Eur J Orthop Surg Traumatol (2015) 25:221–226 DOI 10.1007/s00590-014-1496-y
GENERAL REVIEW
Hypophosphatemic rickets: etiology, clinical features and treatment Vito Pavone • Gianluca Testa • Salvatore Gioitta Iachino Francesco Roberto Evola • Sergio Avondo • Giuseppe Sessa
•
Received: 26 April 2014 / Accepted: 2 June 2014 / Published online: 24 June 2014 Ó Springer-Verlag France 2014
Abstract Hypophosphatemic rickets (HR) is a genetic disorder, which prevents sufficient reabsorption of phosphate in the proximal renal tubule, with increased phosphate excretion, resulting in rickets. The more common form of HR is an X-linked inherited trait, with a prevalence of 1/20,000. The defective gene is located on the X chromosome, but females may present with a wide variety of clinical manifestations. The less common form of HR is caused by autosomal-dominant transmission. Activating mutations of the fibroblast growth factor 23 (FGF-23) gene and inactivating mutations in the phosphate regulating gene (PHEX gene with homologies to endopeptidases on the X chromosome), involved in the regulation of FGF-23, have been identified and have been implicated in the pathogenesis of these disturbances. A review of etiopathogenesis and clinical, differential diagnostic and therapeutic aspects of HR, with a particular emphasis on bone impairment, is reported.
Introduction
Keywords Hypophosphatemic rickets Tibial torsion Calcitriol Surgical care
Etiopathogenesis
V. Pavone (&) G. Testa S. Gioitta Iachino F. R. Evola S. Avondo G. Sessa Orthopaedic Clinic, University of Catania, Catania, Italy e-mail: [email protected] V. Pavone G. Testa S. Gioitta Iachino F. R. Evola S. Avondo G. Sessa Azienda Ospedaliera Universitaria, Policlinico Vittorio Emanuele, Catania, Italy
Hypophosphatemic rickets (HR) is a genetic disorder and the X-linked inheritance (XLI) is the most frequent form of transmission, accounting for about 80 % of the familial cases of hypophosphatemia. The remaining 20 % of familial HR patients belong to the HR autosomal dominant and to the hereditary HR with calciuria types. The XLI responsible for HR was first reported by Albright, Butler and Bloomberg [1, 2]. Previously, HR was termed ‘‘vitamin D-resistant HR,’’ since treatment with Vit D, even at high doses, did not resolve the metabolic and clinical features of this affliction. Currently, the experts prefer to refer to this disorder as HR. In this review, we discuss X-linked HR, as this disorder is more common and more representative of the HR population.
The disorder is reportedly linked to a mutation of the phosphate regulating gene homologous to endopeptidases on the X chromosome (PHEX). This gene is thought to stimulate fibroblast growth factor 23 (FGF-23), widely expressed in bone. With insufficient production of the PHEX gene, there is a decreased degradation of phosphatonins, which act by inhibiting phosphate reabsorption in the proximal renal tubule, resulting in increased phosphate excretion. FGF-23 has been reported to be 5 times higher in X-linked HR (XLH) patients compared to healthy controls. Phosphatonins are also believed to inhibit renal 1 Alfa-hydroxylase, leading to low serum concentration of 1,25-dihydroxyvitamin D3 and, thus, insufficient formation of the vitamin D metabolite. This metabolic anomaly leads
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to both chronic depletion of phosphate by the kidneys and defective mineralization of the bones [3, 4]. Pathophysiology The causative defect in XLH is impaired proximal renal tubular reabsorption of phosphate (TRP), due to reduced expression of sodium-phosphate co-transporters (NaPi-IIa and NaPi-IIc, members of the type II sodium-phosphate symporter family) on the apical surface of proximal renal tubule cells [5–7]. The resulting hyperphosphaturia derives from mutations in the PHEX gene [5, 8, 9]. This gene, whose locus is Xp22.1, encodes a membrane endopeptidase, called PHEX, which is mainly expressed in bone and teeth [10]. The novel hormone FGF-23 inhibits the transcription of the genes encoding NaPi-IIa and NaPi-IIc, and most patients with XLH (as well as Hyp mice) have elevated circulating levels of intact FGF-23 [11]. FGF-23 does not appear to be a physiologic substrate for PHEX and the mechanism by which PHEX disruption results in elevated levels of available FGF-23 remains unclear. However, both FGF-23 and PHEX are products of osteocytes. FGF-23 mediates several inherited phosphate wasting disorders, of which XLH is the most common. Recessive mutations in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can result in FGF-23-mediated phosphate wasting disorders [12]. This enzyme regulates local concentrations of pyrophosphate, a potent inhibitor of mineralization. This loss of function of the encoding gene has also been associated with generalized arterial calcification of infancy, a very rare disorder [13]. Elevated FGF-23 levels cause the abnormal modulation of the vitamin D axis. FGF-23 can down-regulate CYP271B (which encodes 25-OHD-1a-hydroxylase) and up-regulate the Cytochrome P 450 family (c-encoding the 24-hydroxylase), thereby resulting in insufficient (low to normal) levels of 1,25(OH)2D, due to decreased synthesis and increased catabolism [14]. FGF23 acts through specific FGF receptors (FGFRs) on the basolateral surface of renal tubular cells. To transduce its signal, FGF23 must form a ternary complex and requires heparin and klotho protein to bind to the proximal tubule, in order to stimulate phosphaturia. The precise downstream pathway mediating the altered expression of NaPi-II and the vitamin D hydroxylases has not been clarified [15, 16]. PHEX gene mutations inhibit FGF23 inactivation, thus causing increased levels of free FGF-23 in plasma and thereby causing hyperphosphaturia [5, 17, 18]. In addition, increased FGF23 inhibits 1a-hydroxylase, the responsible enzyme for 25(OH)-vitamin D (calcidiol) conversion to its active form, 1,25(OH)2-vitamin D (calcitriol). Through this mechanism, the rise of calcitriol in the plasma is avoided, contributing to enhance hypophosphatemia [5]. However,
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FGF-23 seems to play a central role on this axis [5, 17, 19], through its phosphaturic effects and its autocrine action on osteoblasts, thus modulating bone mineralization. Alterations in the metabolism of FGF23, due to inhibition of its proteolytic cleavage or to its increased resistance to proteolysis, trigger impairments in phosphorus homeostasis and in bone-mineral metabolism [5, 17, 19]. Phosphorus metabolism Phosphorous is the most abundant anion in the human body. It presents primarily as inorganic phosphate, which plays a major role in many biologic systems, including cell membrane function, energy metabolism, cell signaling and oxygen transport. Ninety-nine percent of the total phosphorous pool in the body is intracellular, 85 % of which is found in the skeleton and 15 % in the soft tissues. The extracellular pool of phosphorous, comprising approximately 600 mg, exists primarily as H2PO4- and HPO42-, with a ratio of 4 divalent to 1 monovalent molecules. The concentration of inorganic phosphate in the plasma is between 2.5 and 4.5 mg/dL. Equilibrium between intracellular and extracellular phosphate is regulated by multiple factors, including acid–base status, glucose metabolism and several hormones, especially insulin and catecholamines [20, 21]. Phosphate intake is, on average, about 20 mg/kg/day (about 1,400 mg in a 70 kg man), but the net absorption of phosphorous is less than 900 mg, or 64 % of total intake. This is due to intestinal phosphate absorption, which is both passive by diffusion and active, through sodiumphosphate transporters (Na–Pi-II), located in the luminal membrane of both the renal proximal tubule and the upper intestine [22]. During high phosphate intake, passive absorption is prevalent; at low phosphate intake, absorption mostly occurs actively [23]. Phosphate absorption is regulated by 1,25-vitamin D through the modulation of the number of Na–P transporters in the luminal membrane of enterocytes, primarily in the proximal jejunum [23]. The activation of vitamin D is regulated by both parathyroid hormone (PTH) and serum phosphorous; phosphate absorption is therefore controlled through an interaction between serum phosphorous, PTH, and 1,25-vitamin D [24]. Bone metabolism Bone tissue is dynamic, influenced by both metabolic and mechanical processes, a continuous interaction between genetics and environment, with ontogenetic particularities in each development stage. The bone-remodeling process occurs continuously throughout life and consists in renewal and substitution of
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old with new bone. This mechanism is useful in maintaining strength and integrity. Bone tissue is mainly composed of calcium and phosphorus, critical elements for the systemic electrolytic equilibrium. The parathyroid hormone (PTH)-calcitonin-1,25(OH)2 vitamin D3 (calcitriol) axis plays a fundamental role in this bone-mineral regulation, as has been demonstrated in studies of phosphate wasting bone diseases, such as HR [5].
Clinical features Clinical features of XLH may first be recognized when a delay in walking presents itself in the first years of life and can include short stature, reduced growth rate and bone deformity. General softening of the bone causes a bend in the lower limbs from the weight of the child and muscles pulling on weak bone. Females generally have less relevant bone involvement than males. Coxa vara, femoral and crural bowing, and genua vara and valga are frequently present [1, 7, 24]. Early medical treatment of high-dose vitamin D therapy in childhood may prevent or reduce long-bone deformities and facilitate healing of pseudo-fractures [25]. However, despite adequate medical management or because of delayed diagnosis, many patients still develop significant deformities, especially of the lower extremities, which require operative corrective treatment.
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deformities, which become apparent after the age of 1 or 2 years. The deformities are frequently located around the knee, often involving the bilateral genu varum or valgum and commonly combined with tibial torsion, bowing of the tibia and the femur or displaying the so-called windswept deformity. XLH is often misdiagnosed as rickets vitamin D deficiency, in which the clinical and radiological manifestations are represented by metaphyseal widening, palpable enlargement of the costochondral junctions (rachitic rosary), frontal prominence, malformation of the horizontal depression along the lower border of the chest (Harrison’s groove), insufficient weight gain and physiological bowing. The altered thickness of central parts of parietal and frontal bones may alter the shape of the head. Recurrent fractures, although not common, may worsen bone deformities. Metaphyseal changes of rickets are usually evident on radiographs (we preferentially check the distal femur) when a child presents with XHR. With adequate vitamin D treatment, these abnormalities can be improved, but are not usually entirely resolved [30, 31].
Diagnosis The diagnosis of HR is based in the clinical examination, laboratory findings and alterations found on chest radiograph. Laboratory findings
Rickets Rickets is the presenting clinical feature of XLH. Rickets is a metabolic disorder of the growing bone, which occurs in children before fusion of the epiphysis and is characterized by impaired mineralization of the osteoid matrix during growth. The anomaly is localized in the epiphyseal growth plate, further involving both cortical and trabecular bone [6]. Rickets can result from vitamin D deficiency (nutritional or metabolic disturbances), calcium and/or phosphorus deficiency and distal renal tubular acidosis [26]. Rickets secondary to vitamin D deficiency affects patients who have insufficient exposure to ultraviolet light and also individuals who live in certain susceptible communities [27]. In addition, those who cover the entire body (as is customary in some religious practices), people with dark-pigmented skin who live in temperate climates (due to melanin competition for ultraviolet rays), elderly people, vegetarians and children who have been restrictively breastfed for long periods of time are all at increased risk for this disorder [28, 29]. The clinical manifestations of XLH include growth retardation with a disproportionately short stature and limb
Hypophosphatemia and low-normal circulating 1,25(OH)2D levels are typical biochemical findings for XLH. Serum alkaline phosphatase activity is elevated in children, but not to the degree observed in rickets due to vitamin D deficiency. This elevated activity does, however, represent an important parameter for disease control as well as efficacy of therapy. Serum calcium tests are normal, as are circulating 1, 25-dihydroxyvitamin D, with normal or reduced calciuria [19, 32]. Since the diagnosis of XLH requires long-term medical therapy, it is important to control renal phosphate wasting before initiating treatment. A 2-h fasting urine specimen, together with a blood sample collected at the midpoint of the urine collection period, is the best way to calculate the percentage of TRP and to determine the tubular maximum threshold for phosphate (TMP/GFR). Hyperphosphaturia is characterized by TRP values \85 % concomitant to hypophosphatemia [29]. Diagnosis of rickets is difficult in the first months of life, except for suspected cases when there is a positive family history of the disease, which can be diagnosed as early as the sixth month of life, based on increased alkaline phosphatase and reduced renal phosphate reabsorption [33].
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Further laboratory findings that could lead to diagnosis include increased plasma levels of FGF-23, characterizing the specific disorder, which otherwise is markedly similar to HR and hyperphosphaturia [34]. Imaging studies In XLH, the most typical radiologic alterations are seen in the tibia, distal femur and the radio-ulnar joints. Characteristically, loss of definition, widening and alterations in the zone of provisional calcification in the growth plate are typical physiological results [33]. The bone appears short, with squat long bones and coarse axial skeleton trabeculation. These findings are less severe than those seen in the vitamin D-deficient rickets and the signs are more intense, specifically in the lower limbs [29]. When bone fibrous dysplasia is suspected, 99Tc scintigraphy is useful [19]. In older children and adolescents, in particular when a familial history is present, it is very important to consider other differential diagnoses leading to hypophosphatemic hyperphosphaturic rickets, such as ADHR, TIO, bone fibrous dysplasia and renal Fanconi syndrome [19]. Radiographic images should exclude diagnosis of physiologic bowing and most skeletal dysplasias. Dental abscesses, arthritis and calcification of tendons and ligaments (enthesopathy) often develop in later life [32].
Treatment The most commonly prescribed medical therapy for children consists of calcitriol and phosphate supplementation from the time of diagnosis until growth is complete. Both activated vitamin D (calcitriol or alfacalcidol) and phosphate are usually required. Calciferol is not indicated because of its higher toxicity risks. Phosphate has some side effects, such as abdominal pain or diarrhea, and may require titration in order to minimize unpleasant symptoms. Treatment during growth partially corrects leg deformities, decreases the number of necessary surgeries and improves adult height [35, 36]. In the literature, indicated doses of these supplements vary widely, from 10 to 80 ng/kg/day of calcitriol, and 1–3 g of elemental phosphorus divided in 4–5 doses [36– 40]. This reflects a significant amount of uncertainty regarding optimal doses and indicates concerns regarding the side effects of nephrocalcinosis, hypercalciuria and hyperparathyroidism [38, 39]. Frequent dosing is necessary to avoid a rapid decline of the available drug and to prevent episodes of diarrhea, which is a frequent complication of high doses of phosphorus. Adherence to therapy may be improved with liquid formulations, allowing for more precise dosing in young children.
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Recommended dosage of calcitriol is 20–30 ng/kg/day divided into 2–3 doses, with an elemental phosphorus dosage of 20–40 mg/kg/day (in 3–5 divided doses). To reduce gastrointestinal side effects, doses can be titrated over several days to weeks [41, 42]. Changes in body size, growth velocity and skeletal mineralization will necessitate periodic dose adjustments. The treatment targets of HR are minimization of metabolic disturbances, reduction of bone deformities and improvement of growth velocity. Although the treatment reduces symptoms, hyperphosphaturia persists, since the treatment does not alter the impaired tubular phosphate reabsorption [19]. Total recovery would require normalization of the serum phosphate concentration, which is not a practical goal in children with XHR. In fact, this strategy is likely to do more harm than good, leading to overtreatment with phosphorus and resultant secondary hyperparathyroidism. Rather, the most important endpoints of therapeutic efficacy are increased height, lessened severity of skeletal deformity and radiographic evidence for epiphyseal healing [43]. Another option for treatment is use of growth hormone (GH), often given as an adjunctive therapy in XHR. GH and IGF-I transiently stimulate phosphate reabsorption [44]. While long-term responses to GH in XHR patients could increase levels of serum phosphate and linear growth [45, 46], increased serum alkaline phosphatase activity could also worsen leg deformities and radiographic rickets. Preferential truncal growth may result, exacerbating the disproportion between leg length and trunk length, which is typical of XHR [38]. Surgical care Surgical measures are usually reserved for the treatment of severe bowing, tibial torsion or pathological fractures. Osteotomy with plating, as well as multiple osteotomies and intramedullary fixation are standard methods for operative management [47, 48]. In general, osteotomies are usually deferred for children until growth is mostly complete, but severe deformities may require earlier therapy. One newer, less-invasive approach is epiphysiodesis, which induces corrective differential growth of the growth plate [49]. Prognosis The prognosis for XHR is usually good. When rickets is quickly and properly treated, there is a rapid improvement of the symptomatology, although treatment requires careful and frequent laboratory evaluation. Short stature may persist into adult age. After 20 years of age, the treatment may become less aggressive and patients may be treated only with calcitriol.
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Complications The main complications of XHR treatment are due to an uncorrected balance of phosphate and calcitriol, which could cause hyperparathyroidism or hypercalciuria. Among these, we include secondary and tertiary hyperparathyroidism and nephrocalcinosis, as secondary side effects. High doses of phosphate (above 50 mg/kg/day) could generate a secondary hyperparathyroidism, due to PTH stimulation, also causing a reduction in calcemia [41]. The persistence of hyperparathyroidism for long periods of time could damage normal parathyroid function, in turn causing tertiary hyperparathyroidism, which, although rare, is severe, leading to intense bone resorption, nephrocalcinosis and renal insufficiency [41]. Factors that could influence the progression to tertiary hyperparathyroidism are an early age of treatment onset, longer duration of treatment, high doses of elementary phosphorus (100 mg/kg/day) and very high PTH plasma levels (around 400 pg/mL) [41]. Another complication of rickets in treated patients is nephrocalcinosis. It is caused by deposition of calcium phosphate in the renal pyramids and must be closely watched with ultrasound exams. Patients who exhibit this complication can also present with vascular disturbances, especially systemic hypertension related, not to nephrocalcinosis, but to secondary or tertiary hyperparathyroidism [39, 50]. To avoid the above complications, it is necessary to evaluate treated XHR patients every 3 months [26]. Laboratory work ups must be performed, including serum dosage of calcium, phosphorus, creatinine and alkaline phosphatase, as well as urinary dosage of calcium and creatinine in a 24-h urine sample. Serum PTH has to be evaluated every 6 months and kidney ultrasound performed every 6–12 months [33]. For a correct dosage of calcitriol, it is important to consider the serum levels of PTH and the urinary calcium concentration. The main effect of excessive intake of calcitriol is hypercalciuria, defined as urinary excretion of calcium above 4 mg/kg/day or calcium/creatinine ratio above 0.7 in the first year of life, or above 0.3 after the first year [50]. If hypercalciuria is present, it is necessary to reduce the calcitriol dose. Conflict of interest
None.
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226 26. Root AW, Diamond FB Jr (2002) Disorders of calcium metabolism in the child and adolescent. In: Saunders WB (ed) Pediatric endocrinology, vol 646, 2nd edn. Sperling, Philadelphia 27. Gordon C, DePeter K, Feldman H et al (2004) Prevalence of vitamin D deficiency among healthy adolescents. Arch Pediatr Adolesc Med 158:531–537 28. Pettifor JM (2003) Nutritional and drug-induced rickets and osteomalacia. In: Favus MJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism, vol 399, 5th edn. American Society for Bone and Mineral Research, Washington 29. Mughal Z (2002) Rickets in childhood. Semin Musculoskelet Radiol 6:183–190 30. Holm IA, Econs MJ, Carpenter TO (2003) Familial hypophosphatemia and related disorders. In: Juppner H, Pettifor JM, Glorieux FH (eds) Pediatric bone: biology and diseases. Academic Press, San Diego, pp 603–631 31. Petje G, Meizer R, Radler C et al (2008) Deformity correction in children with hereditary hypophosphatemic rickets. Clin Orthop Relat Res 466(12):3078–3085 32. Carpenter TO, Imel AE, Holm IA et al (2011) A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res 26(7): 1381–1388 33. Sayer JA, Pearce SH (2001) Diagnosis and clinical biochemistry of inherited tubulopathies. Ann Clin Biochem 38:459–470 34. Tenenhouse HS, Econs MJ (2001) Mendelian hypophosphatemias. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular basis of inherited disease, 8th edn. McGraw Hill, New York, pp 5039–5067 35. Moncrieff MW (1982) Early biochemical findings in familial hypophosphatemic, hyperphosphaturic rickets and response to treatment. Arch Dis Child 57:70–72 36. Makitie O, Doria A, Kooh SW et al (2003) Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab 88:3591–3597 37. Verge CF, Lam A, Simpson JM et al (1991) Effects of therapy in X-linked hypophosphatemic rickets. N Engl J Med 325:1843– 1848 38. Petersen DJ, Boniface AM, Schranck FW et al (1992) X-linked hypophosphatemic rickets: a study (with literature review) of linear growth response to calcitriol and phosphate therapy. J Bone Miner Res 7:583–590
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Eur J Orthop Surg Traumatol (2015) 25:221–226 39. Makitie O, Kooh SW, Sochett E (2003) Prolonged high-dose phosphate treatment: a risk factor for tertiary hyperparathyroidism in X-linked hypophosphatemic rickets. Clin Endocrinol 58:163–168 40. Harrell RM, Lyles KW, Harrelson JM et al (1985) Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest 75:1858–1868 41. Carpenter TO (1997) New perspectives on the biology and treatment of X-linked hypophosphatemic rickets. Pediatr Clin North Am 44:443–466 42. Patel L, Clayton PE, Brain C et al (1996) Acute biochemical effects of growth hormone treatment compared with conventional treatment in familial hypophosphataemic rickets. Clin Endocrinol 44:687–696 43. Ariceta G, Langman CB (2007) Growth in X-linked hypophosphatemic rickets. Eur J Pediatr 166:303–309 44. Makitie O, Toiviainen-Salo S, Marttinen E et al (2008) Metabolic control and growth during exclusive growth hormone treatment in X-linked hypophosphatemic rickets. Horm Res 69:212–220 45. Haffner D, Wuhl E, Blum WF et al (1995) Disproportionate growth following long-term growth hormone treatment in short children with X-linked hypophosphataemia. Eur J Pediatr 154:610–613 46. Ferris B, Walker C, Jackson A et al (1991) Orthopaedic management of hypophosphatemic rickets. J Pediatr Orthop 11:367–373 47. Eyres KS, Brown J, Douglas DL (1993) Osteotomy and intramedullary nailing for the correction of progressive deformity in vitamin D-resistant hypophosphatemic rickets. J R Coll Surg Edinb 38:50–54 48. Novais E, Stevens PM (2006) Hypophosphatemic rickets: the role of hemiepiphysiodesis. J Pediatr Orthop 26:238–244 49. Rubinovitch M, Said SE, Glorieux FH et al (1988) Principles and results of corrective lower limb osteotomies for patients with vitamin D-resistant hypophosphatemic rickets. Clin Orthop Relat Res 237:264–270 50. Alon US, Monzavi R, Lilien M et al (2003) Hypertension in hypophosphatemic rickets—role of secondary hyperparathyroidism. Pediatr Nephrol 18:155–158
GENERAL REVIEW
Hypophosphatemic rickets: etiology, clinical features and treatment Vito Pavone • Gianluca Testa • Salvatore Gioitta Iachino Francesco Roberto Evola • Sergio Avondo • Giuseppe Sessa
•
Received: 26 April 2014 / Accepted: 2 June 2014 / Published online: 24 June 2014 Ó Springer-Verlag France 2014
Abstract Hypophosphatemic rickets (HR) is a genetic disorder, which prevents sufficient reabsorption of phosphate in the proximal renal tubule, with increased phosphate excretion, resulting in rickets. The more common form of HR is an X-linked inherited trait, with a prevalence of 1/20,000. The defective gene is located on the X chromosome, but females may present with a wide variety of clinical manifestations. The less common form of HR is caused by autosomal-dominant transmission. Activating mutations of the fibroblast growth factor 23 (FGF-23) gene and inactivating mutations in the phosphate regulating gene (PHEX gene with homologies to endopeptidases on the X chromosome), involved in the regulation of FGF-23, have been identified and have been implicated in the pathogenesis of these disturbances. A review of etiopathogenesis and clinical, differential diagnostic and therapeutic aspects of HR, with a particular emphasis on bone impairment, is reported.
Introduction
Keywords Hypophosphatemic rickets Tibial torsion Calcitriol Surgical care
Etiopathogenesis
V. Pavone (&) G. Testa S. Gioitta Iachino F. R. Evola S. Avondo G. Sessa Orthopaedic Clinic, University of Catania, Catania, Italy e-mail: [email protected] V. Pavone G. Testa S. Gioitta Iachino F. R. Evola S. Avondo G. Sessa Azienda Ospedaliera Universitaria, Policlinico Vittorio Emanuele, Catania, Italy
Hypophosphatemic rickets (HR) is a genetic disorder and the X-linked inheritance (XLI) is the most frequent form of transmission, accounting for about 80 % of the familial cases of hypophosphatemia. The remaining 20 % of familial HR patients belong to the HR autosomal dominant and to the hereditary HR with calciuria types. The XLI responsible for HR was first reported by Albright, Butler and Bloomberg [1, 2]. Previously, HR was termed ‘‘vitamin D-resistant HR,’’ since treatment with Vit D, even at high doses, did not resolve the metabolic and clinical features of this affliction. Currently, the experts prefer to refer to this disorder as HR. In this review, we discuss X-linked HR, as this disorder is more common and more representative of the HR population.
The disorder is reportedly linked to a mutation of the phosphate regulating gene homologous to endopeptidases on the X chromosome (PHEX). This gene is thought to stimulate fibroblast growth factor 23 (FGF-23), widely expressed in bone. With insufficient production of the PHEX gene, there is a decreased degradation of phosphatonins, which act by inhibiting phosphate reabsorption in the proximal renal tubule, resulting in increased phosphate excretion. FGF-23 has been reported to be 5 times higher in X-linked HR (XLH) patients compared to healthy controls. Phosphatonins are also believed to inhibit renal 1 Alfa-hydroxylase, leading to low serum concentration of 1,25-dihydroxyvitamin D3 and, thus, insufficient formation of the vitamin D metabolite. This metabolic anomaly leads
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to both chronic depletion of phosphate by the kidneys and defective mineralization of the bones [3, 4]. Pathophysiology The causative defect in XLH is impaired proximal renal tubular reabsorption of phosphate (TRP), due to reduced expression of sodium-phosphate co-transporters (NaPi-IIa and NaPi-IIc, members of the type II sodium-phosphate symporter family) on the apical surface of proximal renal tubule cells [5–7]. The resulting hyperphosphaturia derives from mutations in the PHEX gene [5, 8, 9]. This gene, whose locus is Xp22.1, encodes a membrane endopeptidase, called PHEX, which is mainly expressed in bone and teeth [10]. The novel hormone FGF-23 inhibits the transcription of the genes encoding NaPi-IIa and NaPi-IIc, and most patients with XLH (as well as Hyp mice) have elevated circulating levels of intact FGF-23 [11]. FGF-23 does not appear to be a physiologic substrate for PHEX and the mechanism by which PHEX disruption results in elevated levels of available FGF-23 remains unclear. However, both FGF-23 and PHEX are products of osteocytes. FGF-23 mediates several inherited phosphate wasting disorders, of which XLH is the most common. Recessive mutations in ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) can result in FGF-23-mediated phosphate wasting disorders [12]. This enzyme regulates local concentrations of pyrophosphate, a potent inhibitor of mineralization. This loss of function of the encoding gene has also been associated with generalized arterial calcification of infancy, a very rare disorder [13]. Elevated FGF-23 levels cause the abnormal modulation of the vitamin D axis. FGF-23 can down-regulate CYP271B (which encodes 25-OHD-1a-hydroxylase) and up-regulate the Cytochrome P 450 family (c-encoding the 24-hydroxylase), thereby resulting in insufficient (low to normal) levels of 1,25(OH)2D, due to decreased synthesis and increased catabolism [14]. FGF23 acts through specific FGF receptors (FGFRs) on the basolateral surface of renal tubular cells. To transduce its signal, FGF23 must form a ternary complex and requires heparin and klotho protein to bind to the proximal tubule, in order to stimulate phosphaturia. The precise downstream pathway mediating the altered expression of NaPi-II and the vitamin D hydroxylases has not been clarified [15, 16]. PHEX gene mutations inhibit FGF23 inactivation, thus causing increased levels of free FGF-23 in plasma and thereby causing hyperphosphaturia [5, 17, 18]. In addition, increased FGF23 inhibits 1a-hydroxylase, the responsible enzyme for 25(OH)-vitamin D (calcidiol) conversion to its active form, 1,25(OH)2-vitamin D (calcitriol). Through this mechanism, the rise of calcitriol in the plasma is avoided, contributing to enhance hypophosphatemia [5]. However,
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FGF-23 seems to play a central role on this axis [5, 17, 19], through its phosphaturic effects and its autocrine action on osteoblasts, thus modulating bone mineralization. Alterations in the metabolism of FGF23, due to inhibition of its proteolytic cleavage or to its increased resistance to proteolysis, trigger impairments in phosphorus homeostasis and in bone-mineral metabolism [5, 17, 19]. Phosphorus metabolism Phosphorous is the most abundant anion in the human body. It presents primarily as inorganic phosphate, which plays a major role in many biologic systems, including cell membrane function, energy metabolism, cell signaling and oxygen transport. Ninety-nine percent of the total phosphorous pool in the body is intracellular, 85 % of which is found in the skeleton and 15 % in the soft tissues. The extracellular pool of phosphorous, comprising approximately 600 mg, exists primarily as H2PO4- and HPO42-, with a ratio of 4 divalent to 1 monovalent molecules. The concentration of inorganic phosphate in the plasma is between 2.5 and 4.5 mg/dL. Equilibrium between intracellular and extracellular phosphate is regulated by multiple factors, including acid–base status, glucose metabolism and several hormones, especially insulin and catecholamines [20, 21]. Phosphate intake is, on average, about 20 mg/kg/day (about 1,400 mg in a 70 kg man), but the net absorption of phosphorous is less than 900 mg, or 64 % of total intake. This is due to intestinal phosphate absorption, which is both passive by diffusion and active, through sodiumphosphate transporters (Na–Pi-II), located in the luminal membrane of both the renal proximal tubule and the upper intestine [22]. During high phosphate intake, passive absorption is prevalent; at low phosphate intake, absorption mostly occurs actively [23]. Phosphate absorption is regulated by 1,25-vitamin D through the modulation of the number of Na–P transporters in the luminal membrane of enterocytes, primarily in the proximal jejunum [23]. The activation of vitamin D is regulated by both parathyroid hormone (PTH) and serum phosphorous; phosphate absorption is therefore controlled through an interaction between serum phosphorous, PTH, and 1,25-vitamin D [24]. Bone metabolism Bone tissue is dynamic, influenced by both metabolic and mechanical processes, a continuous interaction between genetics and environment, with ontogenetic particularities in each development stage. The bone-remodeling process occurs continuously throughout life and consists in renewal and substitution of
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old with new bone. This mechanism is useful in maintaining strength and integrity. Bone tissue is mainly composed of calcium and phosphorus, critical elements for the systemic electrolytic equilibrium. The parathyroid hormone (PTH)-calcitonin-1,25(OH)2 vitamin D3 (calcitriol) axis plays a fundamental role in this bone-mineral regulation, as has been demonstrated in studies of phosphate wasting bone diseases, such as HR [5].
Clinical features Clinical features of XLH may first be recognized when a delay in walking presents itself in the first years of life and can include short stature, reduced growth rate and bone deformity. General softening of the bone causes a bend in the lower limbs from the weight of the child and muscles pulling on weak bone. Females generally have less relevant bone involvement than males. Coxa vara, femoral and crural bowing, and genua vara and valga are frequently present [1, 7, 24]. Early medical treatment of high-dose vitamin D therapy in childhood may prevent or reduce long-bone deformities and facilitate healing of pseudo-fractures [25]. However, despite adequate medical management or because of delayed diagnosis, many patients still develop significant deformities, especially of the lower extremities, which require operative corrective treatment.
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deformities, which become apparent after the age of 1 or 2 years. The deformities are frequently located around the knee, often involving the bilateral genu varum or valgum and commonly combined with tibial torsion, bowing of the tibia and the femur or displaying the so-called windswept deformity. XLH is often misdiagnosed as rickets vitamin D deficiency, in which the clinical and radiological manifestations are represented by metaphyseal widening, palpable enlargement of the costochondral junctions (rachitic rosary), frontal prominence, malformation of the horizontal depression along the lower border of the chest (Harrison’s groove), insufficient weight gain and physiological bowing. The altered thickness of central parts of parietal and frontal bones may alter the shape of the head. Recurrent fractures, although not common, may worsen bone deformities. Metaphyseal changes of rickets are usually evident on radiographs (we preferentially check the distal femur) when a child presents with XHR. With adequate vitamin D treatment, these abnormalities can be improved, but are not usually entirely resolved [30, 31].
Diagnosis The diagnosis of HR is based in the clinical examination, laboratory findings and alterations found on chest radiograph. Laboratory findings
Rickets Rickets is the presenting clinical feature of XLH. Rickets is a metabolic disorder of the growing bone, which occurs in children before fusion of the epiphysis and is characterized by impaired mineralization of the osteoid matrix during growth. The anomaly is localized in the epiphyseal growth plate, further involving both cortical and trabecular bone [6]. Rickets can result from vitamin D deficiency (nutritional or metabolic disturbances), calcium and/or phosphorus deficiency and distal renal tubular acidosis [26]. Rickets secondary to vitamin D deficiency affects patients who have insufficient exposure to ultraviolet light and also individuals who live in certain susceptible communities [27]. In addition, those who cover the entire body (as is customary in some religious practices), people with dark-pigmented skin who live in temperate climates (due to melanin competition for ultraviolet rays), elderly people, vegetarians and children who have been restrictively breastfed for long periods of time are all at increased risk for this disorder [28, 29]. The clinical manifestations of XLH include growth retardation with a disproportionately short stature and limb
Hypophosphatemia and low-normal circulating 1,25(OH)2D levels are typical biochemical findings for XLH. Serum alkaline phosphatase activity is elevated in children, but not to the degree observed in rickets due to vitamin D deficiency. This elevated activity does, however, represent an important parameter for disease control as well as efficacy of therapy. Serum calcium tests are normal, as are circulating 1, 25-dihydroxyvitamin D, with normal or reduced calciuria [19, 32]. Since the diagnosis of XLH requires long-term medical therapy, it is important to control renal phosphate wasting before initiating treatment. A 2-h fasting urine specimen, together with a blood sample collected at the midpoint of the urine collection period, is the best way to calculate the percentage of TRP and to determine the tubular maximum threshold for phosphate (TMP/GFR). Hyperphosphaturia is characterized by TRP values \85 % concomitant to hypophosphatemia [29]. Diagnosis of rickets is difficult in the first months of life, except for suspected cases when there is a positive family history of the disease, which can be diagnosed as early as the sixth month of life, based on increased alkaline phosphatase and reduced renal phosphate reabsorption [33].
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Further laboratory findings that could lead to diagnosis include increased plasma levels of FGF-23, characterizing the specific disorder, which otherwise is markedly similar to HR and hyperphosphaturia [34]. Imaging studies In XLH, the most typical radiologic alterations are seen in the tibia, distal femur and the radio-ulnar joints. Characteristically, loss of definition, widening and alterations in the zone of provisional calcification in the growth plate are typical physiological results [33]. The bone appears short, with squat long bones and coarse axial skeleton trabeculation. These findings are less severe than those seen in the vitamin D-deficient rickets and the signs are more intense, specifically in the lower limbs [29]. When bone fibrous dysplasia is suspected, 99Tc scintigraphy is useful [19]. In older children and adolescents, in particular when a familial history is present, it is very important to consider other differential diagnoses leading to hypophosphatemic hyperphosphaturic rickets, such as ADHR, TIO, bone fibrous dysplasia and renal Fanconi syndrome [19]. Radiographic images should exclude diagnosis of physiologic bowing and most skeletal dysplasias. Dental abscesses, arthritis and calcification of tendons and ligaments (enthesopathy) often develop in later life [32].
Treatment The most commonly prescribed medical therapy for children consists of calcitriol and phosphate supplementation from the time of diagnosis until growth is complete. Both activated vitamin D (calcitriol or alfacalcidol) and phosphate are usually required. Calciferol is not indicated because of its higher toxicity risks. Phosphate has some side effects, such as abdominal pain or diarrhea, and may require titration in order to minimize unpleasant symptoms. Treatment during growth partially corrects leg deformities, decreases the number of necessary surgeries and improves adult height [35, 36]. In the literature, indicated doses of these supplements vary widely, from 10 to 80 ng/kg/day of calcitriol, and 1–3 g of elemental phosphorus divided in 4–5 doses [36– 40]. This reflects a significant amount of uncertainty regarding optimal doses and indicates concerns regarding the side effects of nephrocalcinosis, hypercalciuria and hyperparathyroidism [38, 39]. Frequent dosing is necessary to avoid a rapid decline of the available drug and to prevent episodes of diarrhea, which is a frequent complication of high doses of phosphorus. Adherence to therapy may be improved with liquid formulations, allowing for more precise dosing in young children.
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Recommended dosage of calcitriol is 20–30 ng/kg/day divided into 2–3 doses, with an elemental phosphorus dosage of 20–40 mg/kg/day (in 3–5 divided doses). To reduce gastrointestinal side effects, doses can be titrated over several days to weeks [41, 42]. Changes in body size, growth velocity and skeletal mineralization will necessitate periodic dose adjustments. The treatment targets of HR are minimization of metabolic disturbances, reduction of bone deformities and improvement of growth velocity. Although the treatment reduces symptoms, hyperphosphaturia persists, since the treatment does not alter the impaired tubular phosphate reabsorption [19]. Total recovery would require normalization of the serum phosphate concentration, which is not a practical goal in children with XHR. In fact, this strategy is likely to do more harm than good, leading to overtreatment with phosphorus and resultant secondary hyperparathyroidism. Rather, the most important endpoints of therapeutic efficacy are increased height, lessened severity of skeletal deformity and radiographic evidence for epiphyseal healing [43]. Another option for treatment is use of growth hormone (GH), often given as an adjunctive therapy in XHR. GH and IGF-I transiently stimulate phosphate reabsorption [44]. While long-term responses to GH in XHR patients could increase levels of serum phosphate and linear growth [45, 46], increased serum alkaline phosphatase activity could also worsen leg deformities and radiographic rickets. Preferential truncal growth may result, exacerbating the disproportion between leg length and trunk length, which is typical of XHR [38]. Surgical care Surgical measures are usually reserved for the treatment of severe bowing, tibial torsion or pathological fractures. Osteotomy with plating, as well as multiple osteotomies and intramedullary fixation are standard methods for operative management [47, 48]. In general, osteotomies are usually deferred for children until growth is mostly complete, but severe deformities may require earlier therapy. One newer, less-invasive approach is epiphysiodesis, which induces corrective differential growth of the growth plate [49]. Prognosis The prognosis for XHR is usually good. When rickets is quickly and properly treated, there is a rapid improvement of the symptomatology, although treatment requires careful and frequent laboratory evaluation. Short stature may persist into adult age. After 20 years of age, the treatment may become less aggressive and patients may be treated only with calcitriol.
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Complications The main complications of XHR treatment are due to an uncorrected balance of phosphate and calcitriol, which could cause hyperparathyroidism or hypercalciuria. Among these, we include secondary and tertiary hyperparathyroidism and nephrocalcinosis, as secondary side effects. High doses of phosphate (above 50 mg/kg/day) could generate a secondary hyperparathyroidism, due to PTH stimulation, also causing a reduction in calcemia [41]. The persistence of hyperparathyroidism for long periods of time could damage normal parathyroid function, in turn causing tertiary hyperparathyroidism, which, although rare, is severe, leading to intense bone resorption, nephrocalcinosis and renal insufficiency [41]. Factors that could influence the progression to tertiary hyperparathyroidism are an early age of treatment onset, longer duration of treatment, high doses of elementary phosphorus (100 mg/kg/day) and very high PTH plasma levels (around 400 pg/mL) [41]. Another complication of rickets in treated patients is nephrocalcinosis. It is caused by deposition of calcium phosphate in the renal pyramids and must be closely watched with ultrasound exams. Patients who exhibit this complication can also present with vascular disturbances, especially systemic hypertension related, not to nephrocalcinosis, but to secondary or tertiary hyperparathyroidism [39, 50]. To avoid the above complications, it is necessary to evaluate treated XHR patients every 3 months [26]. Laboratory work ups must be performed, including serum dosage of calcium, phosphorus, creatinine and alkaline phosphatase, as well as urinary dosage of calcium and creatinine in a 24-h urine sample. Serum PTH has to be evaluated every 6 months and kidney ultrasound performed every 6–12 months [33]. For a correct dosage of calcitriol, it is important to consider the serum levels of PTH and the urinary calcium concentration. The main effect of excessive intake of calcitriol is hypercalciuria, defined as urinary excretion of calcium above 4 mg/kg/day or calcium/creatinine ratio above 0.7 in the first year of life, or above 0.3 after the first year [50]. If hypercalciuria is present, it is necessary to reduce the calcitriol dose. Conflict of interest
None.
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