X-linked hypophosphatemic (XLH) rickets is an X-linked dominant disorder first described by Albright in 1939. It is the most common cause of heritable rickets, with an incidence of 1:20,000 live births.[11
] It accounts for more than 80% of familial hypophosphatemic rickets. Phosphate regulating gene with Homologies to Endopeptidase on X chromosome (PHEX
) mutations are also described in familial hypophosphatemic rickets patients of Indian origin.[6
XLH rickets occurs due to inactivating mutations in PHEX
which encodes a metalloprotease that cleaves small peptide hormones. It is expressed in bone, teeth, and parathyroid glands, but not in kidney. It does not seem to cleave FGF23 directly, but is involved in the downregulation of FGF23 by an unknown mechanism.[12
] This is illustrated in . Mutations can be detected in 50–70% of the affected patients.[14
] The severity of the disease and specific clinical manifestations are variable even among members of the same family. In a recent study, patients with clearly deleterious (that resulted in premature stop codons, which included nonsense mutations, insertion or deletion and splice site mutations) PHEX
mutations had lower tubular reabsorption of phosphate and 1,25(OH)2
D levels than those with plausible causative mutations (which included missense mutations and an in-frame three-nucleotide deletion). This finding suggested that the type of PHEX
mutation might predict the XLH phenotype.[16
] In addition to the mineralization defect induced by hypophosphatemia, an intrinsic osteoblast defect also contributes to the bone disease and does not appear to respond to conventional treatment.
Pathophysiology of FGF23-mediated hypophosphatemic rickets (XLH: X-linked hypophosphatemic rickets, ADHR: autosomal dominant hypophosphatemic rickets, TIO: tumor-induced osteomalacia, FGF23: fibroblast growth factor 23)
Unlike vitamin D deficiency, craniotabes and rachitic rosary are not seen, and the first usual finding is frontal bossing which may appear as early as 6 months of age. As the child starts walking, progressive limb deformities become evident leading to disproportionate short stature with short limbs. Lower limbs are more affected leading to coxa vara, genu valgum, and genu varum. Dental abnormalities are common and may often be the presenting complaints.[17
] These abnormalities include abscessed noncarious teeth, enamel defects, enlarged pulp chambers, and taurodontium.[18
] Adults may present with short stature, bone pains, pseudofractures, and enthesopathy.
Biochemical evaluation would reveal low serum phosphorus, normal calcium, normal or slightly elevated PTH, and decreased TMP/GFR (calculated by nomogram).[5
] There is increased FGF23 and low or inappropriately normal 1,25 (OH)2
Current standard of care is phosphate replacement in the form of phosphate mixture and with 1,25(OH)2
. Some patients can have marked improvement in bony deformity with treatment, hence corrective osteotomy should be considered only after adequate duration of medical therapy. As the child progresses to adulthood, the phosphate requirements decrease due to closure of epiphyses and decreased bone turnover.[2
] Some patients may not require treatment in adulthood. Hence, only those adults who are symptomatic in the form of bone pains, muscle weakness, or pseudofractures require therapy.
Phosphate is generally administered at 20–40 mg/kg/day in three to five divided doses (up to a maximum of 2–3 g/day). Calcitriol is used in doses of 1–3 μg/day.[2
] The phosphate dose is titrated gradually to avoid intolerance in the form of diarrhea. Therapy should be targeted to maintain serum phosphorus in the low normal range, normalize alkaline phosphatase, and prevent secondary hyperparathyroidism, hypercalcemia, or hypercalciuria. Serum calcium, phosphorus, creatinine, and spot urinary calcium/creatinine should be monitored every 3–4 months. PTH levels should be checked annually. Nephrocalcinosis and tertiary hyperparathyroidism are the potentially serious complications of therapy.[19
] Renal ultrasound should be done at the baseline and yearly thereafter. Phosphate and calcitriol treatment leads to concurrent increases in circulating FGF23 concentrations, which may diminish therapeutic effect or contribute to complications of therapy.[20
In 2005, a systematic analysis concluded that there is no sufficient evidence to support the use of growth hormone (GH) in children with XLH.[21
] A recent study has demonstrated the efficacy of GH in children with XLH where there was significant improvement in height SDS without worsening of skeletal disproportion.[22
] Administration of single dose of calcitonin in XLH patients causes a significant and sustained drop in the circulating levels of FGF23 and an increase in the serum levels of phosphorus.[23
] Short-term treatment with cinacalcet suppresses PTH, leading to increase in TMP/GFR and serum phosphate.[24
] However, long-term studies are required to verify the persistent benefits of these drugs. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia, while anti-FGF23 antibodies ameliorate hypophosphatemia and improve the muscle strength and movements with no effect on growth in hyp mice.[25
] However, their use in human subjects with hypophosphatemic rickets is still under evaluation.