NCBI Bookshelf. The phenotypic spectrum of X-linked hypophosphatemia XLH ranges from isolated hypophosphatemia to severe lower-extremity bowing. XLH frequently manifests in the first two years of life when lower-extremity bowing becomes evident with the onset of weight bearing; however, it sometimes is not manifest until adulthood, as previously unevaluated short stature. In adults, enthesopathy calcification of the tendons, ligaments, and joint capsules associated with joint pain and impaired mobility may be the initial presenting complaint. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported.
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Phosphate wasting ineluctably leads to hypophosphatemia and numerous consequences including mineralization defects. In children, hypophosphatemia is revealed by vitamin D-resistant rickets and results in variable degrees of delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. Symptoms might be present, although to a lesser degree, in adults who underwent the conventional treatment throughout their childhood and adolescence.
Causes of phosphate wasting are mostly due to genetic defects in factors necessary for phosphate handling; for a review read 1. They have been summarized in Table 1. In this review, we will consider two different types of phosphate wasting. Firstly, phosphate wasting may be secondary to increased fibroblast growth factor 23 FGF23 signaling, which is a circulating factor secreted by osteoblasts, odontoblasts, and osteocytes 2.
As a consequence, both renal and digestive absorption of phosphate are diminished. Recently, extra renal effects of FGF23 have been reported, such as immune function in human monocytes 3 , iron 4, 5 , glucose 6 and lipid metabolism 7, 8. Table 1 Causes of hypophosphatemic rickets HR.
Except for the latter, mineralization defects involving bone and teeth are caused by hypophosphatemia and FGF23 excess and, in addition, by a direct effect of the absence of functional PHEX or DMP1 on bone or tooth extracellular matrix ECM mineralization Secondly, phosphate wasting may be due to a primary renal tubular defect, i. All these conditions share a diminished capacity to transport phosphate from the glomerular filtrate to the blood circulation.
In response to hypophosphatemia, FGF23 secretion is adequately suppressed, and 1,diOH-vitamin D production and absorption of calcium through the gut and urinary calcium excretion are consequently enhanced.
Besides acquired disorders like tumors or drug toxicity, most conditions leading to phosphate wasting are congenital and will continue throughout the patient's lifetime. To this day, therapy has mostly been evaluated in children. Enormous progress has been made since the availability of vitamin D analogs, such as calcitriol and alfacalcidol, in the mids and the evolution of surgical procedures.
However, two major issues remain: i the growth retardation and recurrent dental infections in children and ii the necessity of adequate therapeutic strategies in adults. Indeed, the disease remains physically apparent and the global objective of therapies medical, dental, and surgical should be to limit, and in best cases avoid, sequel by correcting leg deformities, promoting growth and preserving dentition. In this context, we will describe in this review the current and future treatments available to counteract phosphate wasting, restore serum phosphate and allow adequate bone and tooth mineralization.
Healing rickets by normalizing serum alkaline phosphatase ALP levels and radiological signs is the initial endpoint in children. Treating rickets will promote growth, progressively correct leg deformities Fig. In infants diagnosed before they even show signs of rickets, the treatment goal for them will be not to develop rickets Fig. Earlier treatment has been shown to lead to better results Objectives, which could also be described as expected results, are described in Table 2.
The treatment intends to, in the following order: i reduce bone pain, ii normalize or near-normalize ALP levels Fig. Figure 1 Download Figure Download figure as PowerPoint slide Evolution of clinical leg bowing and growth and biochemical parameters alkaline phosphatase levels during treatment with vitamin D analogs and phosphate supplements in children. The same girl is shown at the age of 5 years with straight legs right panel. Patient 3 is a year-old girl who presents with persistent leg bowing despite being treated since she was 3 years old XLHR and a de novo mutation of PHEX.
Patient 4 is a 2-year-old girl who started therapy at the age of 4 months. Diagnosis of XLHR was made in the context of familial disease mother and two sisters affected. B Evolution of alkaline phosphatase levels throughout the first year of therapy in 30 patients affected with HR and elevated FGF Citation: Endocrine Connections 3, 1; Nowadays, the medical treatment is aimed at counteracting consequences of FGF23 excess, i.
Multiple daily doses of phosphate supplements are mandatory throughout childhood and adolescence, because, in the context of diminished phosphate reabsorption, serum phosphate level is back to low baseline few hours after phosphate intake.
At these doses, digestive complaints are extremely rare. The daily dose of phosphate supplements is adjusted to efficacy i. Note that serum phosphate is not used to adjust phosphate therapy. On the contrary, as fasting phosphate is not restored by treatment, increasing phosphate supplement doses leads to intestinal discomfort and secondary sometimes tertiary hyperparathyroidism. Urinary phosphate measured on a h collection should parallel the daily intake of phosphate supplements, and may be used to check for compliance.
Prescribing phosphate intake is a balance between excessive dosage tending to hyperparathyroidism and insufficient dosage slowing the healing of rickets. Their half-life is sufficient to allow for single and twice daily oral doses of alfacalcidol and calcitriol respectively. Vitamin D analog doses are adjusted to give the maximum dose for efficacy based on ALP levels, leg bowing, and growth velocity, without reaching toxicity, mainly hypercalciuria.
Hypercalciuria does not usually occur until ALP levels are normalized. We recommend screening for nephrocalcinosis with yearly ultrasound every second year in the absence of episodes of hypercalciuria. It is common, after healing rickets, for initial dosage of vitamin D analogs to be decreased to maintenance doses. Table 3 Reports of vitamin D analogs and phosphate supplements in patients with HR. Ranges of doses of phosphate supplements and vitamin D analogs throughout life, and their respective markers of efficacy and safety as applied in our center.
As for many chronic diseases, compliance to oral treatment is a major issue, even in expert hands. Our recommendations are based on over 30 years of experience at our center in treating over patients with HR and are similar to the guidelines advised recently by Carpenter et al. In addition, we prescribe OH-vitamin D supplements and optimize dietary calcium intake in children, although no published studies support this point. Healing active rickets promotes growth and after 2 years of successful treatment, patients' growth velocity is restored to its maximal potential in a majority of patients.
Until recently, only limited pilot studies small patient numbers, limited period of observation, lack of controls and randomizations have been conducted, which suggest a beneficial effect of recombinant growth hormone rGH treatment on growth velocity in patients with XLHR 29, 34, 35, 36, 37, The only randomized study by Zivicnjak et al.
Only well-observant patients with healed rickets can benefit from rGH. In patients with HHRH, 1,diOH-vitamin D synthesis is enhanced and PTH secretion often suppressed, both conditions favoring hypercalciuria 40 ; therefore, patients require treatment with phosphate supplements solely. Doses and adjustment rules are similar to that used for XLHR patients.
In this condition, OH-vitamin D supplementation should be monitored very carefully by trained physicians to avoid increase in 1,diOH-vitamin D generation and hypercalciuria. Hypophosphatemia induces progressive bowing of the legs that becomes apparent with the onset of weight bearing Fig.
These mal-alignments are characterized by diaphyseal—metaphyseal regions of lower limbs long bones bowing in frontal plan with varus or valgus combined with a degree of flexion.
Internal torsion of the tibia and fibula is frequent, as well as anteverted femoral neck. As a consequence, patients report lower limb pain; they also may develop patellar dysplasia including chondromalacia, lateral femoro-patellar subluxation, and gait troubles. Physiotherapy can be useful at this stage to prevent complete patellar dislocation and improve muscle fitness; sitting on the feet should be prohibited in children to decrease femoral neck anteversion.
A disproportionate muscular insufficiency was described, but the relative responsibility of hypophosphatemia versus lower limb bowing — which modifies the muscular work — was not evaluated Most of our patients show joint hyperlaxity and increased skin elasticity. Physiotherapy to improve joint stability with muscle reinforcement can be offered to patients. It may be combined with CT scanning to measure the degree of torsion. Surgery during childhood should be avoided.
Because of open epiphyses, patients present a significant risk of recurrence of the bowing at the level of osteotomy or secondary to the adjacent epiphysiodesis Fig. When necessary, due to major bone deformities, surgery should be combined with adjusted doses of phosphate supplements and vitamin D analogs in order to prevent recurrence as previously evoked.
A Bilateral lower limbs mal-alignment including distal right femur valgus and proximal left tibia varus — pre- and post-operative aspects distal right femur varization and proximal left tibia valgization osteotomies.
B Pre- and post-operative radiological aspect of the patient displayed in A. Recurrence of leg bowing after surgery likely due to compliance issues to phosphate and vitamin D analogs.
Bilateral medial proximal tibiae epiphysiodesis inducing varus deformations. The actual place of the surgery is the correction of residual deformities at the end of growth Fig. The achievement of horizontal knee joints often requires bifocal femoral and tibiae metaphyseal—diaphyseal osteotomies. Osteosynthesis is done by locking plates or intramedullary nails Progressive correction using external fixation is an alternative that provides precise 3D angular deformities management Distal tibiae varus with significant ankle joints obliquity should be operated upon with supramalleolar dome osteotomy Fusion is usually acquired, without tendency of delayed fusion or pseudarthrosis.
In case of significant lateral subluxation after alignment correction, surgery of the femoro-patellar joint is also required. However, ever since the implementation of the usage of vitamin D analogs, surgical indications have been considerably diminished. Most hypophosphatemic patients present with increased head length and frontal bossing. Craniosynostosis and sometimes Chiari malformations giving rise to headaches and vertigo may also affect patients and require neurosurgery when symptomatic.
Lessened parental surveillance, poor taste of phosphate preparations, and lack of convincing demonstration of therapeutic benefits in asymptomatic individuals contribute to the low compliance in young adults. Nevertheless, the metabolic and endocrine consequences of chronic phosphate wasting persist life long. Adult endocrinologist following patients with HH thus necessarily faces two key questions: i whom to treat and ii what kind of treatment to give?
There is no consensus regarding indications of the treatment in adult patients. Patients with significant reduction in pain symptoms remain the most compliant. Patients with planed surgical interventions i. The conventional treatment in these adult patients is based on oral phosphate salts, usually given twice daily, and active vitamin D metabolites. The aim of the treatment is to improve the symptoms, not to normalize serum phosphate levels.
Careful monitoring of plasma calcium, PTH, creatinine, and h urinary calcium excretion is required 25, 46 in order to prevent tertiary hyperparathyroidism, induced by phosphate overdose 47 , and hypercalciuria with nephrocalcinosis and renal insufficiency, resulting from calcitriol overtreatment In our experience, tertiary hyperparathyroidism in patients with XLHR is rare A Linglart, P Kamenicky, D Prie, A Rothenbuhler, unpublished observations and should be preferentially treated surgically, even though beneficial effects of adjunctive therapy by 24,dihydroxyvitamin D has also been reported in one study Figure 3 Download Figure Download figure as PowerPoint slide Various burdens of the disease in adults leading to resume therapy with phosphate supplements and vitamin D analogs.
A Osteoarthritis of the knee in a year-old woman with persistent bone deformities after adolescence. C Lower limb deformities in a young adult requiring corrective surgery. D Dramatic consequences of rickets and osteomalacia in a year-old patient who did not receive vitamin D analogs. Arrows show insufficiency fractures.
Therapeutic management of hypophosphatemic rickets from infancy to adulthood
Hypophosphatemia in critically ill children. E-mail: heitorpl terra. The purpose of this paper is to review clinical studies on hypophosphatemia in pediatric intensive care unit patients with a view to verifying prevalence and risk factors associated with this disorder. Search terms included critically ill, pediatric intensive care, trauma, sepsis, infectious diseases, malnutrition, inflammatory response, surgery, starvation, respiratory failure, diuretic, steroid, antiacid therapy, mechanical ventilation. The search period covered those clinical trials published from January to January
Clinical Approach to Hypocalcemia in Newborn Period and Infancy: Who Should Be Treated?
Hypocalcemia is a common metabolic problem in newborn period and infancy. There is consensus on the treatment of the symptomatic cases while the calcium level at which the treatment will be initiated and the treatment options are still controversial in asymptomatic hypocalcemia. This review article will cover hypocalcemia with specific reference to calcium homeostasis and definition, etiology, diagnosis, and treatment of hypocalcemia in newborn and infancy period. Early-onset hypocalcemia is generally asymptomatic; therefore, screening for hypocalcemia at the 24th and 48th hour after birth is warranted for infants with high risk of developing hypocalcemia. Excessive phosphate intake, hypomagnesemia, hypoparathyroidism, and vitamin D deficiency are commonest causes of late-onset hypocalcemia. Hypocalcemia should be treated according to etiology. Calcium replacement is the cornerstone of the treatment.
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