14, 15, 16]
PHEX gene
Nonetheless, great strides have been made in studying hypophosphatemic rickets, particularly with the cloning of the mutant gene known as PHEX. [17] 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. [17, 18, 19]
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. [18]
A study by Zheng et al indicated that in X-linked hypophosphatemic rickets, the specific type of mutation, ie, truncating or nontrunctating, in the PHEX gene does not correlate with the disease’s clinical presentation and severity. [20]
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. [19]
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. [21] 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. [22]
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. [23] 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. [24] 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. [25]
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.
In addition, a study by Baroncelli et al indicated that in persons with X-linked hypophosphatemic rickets, the pulp chambers in the teeth tend to be enlarged, predisposing patients to recurrent periapical abscesses with fistulae. The investigators found significantly greater mean ratios for pulp chamber area/tooth area and pulp chamber height/pulp chamber width. In addition, the pulp horns of the primary and secondary molars of study patients were likely to be more prominent. [26]
In a study of 59 adult patients with X-linked hypophosphatemia, Chesher et al found that 42% required at least one osteotomy, while dental disease, nephrocalcinosis, and hearing impairment were found in 63%, 42%, and 14% of the patients, respectively. [27]
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. [28] 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. [29] Nephrocalcinosis did not need to be present for hypertension to occur. Consequently, patients under treatment should be carefully monitored for laboratory signs of hyperparathyroidism.
