Hypophosphatemic Rickets (PHEX,
FGF23)

Hypophosphatemic rickets is associated with bone deformity in growing children and osteomalacia in adults (1). Most cases of hypophosphatemic rickets, which shows a prevalence of about 1:20,000, are believed to be associated with X-linked dominant loss-of-function mutations in the gene PHEX or autosomal dominant gain-of-function mutation in the gene FGF23 (2, 3). No cure exists for hypophosphatemic rickets, but early initiation of treatment significantly improves the outcome (1, 4). Current diagnostic methods involve multiple biochemical and radiographic studies and do not easily allow diagnosis of hypophosphatemic rickets in infants (1). In cases of adult-onset osteomalacia, differentiation between tumor-induced and genetic forms may be difficult (5).

Genetic testing for mutations in PHEX or FGF23 can permit diagnosis of hypophosphatemic rickets at any age and based on a single blood draw. In addition, genetic testing may help to differentiate genetic from tumor-induced forms of osteomalacia.

Types and Causes of Hypophosphatemic Rickets

Rickets is characterized by defects in bone mineralization at the sites of bone growth or remodeling, leading to bone deformity and stunted growth in children. In adults, the disease is known as osteomalacia. Hypophosphatemic rickets was originally termed vitamin-D resistant rickets to differentiate it from nutritional rickets, which readily responds to vitamin D supplements. However, hypophosphatemic rickets is not due to vitamin D resistance but to renal wasting of phosphate, an important component of bone minerals. X-linked dominant loss-of-function mutations in the gene PHEX present the most frequent cause of hypophosphatemic rickets, accounting for about 80% of all cases (6). In addition, several other causes have been identified.

Phosphate Homeostasis

Phosphate homeostasis is mainly achieved through renal reabsorption of phosphate (7). Intestinal uptake of phosphate is usually not limiting, and serum phosphate is initially freely filtered in the glomerulus. About 80% of the filtered phosphate is subsequently reabsorbed, predominantly along the proximal kidney tubule. Phosphate reabsorption is achieved through sodium-phosphate co-transport across the tubular membrane. Parathyroid hormone decreases renal phosphate reabsorption by inhibiting the expression of the major class of sodium-phosphate co-transporters in the proximal tubule, the NPT2 family. Conversely, hypophosphatemia normally leads to synthesis of 1,25-dihydroxy vitamin D3, which stimulates renal phosphate reabsorption and, through increasing intestinal calcium uptake, decreases release of parathyroid hormone.

X-Linked Hypophosphatemic Rickets
X-linked hypophosphatemic rickets (XLH) is associated with loss-of-function mutations in the gene PHEX, which codes for a protein with homology to M13 zinc metallopeptidases (2, 8, 9). The physiological substrate of the PHEX gene product has not been identified. Loss-of-function mutations in PHEX have been shown to cause renal phosphate wasting indirectly, through a humoral factor (“phosphatonin”). In addition, loss-of-function mutations in PHEX are believed to affect bone mineralization by allowing an increase in the concentration of a mineralization inhibitor (“minhibin”) in bone (10, 11).

“Phosphatonin” and “Minhibin” Candidates (10, 11)

Fibroblastic growth factor 23 (FGF23) is one of the main candidates for the humoral factor (“phospatonin”) mediating renal phosphate wasting in XLH. Full-length, but not processed, FGF23 has been shown to inhibit renal phosphate reabsorption, and loss-of-function mutations in PHEX have been associated with a decrease in the proteolytic degradation of full-length FGF23. However, any effect of mutations in PHEX on FGF23 appears to be indirect, since FGF23 does not seem to constitute a substrate of the PHEX-encoded endopeptidase (12).

Loss-of-function mutations in PHEX have also been associated with an increase in the proteolytic release of a carboxy-terminal peptide from the matrix extracellular phosphoglycoprotein (MEPE). This ASARM (acidic serine-aspartate-rich MEPE-associated motif) peptide has been reported to inhibit bone mineralization and thus represents a candidate for the proposed “minhibin.”

Autosomal Dominant Hypophosphatemic Rickets
Autosomal dominant hypophosphatemic rickets (ADHR) has been associated with gain-of-function mutations in FGF23, the gene coding for FGF23 (3). These gain-of-function mutations affect the conserved proteolytic cleavage site in FGF23 (arginine₁₇₆-X-X-arginine₁₇₉), rendering the mutated FGF23 resistant to processing at this site. Consequently, the full-length FGF23, which has been shown to inhibit renal phosphate reabsorption, is allowed to persist.

Of note, autosomal recessive loss-of-function mutations in FGF23 have been associated with familial tumoral calcinosis, the “mirror” disease of ADHR. They cause increased proteolysis of FGF23, leading to hyperphosphatemia and often severe ectopic calcifications (13-15).

Hereditary Hypophosphatemic Rickets with Hypercalciuria
The genetic cause underlying hereditary hypophosphatemic rickets with hypercalciuria (HHRH) has not been identified, but is thought to be a defect in a renal sodium-phosphate co-transporter other than NPT2 or in a protein regulating NPT2 expression or activity (6).

Tumor-Induced Osteomalacia
Also known as oncogenic osteomalacia or oncogenic hypophosphatemic osteomalacia, tumor-induced osteomalacia (TIO) is associated with oversecretion of FGF23 and/or MEPE from tumors that are mostly benign and of mesenchymal origin (5, 10). The vastly increased concentrations of FGF23 and/or MEPE are believed to overpower the body’s mechanisms for proteolytic degradation of FGF23 and/or prevention of the proteolytic release of the ASARM peptide from MEPE, respectively (see “Phosphatonin” and “Minhibin” Candidates for more detail).

Clinical Presentation of Hypophosphatemic Rickets

XLH is characterized by low serum and high urine phosphate levels, inappropriately normal levels of 1,25-dihydroxy vitamin D3, defective calcification of cartilage and bone, lower extremity deformities, short stature, bone pain, enthesopathy, late dentition, and frequent dental abscesses (1, 6). Severity of the disease is highly variable both within and between families. The first symptom is often bowing of the legs as children start to walk.

ADHR presents very similar to XLH, with the additional symptom of muscle weakness. Compared to XLH, ADHR more often shows delayed onset; late-onset ADHR is not associated with bone deformity or short stature. In some cases of early-onset ADHR, reversal of phosphate wasting after puberty has been observed (16).

HHRH is characterized by low serum and high urine phosphate levels, defective calcification of cartilage and bone, lower extremity deformities, short stature, bone pain, and muscle weakness. In contrast to XLH and ADHR, serum levels of 1,25-dihydroxy vitamin D3 are elevated and hypercalciuria is present (6, 17).

TIO presents similarly to XLH and ADHR (5). Occurrence of TIO in children is rare, although it has been reported (18, 19).

Diagnosis of Hypophosphatemic Rickets

Diagnosis of hypophosphatemic rickets is currently based on detection of low serum phosphate, normal serum calcium, inappropriately normal serum 1,25-dihydroxy vitamin D₃, elevated serum alkaline phosphatase, normal to low serum parathyroid hormone, and a low tubular reabsorption rate of phosphate and radiological demonstration of rachitic bone deformities (1). Rachitic deformities are often most apparent at the end of the long bones in the legs, manifesting as flared metaphyses with frayed borders, but may be difficult to detect in infants. In addition, hypophosphatemia may be easily missed in infants, since the reference range for serum phosphate is age dependent.

In sporadic cases of hypophosphatemic rickets or osteomalacia in older children or adults, an exhaustive search should be conducted for tumors causing hypophosphatemia (5). However, these tumors are often small and difficult to locate.

Genetic testing for loss-of-function mutations in PHEX or gain-of-function mutations in FGF23 can allow diagnosis of XLH and ADHR based on a single blood draw at any age. Thus, genetic testing can simplify diagnosis of hypophosphatemic rickets in infants and help to discriminate XLH and ADHR from TIO in older children and adults.

Treatment of Hypophosphatemic Rickets

Treatment of XLH and ADHR is based on oral phosphate and 1,25-dihydroxy vitamin D₃ (calcitriol) supplements (1). Addition of calcitriol is necessary since unopposed phosphate therapy can lead to secondary hyperparathyroidism, which aggravates renal phosphate wasting. Since calcitriol therapy typically gives rise to some degree of hypercalciuria, nephrocalcinosis is a frequent side effect of treatment for XLH or ADHR. Although skeletal development cannot be completely normalized by oral phosphate and calcitriol treatment, outcomes are best if therapy is initiated in early infancy (1, 4).

Growth hormone therapy in prepubertal children affected with XHL has been shown to increase adult height, but mostly through truncal rather than leg growth (20).

TIO can be cured by removal of the tumor causing the hypophosphatemia.

Genetics of Hypophosphatemic Rickets

XLH has an X-linked dominant mode of inheritance. Severity of hypophosphatemia is similar in males who are hemizygous and females who are heterozygous for a single XLH-associated mutation in PHEX, although skeletal manifestations are often more severe in males, and postpubertal males may have more severe dental disease (8). Males cannot pass on XLH to their sons, but will pass on XLH to all of their daughters. Females can pass on XLH to their sons and their daughters, who both have a 50% chance of inheriting the condition from an affected mother. Over 20% percent of XLH-associated mutations in PHEX are believed to be sporadic (8).

ADHR shows autosomal dominant inheritance. Males and females are equally affected and will pass the condition on to about 50% of their sons and daughters.

Genetic Testing for Hypophosphatemic Rickets

The Hypophosphatemic Rickets Evaluation detects mutations in PHEX and FGF23 and can diagnose hypophosphatemic rickets at any age based on a single blood draw. Early diagnosis of hypophosphatemic rickets is important, since initiation of treatment in infancy may allow minimization of skeletal deformities. Genetic testing can also be used to discriminate between XLH and ADHR, allowing more informed genetic counseling. In addition, genetic testing can identify family members who may not be aware of harboring a mutation associated with hypophosphatemic rickets because they are only very mildy affected by the disease. In cases of late-onset hypophosphatemic rickets or osteomalacia, genetic testing may help to discriminate between mutations in PHEX or FGF23 and a tumor as the cause for the condition.

How Is Genetic Testing for Hypophosphatemic Rickets Performed?

DNA for sequencing is obtained from leukocytes present in a small blood sample. The coding sequences of PHEX and FGF23 are amplified in a highly specific manner through a polymerase chain reaction (PCR), and all PCR products are fully sequenced. Sequencing results are interpreted, and a detailed result report is sent to the patient’s physician.

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