Eur J Paediatr Dent. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. Evaluation of aggressive pulp therapy in a population of vitamin D-resistant rickets patients: a follow-up of 4 cases.
P ediatr Dent. Familial hypophosphatemic vitamin D-resistant rickets: dental findings and histologic study of teeth. Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. J Histochem Cytochem. Resnick D. Implant placement and guided tissue regeneration in a patient with congenital vitamin D-resistant rickets. J Oral Implantol. Kawakami M, Takano-Yamamoto T. Orthodontic treatment of a patient with hypophosphatemic vitamin D-resistant rickets. Protein cDNA cloning of the murine Pex gene implicated in X-linked hypophosphatemia and evidence for expression in bone.
Mineral content of different areas of human dentin in hypophosphataemic vitamin D-resistant rickets. J Biol Buccale. Seow WK. The effect of medical therapy on dentin formation in vitamin D-resistant rickets. Pediatr Dent. Oral manifestations of familial hypophosphatemic rickets after phosphate supplement therapy: a review of the literature and report of case. Prevalence of dental abscess in a population of children with vitamin D-resistant rickets. Fadavi S, Rowold E. Familial hypophosphatemic vitamin D-resistant rickets: review of the literature and report of case.
Am J Hum Genet. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D-resistant rickets. Oral findings in patients with autosomal dominant hypophosphatemic bone disease and X-linked hypophosphatemia: Further evidence that they are different diseases. Breen GH. Prophylactic dental treatment for a patient with vitamin D-resistant rickets: report of case.
Management of the primary dentition in vitamin D-resistant rickets. Oral Surgery. Deformity correction of knee and leg lengthening by Ilizarov method in hypophosphatemic rickets: outcomes and significance of serum phosphate level. J Pediatr Orthop. Stanitski DF. Treatment of deformity secondary to metabolic bone disease with the Ilizarov technique. Deformity correction followed by lengthening with the Ilizarov method. C lin Orthop. Sharkey, Melinda S. Elongation of long bones for short stature in patients with hypophosphatemic rickets. Isr Med Assoc J. Good metabolic control prevents post-surgical imbalance of mineral metabolism in patients with X-linked hypophosphatemic rickets.
Post-surgical metabolic imbalance in adolescents with renal hypophosphatemic rickets. The effect of osteotomy on bowing and height in children with X-linked hypophosphatemia. A simple technique for correction of complicated tibial deformity including rotational deformity. Arch Orthop Trauma Surg.
Unilateral external fixation for corrective osteotomies in patients with hypophosphatemic rickets. Osteotomy and intramedullary nailing for the correction of progressive deformity in vitamin D-resistant hypophosphataemic rickets. J R Coll Surg Edinb. Stone MM. Vitamin D-resistant rickets: osteosynthesis with a table staple. Am J Orthop. Soehle M, Casey AT. Cervical spinal cord compression attributable to a calcified intervertebral disc in a patient with X-linked hypophosphatemic rickets: case report and review of the literature.
Thoracic spinal cord compression caused by hypophosphataemic rickets: a case report and review of the world literature. Eur Spine J. Thoracic spinal stenosis in two brothers due to vitamin D-resistant rickets. Yamamoto Y, Onofrio BM. Spinal canal stenosis with hypophosphatemic vitamin D-resistant rickets: case report. Untreated hypophosphatemic vitamin D-resistant rickets with symptomatic ossification of the ligamentum flavum. J Spinal Disord. Neurological involvement in X-linked hypophosphataemic rickets.
J Neurol Neurosurg Psychiatry. The lumbar spinal canal in hypophosphataemic vitamin D-resistant rickets. Aust N Z J Med. Spinal canal stenosis in adult with hypophosphataemic vitamin D-resistant rickets. A rationale for treatment of hereditary vitamin D-resistant rickets with analogs of 1 alpha,dihydroxyvitamin D 3. J Biol Chem. Thomas O. Glorieux, Caren M. Gundberg, A. Robin Poole and Karl L. Familial hypophosphatemic rickets causing ocular calcification and optic canal narrowing. Chiari malformation associated with vitamin D-resistant rickets: case report.
Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance.
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South Med J. The authors of this web site are not medical professionals, and this information does not substitute for medical care. Information on these pages is based on biomedical research, published in peer-reviewed journals, and international research conferences. A listing of XLH research is available. Please read our full disclaimer. Home What is XLH? XLH Research Citations We have not attempted to provide a complete collection of research on XLH; instead our goal is to provide a reasonable cross-section.
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J Endocrinol ; Osteocyte regulation of phosphate homeostasis and bone mineralization underlies the pathophysiology of the heritable disorders of rickets and osteomalacia. Bone ; Evidence for abnormal translational regulation of renal hydroxyvitamin D-1alpha-hydroxylase activity in the hyp-mouse.
Endocrinology ; Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol ; J Bone Miner Res ; Effects of growth hormone treatment on body proportions and final height among small children with X-linked hypophosphatemic rickets. Pediatrics ;e Seikaly MG, Baum M. Thiazide diuretics arrest the progression of nephrocalcinosis in children with X-linked hypophosphatemia.
Pediatrics ;E6. J Clin Endocrinol Metab ; Mutant FGF responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. SLC34A3 mutations in patients with hereditary hypophosphatemic rickets with hypercalciuria predict a key role for the sodium-phosphate cotransporter NaPi-IIc in maintaining phosphate homeostasis.
Am J Hum Genet ; Scheinman SJ. X-linked hypercalciuric nephrolithiasis: Clinical syndromes and chloride channel mutations. Kidney Int ; Drezner MK. Tumor-induced Osteomalacia. In: Favus MJ, editor. Philadelphia: Lippincott Williams and Wilkins; Oncogenic osteomalacia: Evidence for a humoral phosphaturic factor. Fibroblast growth factor 23 in oncogenic osteomalacia and X-linked hypophosphatemia. The importance of whole body imaging in tumor-induced osteomalacia. Tumor localization and biochemical response to cure in tumor-induced osteomalacia.
Cinacalcet in the management of tumor-induced osteomalacia. Octreotide for tumor-induced osteomalacia. The molecular basis of vitamin D-dependent rickets type I. Endocr J ; Vitamin-D-dependent rickets type II. Resistance of target organs to 1,dihydroxyvitamin D. Two mutations causing vitamin D resistant rickets: Modelling on the basis of steroid hormone receptor DNA-binding domain crystal structures. Clin Endocrinol Oxf ; Hereditary vitamin D resistant rickets caused by a novel mutation in the vitamin D receptor that results in decreased affinity for hormone and cellular hyporesponsiveness.
The remainder of this chapter reviews the pathophysiology of hypophosphatemic rachitic and osteomalacic disorders, and provides a systematic approach to the diagnosis and management of these diseases. View in own window. Mineralization of bone is a complex process in which a calcium-phosphate mineral phase is deposited in a highly ordered fashion within the organic matrix Apart from the availability of calcium and phosphorus, requirements for normal mineralization include: 1 adequate metabolic and transport function of chondrocytes and osteoblasts to regulate the concentration of calcium, phosphorus and other ions at the calcification sites; 2 the presence of collagen with unique type, number and distribution of cross-links, distinct patterns of hydroxylation and glycosylation and abundant phosphate content, which collectively facilitate deposition of mineral at gaps or "hole zones" between the distal ends of collagen molecules; 3 a low concentration of mineralization inhibitors such as pyrophosphates and proteoglycans in bone matrix; and 4 maintenance of an appropriate pH of approximately 7.
The abnormal mineralization in the hypophosphatemic disorders is due most likely to phosphopenia at calcification sites and, in some cases, paracrine inhibitory factors, which result in accumulation of unmineralized osteoid, a sine qua non for the diagnosis of osteomalacia.
Since the resultant abundant osteoid is not unique to osteomalacia, establishing the diagnosis of osteomalacia requires dynamic histopathologic demonstration that abnormal mineralization, and not increased production, underlies the observed excess accumulation of osteoid 54 , Static histomorphometrical parameters seen in osteomalacia include an increase in osteoid volume and thickness, an increase in bone forming surface covered by incompletely mineralized osteoid, and a decrease in the mineralization front the percentage of osteoid-covered bone-forming surface undergoing calcification. The critical dynamic parameter used to confirm that osteoid accumulation is due to osteomalacia is the mineral apposition rate.
Inadequate growth plate cartilage mineralization in rickets is primarily observed in the hypertrophic zone of chondrocytes. Irregular alignment and more extensive disorganization of the growth plate may be evident with increasing severity of disease. Calcification in the interstitial regions of this hypertrophic zone is defective. Grossly, these changes result in increased thickness of the epiphyseal plate, and an increase in transverse diameter that often extends beyond the ends of the bone and causes characteristic cupping or flaring. The disorder is inherited in X-linked dominant fashion and is manifest biochemically by a low renal threshold maximum for renal tubular phosphate reabsorption, consequent hypophosphatemia, and low, or inappropriate circulating levels of 1,25 OH 2D.
Known biochemical characteristics of XLH and other hypophosphatemic disorders are shown in Table 2. Characteristic features of the disease include growth retardation, osteomalacia and rickets in growing children. The clinical expression of the disease is widely variable, ranging from a mild abnormality, the apparent isolated occurrence of hypophosphatemia, to severe bone disease. Most would agree that a wide spectrum of phenotypic severity occurs in both males with a mutated gene on their only X chromosome and females who are heterozygous for the defective X-linked gene , although anecdotal experience suggests that females with some mutations may express less severe disease Evidence of disease may be detected at or shortly after birth or may not become apparent until age 12 months or older The most common clinically evident manifestations of XLH are short stature and limb deformities.
Growth abnormalities and limb deformities are both more evident in the lower extremities, since they represent the fastest growing body segment before puberty. N, normal; , decreased; , increased, , decreased relative to the serum phosphorus concentration;? Figure 4. Such defects may result in waddling gait and leg length abnormalities The severe secondary hyperparathyroidism that occurs in vitamin D deficiency is not present, however mildly elevated circulating levels of PTH occur in many patients naive to therapy.
Other non-specific but typical findings include elevated serum alkaline phosphatase activity and osteocalcin levels. Serum alkaline phosphatase activity, although usually elevated to times the upper limit of normal in childhood, is generally less than the levels observed in overt vitamin D- and calcium-deficiency rickets. Radiograph of the lower extremities in a patient with X-linked hypophosphatemia. Bowing of the femurs is evident bilaterally. The distal femoral metaphysis is cupped, frayed and widened, radiographic features of an expanded and disorganized growth plate.
Additional signs of the disease may include delayed dentition and dental abscesses 59 , 60 , which are thought to arise from the limited mineralization of the dentine compartment of the tooth. An enlarged pulp chamber is evident on dental radiographs. Strikingly absent are features commonly observed in vitamin D deficiency rickets, such as muscle weakness, tetany and convulsions. Adults with XLH may be asymptomatic or present with severe bone pain.
On clinical examination they often display evidence of post-rachitic deformities, such as bowed legs or short stature. However, overt biochemical changes such as elevated serum alkaline phosphatase activity or other biomarkers of bone turnover are often not evident. Symptoms at presentation may reflect the end-result of chronic changes, and may not correlate with apparent current activity of the disease.
In spite of marked variability in the clinical presentation of the disease, bone biopsy in affected children and adults nearly always reveals low turnover osteomalacia without osteopenia Figure 5. Histomorphometry of biopsy samples invariably demonstrates a reduced rate of formation, diffuse patchy hypomineralization, a decrease in mineralizing surfaces and characteristic areas of hypomineralization of the periosteocytic lacunae Section from an undecalcified bone biopsy in an untreated patient with X-linked hypophosphatemia.
The width of the osteoid seams is substantially increased. Osteophytes, enthesopathy 62 and craniosynostosis are not uncommon. A great deal of the morbidity of XLH in adults arises from the high incidence of arthritis, calcified entheses, and osteophytes. Enthesopathy generally is first detectable radiographically by late in the second decade, or early in the third decade.
Older subjects have more sites of involvement, and generally increasing involvement with age; the frequency of involvement is greater in males. With progressive enthesopathy and bony overgrowth, excruciating pain may occur, particularly with fusion of the sacroiliac joint s and spinal stenosis These manifestations do not appear to be affected for the better or worse with respect to exposure to currently available therapies It is peculiar that XLH represents a deficiency of mineralization at many skeletal sites, and pathologic ectopic mineralization elsewhere.
This paradoxical situation raises the possibility that aberrant humoral factors, in addition to the ambient hypophosphatemia, may play a role in the discordant mineralization abnormalities observed. As previously noted, the primary biochemical abnormality of XLH is hypophosphatemia due to increased urinary phosphate excretion. Moreover, mild gastrointestinal phosphate malabsorption is present in the majority of patients, which may contribute to the evolution of the hypophosphatemia Table 2 65 , In contrast, the serum calcium concentration in affected subjects is normal despite gastrointestinal malabsorption of calcium.
However, as a consequence of this defect, urinary calcium is often decreased. As noted above, serum alkaline phosphatase activity is usually elevated in children, although to lesser levels than seen in nutritional forms of rickets. Because of variability in adulthood, this measure is not a reliable marker of disease involvement in the older age group. Prior to the initiation of therapy, serum OHD levels are normal, and serum 1,25 OH 2D levels are in the low normal range 67 , The paradoxical occurrence of hypophosphatemia and normal serum calcitriol levels in affected subjects is consistent with aberrant regulation of both synthesis and clearance of this metabolite due to increased OHDhydroxylase activity 69 , FGF23 levels do not appear to differ between normal adults and older children, nor between children and adults affected with XLH.
With the recognition that hypophosphatemia is the definitive marker for XLH, Winters et al 71 and Burnett et al 72 discovered that this disease is transmitted as an X-linked dominant disorder. Analysis of data from 13 multigenerational pedigrees identified PHEX for phosphate regulating gene with homologies to endopeptidases located on the X chromosome as the gene mutated in XLH PHEX is located on chromosome Xp Further studies have revealed that PHEX is homologous to the M13 family of membrane-bound metalloproteases, or neutral endopeptidases.
M13 family members, including neutral endopeptidase In addition, like other neutral endopeptidases, immunofluorescent studies have revealed a cell-surface location for PHEX in an orientation consistent with a type II integral membrane glycoprotein It has been demonstrated that certain missense mutations in PHEX that substitute a highly conserved cysteine residue will interfere with normal trafficking of the molecule to the plasma membrane Subcellular locations appear to be the plasma membrane, endoplasmic reticulum and Golgi organelle.
Immunohistochemistry studies suggest that Phex is most abundant on the cell surface of the osteocyte. In sum, the ontogeny of Phex expression suggests a possible role in mineralization in vivo. Mutations are scattered throughout the amino acid extracellular domain, encoded by exons , and are diverse, consisting of deletions, insertions and duplications, as well as splice site, nonsense and missense mutations.
In order to confirm this possibility, several investigators have used targeted over-expression of Phex in attempts to normalize osteoblast mineralization, in vitro, and rescue the Hyp phenotype in vivo 89 - Results from these studies have not resulted in a complete skeletal rescue, raising questions as to the role of early developmental expression of PHEX, or at least the success of expression when targeted with osteocalcin or type I collagen promoters.
Nevertheless, partial rescue of the mineralization defect in Hyp mice occurs, suggesting that local effects of the PHEX mutation may play some role in the mineralization process, but cannot completely restore the skeleton to normality. Of note, this partial rescue occurs in concert with a reduction in FGF23 levels, although not lowered to a truly normal range Failure of targeted osteoblastic PHEX overexpression to completely rescue Hyp mice may reflect that critical sites or developmental timing for PHEX expression are not effectively generated with these models to effectively rescue the skeletal phenotype; this effect may be dependent upon the resultant capacity in these transgenic models of normal PHEX to reduce FGF23 production in mutant cells.
The primary inborn error in XLH results in the impaired renal proximal tubule function of Pi reabsorption. The immediate cause of this abnormality is the decreased abundance of NaPi-II mRNA and immunoreactive protein in the proximal convoluted tubule cells 93 - Evidence for humoral mediation of phosphate wasting in XLH was provided by both classical parabiosis experiments, suggested that a cross-circulating factor could mediate renal phosphate wasting 96 , and renal cross-transplantation between Hyp and normal mice.
These experiments demonstrated continued normal renal phosphate handling after transplantation of Hyp kidney to a normal host, as well as the failure to correct the mutant phenotype upon introduction of a normal kidney to a Hyp host These findings, most consistent with humoral mediation of the Pi wasting in the disease, led to the search for candidate mediators of renal phosphate handling, and eventually to the discovery that FGF23 is an important regulator of renal phosphate homeostasis. The hypothesis that PHEX a member of the M13 family of zinc-dependent type II cell surface membrane metalloproteinases could serve as a processor of a phosphaturic hormone such as FGF23 has not been borne out, and the role PHEX plays in this pathway is not clear.
Several other phosphate wasting disorders have been described see below in which elevated FGF23 occurs in the setting of presumably normal PHEX. The specific mutations disrupt an RXXR protease recognition site, and thereby protect FGF23 from proteolysis, resulting in reduced clearance and elevating circulating levels of this protein, with coincident renal Pi wasting.
In yet another genetic disorder, Autosomal Recessive Hypophosphatemic Rickets type I , due to homozygous loss of function mutations in dentin matrix protein-1 DMP1 , renal tubular Pi wasting occurs in the setting of increased FGF23 levels. These findings have suggested the hypothesis that primary inhibition of mineralization may serve to increase FGF23 levels.
In sum, enhanced FGF23 activity is common to several phosphate-wasting disorders. In particular, those disorders that share the combined defects of inappropriately low circulating levels of 1,25 OH 2D and renal tubular Pi wasting are associated with increased FGF23 levels. Circulating FGF23 concentrations may also occur secondary to the increased production associated with various tumors. Signaling through this pathway results in a decrease in NaPi-II mRNAs, thereby reducing the abundance of Pi cotransporters on the apical membrane and the well-described impairment of renal tubular Pi reabsorption.
Likewise, synthesis of 1,25 OH 2D is impaired, while its clearance is augmented. Other recent findings have provided support for the role of klotho in the FGFmediated hypophosphatemia pathway. An unusual patient with renal tubular Pi wasting and abnormally increased serum klotho has been described Investigation revealed a translocation breakpoint disrupting the region upstream of that encoding klotho. Indeed, mice with disruption of the klotho gene manifest hyperphosphatemia and elevated circulating 1,25 OH 2D levels The unexpected finding that overexpression of klotho can upregulate FGF23 production has also been reported Indeed, further evidence for the central role of FGF23 in the Pi-regulating process comes from the investigation of another group of rare disorders of Pi homeostasis in which renal Pi conservation is excessive in the setting of increased circulating Pi levels.
This group of disorders, known as hyperphosphatemic tumoral calcinosis HTC , is manifest clinically by precipitation of amorphous calcium-phosphate crystals in soft tissues. This phenomenon is thought to result from an increase in the ambient Ca x Pi solubility product, and occurs as a direct result of enhanced renal tubular reabsorption of Pi In addition, circulating 1,25 OH 2D levels are inappropriately in the high-normal to high range. Thus, the precise converse of primary metabolic derangements occurs, as compared to the XLH-related group of diseases. Initially, HTC was been shown to directly result from loss of function mutations in GALNT3, a glycosylating enzyme important for appropriate O-glycosylation of proteins.
This modification appears to be necessary for efficient Golgi secretion of full length FGF23 Recent evidence implicates that variant post-translational modification of FGF23 can also be modulated by FAM20C: mutations in this gene can result in elevated FGF23 levels, renal phosphate wasting and hypophosphatemia see table 1 , Loss of function of klotho has also been described in a case of HTC, despite the finding of elevated FGF23 levels, thus rendering the FGF23 inactive at the renal proximal tubule As with hypophosphatemia syndromes, animal models have confirmed the physiologic implications of these clinical scenarios: FGF23 null mice develop a hyperphosphatemic, calcifying phenotype with elevated 1,25 OH 2D levels 39 , similar to mice with disruption of the klotho gene , As noted above, the klotho protein is now known to be an essential co-factor in FGFR1c activation when FGF23 serves as the activating ligand The overall physiologic importance of this regulating system requires further study.
The intriguing aspect of the osteocyte as a potential central cell in this pathway also bears further study. Decades ago, physicians employed pharmacological doses of vitamin D as the cornerstone for treatment of XLH. However, long-term observations indicate that this therapy fails to cure the disease and poses the serious problem of recurrent vitamin D intoxication and renal damage. Indeed, such treatment results only in incomplete healing of the rachitic abnormality, while hypophosphatemia and impaired growth remain. Similar unresponsiveness is typical with use of 25 OH D. With the recognition that phosphate depletion is an important contributor to impaired skeletal mineralization, physicians began to devise treatment strategies that employed oral phosphate supplementation to compensate for the renal phosphate wasting and thereby increasing the available Pi to the mineralizing skeleton.
This strategy was somewhat successful in terms of improving skeletal lesions, although it was soon realized that pharmacologic amounts of vitamin D were necessary in combination with phosphate supplements to counter the exacerbation of hyperparathyroidism observed in this setting.
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Such combination therapy was found to be more effective than either administering vitamin D or phosphate alone. With the recognition that circulating 1,25 OH 2D levels are not appropriately regulated in XLH, the use of this metabolite in combination with phosphate was subsequently used to treat the disease 67 , - The current treatment strategy directly addresses the combined calcitriol and phosphorus deficiency characteristic of the disorder. Although this combination therapy has become the conventional therapy for XLH, complete healing of the skeletal lesions is usually not the case, and late complications of the disease are persistent and often debilitating.
In children the goal of therapy is to improve growth velocity, normalize any lower extremity defects, and heal the attendant bone disease. Hypercalcemia, hypercalciuria, renal calcinosis, and hyperparathyroidism can be sequelae of unmonitored therapy. Detrimental effects on renal function were particularly common prior to the frequent monitoring now generally employed with this therapy. Throughout the treatment course careful attention to renal function, as well as serum and urine calcium is extremely important. Nevertheless, in spite of these varied complications of therapy, treatment of XLH often proceeds with limited interruptions.
Moreover, the improved outcome of this therapeutic intervention, compared to that achieved by previous regimens, justifies the aggressive approach that constitutes this current therapy. While such combined therapy often improves growth velocity, refractoriness to the growth-promoting effects of treatment can be encountered in children who present with markedly short stature prior to 4 years of age. For that reason, the use of recombinant growth hormone as additional treatment has been suggested , however this approach has not been universally recommended in view of the lack of definitive benefits in controlled studies, and a risk of resultant worsening of the disproportional stature , although others have not identified significant concerns in this regard Indications for combined therapy in adults with XLH are less clear.
The occurrence of intractable bone pain and refractory non-union fractures often respond to treatment with calcitriol and phosphorus However, data remain unclear regarding the effects of treatment on fracture incidence which may not be increased in untreated patients , There does not appear to be any effect of this therapy on enthesopathy, however superior dentition appears to occur in the setting of higher medication exposure through adulthood as well as the entire life span Muscle weakness and general well-being may occur with therapy in some adults.
In sum, the decision to treat affected adults must be individualized. In general, it is beneficial to offer adults with significant symptomatology a trial of this therapy, but only if routine biochemical monitoring can be performed. A detailed strategy for the management of children and adults with XLH is available Given the limitations of currently advised treatment for XLH, the quest for new and better therapies for XLH continues.
Correction of serum P levels and improved bony growth in Hyp mice treated with a neutralizing antibody to FGF23 have been shown 40 , and subsequent short-term trials of an antibody to the human FGF23 protein, burosumab KRN23 have been conducted , A trial of monthly dosing in affected adults has been shown to be effective and well-tolerated Most recently, subcutaneous administration of burosumab resulted in improvement of radiographic features of rickets in concert with correction of abnormal biochemical indices in children with XLH previously treated with conventional phosphate and active vitamin D therapy Steady and stable correction of hypophosphatemia was attained with administration of the antibody every 2 weeks.
These findings, together with a favorable safety profile hold promise for improving outcomes observed with current approaches to treating this disorder. Several studies have documented autosomal dominant inheritance of a hypophosphatemic disorder similar to XLH , Affected patients also demonstrate normal serum 25 OH D levels, while maintaining inappropriately normal serum concentrations of 1,25 OH 2D, in the presence of hypophosphatemia, all hallmarks of XLH Table 2. PTH levels are normal. Long-term studies indicate that a few of the affected female patients demonstrate delayed penetrance of clinically apparent disease and an increased tendency for bone fracture, uncommon occurrences in XLH.
In addition, among patients with the expected biochemical features documented in childhood, rare individuals lose the renal phosphate-wasting defect after puberty. These mutations disrupt an RXXR furin protease recognition site, and the resultant mutant molecule is thereby protected from proteolysis, and resultant elevated circulating levels of FGF23 are the likely cause of the renal Pi wasting.
Interestingly, circulating FGF23 levels can vary and reflect the activity of disease status Iron deficiency appears to upregulate FGF23 expression, and in normal individuals, processing of the intact protein to its inactive N- and C-terminal fragments is efficient, thereby compensating for the increased intact FGF23 production seen with iron deficiency. Thus, in normal individuals who become iron deficient normal circulating levels of intact FGF23 are maintained despite the increase in production.
Thus, the waxing and waning clinical severity observed in some cases of ADHR may be amenable to iron supplementation, and provide a straightforward approach to therapy.
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A recently reported case demonstrates that correction of serum iron levels to high normal levels allowed for discontinuation of conventional rickets medications An apparent forme fruste of ADHR autosomal dominant hypophosphatemic bone disease has many of the characteristics of XLH and ADHR, but recent reports indicate that affected children display no evidence of rachitic disease. Because this syndrome is described in only a few small kindreds, and radiographically evident rickets is not universal in children with familial hypophosphatemia, these families may have ADHR.
Further observations are necessary to discriminate this possibility. Families with phosphate wasting rickets inherited in an autosomal recessive manner have been described and demonstrate the same constellation of progressive rachitic deformities seen in both XLH and ADHR , In addition to the expected phenotypic features, and in contrast to XLH, spinal radiographs of patients with ARHR reveal noticeably sclerotic vertebral bodies. In addition to the enlarged pulp chamber characteristic of teeth in individuals with XLH, enamel hypoplasia can be evident in heterozygotes.
Of particular interest is the identification of elevated levels of FGF23 in the affected individuals. Experience with long-term follow-up is not widespread in ARHR and therapeutic response or guidelines have not been definitively established. The identification of a progressive mineralization defect associated with hypophosphatemia in DMP1 knockout mice led to the consideration of homozygous loss of function in this candidate gene as a cause of ARHR. Indeed, this was proven to be the case for the first families identified with the disorder.
These observations reinforce the central role that the osteocyte plays in mineral homeostasis. Moreover, hypophosphatemic rickets in association with renal Pi wasting has been recently described in the setting of the extremely rare disorder, generalized arterial calcification of infancy GACI - Loss-of-function of ENPP1 results in the inability to generate the mineralization inhibitor, pyrophosphate, thereby disrupting the restriction of heterotopic e. The mechanism by which this enzyme influences renal tubular phosphate wasting is not evident, and further study is necessary to understand this intriguing problem.
Although there has been concern that the treatment of rickets in patients affected with GACI patients may promote worsening of vascular calcification, no evidence to sustain this concern has emerged and one long term observational report suggests that treatment does not worsen this finding In many cases, the metabolic disturbances improved or completely disappeared upon removal of the tumor, indicating a causal role of the tumor. Biochemistries include hypophosphatemia secondary to renal phosphate wasting and normal serum levels of calcium and 25 OH D.
Serum 1,25 OH 2D is often overtly low or is otherwise inappropriately normal in the setting of hypophosphatemia Table 2. Radiographic abnormalities include generalized osteopenia, pseudofractures, and coarsened trabeculae, as well as widened epiphyseal plates in children. The histologic appearance of trabecular bone in affected subjects most often reflects the presence of a low turnover osteomalacia.
The large majority of patients with this syndrome harbor tumors of mesenchymal origin, including primitive-appearing, mixed connective tissue lesions. These tumors are often classified as osteoblastomas, osteochondromas, nonossifying fibromas, and ossifying fibromas. In addition, tumors of epidermal and endodermal derivation have been implicated as causal of the disease. Indeed, the observation of tumor-induced osteomalacia concurrent with breast carcinoma, prostate carcinoma, oat cell carcinoma, small cell carcinoma, multiple myeloma and chronic lymphocytic leukemia have been reported.
Although this syndrome is relatively rare compared to XLH, investigation of causative tumors eventually led to the identification and isolation of FGF23 38 , , the mediator of many heritable hypophosphatemic disorders, and the recognition that this protein is the central factor in a major regulatory system affecting Pi homeostasis.
Moreover, the discovery represented the first disorder related to the endocrine subfamily of FGFs, acting at distant sites with specificity of site activity conferred by the family of klotho co-receptors. Regardless of the tumor cell type, the lesions at fault for the syndrome are often small, difficult to locate and present in obscure areas which include the nasopharynx, jaw, sinuses, the popliteal region and the suprapatellar area. Recently newer imaging techniques such as octreotide scintigraphy or PET scans have been used to successfully identify tumors that remained unidentified by other means of localization.
Newer agents with greater specificity for somatostatin receptors type 2 and type 5 appear to increase the sensitivity of PET scanning , , and co-registry with high resolution anatomic imaging has considerably advanced detection of small tumors. Selective venous sampling has been suggested as a complementary approach to diagnosis. This technique may provide confirmation of local FGF23 secretion in suspicious areas identified by imaging as to avoid unnecessary operations from false-positive imaging studies. The technique may serve to direct local imaging to anatomic regions defined by step-ups in FGF23 concentrations, but is limited by the relatively long half-life of FGF23, which may be misleading if the sampling is not in very close proximity to the offending tumor.
Although useful in the settings mentioned above, the technique is not thought to be an optimal first-line approach in identification of TIO causing tumors TIO is a result of Pi wasting secondary to circulating factor s secreted by causal tumors. FGF23 has proven to be the primary factor identified in most patients where examination of serum levels or tumor material has occurred.
It is also possible that these or other tumor products may have direct effects on the mineralization function of the skeleton. A novel genetic mechanism by which TIO tumors may develop autonomous FGF23 production involves a somatic chromosomal rearrangement, which has been identified in a high proportion of TIO tumors The rearrangement sequence predicts a fusion protein consisting of the N-terminal portion of fibronectin and the FGFR1 receptor. The extracellular fibronectin domain is proposed to promote dimerization and activation of the complex leading to downstream signaling resulting in FGF23 secretion.
In contrast to these observations, other rare patients with TIO secondary to hematogenous malignancy manifest abnormalities that would suggest a different pathophysiologic mechanism. In these subjects a nephropathy induced with light chain proteinuria or other immunoglobulin derivatives appears to result in decreased renal tubular reabsorption of phosphate.
Thus, light-chain nephropathy has been considered a possible mechanism for the TIO syndrome. The first and foremost treatment of TIO is complete resection of the tumor.
However, recurrence of mesenchymal tumors, such as giant cell tumors of bone, or inability to resect completely certain malignancies, such as prostatic carcinoma, has resulted in development of alternative therapeutic intervention for the syndrome. In this regard, administration of 1,25 OH 2D alone or in combination with phosphorus supplementation has served as effective therapy for TIO.
Doses of calcitriol required range from 1. Although little information is available regarding the long-term consequences of such treatment, the high doses of medicine required raise the possibility that nephrolithiasis, nephrocalcinosis, and hypercalcemia may frequently complicate the therapeutic course.
Clinical practice recommendations for the diagnosis and management of X-linked hypophosphataemia
Indeed, hypercalcemia secondary to parathyroid hyperfunction has been documented in several subjects. Generally, these patients receive phosphorus as part of a combination regimen, exacerbating the path to parathyroid autonomy. Thus, as with treatment of XLH, careful assessment of parathyroid function, serum and urinary calcium, and renal function are essential to ensure safe and efficacious therapy.
Recent studies using burosumab, the antiFGF23 antibody, have demonstrated improvement in both biochemical indices and biopsy parameters of osteomalacia in inoperable TIO Other primary skeletal disorders in which elevated FGF23 levels have been reported include osteoglophonic dysplasia due to mutations in the FGFR1 receptor , Jansen metaphyseal chondrodysplasia, due to activating mutations of the PTH1 receptor , and in FAM20C mutations The mechanism s by which elevations in FGF23 occur in these settings is not certain at this time. This rare autosomal recessive disease is marked by hypophosphatemic rickets with hypercalciuria Such deformities may include genu varum or genu valgum or anterior bowing of the femur and coxa vara.
Additional disease features include short stature, and radiographic signs of rickets or osteopenia. In contrast to XLH, muscle weakness may be elicited as a presenting symptom. In fact, FGF23 levels tend to be somewhat decreased compared to the normal population. Consequently, in contrast to the previously described disorders in which renal phosphate transport is limited, patients with HHRH exhibit increased 1,25 OH 2D production.
The resultant elevated serum calcitriol levels enhance gastrointestinal calcium absorption, which in turn increases the filtered renal calcium load and inhibits PTH secretion. Collectively these events produce the hypercalciuria observed in affected patients Table 2. Although initially not thought to be part of the syndrome, the propensity for kidney stones to occur has been reported in several patients.