X-linked hypophosphatemic rickets (XLHR) is a rare genetic disorder that causes hypophosphatemia and resultant clinical rickets.
- XLHR is the most common variant among inherited hypophosphatemic rickets.
- Other forms are rare, with fewer than 100 reported cases collectively:
- Autosomal dominant
- Autosomal recessive
- Usually familial, but some cases are sporadic
- Other forms are rare, with fewer than 100 reported cases collectively:
- Not clear if both genders are affected equally
- The estimated incidence is 1 in 20,000 live births.
- X-linked inheritance
- Caused by a mutation in the phosphate-regulating gene with homology to endopeptidases located on the X chromosome (PHEX)
- The pathogenesis is not fully understood.
- Gene mutation leads to increased synthesis of fibroblast growth factor 23 (FGF23) by osteoblasts and osteocytes.
- Physiologic defect in XLHR impairs proximal renal tubular reabsorption of phosphate → hyperphosphaturia → hypophosphatemia → clinical bone and dental symptoms
- FGF23 inhibits the renal tubular reabsorption of phosphate by a mechanism different from that of the parathyroid hormone (PTH).
- FGF23 reduces the circulating levels of 1,25-dihydroxyvitamin D.
- Phosphorus plays a crucial role in:
- Growth and development
- Bone formation
- Acid-base homeostasis
- Cellular metabolism
- Phosphorus exists in both organic and inorganic forms in the human body:
- 85% of the phosphorus in bone is bound to calcium as calcium phosphate, which provides structural strength.
- 14% of the phosphorus is present at the cellular level as a component of lipids, proteins, nucleic acids, and metabolic and signaling pathways.
- 1% of the phosphorus is present in the serum and extracellular fluid.
- When phosphate is needed for homeostasis, it is obtained from bone resorption.
- High phosphate levels are necessary for infants and children to maintain adequate skeletal mineralization; thus, hypophosphatemia leads to rickets.
Clinical Presentation and Diagnosis
The clinical presentation of XLHR may vary from asymptomatic to severely symptomatic. X-linked hypophosphatemic rickets is commonly mistaken for nutritional rickets in infants, and the symptoms include:
- Short stature
- Bone pain
- Genu valgum:
- A knee deformity in which the lower leg bends outward in relation to the axis of the femur
- Results from the “softening” of bones, which causes bowed legs
- May become more prominent when children begin walking
- Flaring of the metaphysis (Erlenmeyer flask deformity) can be seen on an X-ray.
- “Rachitic rosary” is seen on chest X-ray: a row of bead-like prominence at the junction of a rib and its cartilage (enlarged costochondral joints), which resembles a rosary
- Relevant family history coupled with the screening of infants allows for the early recognition and management of XLHR.
- Important for the prevention of rachitic deformities
- Early diagnosis and treatment, initiated prior to walking and the development of leg deformities, is beneficial.
- Used to confirm hypophosphatemia and determine the ratio of tubular maximum reabsorption of phosphate (TmP) to GFR:
- Fasting serum phosphate
- Urine phosphate
- 1,25-dihydroxyvitamin D level is low or normal.
- Normal serum calcium (no hypocalcemia seen with rickets due to vitamin D deficiency)
- PTH levels may be mildly elevated (secondary hyperparathyroidism) or normal.
- High serum alkaline phosphatase
Diagnosis is confirmed by identification of the mutation on the PHEX gene, but the detection rate is approximately 65%.
Radiologic evaluation should be performed to rule out physiological bowing and bone dysplasia.
Management and Monitoring
The goals of treatment are to improve osteomalacia and skeletal deformities, improve growth in infants and physical activity in children, and decrease pain.
- High-dose supplementation:
- Activated vitamin D (calcitriol) twice daily
- Phosphate supplements: 4–5 doses/day
- Adherence to therapy may be difficult for young children.
- Overtreatment with phosphate and the development of secondary hyperparathyroidism could be detrimental and requires monitoring.
- Human anti-FGF23 monoclonal antibody
- Approved in 2018
- Currently, the treatment of choice
- Start treatment at the age of 1 year.
- Minimal side effects and less need for monitoring
- Indicated for previously untreated children or those who show limited benefits after the use of supplements
- Should never be given in combination with oral phosphate and activated vitamin D metabolites (calcitriol)
- Human anti-FGF23 monoclonal antibody
- Growth hormone has been explored as an adjunct therapy for XLHR:
- Leads to an improvement in linear growth
- Leads to a transient increase in serum phosphate
- Decreased excretion of urinary phosphate
- Corrective surgery and dental treatment are possible options.
Some adults with XLHR may have minimal medical problems, whereas others may experience persistent discomfort or complications. Monitoring the therapy for potential complications of hyperparathyroidism and nephrocalcinosis is imperative.
- Lab testing is indicated every 3 months:
- PTH to monitor for hypercalcemia, hypercalciuria, and secondary hyperparathyroidism
- Hypercalciuria may lead to nephrocalcinosis as a complication related to the drug dose.
- Secondary hyperparathyroidism can be corrected by increasing the dose of calcitriol or reducing the dose of phosphate.
- Monitor serum alkaline phosphatase levels (should decrease with treatment).
- Renal ultrasonography is suggested at 2–5-year intervals after treatment initiation for the early detection of nephrocalcinosis.
- To evaluate the healing of skeletal deformities
- When considering surgical management
- Surgical intervention should be avoided in childhood:
- Considered only if there is severe bowing or if tibial torsion does not improve with medical management
- Corrective osteotomies are not usually performed in children < 6 years of age who will likely respond to medical treatment; this intervention is reserved for older patients with more severe deformities.
- Orthopedic surgeons should be actively involved in the management of patients with XLHR.
- Autosomal dominant hypophosphatemic rickets: a rare syndrome characterized by renal phosphate wasting and rickets, which is similar to the X-linked form but transmitted in an autosomal dominant pattern. There is an increase in FGF23 similar to that observed in the X-linked form; however, this increase is inconsistent and the levels of serum phosphate can wax and wane from normal to low. Iron deficiency during menses and pregnancy can trigger FGF23 increase and result in hypophosphatemia. About half of the patients affected with autosomal dominant hypophosphatemic rickets present with symptoms similar to those in XLHR in early childhood, whereas others do not present with symptoms until puberty or early adulthood. The management of autosomal dominant hypophosphatemic rickets is similar to that of XLHR.
- Autosomal recessive hypophosphatemic rickets (ARHR): a condition similar to the X-linked and autosomal dominant forms, but even rarer. Mutations have been described in 3 different genes. Autosomal recessive hypophosphatemic rickets presents in late infancy with hypophosphatemia, rickets, and osteomalacia. These features vary and are mutation specific and age dependent. In addition, some patients develop osteosclerosis and bone overgrowth, nerve deafness, facial and dental abnormalities, and learning disabilities. Management of ARHR is similar to that of XLHR.
- Hypophosphatemic rickets with hypercalciuria (HHRH): a rare autosomal recessive genetic disorder that can present either in childhood or adulthood. The heterozygous form is less severe and presents with mild hypophosphatemia, hypercalciuria, and nephrolithiasis without bone disease. Hypophosphatemic rickets with hypercalciuria differs from XLRH in that the hypophosphatemia is not mediated by FGF23 activity, and impairment is limited to phosphate transport. Serum vitamin D levels are normal. Management requires close monitoring to prevent elevated calcitriol and phosphate levels.
- Fanconi syndrome: a rare autosomal recessive disorder that results in a defect in the absorption function of the proximal renal tubule, leading to electrolyte imbalances, hyperphosphatemia, and excretion of certain amino acids in the urine. The clinical presentation can manifest at any age with several symptoms including slow growth, osteomalacia, polyuria, dehydration, weakness, tremors, and fatigue. The acquired form results from exposure to chemicals, heavy metals, and medications, or due to amyloidosis and multiple myeloma. Diagnosis is based on the clinical presentation and lab results. Management involves the treatment of metabolic acidosis using alkali therapy.
- Rickets and osteomalacia: disorders arising from decreased bone mineralization. Rickets affects the cartilage of the epiphyseal growth plates in children, whereas osteomalacia affects the sites of bone turnover in children and adults. Rickets commonly presents with skeletal deformities and growth abnormalities. Diagnosis is made based on a combination of clinical findings, laboratory tests, and imaging. Treatment is with vitamin D, calcium, and phosphorus supplementation.
- Fibrous dysplasia of bones: a rare disorder in which regular bone is replaced with fibrous, scar-like tissue. Fibrous dysplasia of bones is a genetic disorder that causes weakening of bones and eventual development of bowing and other pathologies; however, this condition cannot be inherited. There is no curative treatment and the management is aimed at controlling pain and stabilizing bones.
- Tumor-induced osteomalacia (osteogenic malacia): a paraneoplastic syndrome characterized by bone pain, muscle weakness, and bone fractures. Osteogenic malacia occurs due to high levels of FGF23 in the blood, which is secreted by mesenchymal tumors. Treatment includes removal of the tumor if it can be located, and supplementation with active vitamin D and phosphate.
- Scheinman, S.J. (2021). Hereditary hypophosphatemic rickets and tumor-induced osteomalacia. UpToDate. Retrieved May 28, 2021, from https://www.uptodate.com/contents/hereditary-hypophosphatemic-rickets-and-tumor-induced-osteomalacia
- NIH. (2018). X-linked hypophosphatemia: Genetic and Rare Diseases Information Center. Retrieved May 28, 2021, from https://rarediseases.info.nih.gov/diseases/12943/hypophosphatemic-rickets-x-linked-dominant
- Emmett, M., Palmer, B.F. (2021). Treatment of distal type 1 and proximal type 2 renal tubular acidosis. UpToDate. Retrieved May 28, 2021, from https://www.uptodate.com/contents/treatment-of-distal-type-1-and-proximal-type-2-renal-tubular-acidosis
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