Publications by authors named "Taichi Kitaoka"

42 Publications

Genotype-phenotype analysis, and assessment of the importance of the zinc-binding site in PHEX in Japanese patients with X-linked hypophosphatemic rickets using 3D structure modeling.

Bone 2021 Jul 29:116135. Epub 2021 Jul 29.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan. Electronic address:

X-linked hypophosphatemic rickets (XLH) is an inheritable type of rickets caused by inactivating variants in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene, which results in the overproduction of fibroblast growth factor 23 (FGF23). The mechanism by which PHEX impairment leads to FGF23 overproduction is unknown. Because little is known regarding the genotype-phenotype correlation in Japanese XLH, we summarized the available clinical and genetic data and analyzed the genotype-phenotype relationships using 3-dimensional (3D) structure modeling to clarify the XLH pathophysiology. We retrospectively reviewed the clinical features and performed genetic analysis of 39 Japanese patients with XLH from 28 unrelated pedigrees carrying any known or novel PHEX variant. To predict changes in the 3D structure of mutant PHEX, we constructed a putative 3D model of each mutant and evaluated the effect of structural alteration by genotype-phenotype correlation analysis. Genetic analysis revealed 23 PHEX variants, including eight novel variants. They were associated with high i-FGF23 levels, hypophosphatemia, phosphaturia, high alkaline phosphatase levels, and short stature. No gene dosage effect or genotype-phenotype correlation was observed when truncating and non-truncating variants were compared. However, the conservation of the zinc-binding site and cavity in PHEX had an impact on the elevation of i-FGF23 levels. Via genotype-phenotype relationship analysis using 3D modeling, we showed that the zinc-binding site and cavity in PHEX can play a critical role in its function. These findings provide new genetic clues for investigating the function of PHEX and the pathogenesis of XLH.
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http://dx.doi.org/10.1016/j.bone.2021.116135DOI Listing
July 2021

Alkaline phosphatase in pediatric patients with genu varum caused by vitamin D-deficient rickets.

Endocr J 2021 Jul 24;68(7):807-815. Epub 2021 Mar 24.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

An elevated serum alkaline phosphatase (ALP) level is one of the markers for the presence of rickets in children, but it is also associated with bone formation. However, its role in diagnosing genu varum in pediatric patients with vitamin D-deficient rickets is still unknown. To clarify the role of the serum ALP level in assessing the severity of genu varum, we retrospectively investigated this issue statistically using data on rickets such as serum intact parathyroid hormone (iPTH), 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, ALP, the level of creatinine as the percentage of the median according to age (%Cr), and the metaphyseal diaphyseal angle (MDA) in the lower extremities as an index of the severity of genu varum. A multiple regression analysis revealed that log ALP and %Cr values were negatively associated with MDA values. The former association was also confirmed by a linear mixed model, while iPTH was positively associated with MDA by path model analysis. To elucidate the association of ALP with MDA in the presence of iPTH, we investigated three-dimensional figures by neural network analysis. This indicated the presence of a biphasic association of ALP with MDA: the first phase increases while the second decreases MDA. The latter phenomenon is considered to be associated with the increase in bone formation due to the mechanical stress loaded on the lower extremities. These findings are important and informative for pediatricians to understand the significance of the serum ALP level in pediatric patients with genu varum caused by vitamin D deficiency.
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http://dx.doi.org/10.1507/endocrj.EJ20-0622DOI Listing
July 2021

Neonatal cholestasis can be the first symptom of McCune-Albright syndrome: A case report.

World J Clin Pediatr 2021 Mar 9;10(2):7-14. Epub 2021 Mar 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Background: McCune-Albright syndrome (MAS) is caused by postzygotic somatic mutations of the gene. It is characterized by the clinical triad of fibrous dysplasia, café-au-lait skin spots, and endocrinological dysfunction. Myriad complications in MAS, including hepatobiliary manifestations, are also reported.

Case Summary: This is a case of a 4-year-old boy who presented with MAS with neonatal cholestasis. He was suspected to have Alagille syndrome due to neonatal cholestasis with intrahepatic bile duct paucity in liver biopsy, peripheral pulmonary artery stenosis, and renal tubular dysfunction. By the age of 2 years, his cholestatic liver injury gradually improved, but he had repeated left femoral fractures. He did not exhibit endocrinological abnormality or café-au-lait skin spots. However, MAS was suspected due to fibrous dysplasia at the age of 4 years. No mutation was identified in the gene in the DNA isolated from the peripheral blood, but an activating point mutation (c.601C>T, p.Arg201Cys) was observed in the DNA extracted from the affected bone tissue and that extracted from the formalin-fixed paraffin-embedded liver tissue, which was obtained at the age of 1 mo.

Conclusion: MAS should be considered as a differential diagnosis for transient cholestasis in infancy.
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http://dx.doi.org/10.5409/wjcp.v10.i2.7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7958557PMC
March 2021

Case Report: Efficacy of Reduced Doses of Asfotase Alfa Replacement Therapy in an Infant With Hypophosphatasia Who Lacked Severe Clinical Symptoms.

Front Endocrinol (Lausanne) 2020 18;11:590455. Epub 2020 Dec 18.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.

Background: Hypophosphatasia is a rare bone disease characterized by impaired bone mineralization and low alkaline phosphatase activity. Here, we describe the course of bone-targeted enzyme replacement therapy with asfotase alpha for a female infant patient with hypophosphatasia who lacked apparent severe clinical symptoms.

Case Presentation: The patient exhibited low serum alkaline phosphatase (60 U/L; age-matched reference range, 520-1,580) in a routine laboratory test at birth. Further examinations revealed skeletal demineralization and rachitic changes, as well as elevated levels of serum calcium (2.80 mmol/L; reference range, 2.25-2.75 mmol/L) and ionic phosphate (3.17 mmol/L; reference range, 1.62-2.48 mmol/L), which are typical features in patients with hypophosphatasia. Sequencing analysis of the tissue-nonspecific alkaline phosphatase () gene identified two pathogenic mutations: c.406C>T, p.Arg136Cys and c.979T>C, p.Phe327Leu. Thus, the patient was diagnosed with hypophosphatasia. At the age of 37 days, she began enzyme replacement therapy using asfotase alpha at the standard dose of 6 mg/kg/week. Initial therapy from the age of 37 days to the age of 58 days substantially improved rickets signs in the patient; it also provided immediate normalization of serum calcium and ionic phosphate levels. However, serum ionic phosphate returned to a high level (2.72 mmol/L), which was presumed to be a side effect of asfotase alpha. Thus, the patient's asfotase alfa treatment was reduced to 2 mg/kg/week, which allowed her to maintain normal or near normal skeletal features thereafter, along with lowered serum ionic phosphate levels. Because the patient exhibited slight distal metaphyseal demineralization in the knee at the age of 2 years and 6 months, her asfotase alfa treatment was increased to 2.4 mg/kg/week. No signs of deterioration in bone mineralization were observed thereafter. At the age of 3 years, the patient's motor and psychological development both appeared normal, compared with children of similar age.

Conclusion: This is the first report in which reduced doses of asfotase alfa were administered to an infant patient with hypophosphatasia who lacked apparent severe clinical symptoms. The results demonstrate the potential feasibility of a tailored therapeutic option based on clinical severity in patients with hypophosphatasia.
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http://dx.doi.org/10.3389/fendo.2020.590455DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775725PMC
June 2021

4-Phenylbutyric acid enhances the mineralization of osteogenesis imperfecta iPSC-derived osteoblasts.

J Biol Chem 2021 Jan-Jun;296:100027. Epub 2020 Nov 23.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.

Osteogenesis imperfecta (OI) is a heritable brittle bone disease mainly caused by mutations in the two type I collagen genes. Collagen synthesis is a complex process including trimer formation, glycosylation, secretion, extracellular matrix (ECM) formation, and mineralization. Using OI patient-derived fibroblasts and induced pluripotent stem cells (iPSCs), we investigated the effect of 4-phenylbutyric acid (4-PBA) on collagen synthesis to test its potential as a new treatment for OI. Endoplasmic reticulum (ER) retention of type I collagen was observed by immunofluorescence staining in OI patient-derived fibroblasts with glycine substitution and exon skipping mutations. Liquid chromatography-mass spectrometry analysis revealed excessive glycosylation of secreted type I collagen at the specific sites in OI cells. The misfolding of the type I collagen triple helix in the ECM was demonstrated by the incorporation of heat-dissociated collagen hybridizing peptide in OI cells. Type I collagen was produced excessively by OI fibroblasts with a glycine mutation, but this excessive production was normalized when OI fibroblasts were cultured on control fibroblast-derived ECM. We also found that mineralization was impaired in osteoblasts differentiated from OI iPSCs. In summary, treatment with 4-PBA normalizes the excessive production of type I collagen, reduces ER retention, partially improves misfolding of the type I collagen helix in ECM, and improves osteoblast mineralization. Thus, 4-PBA may improve not only ER retention, but also type I collagen synthesis and mineralization in human cells from OI patients.
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http://dx.doi.org/10.1074/jbc.RA120.014709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948972PMC
November 2020

Clinical Practice Guidelines for Achondroplasia.

Clin Pediatr Endocrinol 2020 9;29(1):25-42. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Achondroplasia (ACH) is a skeletal dysplasia that presents with limb shortening, short stature, and characteristic facial configuration. ACH is caused by mutations of the gene, leading to constantly activated FGFR3 and activation of its downstream intracellular signaling pathway. This results in the suppression of chondrocyte differentiation and proliferation, which in turn impairs endochondral ossification and causes short-limb short stature. ACH also causes characteristic clinical symptoms, including foramen magnum narrowing, ventricular enlargement, sleep apnea, upper airway stenosis, otitis media, a narrow thorax, spinal canal stenosis, spinal kyphosis, and deformities of the lower extremities. Although outside Japan, papers on health supervision are available, they are based on reports and questionnaire survey results. Considering the scarcity of high levels of evidence and clinical guidelines for patients with ACH, clinical practical guidelines have been developed to assist both healthcare professionals and patients in making appropriate decisions in specific clinical situations. Eleven clinical questions were established and a systematic literature search was conducted using PubMed/MEDLINE. Evidence-based recommendations were developed, and the guidelines describe the recommendations related to the clinical management of ACH. We anticipate that these clinical practice guidelines for ACH will be useful for healthcare professionals and patients alike.
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http://dx.doi.org/10.1297/cpe.29.25DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958518PMC
January 2020

Clinical Practice Guidelines for Hypophosphatasia.

Clin Pediatr Endocrinol 2020 9;29(1):9-24. Epub 2020 Jan 9.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Hypophosphatasia (HPP) is a rare bone disease caused by inactivating mutations in the gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Patients with HPP have varied clinical manifestations and are classified based on the age of onset and severity. Recently, enzyme replacement therapy using bone-targeted recombinant alkaline phosphatase (ALP) has been developed, leading to improvement in the prognosis of patients with life-threatening HPP. Considering these recent advances, clinical practice guidelines have been generated to provide physicians with guides for standard medical care for HPP and to support their clinical decisions. A task force was convened for this purpose, and twenty-one clinical questions (CQs) were formulated, addressing the issues of clinical manifestations and diagnosis (7 CQs) and those of management and treatment (14 CQs). A systematic literature search was conducted using PubMed/MEDLINE, and evidence-based recommendations were developed. The guidelines have been modified according to the evaluations and suggestions from the Clinical Guideline Committee of The Japanese Society for Pediatric Endocrinology (JSPE) and public comments obtained from the members of the JSPE and a Japanese HPP patient group, and then approved by the Board of Councils of the JSPE. We anticipate that the guidelines will be revised regularly and updated.
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http://dx.doi.org/10.1297/cpe.29.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6958520PMC
January 2020

Parental somatogonadal COL2A1 mosaicism contributes to intrafamilial recurrence in a family with type 2 collagenopathy.

Am J Med Genet A 2020 03 19;182(3):454-460. Epub 2019 Dec 19.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

The COL2A1 gene encodes the alpha-1 chain of procollagen type 2. Pathogenic variants in the COL2A1 gene are associated with several different types of skeletal dysplasia collectively known as type 2 collagenopathies. Type 2 collagenopathies have an autosomal dominant inheritance. Some germline or somatogonadal mosaicism cases have been reported. We investigated whether somatogonadal mosaicism occurred in a family with two children suspected of type 2 collagenopathies or related diseases. First, we detected a pathogenic variant in the COL2A1 gene in the two affected children by whole exome sequencing (WES). Next, we performed targeted deep sequencing to their parents without the variant by WES. A low level of COL2A1 mosaicism was revealed in the mother's tissues. We concluded that the mother had somatogonadal mosaicism with the COL2A1 mutation arose in the epiblast, and that the intrafamilial recurrence rate of the disease by the somatogonadal mosaicism was higher than by the germline mosaicism. This report suggests that parental low-level mosaicism should be evaluated in those parents with children carrying de novo germline mutations and the targeted deep sequencing is useful to detect them.
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http://dx.doi.org/10.1002/ajmg.a.61422DOI Listing
March 2020

Japanese nationwide survey of hypophosphatasia reveals prominent differences in genetic and dental findings between odonto and non-odonto types.

PLoS One 2019 10;14(10):e0222931. Epub 2019 Oct 10.

Department of Pediatric Dentistry, Osaka University Graduate School of Dentistry, Osaka, Japan.

Hypophosphatasia (HPP) is a rare and intractable metabolic bone disease caused by mutations in the ALPL gene. Here, we undertook a nationwide survey of HPP in Japan, specifically regarding the prominent genetic and dental manifestations of odonto (n = 16 cases) and other (termed "non-odonto") (n = 36 cases) types. Mean serum alkaline phosphatase (ALP) values in odonto-type patients were significantly greater than those of non-odonto-type patients (P<0.05). Autosomal dominant and autosomal recessive inheritance patterns were detected, respectively, in 89% of odonto-type and 96% of non-odonto-type patients. The ALPL "c.1559delT" mutation, associated with extremely low ALP activity, was found in approximately 70% of cases. Regarding dental manifestations, all patients classified as odonto-type showed early exfoliation of the primary teeth significantly more frequently than patients classified as non-odonto-type (100% vs. 56%; P<0.05). Tooth hypomineralisation was detected in 42% of non-odonto-type patients, but not in any odonto-type patients (0%; P<0.05). Collectively, these results suggest that genetic and dental manifestations of patients with odonto-type and non-odonto-type HPP are significantly different, and these differences should be considered during clinical treatment of patients with HPP.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786601PMC
March 2020

Impact of fracture characteristics and disease-specific complications on health-related quality of life in osteogenesis imperfecta.

J Bone Miner Metab 2020 Jan 13;38(1):109-116. Epub 2019 Aug 13.

Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan.

Osteogenesis imperfecta (OI) is a connective tissue disease with bone fragility. Several studies have indicated that physical function in adult OI was correlated to the disease severity, but there have been no reports delineating the impact of the fracture characteristics and disease-specific complications on health-related quality of life (HRQoL). The purpose of this study is to clarify the factors impacted on HRQoL in adult OI patients. We conducted a cross-sectional study between July 2016 and March 2018 and sent a questionnaire regarding HRQoL using Short Form-36 (SF-36) to the OI patients at the age of 20 years or older who had a medical history of the investigators' institutions. The 40 patients completely answered the SF-36. Mental component summary and role/social component summary were unremarkable. Physical component summary (PCS) was significantly associated with z-score for height, teeth abnormality, and cardiopulmonary insufficiency (partial regression coefficient, 3.04, - 9.70, and - 11.35; p, < 0.001, 0.047, and 0.025, respectively). PCS was also significantly lower in the patients who had an initial fracture before the age of 2 years than those without occurrence of fractures until 2 years old (25.80 ± 17.15 versus 44.20 ± 16.54; p = 0.002), or those who had lower extremity fractures more than five times as compared with normal populations. Physical function was decreased in OI patients who had fractures before 2 years old, especially in lower extremity. Appropriate medical managements for cardiopulmonary insufficiency are required not only to maintain physical function but also to decrease mortality.
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http://dx.doi.org/10.1007/s00774-019-01033-9DOI Listing
January 2020

Metreleptin treatment for congenital generalized lipodystrophy type 4 (CGL4): a case report.

Clin Pediatr Endocrinol 2019 31;28(1):1-7. Epub 2019 Jan 31.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Congenital generalized lipodystrophy type 4 (CGL4) is a rare disease caused by mutations in the gene polymerase I and transcript release factor (), the main symptoms of which are systemic reductions in adipose tissue and muscular dystrophy. The strategy of treating CGL4 is to improve the insulin resistance and hypertriglyceridemia that result from systemic reductions in adipose tissue. Metreleptin, a synthetic analog of human leptin, is effective against generalized lipodystrophies; however, there are no reports of the use of metreleptin in the treatment of CGL4. Herein, we discuss the treatment of a six-year-old boy diagnosed with CGL4 due to a homozygous mutation in with metreleptin. His serum triglyceride level and homeostasis model assessment of insulin resistance (HOMA-IR) value decreased after two months of metreleptin treatment. However, the efficacy of metreleptin gradually decreased, and the treatment was suspended because anaphylaxis occurred after the dosage administered was increased. Subsequently, his serum triglyceride level and HOMA-IR value significantly increased. Anti-metreleptin-neutralizing antibodies were detected in his serum, which suggested that these antibodies reduced the efficacy of metreleptin and caused increased hypersensitivity. Thus, metreleptin appeared to be efficacious in the treatment of CGL4 in the short term, although an adverse immune response resulted in treatment suspension. Further studies are needed to evaluate metreleptin treatments for CGL4.
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http://dx.doi.org/10.1297/cpe.28.1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6356095PMC
January 2019

Physical, Mental, and Social Problems of Adolescent and Adult Patients with Achondroplasia.

Calcif Tissue Int 2019 04 1;104(4):364-372. Epub 2019 Feb 1.

Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya, 466-8550, Japan.

Patients with achondroplasia (ACH) require various medical interventions throughout the lifetime. Survey of health-related quality of life (HRQoL) in adult ACH patients is essential for the evaluation of treatment outcomes performed during childhood such as growth hormone administration and limb lengthening surgeries, but no study focused on the treatment strategy by analyzing HRQoL of ACH patients. The purpose of this study was to assess whether final height impacted on HRQoL and to evaluate what kinds of medical interventions were positively or negatively associated with HRQoL. We included 184 ACH patients (10-67 years old) who were registered in the patients' associations or who had a medical history of the investigators' institutions, and analyzed HRQoL by using Short Form-36 and patient demographics. Physical component summary (PCS) was significantly lower than the standard values in each age, especially in elderly populations, while mental component summary (MCS) was similar to the standard values. Role/social component summary was deteriorated only in elderly populations. The PCS was improved in the patients who had a height of 140 cm or taller (p < 0.001). The PCS and MCS were strongly associated with the past medical history of spine surgeries (p < 0.001 and p = 0.028, respectively). A treatment strategy would be planned to gain a final height of 140 cm or taller during childhood in combination with growth hormone administration and limb lengthening surgeries. Appropriate medical management for neurological complications of adult ACH patients is required to maintain physical and mental function.
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http://dx.doi.org/10.1007/s00223-019-00518-zDOI Listing
April 2019

Japanese patient with Cole-carpenter syndrome with compound heterozygous variants of SEC24D.

Am J Med Genet A 2018 12 21;176(12):2882-2886. Epub 2018 Nov 21.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Cole-Carpenter syndrome is a rare skeletal dysplasia associated with low-bone mass or an osteogenesis imperfecta (OI)-like syndrome. Only 3 and 6 variants in SEC24D have been reported in patients with Cole-Carpenter syndrome type 2 and autosomal recessive OI, respectively. We describe a 15-year-old Japanese boy with short stature of the short-trunk type and craniofacial abnormalities including ocular proptosis, marked frontal bossing, midface hypoplasia, and micrognathia. These features were consistent with a diagnosis of Cole-Carpenter syndrome. He had low-bone mineral density and basilar impression. Whole exome sequencing analysis identified biallelic variants in SEC24D (p.Arg484* and p.Arg313His) in the patient. We will report a patient with compound heterozygous variants of SEC24D causing Cole-Carpenter syndrome type 2.
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http://dx.doi.org/10.1002/ajmg.a.40643DOI Listing
December 2018

Functional analysis of monocarboxylate transporter 8 mutations in Japanese Allan-Herndon-Dudley syndrome patients.

Endocr J 2019 Jan 25;66(1):19-29. Epub 2018 Oct 25.

Department of Pediatrics, Graduate School of Medicine, Osaka University, Suita, Japan.

Monocarboxylate transporter 8 (MCT8) facilitates T3 uptake into cells. Mutations in MCT8 lead to Allan-Herndon-Dudley syndrome (AHDS), which is characterized by severe psychomotor retardation and abnormal thyroid hormone profile. Nine uncharacterized MCT8 mutations in Japanese patients with severe neurocognitive impairment and elevated serum T3 levels were studied regarding the transport of T3. Human MCT8 (hMCT8) function was studied in wild-type (WT) or mutant hMCT8-transfected human placental choriocarcinoma cells (JEG3) by visualizing the locations of the proteins in the cells, detecting specific proteins, and measuring T3 uptake. We identified 6 missense (p.Arg445Ser, p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, and p.Gly312Arg), 2 frameshift (p.Arg355Profs*64 and p.Tyr550Serfs*17), and 1 deletion (p.Pro561del) mutation(s) in the hMCT8 gene. All patients exhibited clinical characteristics of AHDS with high free T3, low-normal free T4, and normal-elevated TSH levels. All tested mutants were expressed at the protein level, except p.Arg355Profs*64 and p.Tyr550Serfs*17, which were truncated, and were inactive in T3 uptake, excluding p.Arg445Ser and p.Pro561del mutants, compared with WT-hMCT8. Immunocytochemistry revealed plasma membrane localization of p.Arg445Ser and p.Pro561del mutants similar with WT-hMCT8. The other mutants failed to localize in significant amount(s) in the plasma membrane and instead localized in the cytoplasm. These data indicate that p.Arg445Ser and p.Pro561del mutants preserve residual function, whereas p.Asp498Asn, p.Gly276Arg, p.Gly196Glu, p.Gly401Arg, p.Gly312Arg, p.Arg355Profs*64, and p.Tyr550Serfs*17 mutants lack function. These findings suggest that the mutations in MCT8 cause loss of function by reducing protein expression, impairing trafficking of protein to plasma membrane, and disrupting substrate channel.
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http://dx.doi.org/10.1507/endocrj.EJ18-0251DOI Listing
January 2019

Development of scoliosis in young children with osteogenesis imperfecta undergoing intravenous bisphosphonate therapy.

J Bone Miner Metab 2019 May 5;37(3):545-553. Epub 2018 Sep 5.

Department of Orthopedic Surgery, Faculty of Medicine, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan.

The purpose of this study was to clarify the prevalence of scoliosis and determine risk factors for the development of scoliosis in young children with osteogenesis imperfecta (OI) who underwent intravenous pamidronate (PAM) therapy. Thirty-four young children with OI who had no scoliosis at the first PAM administration underwent cyclic PAM therapy alone. The medical records and radiographs of these patients were retrospectively reviewed. We examined the relationship between scoliosis (Cobb angle ≥ 10) and type of OI (Sillence classification: types I, III, and IV), physical mobility, Z-scores of bone mineral density in L2-4 of the lumbar spine (L2-4 BMD Z-scores), age of patients at first treatment with PAM, pelvic frontal tilt and leg-length discrepancy. The prevalence of scoliosis was 23.5% in 34 young children with OI who underwent PAM therapy for a mean of 4.2 years. Lower L2-4 BMD Z-scores, the presence of coronal and sagittal vertebral deformities and higher percentage of corrective osteotomy in the lower extremities were significant risk factors for the development of scoliosis. In patients with type III or IV OI, L2-4 BMD Z-scores were significantly lower (p = 0.02) and the percentage of patients who started PAM therapy in early childhood was significantly lower in scoliosis group than in the non-scoliosis group (p = 0.01). Development of scoliosis depends on the severity of OI and has a strong relationship with bone fragility even under PAM therapy. Starting intravenous PAM therapy in infancy or early childhood has a potential to prevent the occurrence and progression of scoliosis associated with bone fragility in young children with severe type III or IV OI.
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http://dx.doi.org/10.1007/s00774-018-0952-xDOI Listing
May 2019

Incidence rate and characteristics of symptomatic vitamin D deficiency in children: a nationwide survey in Japan.

Endocr J 2018 Jun 10;65(6):593-599. Epub 2018 Mar 10.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

There is concern that vitamin D deficiency is prevalent among children in Japan as well as worldwide. We conducted a nationwide epidemiologic survey of symptomatic vitamin D deficiency to observe its incidence rate among Japanese children. A questionnaire inquiring the number of new patients with vitamin D deficiency rickets and/or hypocalcemia for 3 years was sent to 855 randomly selected hospitals with a pediatrics department in Japan. In this survey, we found that 250 children were diagnosed with symptomatic vitamin D deficiency. The estimated number of patients with symptomatic vitamin D deficiency per year was 183 (95% confidence interval (CI): 145-222). The overall annual incidence rate among children under 15 years of age was 1.1 per 100,000 population (95% CI: 0.9-1.4). The second survey has provided detailed information on 89 patients with symptomatic vitamin D deficiency under 5 years of age in hospitals in the current research group. The nationwide and second surveys estimated the overall annual incidence rate of symptomatic vitamin D deficiency in children under 5 years of age to be 3.5 (2.7-4.2) per 100,000 population. The second survey revealed 83% had bowed legs, 88% had exclusive breastfeeding, 49% had a restricted and/or unbalanced diet and 31% had insufficient sun exposure among the 89 patients. This is the first nationwide survey on definitive clinical vitamin D deficiency in children in Japan. Elucidating the frequency and characteristics of symptomatic vitamin D deficiency among children is useful to develop preventative public health strategies.
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http://dx.doi.org/10.1507/endocrj.EJ18-0008DOI Listing
June 2018

Endocrinological and phenotype evaluation in a patient with acrodysostosis.

Clin Pediatr Endocrinol 2017 27;26(3):177-182. Epub 2017 Jul 27.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Acrodysostosis is characterized by distinctive facial features and severe brachydactyly. Mutations in or are known to be responsible for this disease. Cases of hormonal resistance have been reported, particularly in patients with mutations. The physical characteristics and endocrine function of pseudohypoparathyroidism type Ia is known to resemble acrodysostosis. We report the case of a 4-yr-old patient with a mutation. He had characteristic facies with an upturned nose and cone-shaped epiphyses of most phalanges. These findings have not been reported as extensive for cases of pseudohypoparathyroidism type Ia. He also had TSH resistance from birth. We performed endocrinological stimulation tests to further evaluate his endocrine status. These examinations revealed resistance to TSH and PTH, but there was normal secretion of ACTH, GH, and cortisol. An Ellsworth-Howard test resulted in normal urinary cAMP excretion. This response differs from that of pseudohypoparathyroidism type Ia. In summary, the constellation of an upturned nose, cone-shaped epiphyses of most if not all phalanges, and PTH resistance with a normal urinary cAMP response may satisfactorily enable clinical diagnosis of acrodysostosis.
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http://dx.doi.org/10.1297/cpe.26.177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537214PMC
July 2017

Safety and efficacy of treatment with asfotase alfa in patients with hypophosphatasia: Results from a Japanese clinical trial.

Clin Endocrinol (Oxf) 2017 Jul 2;87(1):10-19. Epub 2017 May 2.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: Hypophosphatasia (HPP) is a rare skeletal disease characterized by hypomineralization and low alkaline phosphatase activity. Asfotase alfa (AA) has been recently developed to treat HPP complications. This study evaluated its safety and efficacy in Japan.

Design: Open-label, multicentre, prospective trial. Patients were enrolled in 11 hospitals from June 2014 to July 2015.

Patients: Thirteen patients (9 females, 4 males) ages 0 days to 34 years at baseline were enrolled and treated with AA (2 mg/kg three times weekly subcutaneously in all but one patient). All had ALPL gene mutations. HPP forms were perinatal (n=6), infantile (n=5), childhood (n=1) and adult (n=1).

Measurements: Safety determined from adverse events (AEs) and laboratory data was the primary outcome measure. Efficacy was assessed as a secondary outcome measure from overall survival, respiratory status, rickets severity and gross motor development.

Results: Injection site reactions were the most frequent AEs. Serious AEs possibly related to treatment were convulsion and hypocalcaemia observed in a patient with the perinatal form. In addition, hypercalcaemia and/or hyperphosphatemia was observed in three patients with the infantile form and a low-calcium and/or low-phosphate formula was given to these patients. With respect to efficacy, all patients survived and the radiographic findings, developmental milestones and respiratory function improved.

Conclusion: Asfotase alfa therapy improved skeletal, respiratory and physical symptoms with a few serious AEs in patients with HPP. Our results add support to the safety and efficacy of AA therapy for HPP patients.
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http://dx.doi.org/10.1111/cen.13343DOI Listing
July 2017

Pheochromocytoma complicated by cyanotic congenital heart disease: a case report.

Clin Pediatr Endocrinol 2016 Apr 28;25(2):59-65. Epub 2016 Apr 28.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Coincidental cyanotic congenital heart disease and pheochromocytoma is uncommon, although some cases have been reported. We describe a girl aged 15 yr and 11 mo with pheochromocytoma and tricuspid atresia treated by performing the Fontan surgery. The patient did not have any specific symptoms of syndrome related to pheochromoytoma or a family history of pheochromocytoma. During cardiac catheterization, her blood pressure increased markedly, and an α-blocker was administered. Catecholamine hypersecretion was observed in the blood and urine, and abdominal computed tomography revealed a tumor in the right adrenal gland. Scintigraphy showed marked accumulation of (123)I-metaiodobenzylguanidine in the tumor, which led to a diagnosis of pheochromocytoma. We did not detect any germline mutations in the RET, VHL, SDHB, SDHD, TMEM127, or MAX genes. This patient had experienced mild systemic hypoxia since birth, which may have contributed to the development of pheochromocytoma.
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http://dx.doi.org/10.1297/cpe.25.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860516PMC
April 2016

Successful induction of sclerostin in human-derived fibroblasts by 4 transcription factors and its regulation by parathyroid hormone, hypoxia, and prostaglandin E2.

Bone 2016 Apr 2;85:91-8. Epub 2016 Feb 2.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan. Electronic address:

Sclerostin, coded by SOST, is a secretory protein that is specifically expressed in osteocytes and suppresses osteogenesis by inhibiting WNT signaling. The regulatory mechanism underlying SOST expression remains unclear mainly due to the absence of an adequate human cell model. Thus, we herein attempted to establish a cell model of human dermal fibroblasts in order to investigate the functions of sclerostin. We selected 20 candidate transcription factors (TFs) that induce SOST expression by analyzing gene expression patterns in the human sarcoma cell line, SaOS-2, between differentiation and maintenance cultures using microarrays. An effective set of TFs to induce SOST expression was sought by their viral transduction into fibroblasts, and a combination of four TFs: ATF3, KLF4, PAX4, and SP7, was identified as the most effective inducer of SOST expression. Quantitative PCR demonstrated that the expression levels of SOST in fibroblasts treated with the 4 TFs were 199- and 1439-fold higher than those of the control after 1-week and 4-week cultures, respectively. The level of sclerostin in the conditioned medium, as determined by ELISA, was 21.2pmol/l 4weeks after the transduction of the 4 TFs. Interestingly, the production of Dickkopf1 (DKK1), another secreted inhibitor of WNT signaling, was also increased by transduction of these 4 TFs. Parathyroid hormone (PTH) significantly suppressed the induced SOST by 38% and sclerostin by 82% that of the vehicle. Hypoxia increased the induced SOST by 62% that of normoxia. Furthermore, prostaglandin E2 (PGE2) increased SOST expression levels to 16-fold those of the vehicle. In conclusion, the efficient induction of SOST expression and sclerostin production was achieved in human dermal fibroblasts by the transduction of ATF3, KLF4, PAX4, and SP7, and the induced SOST and sclerostin were regulated by PTH, hypoxia, and PGE2. This model may contribute to elucidating the regulatory mechanisms underlying SOST expression and advancing drug development for metabolic bone diseases.
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http://dx.doi.org/10.1016/j.bone.2016.01.024DOI Listing
April 2016

Serum NT-proCNP levels increased after initiation of GH treatment in patients with achondroplasia/hypochondroplasia.

Clin Endocrinol (Oxf) 2016 06 25;84(6):845-50. Epub 2016 Feb 25.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka, Japan.

Objective: Serum amino-terminal propeptide of C-type natriuretic peptide (NT-proCNP) levels have been proposed as a biomarker of linear growth in healthy children. The usefulness of NT-proCNP in patients with achondroplasia (ACH)/hypochondroplasia (HCH) remains to be elucidated. The objective was to study whether serum NT-proCNP level is a good biomarker for growth in ACH/HCH and other patients of short stature.

Design: This was a longitudinal cohort study.

Patients: Sixteen children with ACH (aged 0·4-4·3 years), six children with HCH (2·7-6·3 years), 23 children with idiopathic short stature (ISS) (2·2-9·0 years), eight short children with GH deficiency (GHD) (2·9-6·8 years) and five short children born small for gestational age (SGA) (2·0-6·6 years). Patients with ACH/HCH received GH treatment for 1 year.

Measurements: Serum NT-proCNP levels and height were measured.

Results: NT-proCNP levels positively correlated with height velocity in these short children (P < 0·05, r = 0·27). NT-proCNP levels inversely correlated with age in children with ISS alone (P < 0·01, r = -0·55). Serum NT-proCNP levels in patients with ACH/HCH were increased 3 months following the initiation of GH treatment (P < 0·05). Height SDS gain during GH treatment for 1 year was positively correlated with the changes in NT-proCNP levels after the initiation of GH (P < 0·01, r = 0·72).

Conclusion: Serum NT-proCNP levels may be a good biomarker to indicate the effect of GH treatment on growth in patients with ACH/HCH at least in the first year and height velocity in short stature patients.
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http://dx.doi.org/10.1111/cen.13025DOI Listing
June 2016

Acromesomelic dysplasia, type maroteaux caused by novel loss-of-function mutations of the NPR2 gene: Three case reports.

Am J Med Genet A 2016 Feb 14;170A(2):426-434. Epub 2015 Nov 14.

Division of Pediatric Orthopaedics, Seoul National University Children's Hospital, Seoul, Republic of Korea.

The C-type natriuretic peptide (CNP)-natriuretic peptide receptor 2 (NPR2) signaling pathway plays an important role in chondrocyte development. Homozygous loss-of-function mutations of the NPR2 gene cause acromesomelic dysplasia, type Maroteaux (AMDM). The aim of this study was to identify and characterize NPR2 loss-of-function mutations in patients with AMDM. The NPR2 gene was sequenced in three Korean patients with AMDM and functional analysis of the mutated proteins was performed in vitro. Five novel NPR2 mutations were found in the three patients: two compound heterozygous mutations [c.1231T>C (Tyr411His) and c.2761C>T (Arg921X) in Patient 1 and c.1663A>T (Lys555X) and c.1711-1G>C (M571VfsX12) in Patient 3] and a homozygous mutation [c.2762G>A (Arg921Gln) in Patient 2]. Serum NT-proCNP concentration was significantly increased in each patient compared to control subjects. Cells transfected with the expression vector of each mutant except those found in Patient 3 showed a negligible or a markedly low cGMP response after treatment with CNP. HA-tagged wild-type (wt) and HA-mutant NPR2 were expressed at comparable levels: there were two bands of ∼130 and ∼120 kDa in wt and Arg921Gln, a single ∼120 kDa band in Tyr411His, and a single ∼110 kDa in the nonsense mutant. With respect to subcellular localization, Arg921Gln as well as wt-NPR2 reached the cell surface, whereas Tyr411His and Arg921X mutants did not. The Tyr411His and Arg921X NPR2 proteins were co-localized with an endoplasmic reticulum (ER) marker and failed to traffic from the ER to the Golgi apparatus. These results are consistent with deglycosylation experiments. Tyr411His and Arg921X NPR2 are complete loss-of-function mutations, whereas Arg921Gln behaves as a receptor for CNP with limited function.
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http://dx.doi.org/10.1002/ajmg.a.37463DOI Listing
February 2016

Lethal hypophosphatasia successfully treated with enzyme replacement from day 1 after birth.

Eur J Pediatr 2016 Mar 12;175(3):433-7. Epub 2015 Oct 12.

Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, Japan.

Unlabelled: Hypophosphatasia (HPP) is a rare metabolic bone disease caused by loss-of-function mutations in the gene ALPL encoding the tissue nonspecific alkaline phosphatase (TNSALP). There is a broad range of severity in the phenotype of HPP, and the most severe form exhibits perinatal lethality without mineralization of the skeleton. Here, we describe a female infant with perinatal lethal HPP diagnosed in utero. She was treated with a recombinant ALP (asfotase alfa) as an enzyme replacement therapy (ERT), which started from 1 day after birth. She required invasive ventilation immediately upon birth and demonstrated severe hypomineralization of whole body bone. Severe respiratory insufficiency was controlled by intensive respiratory care with high-frequency oscillation ventilation and nitric oxide inhalation and deep sedation just after birth. Bone mineralization improved with treatment; improvements were visible by 3 weeks of age and continued with treatment. Serum calcium levels decreased following treatment, resulting in hypocalcemia and convulsion, and calcium supplementation was required until 3 months of treatment. She was weaned from mechanical ventilation and has now survived more than 1 year.

Conclusion: This case demonstrates the success of ERT in treating the severest HPP and highlights the importance of early diagnosis and intervention for these patients.
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http://dx.doi.org/10.1007/s00431-015-2641-2DOI Listing
March 2016

Detection of Hereditary 1,25-Hydroxyvitamin D-Resistant Rickets Caused by Uniparental Disomy of Chromosome 12 Using Genome-Wide Single Nucleotide Polymorphism Array.

PLoS One 2015 8;10(7):e0131157. Epub 2015 Jul 8.

Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.

Context: Hereditary 1,25-dihydroxyvitamin D-resistant rickets (HVDRR) is an autosomal recessive disease caused by biallelic mutations in the vitamin D receptor (VDR) gene. No patients have been reported with uniparental disomy (UPD).

Objective: Using genome-wide single nucleotide polymorphism (SNP) array to confirm whether HVDRR was caused by UPD of chromosome 12.

Materials And Methods: A 2-year-old girl with alopecia and short stature and without any family history of consanguinity was diagnosed with HVDRR by typical laboratory data findings and clinical features of rickets. Sequence analysis of VDR was performed, and the origin of the homozygous mutation was investigated by target SNP sequencing, short tandem repeat analysis, and genome-wide SNP array.

Results: The patient had a homozygous p.Arg73Ter nonsense mutation. Her mother was heterozygous for the mutation, but her father was negative. We excluded gross deletion of the father's allele or paternal discordance. Genome-wide SNP array of the family (the patient and her parents) showed complete maternal isodisomy of chromosome 12. She was successfully treated with high-dose oral calcium.

Conclusions: This is the first report of HVDRR caused by UPD, and the third case of complete UPD of chromosome 12, in the published literature. Genome-wide SNP array was useful for detecting isodisomy and the parental origin of the allele. Comprehensive examination of the homozygous state is essential for accurate genetic counseling of recurrence risk and appropriate monitoring for other chromosome 12 related disorders. Furthermore, oral calcium therapy was effective as an initial treatment for rickets in this instance.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131157PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4496068PMC
April 2016

Hypophosphatemic osteomalacia and bone sclerosis caused by a novel homozygous mutation of the FAM20C gene in an elderly man with a mild variant of Raine syndrome.

Bone 2014 Oct 27;67:56-62. Epub 2014 Jun 27.

Department of Pediatrics, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan.

Background: Hypophosphatemia and increased serum fibroblast growth factor 23 (FGF23) levels have been reported in young brothers with compound heterozygous mutations for the FAM20C gene; however, rickets was not observed in these cases. We report an adult case of Raine syndrome accompanying hypophosphatemic osteomalacia with a homozygous FAM20C mutation (R408W) associated with increased periosteal bone formation in the long bones and an increase in bone mineral density in the femoral neck.

Case: The patient, a 61-year-old man, was born from a cousin-to-cousin marriage. A short stature and severe dental demineralization were reported at an elementary school age. Hypophosphatemia was noted inadvertently at 27years old, at which time he started to take an active vitamin D metabolite (alphacalcidol) and phosphate. He also manifested ossification of the posterior longitudinal ligament. On bone biopsy performed at the age of 41years, we found severe osteomalacia surrounding osteocytes, which appeared to be an advanced form of periosteocytic hypomineralized lesions compared to those reported in patients with X-linked hypophosphatemic rickets. Laboratory data at 61years of age revealed markedly increased serum intact-FGF23 levels, which were likely to be the cause of hypophosphatemia and the decreased level of 1,25(OH)2D. We recently identified a homozygous FAM20C mutation, which was R408W, in this patient. When expressed in HEK293 cells, the R408W mutant protein exhibited impaired kinase activity and secretion.

Discussion: Our findings suggest that certain homozygous FAM20C mutations can cause FGF23-related hypophosphatemic osteomalacia and indicate the multiple roles of FAM20C in bone.
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http://dx.doi.org/10.1016/j.bone.2014.06.026DOI Listing
October 2014

Serum fibroblast growth factor 23 is a useful marker to distinguish vitamin D-deficient rickets from hypophosphatemic rickets.

Horm Res Paediatr 2014 26;81(4):251-7. Epub 2014 Feb 26.

Department of Pediatrics, Graduate School of Medicine, Osaka, Japan.

Background/aims: Vitamin D-deficient rickets (DR) has recently re-emerged among developed countries. Vitamin D deficiency can influence biochemical results of patients with fibroblast growth factor 23 (FGF23)-related hereditary hypophosphatemic rickets (HR), making differential diagnosis difficult. In the present study we evaluated the utility of serum FGF23 levels in the diagnosis of DR and during its treatment.

Methods: The study group comprised 24 children with DR and 8 children with HR. Serum FGF23 levels and bone metabolism-related measurements were assessed.

Results: Serum FGF23 levels in patients with DR were less than 19 pg/ml, while those in patients with HR were more than 57 pg/ml. There were significant differences in serum levels of calcium, phosphate, parathyroid hormone, and 1,25-dihydroxyvitamin D, as well as tubular maximum phosphate reabsorption per glomerular filtration rate between patients with DR and HR, but these values were not fully mutually exclusive. In addition, serum FGF23 and phosphate levels were increased following treatment.

Conclusion: Serum FGF23 level is the most critical biochemical marker for distinguishing DR from HR and might be a good indicator of biochemical response to the intervention. Serum FGF23 levels show utility for the diagnosis of DR and in the assessment of its response to treatment.
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http://dx.doi.org/10.1159/000357142DOI Listing
January 2015

Therapeutic use of oral sodium phosphate (phosribbon(®) combination granules) in hereditary hypophosphatemic rickets.

Clin Pediatr Endocrinol 2014 Jan 3;23(1):9-15. Epub 2014 Feb 3.

Clinical Research 1, Zeria Pharmaceutical Co., Ltd., Tokyo, Japan.

Oral sodium phosphate formulations indicated for hypophosphatemia are commercially available worldwide. In Japan, however, many medical institutes have used hospital dispensary or foreign over-the-counter formulations because no such medication with an indication covered by the health insurance system is domestically available. To address this problem, we initiated the development of Phosribbon(®). The present study evaluated the efficacy and safety of Phosribbon(®) in 16 patients with hereditary hypophosphatemic rickets. The optimal dosage and an administration pattern were also investigated. Administration of the agent resulted in an increase in the level of serum phosphorus in all patients, which implied that the employed dosage was appropriate. The dosage and administration pattern were adjusted based on comprehensive considerations, including changes in clinical laboratory values such as serum phosphorus, alkaline phosphatase and intact PTH, the dosage of a concomitantly administered activated vitamin D formulation and characteristics of individual patients. Adverse drug reactions were observed in 2 patients, neither of which were serious or necessitated therapy dose reduction or discontinuation. We conclude that Phosribbon(®) is a safe and effective treatment for patients with hypophosphatemic rickets and that dose adjustment in this therapy can be guided by the results of regular clinical examination and renal ultrasonography. (ClinicalTrials.gov Identifier: NCT01237288).
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http://dx.doi.org/10.1292/cpe.23.9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3924172PMC
January 2014

Two Japanese familial cases of Caffey disease with and without the common COL1A1 mutation and normal bone density, and review of the literature.

Eur J Pediatr 2014 Jun 4;173(6):799-804. Epub 2014 Jan 4.

Department of Pediatrics, Osaka University Graduate School of Medicine, 2-2 Yamada-oka, Suita, Osaka, 565-0871, Japan.

Unlabelled: Caffey disease, also known as infantile cortical hyperostosis, is a rare bone disease characterized by acute inflammation with swelling of soft tissues and hyperostosis of the outer cortical surface in early infancy. The common heterozygous mutation of the COL1A1 gene, p.Arg1014Cys, has been reported in patients with Caffey disease. However, its pathogenesis remains to be elucidated, and the reason for the incomplete penetrance and transient course of the disease is still unclear. In the present study, we performed mutation analysis of the COL1A1 and COL1A2 genes and measured bone mineral density in two Japanese familial cases of Caffey disease. The index case and two clinically healthy members of one family carry the common heterozygous mutation; in contrast, no mutation in COL1A1 or COL1A2 was identified in the affected members of the second family. In addition, we found normal bone mineral density in adult patients of both families who have had an episode of cortical hyperostosis regardless of the presence or absence of the common p.Arg1014Cys mutation.

Conclusion: The results reveal that Caffey disease is genetically heterogeneous and that affected and unaffected adult patients with or without the common COL1A1 mutation have normal bone mineral density.
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http://dx.doi.org/10.1007/s00431-013-2252-8DOI Listing
June 2014

Detection and characterization of two novel mutations in the HNF4A gene in maturity-onset diabetes of the young type 1 in two Japanese families.

Horm Res Paediatr 2013 1;79(4):220-6. Epub 2013 May 1.

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Japan.

Background: Maturity-onset diabetes of the young (MODY) is a subgroup of monogenic diabetes mellitus, of which MODY1, caused by HNF4A mutations, accounts for only 5% or less and has been rarely reported in East Asian countries. Here we report two novel HNF4A mutations in two Japanese families with MODY1.

Methods: Proband 1 is an 8-year-old girl and proband 2 is a 14-year-old girl. Both were nonobese, demonstrated elevated HbA1c and negative serum anti-glutamic acid decarboxylase antibodies, and had a family history of diabetes. We directly sequenced HNF4A and performed functional analysis of the detected missense mutation.

Results: Proband 1 had a heterozygous missense mutation, c.824A>G (p.Asn275Ser). Luciferase assay demonstrated a significant reduction in transcriptional activity. A heterozygous frame shift mutation, c.692-695delAGGA (p.Lys231ThrfsX5), was detected in proband 2. Affected family members shared the same mutations, showing high penetrance. Both mutations reside in the HNF4α dimerization domain and the corresponding amino acids are well conserved between species.

Conclusions: These two mutations are most likely the cause of MODY1 in these families. Considering the effectiveness of sulfonylureas, it is important to correctly diagnose MODY1.
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http://dx.doi.org/10.1159/000350520DOI Listing
December 2013

Pediatric aspects of skeletal dysplasia.

Pediatr Endocrinol Rev 2012 Oct;10 Suppl 1:35-43

Department of Pediatrics, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.

Skeletal dysplasia is a disorder of skeletal development characterized by abnormality in shape, length, a number and mineral density of the bone. Skeletal dysplasia is often associated with manifestation of other organs such as lung, brain and sensory systems. Skeletal dysplasias or dysostosis are classified with more than 400 different names. Enchondral bone formation is a coordinated event of chondrocyte proliferation, differentiation and exchange of terminally maturated chondrocyte with bone. Impaired enchondral bone formation will lead to skeletal dysplasia, especially associated with short long bones. Appropriate bone volume and mineral density are achieved by balance of bone formation and bone resorption and mineralization. The gene encoding fibroblast growth factor receptor 3 is responsible for achondroplasia, representative skeletal dysplasia with short stature. The treatment with growth hormone is approved for achondroplasia in Japan. Osteogenesis imperfecta is characterized by low bone mineral density and fragile bone. Data on the beneficial effect of bisphosphonate for osteogenesis imperfecta are accumulating. Osteopetrosis has high bone mineral density, but sometimes show bone fragility. In Japan as well as other countries, pediatrician treat larger numbers of patients with skeletal dysplasia with short stature and fragile bones compared to 20 years ago.
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October 2012
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