1.PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets.
Hae Ryong SONG ; Joo Won PARK ; Dae Yeon CHO ; Jae Hyuk YANG ; Hye Ran YOON ; Sung Chul JUNG
Journal of Korean Medical Science 2007;22(6):981-986
X-linked hypophosphatemic rickets (XLH) results from mutations in the PHEX gene. Mutational analysis of the PHEX gene in 15 unrelated Korean patients with hypophosphatemic rickets revealed eight mutations, including five novel mutations, in nine patients: two nonsense mutations, two missense mutations, one insertion, and three splicing acceptor/donor site mutations. Of these, c.64G>T, c.1699C>T, c.466_467 insAC, c.1174-1G>A, and c.1768+5G>A were novel mutations. To analyze the correlation between genotype and phenotype, phenotypes were compared between groups with and without a mutation, in terms of mutation location, mutation type, and sex. Skeletal disease tended to be more severe in the group with a mutation in the C-terminal half of the PHEX gene, but no genotype-phenotype correlation was detected in other comparisons. Further extensive studies of the PHEX gene mutations and analyses of the genotype-phenotype relationships are required to understand PHEX function and the pathogenesis of XLH.
Adolescent
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Adult
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Child
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Child, Preschool
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Female
;
Gene Dosage
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Genotype
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Humans
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Hypophosphatemic Rickets, X-Linked Dominant/*genetics
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Infant
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Male
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Middle Aged
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*Mutation
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PHEX Phosphate Regulating Neutral Endopeptidase/*genetics
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Phenotype
2.A Case of Fanconi-Bickel Syndrome with Mild Clinical Signs.
So Mi KIM ; Han Wook YOO ; Hyun Woo KIM
Korean Journal of Medicine 2013;85(2):210-213
Fanconi-Bickel syndrome is a rare autosomal recessive disorder caused by a mutation in the facilitative glucose transporter 2 gene (GLUT2 or SLC2A2 gene) that codes for the glucose transporter protein 2 expressed in hepatocytes, pancreatic beta-cells, enterocytes, and renal tubular cells. Mutation of this gene leads to defective carbohydrate metabolism, hepatomegaly, glucose intolerance, proximal renal tubular dysfunction, and hypophosphatemic rickets. We report a case of Fanconi-Bickel syndrome in an 18-year-old man who presented due to renal glycosuria; a mutation was identified in the GLUT2 gene (c.482C > A + c.1556G > A). To the best of our knowledge, unlike previous reports of Fanconi-Bickel syndrome, this case was relatively unusual in that it caused only mild clinical signs.
Carbohydrate Metabolism
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Enterocytes
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Fanconi Syndrome
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Glucose Intolerance
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Glucose Transport Proteins, Facilitative
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Glucose Transporter Type 2
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Hepatocytes
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Hepatomegaly
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Hypophosphatemic Rickets, X-Linked Dominant
3.Successful Treatment of Alopecia Areata with Topical Calcipotriol.
Dong Ha KIM ; Jin Woong LEE ; In Su KIM ; Sun Young CHOI ; Yun Young LIM ; Hyeong Mi KIM ; Beom Joon KIM ; Myeung Nam KIM
Annals of Dermatology 2012;24(3):341-344
Alopecia areata (AA) is an inflammatory hair loss of unknown etiology. AA is chronic and relapsing, and no effective cure or preventive treatment has been established. Vitamin D was recently reported to be important in cutaneous immune modulation as well as calcium regulation and bone metabolism. It is well known that areata is common clinical finding in patients with vitamin D deficiency, vitamin D-resistant rickets, or vitamin D receptor (VDR) mutation. The biological actions of vitamin D3 derivatives include regulation of epidermal cell proliferation and differentiation and modulation of cytokine production. These effects might explain the efficacy of vitamin D3 derivatives for treating AA. In this study, we report a 7-year-old boy with reduced VDR expression in AA, recovery of whom was observed by topical application of calcipotriol, a strong vitamin D analog.
Alopecia
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Alopecia Areata
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Calcitriol
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Calcium
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Cell Proliferation
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Child
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Cholecalciferol
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Hair
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Humans
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Hypophosphatemic Rickets, X-Linked Dominant
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Receptors, Calcitriol
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Vitamin D
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Vitamin D Deficiency
4.Novel Compound Heterozygous Mutations in the Vitamin D Receptor Gene in a Korean Girl with Hereditary Vitamin D Resistant Rickets.
Jun Kyu SONG ; Kyung Sik YOON ; Kye Shik SHIM ; Chong Woo BAE
Journal of Korean Medical Science 2011;26(8):1111-1114
Hereditary vitamin D resistant rickets (HVDRR) is a rare genetic disorder caused by a mutation of vitamin D receptor (VDR) gene. A number of cases had been reported in many countries but not in Korea. We examined a three-year old Korean girl who had the typical clinical features of HVDRR including rickets, hypocalcemia, hypophosphatemia, elevated serum calcitriol level and secondary hyperparathyroidism. The girl and her father were both heterozygous for the 719 C-to-T (I146T) mutation in exon 4, whereas she and her mother were both heterozygous for 754 C-to-T (R154C) mutation in exon 5 of the VDR gene. In this familial study, we concluded that the girl had compound heterozygous mutations in her VDR gene which caused HVDRR. This is the first report of a unique mutation in the VDR gene in Korea.
Asian Continental Ancestry Group/*genetics
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Base Sequence
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Bone and Bones/abnormalities/radiography
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Child, Preschool
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DNA Mutational Analysis
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Exons
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Female
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Heterozygote
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Humans
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Hypophosphatemic Rickets, X-Linked Dominant/*genetics/radiography
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Point Mutation
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Receptors, Calcitriol/*genetics
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Republic of Korea
5.Value of serum fibroblast growth factor 23 in diagnosis of hypophosphatemic rickets in children.
Sha-Sha DONG ; Ruo-Chen CHE ; Bi-Xia ZHENG ; Ai-Hua ZHANG ; Chun-Li WANG ; Mi BAI ; Ying CHEN
Chinese Journal of Contemporary Pediatrics 2023;25(7):705-710
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 (rs=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (rs=-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
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Humans
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Fibroblast Growth Factor-23
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Fibroblast Growth Factors
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Familial Hypophosphatemic Rickets/diagnosis*
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Rickets, Hypophosphatemic/diagnosis*
6.A novel de novo mosaic mutation in PHEX in a Korean patient with hypophosphatemic rickets.
Misun YANG ; Jinsup KIM ; Aram YANG ; Jahyun JANG ; Tae Yeon JEON ; Sung Yoon CHO ; Dong Kyu JIN
Annals of Pediatric Endocrinology & Metabolism 2018;23(4):229-234
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
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Alleles
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Codon, Nonsense
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Congenital Abnormalities
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Familial Hypophosphatemic Rickets
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Genu Valgum
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Humans
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Korea
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Mothers
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Phenotype
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Rickets, Hypophosphatemic*
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Vitamin D
7.Sclerostin antibody improves alveolar bone quality in the Hyp mouse model of X-linked hypophosphatemia (XLH).
Kelsey A CARPENTER ; Delia O ALKHATIB ; Bryan A DULION ; Elizabeth GUIRADO ; Shreya PATEL ; Yinghua CHEN ; Anne GEORGE ; Ryan D ROSS
International Journal of Oral Science 2023;15(1):47-47
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
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Male
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Female
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Animals
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Familial Hypophosphatemic Rickets/metabolism*
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Bone and Bones/metabolism*
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Tooth/metabolism*
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Periodontal Ligament/metabolism*
8.Wnt pathway inhibitors are upregulated in XLH dental pulp cells in response to odontogenic differentiation.
Elizabeth GUIRADO ; Cassandra VILLANI ; Adrienn PETHO ; Yinghua CHEN ; Mark MAIENSCHEIN-CLINE ; Zhengdeng LEI ; Nina LOS ; Anne GEORGE
International Journal of Oral Science 2023;15(1):13-13
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
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Familial Hypophosphatemic Rickets
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Wnt Signaling Pathway
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Dental Pulp
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Quality of Life
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Cell Differentiation
9.Cervical Ossification of Posterior Longitudinal Ligament in X-Linked Hypophosphatemic Rickets Revealing Homogeneously Increased Vertebral Bone Density.
Masato SHIBA ; Masaki MIZUNO ; Keita KURAISHI ; Hidenori SUZUKI
Asian Spine Journal 2015;9(1):106-109
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*
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Familial Hypophosphatemic Rickets*
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Humans
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Longitudinal Ligaments
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Magnetic Resonance Imaging
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Ossification of Posterior Longitudinal Ligament*
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Rickets
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Spinal Cord Compression
10.Sporadic Nonfamilial Hypophosphatemic Osteomalacia
Young Kee SHONG ; Joong Yeol PARK ; Ghi Su KIM ; You Sook CHO ; Goo Yeong CHO ; Sang Wook KIM ; Jung Sik PARK ; Ki Up LEE
Journal of Korean Society of Endocrinology 1994;9(1):25-31
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
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Diagnosis
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Familial Hypophosphatemic Rickets
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Fanconi Syndrome
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Follow-Up Studies
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Humans
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Hypophosphatemia
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Intestinal Absorption
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Male
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Osteomalacia
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Rickets