Hypophosphatemic rickets is a genetic disorder characterized by hypophosphatemia, defective intestinal absorption of calcium, and rickets or osteomalacia unresponsive to vitamin Dburosumab is given for X-linked hypophosphatemia.
Familial hypophosphatemic rickets is usually inherited as an X-linked dominant trait; other familial patterns occur but are rarer (1).
Sporadic acquired cases sometimes are caused by benign mesenchymal tumors that produce a humoral factor that decreases proximal renal tubular resorption of phosphate (tumor-induced osteomalacia).
General reference
1. Bitzan M, Goodyer PR: Hypophosphatemic rickets. Pediatr Clin N Am 66(1):179–207, 2019. doi: 10.1016/j.pcl.2018.09.004
Pathophysiology of Hypophosphatemic Rickets
The observed abnormality is decreased proximal renal tubular resorption of phosphate, resulting in renal phosphate wasting and hypophosphatemia. This defect is due to circulating factors called phosphatonins. The principle phosphatonin in hereditary hypophosphatemic rickets is fibroblast growth factor-23 (FGF-23). Decreased intestinal calcium and phosphate absorption also occurs. Deficient bone mineralization is due to low phosphate levels and osteoblast dysfunction rather than to the low calcium and elevated parathyroid hormone (PTH) levels as in calcipenic rickets (see ). Because 1,25-dihydroxyvitamin D3 levels are normal to slightly low, a defect in conversion is presumed; hypophosphatemia would normally cause elevated 1,25-dihydroxyvitamin D3 levels.
There are several forms of hypophosphatemic rickets (see table Forms of Hereditary Hypophosphatemic Rickets). A form of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is known to occur due to mutations in the proximal tubule type 2c sodium-phosphate cotransporter (NaPi2c). Defective phosphate transport and hypophosphatemia in this case result in appropriately increased 1,25-dihydroxyvitamin D3 levels, thus leading to hypercalciuria.
Tumor-induced osteomalacia is a nongenetic cause of hypophosphatemia with rickets in children. This disorder is caused by a paraneoplastic phenomenon in which ectopic fibroblast growth factor-23 (FGF-23) is produced, leading to phosphaturia and complications similar to hereditary hypophosphatemic rickets.
Forms of Hereditary Hypophosphatemic Rickets*
Form | Pattern of Inheritance | Gene (Location) | Gene Mutation Effect | Clinical Features |
|---|---|---|---|---|
X-linked hypophosphatemia (XLH) | PHEX (Xp22.1) | Inactivating mutation results in increased phosphatonin (FGF-23) production | Renal phosphate wasting with normal serum calcium, normal or low urine calcium, high alkaline phosphatase, normal or paradoxically high intact parathyroid hormone Rickets/osteomalacia, delayed dentition, dental abscess, craniofacial anomalies, hearing loss, hypertension, nephrocalcinosis (results from management) | |
Autosomal recessive hypophosphatemic rickets (ARHR) | ARHR1: DMP1 (4q22.1) ARHR2: ENPP1 (6q23.2) ARHR3: FAM20C (7p22.3)† | Loss-of-function mutations associated with inappropriate increases in FGF-23 | General features of renal phosphate wasting, normal serum calcium, low/normal urine calcium, and high alkaline phosphatase Rickets/osteomalacia, short stature, long bone deformities, spinal immobility, enthesopathies, dental and facial bony anomalies, learning disabilities | |
Autosomal dominant hypophosphatemic rickets (ADHR) | Autosomal dominant (variable penetrance) | FGF23 (12p13.32) | Unable to cleave FGF-23, leading to elevated serum levels | Although features can be similar to XLH, age at presentation and penetrance is variable. |
Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) | SLC34A3 (9q34.3) | Normal/low FGF-23 Defect in the proximal tubule NaPi2c | Phosphate wasting and high 1,25-dihydroxyvitamin D3, causing hypercalciuria, stones, and nephrolithiasis and/or nephrocalcinosis | |
Hypophosphatemia, hypercalcemia, and nephrocalcinosis (HHN) | SLC34A1 (5q35) | Suppressed FGF-23 Abnormal NaPi2a | Elevated levels of 1,25-dihydroxyvitamin D3, hypophosphatemia, hypercalcemia, hypercalciuria, and nephrocalcinosis | |
Dent disease and Lowe syndrome | Dent disease: CLCN5 (Xp11.23) Lowe syndrome: OCRL1 (Xq26.1) | Proximal tubule cytotoxicity | Renal Fanconi syndrome with wasting of phosphorus as well as low-molecular weight proteinuria and renal tubular acidosis Hypercalciuria known to occur with features of nephrolithiasis and nephrocalcinosis | |
* This table provides a brief overview of single-gene forms of hereditary hypophosphatemic rickets associated with either increased FGF-23 or normal to suppressed FGF-23. | ||||
† This form can occur in osteosclerotic dysplasia and as part of Raine syndrome (a rare skeletal dysplasia). | ||||
FGF-23 = fibroblast growth factor-23; NaPi2a = renal type 2a sodium-phosphate cotransporter; NaPi2c = renal type 2c sodium-phosphate cotransporter. | ||||
Adapted from Bitzan M, Goodyer PR. Hypophosphatemic rickets. Pediatr Clin N Am. 2019;66(1):179–207. doi:10.1016/j.pcl.2018.09.004 | ||||
Symptoms and Signs of Hypophosphatemic Rickets
The disease presents as a spectrum of abnormalities, from hypophosphatemia alone to growth retardation and short stature to severe rickets or osteomalacia. Children usually present after they begin walking, with bowing of the legs and other bone deformities, pseudofractures (ie, radiograph findings in osteomalacia that may represent areas of prior stress fractures that have been replaced by inadequately mineralized osteoid vs areas of bony erosions), bone pain, and short stature. Bony outgrowth at muscle attachments may limit motion.
Rickets of the spine or pelvis, dental enamel defects, and tetany that occur in dietary vitamin D deficiency are rarely present in hypophosphatemic rickets.
Patients with HHRH may present with nephrolithiasis and/or nephrocalcinosis.
Hypophosphatemic rickets is a common metabolic cause of craniosynostosis.
Diagnosis of Hypophosphatemic Rickets
Serum levels of calcium, phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D3, parathyroid hormone (PTH), FGF-23, and creatinine
Urinary phosphate and creatinine levels (for calculation of the tubular reabsorption of phosphate)
Bone radiographs
Often genetic testing
In calcipenic rickets, hypocalcemia is present, hypophosphatemia is mild or absent, and urinary phosphate is not elevated.
Bone radiographs are useful.
The different forms of hypophosphatemic rickets are diagnosed based on a combination of family history, clinical presentation, laboratory tests (blood and urine), and imaging tests (see table Forms of Hereditary Hypophosphatemic Rickets). Genetic testing using specific gene panels or whole exome sequencing, often in consultation with a genetic specialist, is helpful to confirm the diagnosis.
Because forms with elevated serum levels of FGF-23 are worsened by iron deficiency, complete blood count and iron tests are indicated in patients with those forms.
Family members of patients with hypophosphatemic rickets may be carriers or potentially affected. Full siblings of patients who have an autosomal recessive disorder have a 25% chance of having the disorder. Boys born to a mother with a pathogenic PHEX variant have a 50% chance of having X-linked hypophosphatemia (XLH), and all children born to a parent affected by autosomal dominant hypophosphatemic rickets (ADHR) have a 50% chance of having ADHR.
Prenatal and preimplantation genetic screening can be offered to families where a member is known to have hypophosphatemic rickets.
Children of people with a known family history of XLH or ADHR and siblings of people with autosomal recessive forms of hypophosphatemic rickets should be evaluated for prior fractures as well as for features of poor growth, bone deformities, and rickets (which can be confirmed by radiograph studies). Serum calcium and phosphate levels also should be measured. Further tests can include measurement of vitamin D, intact PTH, and alkaline phosphatase levels. Urine tests, including random measurement of calcium, phosphate, and creatinine levels or a 24-hour urine collection, also can be done (see table Forms of Hereditary Hypophosphatemic Rickets).
Treatment of Hypophosphatemic Rickets
Oral phosphate and calcitriol
Burosumab for X-linked hypophosphatemia and tumor-induced osteomalacia
Treatment of hypophosphatemic rickets consists of neutral phosphate solution or tablets. Phosphate supplementation lowers ionized calcium concentrations and further inhibits calcitriolcalcitriol can be detrimental.
Phosphate dose may need to be increased to achieve bone growth or relieve bone pain. Diarrhea may limit oral phosphate dosage. Increase in plasma phosphate and decrease in alkaline phosphatase concentrations, healing of rickets, and improvement of growth rate occur. Hypercalcemia, hypercalciuria, and nephrocalcinosis with reduced renal function may complicate treatment. Patients undergoing treatment need frequent follow-up evaluations.
1). The dose may be titrated upwards as needed to normalize serum phosphate (2).
Iron deficiency upregulates expression of bone FGF-23 and can exacerbate conditions with high FGF-23 levels/impaired FGF cleavage. Therefore, repletion of iron is essential for patients with iron deficiency in the setting of high FGF-23 hypophosphatemic conditions.
3).
Craniosynostoses, in some cases, need surgical correction.
Treatment references
1. Imel EA, Glorieux FH, Whyte MP, et al. Burosumab versus conventional therapy in children with X-linked hypophosphataemia: A randomised, active-controlled, open-label, phase 3 trial. Lancet. 2019;393(10189):2416–2427. doi:10.1016/S0140-6736(19)30654-3. Clarification and additional information. Lancet. 2019;394(10193):120. doi:10.1016/S0140-6736(19)31426-6
2. Sandy JL, Simm PJ, Biggin A, et al. Clinical practice guidelines for paediatric X-linked hypophosphataemia in the era of burosumab. J Paediatr Child Health. 2022;58(5):762-768. doi:10.1111/jpc.15976
3. Jan de Beur SM, Miller PD, Weber TJ, et al. Burosumab for the Treatment of Tumor-Induced Osteomalacia. J Bone Miner Res. 2021;36(4):627-635. doi:10.1002/jbmr.4233
Key Points
Decreased renal resorption of phosphate results in renal phosphate wasting and hypophosphatemia.
There is deficient bone mineralization due to low phosphate levels and osteoblast dysfunction.
Children have growth retardation, bone pain and deformities (eg, leg bowing), and short stature.
Patients with hypophosphatemic rickets with hypercalciuria (HHRH) may present with nephrolithiasis and/or nephrocalcinosis.
Diagnose by finding low serum phosphate levels, elevated urinary phosphate, and normal serum calcium and parathyroid hormone.
