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1.  Serum MEPE-ASARM-peptides are elevated in X-linked rickets (HYP): implications for phosphaturia and rickets 
The Journal of Endocrinology  2004;183(3):R1-R9.
MEPE (Matrix Extracellular PhosphoglycoprotEin) expression is markedly elevated in X-linked-hypophosphatemic-rickets (HYP) and tumor-induced osteomalacia (TIO). In normal individuals, circulating serum-levels of MEPE are tightly correlated with serum-phosphorus, parathyroid hormone (PTH) and bone mineral density (BMD). Also, MEPE derived, C-terminal ASARM-peptides are candidate minhibins and/or phosphatonins. Our aims were to determine: 1. whether MEPE-ASARM-peptide(s) are abnormally elevated in HYP/hyp serum, and, 2. whether the ASARM-peptide(s) accumulate in hyp mice kidney renal-tubules. Using a specific competitive ELISA we measured a five fold increase (P=0·007) of serum ASARM-peptide(s) in human HYP patients (normal subjects 3·25 μM n=9; S.E.M.=0·51 and HYP-patients 15·74 μM, n=9; S.E.M.=3·32). A 6·23 fold increase (P=0·008) was measured in hyp male mice compared with their normal male siblings (normal-siblings, 3·73 μM, S.E.M.=0·57, n=3; and hyp-mice 23·4 μM, n=3, S.E.M.=4·01). Renal immuno-histological screening also revealed a dramatic increase of ASARM-peptides in regions anatomically consistent with the proximal convoluted tubules. This study demonstrates for the first time that markedly elevated serum levels of protease-resistant ASARM-peptide(s) occur in HYP/hyp and they accumulate in murine hyp kidneys. These peptides are thus likely responsible for the phosphaturia and defective mineralization in HYP/hyp and TIO.
PMCID: PMC3357083  PMID: 15590969
2.  Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets 
Clinical endocrinology  2011;74(3):312-318.
X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets make up a group of renal phosphate wasting disorders with common clinical and biochemical characteristics. These three types of rickets are related to mutations in PHEX, FGF23 and DMP1, respectively.
The objective of the study was to evaluate the frequency of mutations that occur in these three genes associated with hypophosphatemic rickets.
Patients and Methods
In this study, we sequenced these genes in 76 members of 46 kindreds from a large hypophosphatemic rickets cohort.
Forty two individuals from 27 kindreds were found to have mutations in PHEX, 16 of which were novel. One subject had an FGF23 mutation. No individuals were found to have mutations in DMP1 consistent with the presence of recessive hypophosphatemic rickets.
Our data highlight the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets.
PMCID: PMC3035757  PMID: 21050253
PHEX; FGF23; DMP1 in phosphate rickets
3.  Three Novel Mutations in the PHEX Gene in Chinese Subjects with Hypophosphatemic Rickets Extends Genotypic Variability 
Calcified Tissue International  2011;88(5):370-377.
Mutations in the phosphate-regulating endopeptidase homolog, X-linked, gene (PHEX), which encodes a zinc-dependent endopeptidase that is involved in bone mineralization and renal phosphate reabsorption, cause the most common form of hypophosphatemic rickets, X-linked hypophosphatemic rickets (XLH). The distribution of PHEX mutations is extensive, but few mutations have been identified in Chinese with XLH. We extracted genomic DNA and total RNA from leukocytes obtained from nine unrelated Chinese subjects (three males and six females, age range 11–36 years) who were living in Taiwan. The PHEX gene was amplified from DNA by PCR, and the amplicons were directly sequenced. Expression studies were performed by reverse-transcription PCR of leukocyte RNA. Serum levels of FGF23 were significantly greater in the patients than in normal subjects (mean 69.4 ± 18.8 vs. 27.2 ± 8.4 pg/mL, P < 0.005), and eight of the nine patients had elevated levels of FGF23. Germline mutations in the PHEX gene were identified in five of 9 patients, including novel c.1843 delA, donor splice site mutations c.663+2delT and c.1899+2T>A, and two previously reported missense mutations, p.C733Y and p.G579R. These data extend the spectrum of mutations in the PHEX gene in Han Chinese and confirm variability for XLH in Taiwan.
PMCID: PMC3075400  PMID: 21293852
X-linked hypophosphatemic rickets; PHEX; FGF23; Mutation analysis
4.  Hypophosphatemic rickets: A case of recurrent pathological fractures 
Renal phosphate-wasting disorders are the most common form of hereditary rickets and osteomalacia in western countries, but are rarely reported in India. Therefore, we report here a case of hypophosphatemic rickets.
Aim and objective:
To report a case of hypophosphatemic rickets presenting with recurrent pathological fractures.
Material and Methods:
A 34-year-old premenopausal lady presented with recurrent pathological fractures, bone pain, and muscle weakness since 14 years of age. A thorough history was taken followed by clinical examination, and relevant biochemical and radiological investigations were done.
Height was 125 cm, arm span 145 cm, body weight 30 kg, and body mass index (BMI) 19.2 kg/m2. Dental caries, kyphoscoliosis, shortening of left lower limb, bilateral coxa vara deformity of knee, muscle weakness, and bone tenderness were present. Calcium was 9.4 mg/dL, phosphorus: 1.8 mg/dL, albumin: 4.0 gm/dL, alkaline phosphatase: 360 U/L, creatinine: 0.4 mg/dL, a normal ammonium chloride (NH4Cl) loading test,24-hour urine calcium excretion: 102 mg/day, 25-hydroxyvitamin D3 [25(OH)D3]: 21.6 ng/mL, intact parathyroid hormone (PTH): 43.74 pg/mL, fraction excretion of phosphate (PO4): 40%, tubular maximum reabsorption of phosphate per unit of glomerular filtrate (TmP/GFR): 0.65 mg/dL, and fibroblast growth factor (FGF)23: 321.4 RU/mL. Skeletal X-rays showed multiple old fractures and pseudofractures. Magnetic resonance imaging (MRI) of the whole body showed no evidence of tumor. Fludeoxyglucose (18F)-positron emission tomography (FDG-PET) computed tomography (CT) scan revealed metabolically active marrow with multiple areas of fracture and FDG-avid lesions in both lungs but no CT-based findings.
Hypophosphatemic rickets or osteomalacia, possibly hereditary, is a rare cause of recurrent pathological fractures.
PMCID: PMC3603091  PMID: 23565443
Hypophosphatemic rickets; osteomalacia; pathological fracture
5.  Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism 
Nature genetics  2006;38(11):1310-1315.
The osteocyte, a terminally differentiated cell comprising 90%–95% of all bone cells1,2, may have multiple functions, including acting as a mechanosensor in bone (re)modeling3. Dentin matrix protein 1 (encoded by DMP1) is highly expressed in osteocytes4 and, when deleted in mice, results in a hypomineralized bone phenotype5. We investigated the potential for this gene not only to direct skeletal mineralization but also to regulate phosphate (Pi) homeostasis. Both Dmp1- null mice and individuals with a newly identified disorder, autosomal recessive hypophosphatemic rickets, manifest rickets and osteomalacia with isolated renal phosphate-wasting associated with elevated fibroblast growth factor 23 (FGF23) levels and normocalciuria. Mutational analyses showed that autosomal recessive hypophosphatemic rickets family carried a mutation affecting the DMP1 start codon, and a second family carried a 7-bp deletion disrupting the highly conserved DMP1 C terminus. Mechanistic studies using Dmp1-null mice demonstrated that absence of DMP1 results in defective osteocyte maturation and increased FGF23 expression, leading to pathological changes in bone mineralization. Our findings suggest a bone-renal axis that is central to guiding proper mineral metabolism.
PMCID: PMC1839871  PMID: 17033621
6.  Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets 
Cells, Tissues, Organs  2008;189(1-4):219-223.
Familial hypophosphatemic rickets is transmitted in most cases as an X-linked dominant trait and results from the mutation of the PHEX gene predominantly expressed in osteoblast and odontoblast. Patients with rickets have been reported to display important dentin defects. Our purpose was to explore the structure, composition and distribution of noncollagenous proteins (NCPs) of hypophosphatemic dentin. We collected teeth from 10 hypophosphatemic patients whose mineralization occurred either in a hypophosphatemic environment or in a corrected phosphate and vitamin environment. Teeth were examined by scanning electron microscopy, immunohistochemistry and Western blot analysis. An abnormal distribution (accumulation in interglobular spaces) and cleavage of the NCPs and particularly of matrix extracellular phosphoglycoprotein were observed in deciduous dentin. In contrast, it was close to normal in permanent dentin mineralized under corrected conditions. In conclusion, dentin mineralization in a corrected phosphate and vitamin D environment compensates the adverse effect of PHEX mutation.
PMCID: PMC3352030  PMID: 18701809
Hypophosphatemic rickets; Dentin; Mineralization; Noncollagenous proteins; Matrix extracellular phosphoglycoprotein
7.  Dentin Noncollagenous Matrix Proteins in Familial Hypophosphatemic Rickets 
Cells, Tissues, Organs  2008;189(1-4):219-223.
Familial hypophosphatemic rickets is transmitted in most cases as an X-linked dominant trait and results from the mutation of the PHEX gene predominantly expressed in osteoblast and odontoblast. Patients with rickets have been reported to display important dentin defects. Our purpose was to explore the structure, composition and distribution of noncollagenous proteins (NCPs) of hypophosphatemic dentin. We collected teeth from 10 hypophosphatemic patients whose mineralization occurred either in a hypophosphatemic environment or in a corrected phosphate and vitamin environment. Teeth were examined by scanning electron microscopy, immunohistochemistry and Western blot analysis. An abnormal distribution (accumulation in interglobular spaces) and cleavage of the NCPs and particularly of matrix extracellular phosphoglycoprotein were observed in deciduous dentin. In contrast, it was close to normal in permanent dentin mineralized under corrected conditions. In conclusion, dentin mineralization in a corrected phosphate and vitamin D environment compensates the adverse effect of PHEX mutation.
PMCID: PMC3352030  PMID: 18701809
Hypophosphatemic rickets; Dentin; Mineralization; Noncollagenous proteins; Matrix extracellular phosphoglycoprotein
8.  Therapeutic management of hypophosphatemic rickets from infancy to adulthood 
Endocrine Connections  2014;3(1):R13-R30.
In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.
PMCID: PMC3959730  PMID: 24550322
calcium; bone; rare diseases/syndromes; X-linked hypophosphatemic rickets
9.  Genetic diagnosis of X-linked dominant hypophosphatemic rickets in a cohort study: Tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type 
BMC Medical Genetics  2011;12:116.
Genetic Hypophosphatemic Rickets (HR) is a group of diseases characterized by renal phosphate wasting with inappropriately low or normal 1,25-dihydroxyvitamin D3 (1,25(OH)2D) serum levels. The most common form of HR is X-linked dominant HR (XLHR) which is caused by inactivating mutations in the PHEX gene. The purpose of this study was to perform genetic diagnosis in a cohort of patients with clinical diagnosis of HR, to perform genotype-phenotype correlations of those patients and to compare our data with other HR cohort studies.
Forty three affected individuals from 36 non related families were analyzed. For the genetic analysis, the PHEX gene was sequenced in all of the patients and in 13 cases the study was complemented by mRNA sequencing and Multiple Ligation Probe Assay. For the genotype-phenotype correlation study, the clinical and biochemical phenotype of the patients was compared with the type of mutation, which was grouped into clearly deleterious or likely causative, using the Mann-Whitney and Fisher's exact test.
Mutations in the PHEX gene were identified in all the patients thus confirming an XLHR. Thirty four different mutations were found distributed throughout the gene with higher density at the 3' end. The majority of the mutations were novel (69.4%), most of them resulted in a truncated PHEX protein (83.3%) and were family specific (88.9%). Tubular reabsorption of phosphate (TRP) and 1,25(OH)2D serum levels were significantly lower in patients carrying clearly deleterious mutations than in patients carrying likely causative ones (61.39 ± 19.76 vs. 80.14 ± 8.80%, p = 0.028 and 40.93 ± 30.73 vs. 78.46 ± 36.27 pg/ml, p = 0.013).
PHEX gene mutations were found in all the HR cases analyzed, which was in contrast with other cohort studies. Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.
PMCID: PMC3189111  PMID: 21902834
10.  Molecular Analysis of DMP1 Mutants Causing Autosomal Recessive Hypophosphatemic Rickets 
Bone  2008;44(2):287-294.
We previously demonstrated that the mutations Met1Val (M1V) and the deletion of nucleotides 1484-1490 (1484-1490del) in Dentin matrix protein-1 (DMP1) cause the novel disorder autosomal recessive hypophosphatemic rickets (ARHR), which is associated with elevated Fibroblast growth factor-23 (FGF23). To further understand the role of DMP1 in ARHR, we undertook molecular genetic and in vitro expression studies. First, we examined a kindred with a severe hypophosphatemic rickets phenotype and recessive inheritance. Analyses of this family demonstrated that the affected members had elevated serum FGF23 and carried a large, biallelic deletion that removed the majority of DMP1. At a minimum, this deletion encompassed 49 kb between DMP1 exon 3 and an intergenic region 5′ to the next telomeric gene, integrin-binding sialoprotein (IBSP). We next performed immunofluorescent studies in cells to understand the effects of the known ARHR mutations on DMP1 cellular processing. These analyses showed that the M1V DMP1 mutant was not sorted to the trans-Golgi network (TGN) and secretory pathway, but filled the entire cytoplasm. In contrast, the 1484-1490del mutant localized to the TGN and was secreted, similar to wild type DMP1. The 1484-1490del mutation replaces the DMP1 18 C-terminal amino acids with 33 non-native residues. Truncation of wild type DMP1 by these native 18 residues followed by Western blot and confocal microscopic analyses demonstrated a wild type expression pattern when compared with the 1484-1490del mutant, indicating that the last 18 residues are not critical for cellular trafficking, but that the 33 additional residues arising from the 1484-1490del mutation likely compromise DMP1 processing. The relationship between DMP1 and FGF23 is unclear. To test endogenous DMP1 response to serum metabolites that also regulate FGF23, UMR-106 cells were treated with 1,25(OH)2 vitamin D (1×10−7M) and showed a 12-fold increase in DMP1 mRNA and protein at 24 hr. In summary, we have identified a novel DMP1 deletion as the cause of ARHR, as well as demonstrated that the ARHR mutations alter DMP1 cellular processing, and that DMP1 can be regulated by vitamin D. Taken together, this work expands our understanding of the genetic and molecular mechanisms associated with DMP1 alterations causing ARHR.
PMCID: PMC2669955  PMID: 19007919
FGF23; vitamin D; ARHR; SIBLING; hypophosphatemia
11.  Successful Medical Therapy for Hypophosphatemic Rickets due to Mitochondrial Complex I Deficiency Induced de Toni-Debré-Fanconi Syndrome 
Case Reports in Pediatrics  2013;2013:354314.
Primary de Toni-Debré-Fanconi syndrome is a non-FGF23-mediated hypophosphatemic disorder due to a primary defect in renal proximal tubule cell function resulting in hyperphosphaturia, renal tubular acidosis, glycosuria, and generalized aminoaciduria. The orthopaedic sequela and response to treatment of this rare disorder are limited in the literature. Herein we report a long term followup of a 10-year-old female presenting at 1 year of age with rickets initially misdiagnosed as vitamin D deficiency rickets. She was referred to the metabolic bone and genetics clinics at 5 years of age with severe genu valgum deformities of 24 degrees and worsening rickets. She had polyuria, polydipsia, enuresis, and bone pain. Diagnosis of hypophosphatemic rickets due to de Toni-Debré-Fanconi syndrome was subsequently made. Respiratory chain enzyme analysis identified a complex I mitochondrial deficiency as the underlying cause. She was treated with phosphate (50–70 mg/kg/day), calcitriol (30 ng/kg/day), and sodium citrate with resolution of bone pain and normal growth. By 10 years of age, her genu valgus deformities were 4 degrees with healing of rickets. Her excellent orthopaedic outcome despite late proper medical therapy is likely due to the intrinsic renal tubular defect that is more responsive to combined alkali, phosphate, and calcitriol therapy.
PMCID: PMC3872385  PMID: 24386581
12.  Evaluation of a Role for 1,25-Dihydroxyvitamin D3 in the Pathogenesis and Treatment of X-linked Hypophosphatemic Rickets and Osteomalacia 
Journal of Clinical Investigation  1980;66(5):1020-1032.
Although a defect in renal transport of phosphate seems well established as the primary abnormality underlying the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia, several observations indicate that renal phosphate wasting and hypophosphatemia cannot solely account for the spectrum of abnormalities characteristic of this disease. Thus, in the present study, we investigated the potential role of abnormal vitamin D metabolism in the pathogenesis of this disorder and the effect of 1,25-dihydroxyvitamin D3 therapy on both the biochemical abnormalities characteristic of this disease and the osteomalacia. Four untreated patients, ages 14-30 yr, had normocalcemia (9.22±0.06 mg/dl); hypophosphatemia (2.25±0.11 mg/dl); a decreased renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate (2.12±0.09 mg/dl); normal serum immunoreactive parathyroid hormone concentration; negative phosphate balance; and bone biopsy evidence of osteomalacia. The serum 25-hydroxyvitamin D3 concentration was 33.9±7.2 ng/ml and, despite hypophosphatemia, the serum level of 1,25-dihydroxyvitamin D3 was not increased, but was normal at 30.3±2.8 pg/ml. These data suggested that abnormal homeostasis of vitamin D metabolism might be a second defect central to the phenotypic expression of X-linked hypophosphatemic rickets/osteomalacia. This hypothesis was supported by evaluation of the long-term response to pharmacological amounts of 1,25-dihydroxyvitamin D3 therapy in three subjects. The treatment regimen resulted in elevation of the serum 1,25-dihydroxyvitamin D levels to values in the supraphysiological range. Moreover, the serum phosphate and renal tubular maximum for the reabsorption of phosphate per liter of glomerular filtrate increased towards normal whereas the phosphate balance became markedly positive. Most importantly, however, repeat bone biopsies revealed that therapy had positively affected the osteomalacic component of the disease, resulting in normalization of the mineralization front activity. Indeed, a central role for 1,25-dihydroxyvitamin D3 in the mineralization of the osteomalacic bone is suggested by the linear relationship between the serum level of this active vitamin D metabolite and the mineralization front activity. We, therefore, suggest that a relative deficiency of 1,25-dihydroxyvitamin D3 is a factor in the pathogenesis of X-linked hypophosphatemic rickets and osteomalacia and may modulate the phenotypic expression of this disease.
PMCID: PMC371539  PMID: 6253520
13.  Mutational Survey of the PHEX Gene in Patients with X-linked Hypophosphatemic Rickets 
Bone  2008;43(4):663-666.
X-linked hypophosphatemic rickets (XLH) is a dominantly inherited disorder characterized by renal phosphate wasting, aberrant vitamin D metabolism, and abnormal bone mineralization. XLH is caused by inactivating mutations in PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). In this study, we sequenced the PHEX gene in subjects from 26 kindreds who were clinically diagnosed with XLH. Sequencing revealed 18 different mutations, of which thirteen have not been reported previously. In addition to deletions, splice site mutations, and missense and nonsense mutations, a rare point mutation in the 3’-untranslated region (3’-UTR) was identified as a novel cause of XLH. In summary, we identified a wide spectrum of mutations in the PHEX gene. Our data, in accord with those of others, indicate that there is no single predominant PHEX mutation responsible for XLH.
PMCID: PMC2579265  PMID: 18625346
Mutation; PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome); 3’-untranslated region; X-linked hypophosphatemic rickets
14.  Autosomal dominant hypophosphatemic rickets is linked to chromosome 12p13. 
Journal of Clinical Investigation  1997;100(11):2653-2657.
Autosomal dominant hypophosphatemic rickets (ADHR) is an inherited disorder of isolated renal phosphate wasting, the pathogenesis of which is unknown. We performed a genome-wide linkage study in a large kindred to determine the chromosome location of the ADHR gene. Two-point LOD scores indicate that the gene is linked to the markers D12S314 [Z(theta) = 3.15 at theta = 0.0], vWf [Z(theta) = 5.32 at theta = 0.0], and CD4 [Z(theta) = 3.53 at theta = 0.0]. Moreover, multilocus analysis indicates that the ADHR gene locus is located on chromosome 12p13 in the 18-cM interval between the flanking markers D12S100 and D12S397. These data are the first to establish a chromosomal location for the ADHR locus and to provide a framework map to further localize the gene. Such studies will permit ultimate identification of the ADHR gene and provide further insight into phosphate homeostasis.
PMCID: PMC508467  PMID: 9389727
15.  Rickets–vitamin D deficiency and dependency 
Rickets is an important problem even in countries with adequate sun exposure. The causes of rickets/osteomalacia are varied and include nutritional deficiency, especially poor dietary intake of vitamin D and calcium. Non-nutritional causes include hypophosphatemic rickets primarily due to renal phosphate losses and rickets due to renal tubular acidosis. In addition, some varieties are due to inherited defects in vitamin D metabolism and are called vitamin D dependent rickets. This chapter highlights rickets/osteomalacia related to vitamin D deficiency or to inherited defects in vitamin D metabolism. Hypophosphatemic rickets and rickets due to renal tubular acidosis are discussed in other sections of the journal.
PMCID: PMC3313732  PMID: 22470851
Osteomalacia; rickets; Vitamin D; Vitamin D deficiency; Vitamin D dependent rickets
16.  Three-Year Successful Cinacalcet Treatment of Secondary Hyperparathyroidism in a Patient with X-Linked Dominant Hypophosphatemic Rickets: A Case Report 
Case Reports in Endocrinology  2014;2014:479641.
Hypophosphatemic rickets (HR) is a rare inherited disorder characterized by a classic rickets phenotype with low plasma phosphate levels and resistance to treatment with vitamin D. Development of secondary hyperparathyroidism (SHPT) as a direct consequence of treatment is a frequent complication and a major clinical challenge, as this may increase risk of further comorbidity. Cinacalcet, a calcimimetic agent that reduces the secretion of PTH from the parathyroid glands, has been suggested as adjuvant treatment to SHPT in patients with HR. However, only two papers have previously been published and no data are available on effects of treatment for more than six months. We now report a case of 3-year treatment with cinacalcet in a patient with HR complicated by SHPT. A 53-year-old woman with genetically confirmed X-linked dominant hypophosphatemic rickets developed SHPT after 25 years of conventional treatment with alfacalcidol and phosphate supplements. Cinacalcet was added to her treatment, causing a sustained normalization of PTH. Ionized calcium decreased, requiring reduction of cinacalcet, though asymptomatical. Level of phosphate was unchanged, but alkaline phosphatase increased in response to treatment. Cinacalcet appeared to be efficient, safe, and well tolerated. We recommend close control of plasma calcium to avoid hypocalcemia.
PMCID: PMC3934321  PMID: 24660072
17.  Dental abnormalities and oral health in patients with Hypophosphatemic rickets 
Clinics  2010;65(10):1023-1026.
Hypophosphatemic rickets represents a group of heritable renal disorders of phosphate characterized by hypophosphatemia, normal or low serum 1,25 (OH)2 vitamin D and calcium levels. Hypophosphatemia is associated to interglobular dentine and an enlarged pulp chambers.
Our goal was to verify the dental abnormalities and the oral health condition in these patients.
Prospective study of oral conditions in patients with Hypophosphatemic rickets. This report employed a simple method to be easily reproducible: oral clinical exam and radiographic evaluation.
Fourteen patients were studied, 5 males, median age of 11years (4 to 26). Occlusion defects (85,7%) and enamel hypoplasia (57,1%) were significant more frequently than dental abscesses (one patient). We observed enlarged pulp chambers in 43% of the patients and hypoplasia and dentin abnormalities in 14,3%. We could not detect a significant correlation between dental abnormalities and delayed treatment (p>0,05). DMFT index for 6 to 12 years patients (n = 12) showed that the oral health is unsatisfactory (mean DMFT =  5).
Patients with Hypophosphatemic Rickets frequently present dental alterations and these are not completely recovered with the treatment, unless dental abscess and they need a periodical oral examination.
PMCID: PMC2972601  PMID: 21120305
Hypophosphatemic rickets; Children; Dental abscess; Malocclusion; Dentin alterations
18.  What’s new in hypophosphataemic rickets? 
European Journal of Pediatrics  2008;167(5):493-499.
Although relatively uncommon individually, the various causes of hypophosphataemic rickets have provided an impetus for unravelling the mechanisms of phosphate homeostasis and bone mineralisation. Over the past 10 years, considerable advances have been made in establishing the gene mutations responsible for a number of the inherited causes and in understanding the mechanisms responsible for tumour-induced osteomalacia/rickets. The most exciting aspects of these discoveries have been the discovery of a whole new class of hormones or phosphatonins which are thought to control phosphate homoeostasis and 1 alpha-hydroxylase activity in the kidney, through a bone–kidney–intestinal tract axis. Although our understanding of the interrelationships is far from complete, it raises the possibilities of improved therapeutic agents in the long-term, and has resulted in improved diagnostic abilities in the short-term.
PMCID: PMC2668657  PMID: 18214537
Hypophosphataemic rickets; Phosphatonins; Renal tubular reabsorption of phosphate; FGF-23; PHEX; MEPE; Tumour-induced rickets; Polyostotic fibrous dysplasia
19.  Hypophosphatemic rickets associated with giant hairy nevus 
The association of multisystem pathologic conditions and epidermal nevi, known as the epidermal nevus syndrome, includes disorders of bone, central nervous system, eye, kidney, vasculature and skin. Rarely, congenital nevomelanocytic nevus also known as hairy nevus has also been reported in association with hypophosphatemic rickets. Studies suggest that phosphaturia, caused by circulating factors, called “phosphatonins” may be secreted by an epidermal or hairy nevus. We report here, a rare case of hypophosphatemic rickets associated with a giant hairy nevus in a 10-year-old boy.
PMCID: PMC3830300  PMID: 24251154
Giant hairy nevus; hypophosphatemia; rickets
20.  Regulation of phosphate homeostasis by the phosphatonins and other novel mediators 
A variety of factors regulate the efficiency of phosphate absorption in the intestine and phosphate reabsorption in kidney. Apart from the well-known regulators of phosphate homeostasis, namely parathyroid hormone (PTH) and the vitamin D–endocrine system, a number of peptides collectively known as the “phosphatonins” have been recently identified as a result of the study of various diseases associated with hypophosphatemia. These factors, fibroblast growth factor 23 (FGF-23), secreted frizzled-related protein 4 (sFRP-4), fibroblast growth factor 7 (FGF-7) and matrix extracellular phosphoglycoprotein (MEPE), have been shown to play a role in the pathogenesis of various hypophosphatemic and hyperphosphatemic disorders, such as oncogenic osteomalacia, X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets, autosomal recessive hypophosphatemia and tumoral calcinosis. Whether these factors are true hormones, in the sense that they are regulated by the intake of dietary phosphorus and the needs of the organism for higher or lower amounts of phosphorus, remains to be firmly established in humans. Additionally, new information demonstrates that the intestine “senses” luminal concentrations of phosphate and regulates the excretion of phosphate in the kidney by elaborating novel factors that alter renal phosphate reabsorption.
PMCID: PMC2441591  PMID: 18288501
Phosphate; Vitamin D; Phosphatonins; PTH; Fibroblast growth factors
21.  Increased renal catabolism of 1,25-dihydroxyvitamin D3 in murine X-linked hypophosphatemic rickets. 
Journal of Clinical Investigation  1988;81(2):461-465.
The hypophosphatemic (Hyp) mouse, a murine homologue of human X-linked hypophosphatemic rickets, is characterized by renal defects in brush border membrane phosphate transport and vitamin D3 metabolism. The present study was undertaken to examine whether elevated renal 25-hydroxyvitamin D3-24-hydroxylase activity in Hyp mice is associated with increased degradation of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] by side chain oxidation. Metabolites of 1,25(OH)2D3 were separated by HPLC on Zorbax SIL and identified by comparison with standards authenticated by mass spectrometry. Production of 1,24,25-trihydroxyvitamin D3, 24-oxo-1,25-dihydroxyvitamin D3, and 24-oxo-1,23,25-trihydroxyvitamin D3 was twofold greater in mitochondria from mutant Hyp/Y mice than from normal +/Y littermates. Enzyme activities, estimated by the sum of the three products synthesized per milligram mitochondrial protein under initial rate conditions, were used to estimate kinetic parameters. The apparent Vmax was significantly greater for mitochondria from Hyp/Y mice than from +/Y mice (0.607 +/- 0.064 vs. 0.290 +/- 0.011 pmol/mg per protein per min, mean +/- SEM, P less than 0.001), whereas the apparent Michaelis-Menten constant (Km) was similar in both genotypes (23 +/- 2 vs. 17 +/- 5 nM). The Km for 1,25(OH)2D3 was approximately 10-fold lower than that for 25-hydroxyvitamin D3 [25(OH)D3], indicating that 1,25(OH)2D3 is perhaps the preferred substrate under physiological conditions. In both genotypes, apparent Vmax for 25(OH)D3 was fourfold greater than that for 1,25(OH)2D3, suggesting that side chain oxidation of 25(OH)D3 may operate at pharmacological concentrations of substrate. The present results demonstrate that Hyp mice exhibit increased renal catabolism of 1,25(OH)2D3 and suggest that elevated degradation of vitamin D3 hormone may contribute significantly to the clinical phenotype in this disorder.
PMCID: PMC329592  PMID: 3339128
22.  A novel CYP27B1 mutation causes a feline vitamin D-dependent rickets type IA 
A 12-week-old domestic cat presented at a local veterinary clinic with hypocalcemia and skeletal abnormalities suggestive of rickets. Osteomalacia (rickets) is a disease caused by impaired bone mineralization leading to an increased prevalence of fractures and deformity. Described in a variety of species, rickets is most commonly caused by vitamin D or calcium deficiencies owing to both environmental and or genetic abnormalities. Vitamin D-dependent rickets type 1A (VDDR-1A) is a result of the enzymatic pathway defect caused by mutations in the 25-hydroxyvitamin D3-1-alpha-hydroxylase gene [cytochrome P27 B1 (CYP27B1)]. Calcitriol, the active form of vitamin D3, regulates calcium homeostasis, which requires sufficient dietary calcium availability and correct hormonal function for proper bone growth and maintenance. Patient calcitriol concentrations were low while calcidiol levels were normal suggestive of VDDR-1A. The entire DNA coding sequencing of CYP27B1 was evaluated. The affected cat was wild type for previously identified VDDR-1A causative mutations. However, six novel mutations were identified, one of which was a nonsense mutation at G637T in exon 4. The exon 4 G637T nonsense mutation results in a premature protein truncation, changing a glutamic acid to a stop codon, E213X, likely causing the clinical presentation of rickets. The previously documented genetic mutation resulting in feline VDDR-1A rickets, as well as the case presented in this research, result from novel exon 4 CYP27B1 mutations, thus exon 4 should be the initial focus of future sequencing efforts.
PMCID: PMC3541000  PMID: 22553308
23.  Genetic and clinical peculiarities in a new family with hereditary hypophosphatemic rickets with hypercalciuria: a case report 
Hereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder (OMIM #241530), characterized by decreased renal phosphate reabsorption that leads to hypophosphatemia, rickets, and bone pain; hypophosphatemia is believed to stimulate 1,25 dihydroxyvitamin D synthesis which, in turn, results in hypercalciuria. Hereditary hypophosphatemic rickets with hypercalciuria is caused by loss-of-function in the type 2c sodium phosphate cotransporter encoded by the SLC34A3 gene. This report shows a family with a non-previously identified mutation in the SLC34A3 gene and exhibiting mild and different manifestations of HHRH. The probandus had hypophosphatemia, elevated serum 1,25 dihydroxyvitamin D concentrations, high serum alkaline phosphatase levels, hypercalciuria and nephrocalcinosis. The other members of the family presented some of these alterations: the mother, hypercalciuria and high 1,25 dihydroxyvitamin D concentrations; the son, hypercalciuria, high 1,25 dihydroxyvitamin D values and elevated alkaline phosphatases; the father, high alkaline phosphatases. The genetic analysis revealed the existence of a single mutation (G78R) in heterozygosis in the SLC34A3 gene in the probandus, her mother and her brother, but not in the father. These findings suggest that he mutation in heterozygosis likely gave rise to a mild phenotype with different penetrance in the three relatives and also indicates that the elevation of 1,25 dihydroxyvitamin D does not result from hypophosphatemia. Thus, this family raises some issues on the transmission and pathophysiology of hereditary hypophosphatemic rickets with hypercalciuria.
PMCID: PMC2821378  PMID: 20074341
24.  Healing of rickets with phosphate supplementation in the hypophosphatemic male mouse. 
Journal of Clinical Investigation  1981;67(3):911-914.
The hypophosphatemic male mouse, an animal model for human vitamin D-resistant rickets, is characterized by low serum phosphorus concentration due to increased urinary phosphate excretion, rickets, osteomalacia, and dwarfism. Because phosphate administration can heal rickets but not osteomalacia in the human disease, we have compared the effect of phosphate supplementation on the epiphyseal and endosteal bone mineralization in the mutant animal. Phosphate was given in drinking water for 137 d and the biochemical and bone responses were assessed by analytical and histomorphometric methods. Treatment with phosphate normalized the endochondral calcification (vertebral growthplate thickness: 83 +/- 5 SD vs. controls [+/Y] 73 +/- 8 micrometers, NS), but did not correct the endosteal bone mineralization (mineralization front: 13.6 +/- 2.7 vs. +/Y 67.1 +/- 6.9% osteoid surface, P less than 0.001, endosteal mean osteoid seam thickness: 46.4 +/- 6.1 vs. +/Y 3.3 +/- 0.3 micrometers, P less than 0.001). In addition, both osteoblastic and osteoclastic recruitment and activity were stimulated, as a result of a probable increase in parathyroid hormone secretion following the phosphate induced fall in serum calcium. Our results show that in the hypophosphatemic mouse, phosphate supplementation can heal the epiphyseal, but not the endosteal defective bone mineralization. Then, the biochemical and skeletal response to phosphate therapy appear to be similar to what we have observed in the human disease, further stressing the interest of the animal model.
PMCID: PMC370644  PMID: 6259210
25.  Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. 
Journal of Clinical Investigation  1985;75(6):1858-1868.
Although conventional therapy (pharmacologic doses of vitamin D and phosphorus supplementation) is usually successful in healing the rachitic bone lesion in patients with X-linked hypophosphatemic rickets, it does not heal the coexistent osteomalacia. Because serum 1,25-dihydroxyvitamin D levels are inappropriately low in these patients and high calcitriol concentrations may be required to heal the osteomalacia, we chose to treat five affected subjects with high doses of calcitriol (68.2 +/- 10.0 ng/kg total body weight/d) and supplemental phosphorus (1-2 g/d) performing metabolic studies and bone biopsies before and after 5-8 mo of this therapy in each individual. Of these five patients, three (aged 13, 13, and 19 yr) were receiving conventional treatment at the inception of the study and therefore showed base-line serum phosphorus concentrations within the normal range. The remaining two untreated patients (aged 2 and 37 yr) displayed characteristic hypophosphatemia before calcitriol therapy. All five patients demonstrated serum calcitriol levels in the low normal range (22.5 +/- 3.2 pg/ml), impaired renal phosphorus conservation (tubular maximum for the reabsorption of phosphate per deciliter of glomerular filtrate, 2.13 +/- 0.20 mg/dl), and osteomalacia on bone biopsy (relative osteoid volume, 14.4 +/- 1.7%; mean osteoid seam width, 27.7 +/- 3.7 micron; mineral apposition rate, 0.46 +/- 0.12 micron/d). On high doses of calcitriol, serum 1,25-dihydroxyvitamin D levels rose into the supraphysiologic range (74.1 +/- 3.8 pg/ml) with an associated increment in the serum phosphorus concentration (2.82 +/- 0.19 to 3.78 +/- 0.32 mg/dl) and improvement of the renal tubular maximum for phosphate reabsorption (3.17 +/- 0.22 mg/dl). The serum calcium rose in each patient while the immunoactive parathyroid hormone concentration measured by three different assays remained within the normal range. Most importantly, repeat bone biopsies showed that high doses of calcitriol and phosphorus supplements had reversed the mineralization defect in all patients (mineral apposition rate, 0.88 +/- 0.04 micron/d) and consequently reduced parameters of bone osteoid content to normal (relative osteoid volume, 4.1 +/- 0.7%; mean osteoid seam width, 11.0 +/- 1.0 micron). Complications (hypercalcemia and hypercalciuria) ensued in four of these five patients within 1-17 mo of documented bone healing, necessitating reduction of calcitriol doses to a mean of 1.6 +/- 0.2 micrograms/d (28 +/- 4 ng/kg ideal body weight per day). At follow-up bone biopsy, these four subjects continued to manifest normal bone mineralization dynamics (mineral apposition rate, 0.88 +/-0.10 micrometer/d) on reduced doses of 1.25-dihydroxyvitamin D with phosphorus supplements (2 g/d) for a mean of 21.3 +/- 1.3 mo after bone healing was first documented. Static histomorphometric parameters also remained normal (relative osteoid volume, 1.5 +/- 0.4%; mean osteoid seam width, 13.5 +/- 0.8 micrometer). These data indicate that administration of supraphysiologic amounts of calcitriol, in conjunction with oral phosphorus, results in complete healing of vitamin D resistant osteomalacia in patients with X-linked hypophosphatemic rickets. Although complications predictably require calcitriol dose reductions once healing is achieved, continued bone healing can be maintained for up to 1 yr with lower doses of 1,25-dihydroxyvitamin D and continued phosphorus supplementation.
PMCID: PMC425542  PMID: 3839245

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