Chronic hypophosphatemia caused by decreased intestinal absorption or increased renal clearance, may lead to rickets or osteomalacia independently of other predisposing abnormalities. The conditions commonly associated with increased renal clearance of phosphate are X-linked hypophosphatemic rickets, tumor associated rickets/osteomalacia, RTA and Fanconi syndrome. Recently we experienced 3 men with adult-onset, histologically proven osteomalacia associated with increased renal clearance of phosphate. None of them had a family history of bone disease, tumors or other tubular defects. All of these had remarkable biochemical and clinical improvement with medical treatment such as 1, 25-dihydroxyvitamin D and phosphate supplementation. Although we did not find tumors yet, we could not rule out the possibility of tumor-associated osteomalcia since it often takes several years to make a diagnosis because of small size, benign nature and unusual location of tumors. Thus, careful long-term follow up for tumor occurrence will be maintained in these patients with sporadic nonfamilial hypophosphatemic osteomalacia.
Bone Diseases ; Diagnosis ; Familial Hypophosphatemic Rickets ; Fanconi Syndrome ; Follow-Up Studies ; Humans ; Hypophosphatemia ; Intestinal Absorption ; Male ; Osteomalacia ; Rickets

PURPOSE: Hypophosphatemic rickets is a hereditary disease, characterized by hypophosphatemia due to renal phosphate wasting, impaired renal production of 1,25-dihydroxyvitamin D3, rachitic bone deformities and impaired growth. The purpose of this study is to provide clinical profiles of patients with hypophosphatemic rickets in our hospital. METHODS: Between July 1983 and February 2004, 56 patients were diagnosed as having hypophosphatemic rickets. The medical records of these patients were reviewed retrospectively. Clinical manifestations, family histories, laboratory data, treatment outcomes were described. RESULTS: Fifty six patients were enrolled in this study. The average age at symptom onset and diagnosis were 20 months and 5 years respectively. Fourteen patients had family histories. The main clinical manifestations were bow legs and short stature. There was a significant negative correlation between the ages and the height z-scores at the time of diagnosis(r=-0.47, P=0.005). Initial laboratory data showed normocalcemia, hypophosphatemia, elevated serum alkaline phosphatase, decreased tubular reabsorption of phosphate and a normal range of 1,25-dihydroxyvitamin D3. Radiographic examinations of bone revealed fraying, widening and cupping of the metaphyseal ends. Treatment consisted of Joulie solution and vitamin D metabolites, and resulted in improved biochemical and radiographic findings. However, height z-scores remained essentially unchanged(P=0.224). Complications of treatment were frequently observed, including hyperparathyroidism, nephrocalcinosis, and hypercalciuria. Sixteen patients had corrective osteotomy and 4 of them underwent leg lengthening together. CONCLUSION: There was a gap of several years between the onset of symptoms and the diagnosis. Early treatment seems to be essential to growth. For the earlier treatment, the offsprings of affected parents should be followed up closely.
Alkaline Phosphatase ; Calcitriol ; Congenital Abnormalities ; Diagnosis ; Familial Hypophosphatemic Rickets ; Genetic Diseases, Inborn ; Genu Varum ; Humans ; Hypercalciuria ; Hyperparathyroidism ; Hypophosphatemia ; Hypophosphatemia, Familial ; Leg ; Medical Records ; Nephrocalcinosis ; Osteotomy ; Parents ; Reference Values ; Retrospective Studies ; Rickets, Hypophosphatemic* ; Vitamin D

X-linked hypophosphatemia (XLH) is a hereditary metabolic disease caused by the loss of phosphate through the renal tubules into the urine, and an associated decrease in serum calcium and potassium phosphate. Its dental features include spontaneous dental abscesses that occur in the absence of trauma or dental caries. The aim of this case report was to describe the dental problems of XLH patients and to evaluate limitations in their treatment. A 14 year old male and a 38 year old female with XLH were referred to the Department of Conservative Dentistry for endodontic treatment. The dental findings were periapical abscesses without obvious trauma or caries. Conservative endodontic treatment was performed in teeth with pulp necrosis and abscess. In case 1, the treated teeth showed improvements in bone healing, without clinical symptoms. However, in case 2, the implants and the treated tooth showed hypermobility, and the final restoration was therefore postponed. Early diagnosis, periodic examinations, and communication with the patient's pediatrician are important in the dental management of patients with XLH.
Abscess ; Calcium ; Dental Caries ; Dental Pulp Necrosis ; Dentistry ; Early Diagnosis ; Familial Hypophosphatemic Rickets* ; Female ; Humans ; Hypophosphatemia ; Male ; Metabolic Diseases ; Periapical Abscess ; Potassium ; Tooth

Skeletal mineralization is initiated in matrix vesicles (MVs), the small extracellular vesicles derived from osteoblasts and chondrocytes. Calcium and inorganic phosphate (Pi) taken up by MVs form hydroxyapatite crystals, which propagate on collagen fibrils to mineralize the extracellular matrix. Insufficient calcium or phosphate impairs skeletal mineralization. Because active vitamin D is necessary for intestinal calcium absorption, vitamin D deficiency is a significant cause of rickets/osteomalacia. Chronic hypophosphatemia also results in rickets/osteomalacia. Excessive action of fibroblast growth factor 23 (FGF23), a key regulator of Pi metabolism, leads to renal Pi wasting and impairs vitamin D activation. X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary FGF23-related hypophosphatemia, and enhanced FGF receptor (FGFR) signaling in osteocytes may be involved in the pathogenesis of this disease. Increased extracellular Pi triggers signal transduction via FGFR to regulate gene expression, implying a close relationship between Pi metabolism and FGFR. An anti-FGF23 antibody, burosumab, has recently been developed as a new treatment for XLH. In addition to various forms of rickets/osteomalacia, hypophosphatasia (HPP) is characterized by impaired skeletal mineralization. HPP is caused by inactivating mutations in tissue-nonspecific alkaline phosphatase, an enzyme rich in MVs. The recent development of enzyme replacement therapy using bone-targeting recombinant alkaline phosphatase has improved the prognosis, motor function, and quality of life in patients with HPP. This links impaired skeletal mineralization with various conditions, and unraveling its pathogenesis will lead to more precise diagnoses and effective treatments.
Absorption ; Alkaline Phosphatase ; Calcium ; Chondrocytes ; Collagen ; Diagnosis ; Durapatite ; Enzyme Replacement Therapy ; Extracellular Matrix ; Extracellular Vesicles ; Familial Hypophosphatemic Rickets ; Fibroblast Growth Factors ; Gene Expression ; Humans ; Hypophosphatasia ; Hypophosphatemia ; Metabolism ; Miners ; Osteoblasts ; Osteocytes ; Prognosis ; Quality of Life ; Receptors, Fibroblast Growth Factor ; Rickets ; Signal Transduction ; Vitamin D ; Vitamin D Deficiency

OBJECTIVES: To study the value of serum fibroblast growth factor 23 (FGF23) in the diagnosis of hypophosphatemic rickets in children. METHODS: A total of 28 children who were diagnosed with hypophosphatemic rickets in Children's Hospital of Nanjing Medical University from January 2016 to June 2021 were included as the rickets group. Forty healthy children, matched for sex and age, who attended the Department of Child Healthcare of the hospital were included as the healthy control group. The serum level of FGF23 was compared between the two groups, and the correlations of the serum FGF23 level with clinical characteristics and laboratory test results were analyzed. The value of serum FGF23 in the diagnosis of hypophosphatemic rickets was assessed. RESULTS: The rickets group had a significantly higher serum level of FGF23 than the healthy control group (P<0.05). In the rickets group, the serum FGF23 level was positively correlated with the serum alkaline phosphatase level (r_s=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (r_s=-0.64, P<0.05), while it was not correlated with age, height Z-score, sex, and parathyroid hormone (P>0.05). Serum FGF23 had a sensitivity of 0.821, a specificity of 0.925, an optimal cut-off value of 55.77 pg/mL, and an area under the curve of 0.874 in the diagnosis of hypophosphatemic rickets (P<0.05). CONCLUSIONS Serum FGF23 is of valuable in the diagnosis of hypophosphatemic rickets in children, which providing a theoretical basis for early diagnosis of this disease in clinical practice.
Child ; Humans ; Fibroblast Growth Factor-23 ; Fibroblast Growth Factors ; Familial Hypophosphatemic Rickets/diagnosis* ; Rickets, Hypophosphatemic/diagnosis*

X-linked hypophosphatemic rickets is caused by loss-of-function mutations in PHEX, which encodes a phosphate-regulating endopeptidase homolog. We report a 26-year-old man with X-linked hypophosphatemic rickets who showed decreased serum phosphate accompanied by bilateral genu valgum and short stature. He had received medical treatment with vitamin D (alfacalcidol) and phosphate from the age of 3 to 20 years. He underwent surgery due to valgus deformity at the age of 14 and 15. Targeted gene panel sequencing for Mendelian genes identified a nonsense mutation in PHEX (c.589C>T; p.Gln197Ter) and a mosaic pattern where only 38% of sequence reads showed the variant allele. This mutation was not found in his mother, who had a normal phenotype. This is a case of a sporadic nonsense mutation in PHEX and up to date, this is the first case of a mosaic mutation in PHEX in Korea.
Adult ; Alleles ; Codon, Nonsense ; Congenital Abnormalities ; Familial Hypophosphatemic Rickets ; Genu Valgum ; Humans ; Korea ; Mothers ; Phenotype ; Rickets, Hypophosphatemic* ; Vitamin D

There is no report that describes in detail the radiological and intraoperative findings of rickets with symptomatic cervical ossification of the posterior longitudinal ligament. Here, we describe a case of X-linked hypophosphatemic rickets with cervical ossification of the posterior longitudinal ligament presenting unique radiological and intraoperative findings. The patient presented progressive tetraparesis. Magnetic resonance imaging studies revealed severe cervical spinal cord compression caused by ossification of the posterior longitudinal ligament. Computed tomography scans revealed homogeneously increased vertebral bone density. An expansive laminoplasty was performed. At surgery, homogeneously hard lamina bone was burdened in drilling and opening of the laminae. The patient's neurological symptoms were improved postoperatively. Bony fusion of the hinges occurred postoperatively. Therefore, expansive laminoplasty could be performed for symptomatic cervical ossification of the posterior longitudinal ligament with X-linked hypophosphatemic rickets. However, unusual bone characters should be taken into consideration for careful operation during surgery.
Bone Density* ; Familial Hypophosphatemic Rickets* ; Humans ; Longitudinal Ligaments ; Magnetic Resonance Imaging ; Ossification of Posterior Longitudinal Ligament* ; Rickets ; Spinal Cord Compression

The discovery and synthesis of vitamin D and the elucidation of the role of sunlight in the activation of the vitamin D precursors changed the syndromes of rickets from a therapeutic enigma to a socioeconomic and public health problem. Since Albright in 1937 first described vitamin D resistsnt rickets, which did not respond to treatment with the usual dose of vitamin D, it has progressively become a common form of rickets in practice. In addition, as the result of increasing understanding of renal physiology and careful investigation, a spectrum of renal tubular abnormalities have been identified which cause clinical rickets and which in many cases are insensitive to even large doses of vitamin D. We have reported a case of an unusual form of vitamin D resistant rickets which did not easily respond to treatment with high doses of vitamin D and was associated with hypocalcemia in multiple pathologic fractures in the lower extremities of the patient.
Familial Hypophosphatemic Rickets ; Fractures, Spontaneous ; Humans ; Hypocalcemia ; Lower Extremity ; Physiology ; Public Health ; Rickets ; Sunlight ; Vitamin D ; Vitamins

X-linked hypophosphatemia (XLH) represents the most common form of familial hypophosphatemia. Although significant advances have been made in the treatment of bone pathology, patients undergoing therapy continue to experience significantly decreased oral health-related quality of life. The following study addresses this persistent oral disease by further investigating the effect of DMP1 expression on the differentiation of XLH dental pulp cells. Dental pulp cells were isolated from the third molars of XLH and healthy controls and stable transduction of full-length human DMP1 were achieved. RNA sequencing was performed to evaluate the genetic changes following the induction of odontogenic differentiation. RNAseq data shows the upregulation of inhibitors of the canonical Wnt pathway in XLH cells, while constitutive expression of full-length DMP1 in XLH cells reversed this effect during odontogenic differentiation. These results imply that inhibition of the canonical Wnt pathway may contribute to the pathophysiology of XLH and suggest a new therapeutic strategy for the management of oral disease.
Humans ; Familial Hypophosphatemic Rickets ; Wnt Signaling Pathway ; Dental Pulp ; Quality of Life ; Cell Differentiation

X-linked hypophosphatemia (XLH) is a rare disease of elevated fibroblast growth factor 23 (FGF23) production that leads to hypophosphatemia and impaired mineralization of bone and teeth. The clinical manifestations of XLH include a high prevalence of dental abscesses and periodontal disease, likely driven by poorly formed structures of the dentoalveolar complex, including the alveolar bone, cementum, dentin, and periodontal ligament. Our previous studies have demonstrated that sclerostin antibody (Scl-Ab) treatment improves phosphate homeostasis, and increases long bone mass, strength, and mineralization in the Hyp mouse model of XLH. In the current study, we investigated whether Scl-Ab impacts the dentoalveolar structures of Hyp mice. Male and female wild-type and Hyp littermates were injected with 25 mg·kg^-1 of vehicle or Scl-Ab twice weekly beginning at 12 weeks of age and euthanized at 20 weeks of age. Scl-Ab increased alveolar bone mass in both male and female mice and alveolar tissue mineral density in the male mice. The positive effects of Scl-Ab were consistent with an increase in the fraction of active (nonphosphorylated) β-catenin, dentin matrix protein 1 (DMP1) and osteopontin stained alveolar osteocytes. Scl-Ab had no effect on the mass and mineralization of dentin, enamel, acellular or cellular cementum. There was a nonsignificant trend toward increased periodontal ligament (PDL) attachment fraction within the Hyp mice. Additional PDL fiber structural parameters were not affected by Scl-Ab. The current study demonstrates that Scl-Ab can improve alveolar bone in adult Hyp mice.
Mice ; Male ; Female ; Animals ; Familial Hypophosphatemic Rickets/metabolism* ; Bone and Bones/metabolism* ; Tooth/metabolism* ; Periodontal Ligament/metabolism*