Publications by authors named "Yumi Asakura"

61 Publications

Quantification of serum thyroid hormones using tandem mass spectrometry in patients with Down syndrome.

Biomed Chromatogr 2022 Jan 19;36(1):e5249. Epub 2021 Oct 19.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Thyroid dysfunction is common in patients with Down syndrome (DS), the most common chromosomal disorder. Thyroid hormones (THs) are important for normal growth, neurodevelopment, and metabolism, highlighting the importance of quantifying the levels in patients with DS. However, current methods possess cross-reactivity that results in inaccuracies in quantification. We aimed at developing a new analytical method for quantifying the total 3,3',5-triiodo-l-thyronine (TT3), total 3,3',5,5'-tetraiodo-l-thyronine (TT4), 3,3',5'-triiodo-l-thyronine, and reverse T3 (rT3) levels using LC-MS/MS. Repeatability and reproducibility with coefficient of variation values of 2-9 and 3-13%, respectively, were acceptable, suggesting that the assay was suitable for measuring serum THs. We measured the serum TH levels of patients with DS but without thyroid dysfunction (age, 3-20 years) and compared the levels to those of controls (patients with idiopathic short stature; age, 3-17 years). When TH levels were summarized by age group, the serum TT4 concentrations were not significantly different between the controls and patients with DS across all age groups. Meanwhile, the serum TT3 concentrations differed according to age. In addition, the serum rT3 concentrations were significantly higher in patients with DS than in controls, except for those in the 12-14 age group. We also calculated the T3/T4 and rT3/T4 ratios to elucidate the reason for the higher rT3 in patients with DS; however, no useful findings were obtained. Thus, further investigation is needed to clarify our findings.
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http://dx.doi.org/10.1002/bmc.5249DOI Listing
January 2022

Identification of the first promoter-specific gain-of-function SOX9 missense variant (p.E50K) in a patient with 46,XX ovotesticular disorder of sex development.

Am J Med Genet A 2021 04 5;185(4):1067-1075. Epub 2021 Jan 5.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

SOX9, a transcription factor, is expressed in the undifferentiated XX and XY gonads. SRY induces significant upregulation of SOX9 expression in XY gonads. Loss-of-function SOX9 variants cause testicular dysgenesis in 46,XY patients, while duplication of the total gene or the upstream regulatory region results in testicular development in 46,XX patients. However, gain-of-function (GoF) SOX9 variants have not been reported previously. We report the case of a 16-year-old female patient with a 46,XX karyotype who had masculinized external genitalia and unilateral ovotestis. Next-generation sequencing-based genetic screening for disorders of sex development led to the identification of a novel SOX9 variant (p.Glu50Lys), transmitted from the phenotypically normal father. Expression analysis showed that E50K-SOX9 enhanced transactivation of the luciferase reporter containing the testis enhancer sequence core element compared with that containing the wildtype-SOX9. This GoF activity was not observed in the luciferase reporter containing Amh, the gene for anti-Müllerian hormone. We genetically engineered female mice (Sox9 ), and they showed no abnormalities in the external genitalia or ovaries. In conclusion, a novel SOX9 variant with a promoter-specific GoF activity was identified in vitro; however, the disease phenotype was not recapitulated by the mouse model. At present, the association between the GoF SOX9 variant and the ovotestis phenotype remains unclear. Future studies are needed to verify the possible association.
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http://dx.doi.org/10.1002/ajmg.a.62063DOI Listing
April 2021

Metreleptin worked in a diabetic woman with a history of hematopoietic stem cell transplantation (HSCT) during infancy: further support for the concept of 'HSCT-associated lipodystrophy'.

Endocr J 2021 Apr 21;68(4):399-407. Epub 2020 Nov 21.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.

A 17-year-old woman with a history of childhood leukemia and hematopoietic stem cell transplantation (HSCT), preceded by total body irradiation, developed diabetes, dyslipidemia, fatty liver, and marked insulin resistance. Based on Dunnigan phenotype, HSCT-associated lipodystrophy was suspected. Because of rapid deterioration of diabetes control, metreleptin was introduced at 23 years of age upon receipt of her caregiver's documented consent. This trial was initially planned as a prospective 18 month-long study, with regular assessments of the patient's physical activity, food intake, and body composition analysis. However, because an abrupt and transient attenuation of the metreleptin effect occurred 16 months after the treatment initiation, the entire course of 28 months is reported here. Over the period, her HbA1c decreased from 10.9% to 6.7% despite no significant increase of physical activity and with a stable food intake. Decreased levels of triglyceride and non-HDL cholesterol were found. Her liver function improved, indicating the amelioration of fatty liver. In addition, a 25% reduction in the subcutaneous fat area at umbilical level was found, accompanied by a decrease in fat percentage of both total-body and trunk. The formation of neutralizing antibodies to metreleptin may be responsible for the transient loss of efficacy, considering a sudden elevation in her serum leptin level. In conclusion, metreleptin is useful for the management of HSCT-associated lipodystrophy, supporting the concept that adipose tissue dysfunction is responsible for diverse post-HSCT metabolic aberrations.
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http://dx.doi.org/10.1507/endocrj.EJ20-0325DOI Listing
April 2021

Congenital Hypothyroidism Due to Truncating PAX8 Mutations: A Case Series and Molecular Function Studies.

J Clin Endocrinol Metab 2020 11;105(11)

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

Context: PAX8 is a transcription factor required for thyroid development, and its mutation causes congenital hypothyroidism (CH). More than 20 experimentally verified loss-of-function PAX8 mutations have been described, and all but one were located in the DNA-binding paired domain.

Objective: We report the identification and functional characterization of 3 novel truncating PAX8 mutations located outside the paired domain.

Methods: Three CH probands, diagnosed in the frame of newborn screening, had thyroid hypoplasia and were treated with levothyroxine. Next-generation sequencing-based mutation screening was performed. Functionality of the identified mutations were verified with Western blotting, intracellular localization assays, and transactivation assays with use of HeLa cells. Luciferase complementation assays were used to evaluate the effect of mutations on the interaction between PAX8 and its partner, NKX2-1.

Results: Each proband had novel truncating PAX8 mutations that were I160Sfs*52, Q213Efs*27, and F342Rfs*85. Western blotting showed destabilization of the I160fs-PAX8 protein. Q213fs-PAX8 and F342fs-PAX8 showed normal protein expression levels and normal nuclear localization, but showed loss of transactivation of the luciferase reporter. By luciferase complementation assays, we showed that PAX8-NKX2-1 interaction was defective in Q213fs-PAX8. We also characterized the recombinant PAX8 proteins, and found that the protein sequence corresponding to exon 10 (363-400 aa residues) was essential for the PAX8-NKX2-1 interaction.

Conclusions: Clinical and molecular findings of 3 novel truncating PAX8 mutations located outside the paired domain were reported. Experiments using cultured cells and recombinant proteins showed that the C-terminal portion (ie, 363-400 aa) of PAX8 is required for the PAX8-NKX2-1 interaction.
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http://dx.doi.org/10.1210/clinem/dgaa584DOI Listing
November 2020

Previous Immune Checkpoint Inhibitor Treatment to Increase the Efficacy of Docetaxel and Ramucirumab Combination Chemotherapy.

Anticancer Res 2019 Sep;39(9):4987-4993

Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.

Background/aim: For immune checkpoint inhibitor (ICI)-pretreated patients, docetaxel and ramucirumab (DOC+RAM) combination therapy may be more effective compared to patients not receiving ICI treatment.

Patients And Methods: From June 2013 to July 2018, 39 patients with advanced/recurrent non-small cell lung cancer underwent DOC+RAM therapy. We analyzed the efficacy and safety of DOC+RAM therapy based on the presence (pre-ICI+) or absence (pre-ICI-) of ICI pretreatment history.

Results: Of the 39 patients treated with DOC+RAM, we identified 18 (46%) pre-ICI+ patients. Overall response rates for DOC+RAM concerning pre-ICI+ and pre-ICI- patients were 38.9% vs. 19.0%, respectively. Median progression-free survival (PFS) was 5.7 vs. 2.3 months [hazard ratio(HR)=0.36; 95% confidence interval (CI)=0.16-0.80]. Adverse events such as fever, myalgia, arthritis, pleural effusion, and pneumonitis tended to be increased in pre-ICI+ patients.

Conclusion: Despite increased toxicity concerns, DOC+RAM therapy in pre-ICI+ patients showed a trend for tumor regression improvement and statistically significant prolongation of PFS.
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http://dx.doi.org/10.21873/anticanres.13688DOI Listing
September 2019

Genetics of Congenital Isolated TSH Deficiency: Mutation Screening of the Known Causative Genes and a Literature Review.

J Clin Endocrinol Metab 2019 12;104(12):6229-6237

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Context: Congenital isolated TSH deficiency (i-TSHD) is a rare form of congenital hypothyroidism. Five genes (IGSF1, IRS4, TBL1X, TRHR, and TSHB) responsible for the disease have been identified, although their relative frequencies and hypothalamic/pituitary unit phenotypes have remained to be clarified.

Objectives: To define the relative frequencies and hypothalamic/pituitary unit phenotypes of congenital i-TSHD resulting from single gene mutations.

Patients And Methods: Thirteen Japanese patients (11 boys and 2 girls) with congenital i-TSHD were enrolled. IGSF1, IRS4, TBL1X, TRHR, and TSHB were sequenced. For a TBL1X mutation (p.Asn382del), its pathogenicity was verified in vitro. For a literature review, published clinical data derived from 74 patients with congenital i-TSHD resulting from single-gene mutations were retrieved and analyzed.

Results: Genetic screening of the 13 study subjects revealed six mutation-carrying patients (46%), including five hemizygous IGSF1 mutation carriers and one hemizygous TBL1X mutation carrier. Among the six mutation carriers, one had intellectual disability and the other one had obesity, but the remaining four did not show nonendocrine phenotypes. Loss of function of the TBL1X mutation (p.Asn382del) was confirmed in vitro. The literature review demonstrated etiology-specific relationship between serum prolactin (PRL) levels and TRH-stimulated TSH levels with some degree of overlap.

Conclusions: The mutation screening study covering the five causative genes of congenital i-TSHD was performed, showing that the IGSF1 defect was the leading genetic cause of the disease. Assessing relationships between serum PRL levels and TRH-stimulated TSH levels would contribute to predict the etiologies of congenital i-TSHD.
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http://dx.doi.org/10.1210/jc.2019-00657DOI Listing
December 2019

Severe in utero under-virilization in a 46,XY patient with Silver-Russell syndrome with 11p15 loss of methylation.

J Pediatr Endocrinol Metab 2019 Feb;32(2):191-196

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Background Silver-Russell syndrome (SRS) is characterized by growth retardation and variable features including macrocephaly, body asymmetry, and genital manifestations such as cryptorchidism in 46,XY patients. Case presentation The patient was born at 39 weeks with a birth weight of 1344 g. Subtle clitoromegaly warranted a thorough evaluation, which disclosed 46,XY karyotype, bilateral undescended testes, and a rudimentary uterus. Because of severe under-virilization, the patient was assigned as female. Failure to thrive, macrocephaly, and body asymmetry led to the diagnosis of SRS, confirmed by marked hypomethylation of H19/IGF2 intergenic differentially methylated region (IG-DMR). From age 9 years, progressive virilization occurred, which necessitated luteinizing hormone-releasing hormone analog (LHRHa) treatment. Gonadal resection at 15 years revealed immature testes with mostly Sertoli-cell-only tubules. Panel analysis for 46,XY-differences of sex development (DSD) failed to detect any pathogenic variants. Conclusions This is the second reported case of molecularly proven 46,XY SRS accompanied by severe under-virilization. SRS should be included in the differential diagnosis of 46,XY-DSD.
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http://dx.doi.org/10.1515/jpem-2018-0464DOI Listing
February 2019

Spontaneous virilization around puberty in NR5A1-related 46,XY sex reversal: additional case and a literature review.

Endocr J 2018 Dec 15;65(12):1187-1192. Epub 2018 Sep 15.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.

A heterozygous NR5A1 mutation is one of the most frequent causes of 46,XY DSD (disorders of sex development). We here reported a NR5A1-related 46,XY DSD patient, who first received endocrinological attention at 10 years of age for clitoromegaly. The patient had been reared as a girl, and no signs of virilization had been detected before. On examination, her clitoris was 35 mm long and 10 mm wide, with Tanner 3° pubic hair. Urogenital sinus and labial fusion was absent, while her uterus was found to be severely hypoplastic. Her basal testosterone level was 94.8 ng/dL, suggesting the presence of functioning Leydig cells. Gonadal histology revealed bilateral dysplastic testes consisting of mostly Sertoli cell-only tubules and Leydig cell hyperplasia. Novel heterozygous Arg313Leu substitution in NR5A1 was identified in the patient. Literature search confirmed twelve other cases of this scenario, namely, severe under-virilization in utero followed by spontaneous virilization around puberty in NR5A1-related 46,XY DSD. Of interest, Leydig cell hyperplasia was documented in 6 out of 9 patients for whom testicular histology was available. To keep in mind about the possible restoration of Leydig cell function around puberty, even in patients without discernible in utero androgen effect, may be of clinical significance, because it will give a great impact on the judgement about sex assignment.
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http://dx.doi.org/10.1507/endocrj.EJ18-0218DOI Listing
December 2018

Association between monoallelic mutations and congenital hypothyroidism: a statistical approach.

Eur J Endocrinol 2018 Feb 1;178(2):137-144. Epub 2017 Nov 1.

Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Objective: Biallelic mutations cause congenital hypothyroidism (CH). Serum TSH levels of monoallelic mutation carriers range from normal to mildly elevated, and thus the size of its effect remains unclear. The objectives were to examine the association between monoallelic mutations and positivity at newborn screening (NBS) for CH, and to test whether the association was modified by another genetic factor.

Subjects And Methods: We enrolled 395 patients that had a positive result in NBS and sequenced Monoallelic mutation carriers were further sequenced for . Molecular functions of the mutations were verified . The frequency of the mutations in the study subjects was compared with a theoretical value in the Japanese general population. Odds ratio (OR) for NBS positivity associated with the mutation was calculated. Using Bayes' theorem, we estimated a posterior probability of NBS positivity given the mutation.

Results: Twenty-six monoallelic mutation carriers were found. Four out of the 26 also had a monoallelic mutation (double heterozygotes). The frequencies of monoallelic mutation carriers (6.6%) and double heterozygotes (1.0%) were significantly higher than those in the general population (0.58% and 0.0087%, respectively). OR for NBS positivity of having a monoallelic mutation or being a double heterozygote was 12.0 or 117.9, respectively. Posterior probability of NBS positivity was 0.38% in monoallelic mutation carriers and 3.8% in double heterozygotes.

Conclusions: Monoallelic mutations are significantly associated with NBS positivity, and the association is further strengthened by the coexistence of monoallelic mutations.
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http://dx.doi.org/10.1530/EJE-16-1049DOI Listing
February 2018

Partial lipodystrophy in patients who have undergone hematopoietic stem cell transplantation during childhood: an institutional cross-sectional survey.

Clin Pediatr Endocrinol 2017 22;26(2):99-108. Epub 2017 Apr 22.

Department of Hematology and Regenerative Medicine, Kanagawa Children's Medical Center, Yokohama, Japan.

Partial lipodystrophy (PD), a condition similar to metabolic syndrome without obesity, is one of the late complications of hematopoietic stem cell transplantation (HSCT) performed during childhood. We aimed to investigate the prevalence and risk factors of PD. A cross-sectional survey was performed in a children's hospital, targeting patients treated for a malignancy or hematological disorder, and who were disease-free for > 24 mo. PD was defined as gluteal lipoatrophy and lipohypertrophy of the cheeks or neck associated with diabetes and/or fatty liver disease. In total, 65 patients were enrolled. Six patients (9.2%) were judged to have PD, all of whom had received 10-14 Gy total body irradiation. Compared with the patients without PD, patients with PD were older at investigation (P < 0.01), had a longer elapsed time following HSCT (P < 0.01), had more frequent disease recurrence (P < 0.05), and were more likely to have undergone multiple HSCT (P < 0.05). In addition, they had higher blood pressure and showed higher levels of low-density lipoprotein-cholesterol and triglycerides, whereas their adiponectin levels were significantly lower. In conclusion, a large number of patients developed PD following HSCT, with unfavorable metabolic profiles at a later age, especially when they experienced a complex disease course.
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http://dx.doi.org/10.1297/cpe.26.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5402311PMC
April 2017

Increased Wnt and Notch signaling: a clue to the renal disease in Schimke immuno-osseous dysplasia?

Orphanet J Rare Dis 2016 11 5;11(1):149. Epub 2016 Nov 5.

Department of Anatomic Pathology, Children's and Women's Health Centre of British Columbia, Vancouver, BC, Canada.

Background: Schimke immuno-osseous dysplasia (SIOD) is a multisystemic disorder caused by biallelic mutations in the SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily A-like 1 (SMARCAL1) gene. Changes in gene expression underlie the arteriosclerosis and T-cell immunodeficiency of SIOD; therefore, we hypothesized that SMARCAL1 deficiency causes the focal segmental glomerulosclerosis (FSGS) of SIOD by altering renal gene expression. We tested this hypothesis by gene expression analysis of an SIOD patient kidney and verified these findings through immunofluorescent analysis in additional SIOD patients and a genetic interaction analysis in Drosophila.

Results: We found increased expression of components and targets of the Wnt and Notch signaling pathways in the SIOD patient kidney, increased levels of unphosphorylated β-catenin and Notch1 intracellular domain in the glomeruli of most SIOD patient kidneys, and genetic interaction between the Drosophila SMARCAL1 homologue Marcal1 and genes of the Wnt and Notch signaling pathways.

Conclusions: We conclude that increased Wnt and Notch activity result from SMARCAL1 deficiency and, as established causes of FSGS, contribute to the renal disease of most SIOD patients. This further clarifies the pathogenesis of SIOD and will hopefully direct potential therapeutic approaches for SIOD patients.
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http://dx.doi.org/10.1186/s13023-016-0519-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5097426PMC
November 2016

Potential utility of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism: a case report.

Clin Pediatr Endocrinol 2016 Jul 20;25(3):91-8. Epub 2016 Jul 20.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

We report a Japanese pedigree with familial primary hyperparathyroidism due to a CDC73 mutation. To our knowledge, this is the first report of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism. The proband had severe psychomotor retardation and received laryngotracheal separation surgery. At 19 yr of age, he developed acute pancreatitis. Hypercalcemia (12.2-13.8 mg/dL), elevated levels of intact PTH (86-160 pg/mL), and a tumor detected upon neck ultrasonography led to the diagnosis of primary hyperparathyroidism. Family history and biochemical examinations revealed that three family members (the proband's mother, elder brother, and maternal grandfather) had primary hyperparathyroidism. We identified a novel heterozygous mutation, c.240delT, p.Glu81Lysfs*28, in the CDC73 gene in three affected family members, excluding the proband's elder brother who refused genetic testing. Parathyroidectomy for the proband was considered as high-risk, because the tumor was located close to the tracheostomy orifice. After receiving approval from the institutional review board and obtaining the consent, we initiated cinacalcet treatment. At 22 yr of age, treatment with 100 mg of cinacalcet maintained serum calcium levels below 11.0 mg/dL with no apparent side effects. Our report presents the potential efficacy of cinacalcet as a treatment for CDC73-related primary hyperparathyroidism, in particularly inoperative cases.
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http://dx.doi.org/10.1297/cpe.25.91DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965508PMC
July 2016

Systematic molecular analyses of SHOX in Japanese patients with idiopathic short stature and Leri-Weill dyschondrosteosis.

J Hum Genet 2016 Jul 17;61(7):585-91. Epub 2016 Mar 17.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.

The etiology of idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD) in European patients is known to include SHOX mutations and copy-number variations (CNVs) involving SHOX and/or the highly evolutionarily conserved non-coding DNA elements (CNEs) flanking the gene. However, the frequency and types of SHOX abnormalities in non-European patients and the clinical importance of mutations in the CNEs remains to be clarified. Here, we performed systematic molecular analyses of SHOX for 328 Japanese patients with ISS or LWD. SHOX abnormalities accounted for 3.8% of ISS and 50% of LWD cases. CNVs around SHOX were identified in 16 cases, although the ~47 kb deletion frequently reported in European patients was absent in our cases. Probably damaging mutations and benign/silent substitutions were detected in four cases, respectively. Although CNE-linked substitutions were detected in 15 cases, most of them affected poorly conserved nucleotides and were shared by unaffected individuals. These results suggest that the frequency and mutation spectrum of SHOX abnormalities are comparable between Asian and European patients, with the exception of a European-specific downstream deletion. Furthermore, this study highlights the clinical importance and genetic heterogeneity of the SHOX-flanking CNVs, and indicates a limited clinical significance of point mutations in the CNEs.
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http://dx.doi.org/10.1038/jhg.2016.18DOI Listing
July 2016

Combined Growth Hormone and Thyroid-Stimulating Hormone Deficiency in a Japanese Patient with a Novel Frameshift Mutation in IGSF1.

Horm Res Paediatr 2015 19;84(5):349-54. Epub 2015 Aug 19.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Background: Recent reports have indicated that loss-of-function mutations in the immunoglobulin superfamily member 1 gene (IGSF1, OMIM 300888) cause congenital central hypothyroidism with macroorchidism.

Methods: We conducted a next-generation sequencing-based comprehensive mutation screening for pituitary hormone deficiencies to elucidate molecular mechanisms other than anatomical abnormalities of the pituitary that might be responsible for multiple anterior hormone deficiency in a male patient who originally visited our institute complaining of short stature. He was born large for gestational age (4,370 g, +3.0 SD) after an obstructed labour. Endocrinological evaluation revealed growth hormone and thyroid-stimulating hormone deficiency. Magnetic resonance imaging showed a discontinuity of the pituitary stalk with an ectopic posterior lobe and a hypoplastic anterior lobe, likely explaining multiple anterior pituitary hormone deficiency.

Result: We identified a novel hemizygous IGSF1 mutation (c.1137_1138delCA, p.Asn380Glnfs*6) in the patient. In reviewing the literature, we noticed that all reported Japanese male IGSF1 mutation carriers were born larger than mean standards for gestational age (mean birth weight SD score of +2.0, 95% confidence interval 1.0-3.0).

Conclusion: This case suggests that more attention should be paid to intrauterine growth and birth history when patients are suspected of having an IGSF1 mutation.
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http://dx.doi.org/10.1159/000438672DOI Listing
August 2016

The ratio of serum free triiodothyronine to free thyroxine in children: a retrospective database survey of healthy short individuals and patients with severe thyroid hypoplasia or central hypothyroidism.

Thyroid Res 2015 8;8:10. Epub 2015 Jul 8.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku Yokohama, 232-8555 Japan.

Background: The ratio of serum free triiodothyronine (FT3) to free thyroxine (FT4) has been shown to be constant in healthy adults. However, this ratio has been found to be decreased in athyreotic adult patients on levothyroxine (L-T4) supplementation. In order to better evaluate thyroid-related pathologies in children as well as to establish a reference range, we investigated the FT3/FT4 ratio in a pediatric population. Furthermore, we evaluated this ratio in children with congenital hypothyroidism as well as those with central hypothyroidism.

Methods: A reference range for the FT3/FT4 ratio was obtained from 129 Japanese children (3-17 y) with idiopathic short stature who were designated as the 'Control' group. Patients with congenital hypothyroidism due to athyreosis or severe thyroid hypoplasia (designated as 'A/Hypoplasia'), as well as patients with central hypothyroidism ('Central'), were recruited from the institutional database. For each group, the mean FT3/FT4 ratio was obtained.

Results: In the Control group, the FT3/FT4 ratio was 3.03 ± 0.38 10(-2) pg/ng (mean ± standard deviation) with no age or gender differences. A/Hypoplasia patients showed a significantly decreased mean FT3/FT4 ratio (2.17 ± 0.33, P < 0.001) compared to Control patients, with decreased FT3 and elevated FT4 levels. The Central group also showed a significantly decreased FT3/FT4 ratio (2.55 ± 0.45, P < 0.001) compared to the Control group, with decreased FT3 and equivalent FT4 levels.

Conclusions: The FT3/FT4 ratio appears to be constant between the ages of 3-17 y. Children on L-T4 due to congenital thyroid a/hypoplasia or central hypothyroidism have a decreased FT3/FT4 ratio compared to short normal children.
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http://dx.doi.org/10.1186/s13044-015-0023-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4495644PMC
July 2015

Clinical manifestations and enzymatic activities of mitochondrial respiratory chain complexes in Pearson marrow-pancreas syndrome with 3-methylglutaconic aciduria: a case report and literature review.

Eur J Pediatr 2015 Dec 16;174(12):1593-602. Epub 2015 Jun 16.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama, 232-8555, Japan.

Unlabelled: Pearson marrow-pancreas syndrome (PS) is a rare mitochondrial disorder. Impaired mitochondrial respiratory chain complexes (MRCC) differ among individuals and organs, which accounts for variable clinical pictures. A subset of PS patients develop 3-methylglutaconic aciduria (3-MGA-uria), but the characteristic symptoms and impaired MRCC remain unknown. Our patient, a girl, developed pancytopenia, hyperlactatemia, steatorrhea, insulin-dependent diabetes mellitus, liver dysfunction, Fanconi syndrome, and 3-MGA-uria. She died from cerebral hemorrhage at 3 years of age. We identified a novel 5.4-kbp deletion of mitochondrial DNA. The enzymatic activities of MRCC I and IV were markedly reduced in the liver and muscle and mildly reduced in skin fibroblasts and the heart. To date, urine organic acid analysis has been performed on 29 PS patients, including our case. Eight patients had 3-MGA-uria, while only one patient did not. The remaining 20 patients were not reported to have 3-MGA-uria. In this paper, we included these 20 patients as PS patients without 3-MGA-uria. PS patients with and without 3-MGA-uria have similar manifestations. Only a few studies have examined the enzymatic activities of MRCC.

Conclusion: No clinical characteristics distinguish between PS patients with and without 3-MGA-uria. The correlation between 3-MGA-uria and the enzymatic activities of MRCC remains to be elucidated.

What Is Known: • The clinical characteristics of patients with Pearson marrow-pancreas syndrome and 3-methylglutaconic aciduria remain unknown.

What Is New: • No clinical characteristics distinguish between Pearson marrow-pancreas syndrome patients with and without 3-methylglutaconic aciduria.
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http://dx.doi.org/10.1007/s00431-015-2576-7DOI Listing
December 2015

Polyostotic osteolysis and hypophosphatemic rickets with elevated serum fibroblast growth factor 23: A case report.

Am J Med Genet A 2015 Oct 8;167A(10):2430-4. Epub 2015 Jun 8.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

We report on a boy who presented with hypophosphatemic rickets with elevated serum fibroblast growth factor 23 (FGF23) and polyostotic osteolytic lesions at age 2 years. Tumor-induced hypophosphatemic rickets was suspected; however, bone biopsy for osteolytic changes revealed no tumorous change, except for irregularly dilated vessels associated with osteoclasts and fibrous proliferation. Venous sampling failed to point to FGF23-producing foci. After alfacalcidol and phosphate supplementation, the rachitic skeletal changes improved, but FGF23 increased and new osteolytic lesions developed. Serum levels of neopterin and a few cytokines, including plasma transforming growth factor-β and soluble tumor necrosis factor receptor type II, were elevated. At age 4 years, high doses of phosphate resulted in increased serum phosphate levels, decreased neopterin and cytokines, decreased FGF23, and stabilization of osteolysis. We excluded germline mutations in PHEX, FGF23, DMP1, and ENPP1 (genes for hereditary hypophosphatemic rickets) and somatic mutations in the GNAS and HRAS/KRAS (the disease-causing genes for McCune-Albright syndrome and linear nevus sebaceous syndrome, respectively). We could not perform octreotide scintigraphy or fluorodeoxyglucose-positron emission tomography, and thus could not completely exclude occult FGF23-producing tumors. However, considering the course of the disease, it is intriguing to assume that dysregulation of osteoclast-macrophage lineage may have induced increased neopterin levels, increased cytokine levels, osteolytic process, and possibly FGF23 overproduction.
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http://dx.doi.org/10.1002/ajmg.a.37193DOI Listing
October 2015

Rare pseudoautosomal copy-number variations involving SHOX and/or its flanking regions in individuals with and without short stature.

J Hum Genet 2015 Sep 4;60(9):553-6. Epub 2015 Jun 4.

Division of Pediatrics and Perinatology, Tottori University Faculty of Medicine, Tottori, Japan.

Pseudoautosomal region 1 (PAR1) contains SHOX, in addition to seven highly conserved non-coding DNA elements (CNEs) with cis-regulatory activity. Microdeletions involving SHOX exons 1-6a and/or the CNEs result in idiopathic short stature (ISS) and Leri-Weill dyschondrosteosis (LWD). Here, we report six rare copy-number variations (CNVs) in PAR1 identified through copy-number analyzes of 245 ISS/LWD patients and 15 unaffected individuals. The six CNVs consisted of three microduplications encompassing SHOX and some of the CNEs, two microduplications in the SHOX 3'-region affecting one or four of the downstream CNEs, and a microdeletion involving SHOX exon 6b and its neighboring CNE. The amplified DNA fragments of two SHOX-containing duplications were detected at chromosomal regions adjacent to the original positions. The breakpoints of a SHOX-containing duplication resided within Alu repeats. A microduplication encompassing four downstream CNEs was identified in an unaffected father-daughter pair, whereas the other five CNVs were detected in ISS patients. These results suggest that microduplications involving SHOX cause ISS by disrupting the cis-regulatory machinery of this gene and that at least some of microduplications in PAR1 arise from Alu-mediated non-allelic homologous recombination. The pathogenicity of other rare PAR1-linked CNVs, such as CNE-containing microduplications and exon 6b-flanking microdeletions, merits further investigation.
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http://dx.doi.org/10.1038/jhg.2015.53DOI Listing
September 2015

Combined pituitary hormone deficiency with unique pituitary dysplasia and morning glory syndrome related to a heterozygous PROKR2 mutation.

Clin Pediatr Endocrinol 2015 Jan 10;24(1):27-32. Epub 2015 Feb 10.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Recent reports have indicated the role of the prokineticin receptor 2 gene (PROKR2) in the etiology of congenital hypopituitarism, including septo-optic dysplasia and Kallmann syndrome. In the present study, using next-generation targeted sequencing, we identified a novel heterozygous PROKR2 variant (c.742C>T; p.R248W) in a female patient who had combined pituitary hormone deficiency (CPHD), morning glory syndrome and a severely malformed pituitary gland. No other mutation was present in 27 genes related to hypogonadotropic hypogonadism, pituitary hormone deficiency and optic nerve malformation. The substituted amino acid was located on the third intracellular loop of the PROKR2 protein, which is a G protein-coupled receptor. Computational analyses with two programs (SIFT and PolyPhen-2) showed that the substitution was deleterious to PROKR2 function. The p.R248W mutation was transmitted from the patient's mother, who had a slightly delayed menarche. Collectively, we provide further genetic evidence linking heterozygous PROKR2 mutations and the development of CPHD.
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http://dx.doi.org/10.1297/cpe.24.27DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4322290PMC
January 2015

Heterozygous defects in PAX6 gene and congenital hypopituitarism.

Eur J Endocrinol 2015 Jan 23;172(1):37-45. Epub 2014 Oct 23.

Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan

Background: The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases.

Objective: To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH.

Subjects And Methods: We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing.

Results: We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements.

Conclusions: This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients.
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http://dx.doi.org/10.1530/EJE-14-0255DOI Listing
January 2015

Myhre syndrome: a rare craniofacial disorder.

Cranio 2014 Oct 30;32(4):300-6. Epub 2014 Jun 30.

Aims: Myhre syndrome is a rare disorder characterized by abnormal growth of the skeleton, muscles, and joints. The relationship of this syndrome to craniofacial growth and development is unknown. To the authors' knowledge, this is the first Japanese case ever studied.

Methodology: At 10 years and 7 months of age, the patient was referred to the Department of Pediatric Dentistry in the authors' hospital, complaining of a dental problem.

Results: The craniofacial region exhibited a long lower face, high and narrowed palate with submucous cleft palate, maxillary constriction, prognathism, open bite, and crowding of the dental arch. Some of these morphological disorders could be affected by the functional manifestations of muscular hypertrophy of the cheek region, muscle tenseness, or the low position of the tongue. General disorders of muscular hypertrophy, thickened bones, and limited joint mobility are consistent with craniofacial findings of muscle tension in the cheek region, thickened calvarium, and limitation of temporomandibular joint movement. The submucous cleft palate and crown deformation of the mandibular central incisor may be affected by dysfunctions of SMAD4 signaling.

Conclusions: Craniofacial growth and development is affected by the general characteristics of Myhre syndrome, and could be important in its diagnosis.
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http://dx.doi.org/10.1179/0886963413Z.00000000024DOI Listing
October 2014

Overall usefulness of newborn screening for congenital hypothyroidism by using free thyroxine measurement.

Endocr J 2014 2;61(10):1025-30. Epub 2014 Aug 2.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama 232-8555, Japan.

In Kanagawa Prefecture, Japan, simultaneous measurements of free T4 (FT4) and TSH levels are performed during newborn screening for congenital hypothyroidism (CH). FT4 measurement enables the detection of CH of central origin (CH-C), the incidence of which is estimated to be 1 in 30,833 live births in Kanagawa Prefecture. In this study, we aimed to evaluate the efficacy of FT4 screening when transient CH-C and thyroidal CH (CH-T) with delayed TSH elevation are included as screening targets. Data collected on CH-C patients using a regional survey, as well as data from a database created by a screening organization, were used. Of the 24 CH-C patients who had been born in Kanagawa Prefecture between 1999 and 2008, a positive screening result for FT4 (<0.7 ng/dL) was obtained in 13 newborns; of these, 12 were identified solely through newborn screening. Of the 113 patients for whom positive screening results were obtained during the study period, 5 and 6 were found to have transient CH-C and CH-T with delayed TSH elevation, respectively. Remarkably, 4 out of 5 patients with transient CH-C and all patients with CH-T with delayed TSH elevation were diagnosed through the evaluation of low FT4 at screening. These results indicate that the use of this FT4 screening system facilitates the identification of transient CH-C and CH-T with delayed TSH elevation, thus justifying the inclusion of these entities as screening targets.
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http://dx.doi.org/10.1507/endocrj.ej14-0143DOI Listing
June 2015

Discordant genotype-phenotype correlation in familial hyperaldosteronism type III with KCNJ5 gene mutation: a patient report and review of the literature.

Horm Res Paediatr 2014 10;82(2):138-42. Epub 2014 May 10.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

Background: Familial hyperaldosteronism type III (FH-III) is a rare autosomal dominant disease for which five missense mutations in KCNJ5 have been identified. FH-III has a wide phenotypic variability from spironolactone-responsive hyperaldosteronism to massive adrenal hypertrophy with drug-resistant hypertension. This variation has mainly been attributed to genotype, because, in contrast to other genotypes (G151R, T158A, I157S, and Y152C), (1) FH-III patients with G151E have shown milder phenotype, and (2) G151E-harboring cells were found to have rapid lethality due to much larger sodium conductance of the encoded channel (Kir3.4), which prevents adrenal hypertrophy.

Methods: Here we describe the clinical course of a sporadic case of FH-III, with de novo G151R mutation.

Results: The patient developed polyuria at around 1.5 years of age and developed hypertension and hypokalemia by 4 years of age. Thereafter, spironolactone treatment successfully ameliorated hyperaldosteronism for 7 years with no discernible adrenal enlargement.

Conclusion: Diverse clinical severity in FH-III cannot be defined solely by KCNJ5 genotype.
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http://dx.doi.org/10.1159/000358197DOI Listing
May 2015

Neonatal case of classic maple syrup urine disease: usefulness of (1) H-MRS in early diagnosis.

Pediatr Int 2014 Feb;56(1):112-5

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

We describe a male neonate with classic maple syrup urine disease (MSUD) in metabolic crisis. On day 7 of life, he was referred to hospital because of coma and metabolic acidosis with maple syrup odor. On day 4 after admission, brain magnetic resonance imaging findings were consistent with encephalopathy due to MSUD. Proton magnetic resonance spectroscopy ((1) H-MRS) showed a large methyl resonance peak at 0.9 p.p.m. The diagnosis of MSUD was confirmed on low branched-chain α-keto acid dehydrogenase complex activity in lymphocyte. (1) H-MR spectra were obtained in 10 min, while it took at least several days to obtain the results of other diagnostic examinations. In convalescence, the peak at 0.9 p.p.m. decreased. The large methyl resonance peak at 0.9 p.p.m. in brain (1) H-MRS would be one of the earliest clues to the diagnosis of classic MSUD in the neonatal period, especially in metabolic crisis.
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http://dx.doi.org/10.1111/ped.12211DOI Listing
February 2014

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

A novel mutation in SOX2 causes hypogonadotropic hypogonadism with mild ocular malformation.

Horm Res Paediatr 2014 18;81(2):133-8. Epub 2014 Jan 18.

Department of Pediatrics, Keio University School of Medicine Tokyo, Tokyo, Japan.

Background: Heterozygous SOX2 mutations have been reported to cause isolated hypogonadotropic hypogonadism (HH) in addition to ocular and brain abnormalities.

Objective: We report a novel missense SOX2 (Y110C) mutation in an HH patient with mild ocular malformation.

Patients: The 20-year-old male was referred because of typical signs of complete hypogonadism, with small intrascrotal testes (2 ml), no pubic hair (P1), and a micropenis. Hormone assays revealed very low plasma testosterone levels and very low levels of plasma gonadotropin. He was found to have retinal detachment in his right eye and surgery was performed at the age of 14 years.

Results: Using a next-generation sequencing strategy, we identified a novel heterozygous SOX2 mutation, c.329A>G (p.Y110C). Y110C SOX2 had reduced transactivation and no dominant negative effect. Subcellular localization revealed no significant difference between wild-type and mutant SOX2. EMSA experiments showed that the Y110C SOX2 abrogated DNA-binding ability.

Conclusion: The Y110C mutation affects a critical residue in the SOX2 protein. This study extends our understanding of the phenotypic features, molecular mechanism, and developmental course associated with mutations in SOX2. When multiple genes need to be analyzed for mutations simultaneously, targeted sequence analysis of interesting genomic regions is an attractive approach.
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http://dx.doi.org/10.1159/000355279DOI Listing
January 2015

Classic Bartter syndrome complicated with profound growth hormone deficiency: a case report.

J Med Case Rep 2013 Dec 30;7:283. Epub 2013 Dec 30.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4 Minami-ku, Yokohama 232-8555, Japan.

Introduction: Classic Bartter syndrome is a salt-wasting tubulopathy caused by mutations in the CLCNKB (chloride channel Kb) gene. Although growth hormone deficiency has been suggested as a cause for persistent growth failure in patients with classic Bartter syndrome, in our opinion the diagnoses of growth hormone deficiency has been unconvincing in some reports. Moreover, Gitelman syndrome seems to have been confused with Bartter syndrome in some cases in the literature. In the present work, we describe a new case with CLCNKB gene mutations and review the reported cases of classic Bartter syndrome associated with growth hormone deficiency.

Case Presentation: Our patient was a Japanese boy diagnosed as having classic Bartter syndrome at eight months of age. The diagnosis of Bartter syndrome was confirmed by CLCNKB gene analysis, which revealed compound heterozygous mutations with deletion of exons 1 to 3 (derived from his mother) and ΔL130 (derived from his father). His medical therapy consisted of potassium (K), sodium chloride, spironolactone, and anti-inflammatory agents; this regime was started at eight months of age. Our patient was very short (131.1cm, -4.9 standard deviation) at 14.3 years and showed profoundly impaired growth hormone responses to pharmacological stimulants: 0.15μg/L to insulin-induced hypoglycemia and 0.39μg/L to arginine. His growth response to growth hormone therapy was excellent.

Conclusions: The present case strengthens the association between classic Bartter syndrome and growth hormone deficiency. We propose that growth hormone status should be considered while treating children with classic Bartter syndrome.
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http://dx.doi.org/10.1186/1752-1947-7-283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3880170PMC
December 2013

Abnormal adipose tissue distribution with unfavorable metabolic profile in five children following hematopoietic stem cell transplantation: a new etiology for acquired partial lipodystrophy.

Clin Pediatr Endocrinol 2013 Oct 26;22(4):53-64. Epub 2013 Oct 26.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.

We report five consecutive patients who underwent hematopoietic stem cell transplantation (HSCT) to treat leukemia or neuroblastoma early in their lives and later manifested abnormal patterns of adipose tissue distribution. Lipoatrophy was remarkable in the gluteal regions and extremities, whereas subcutaneous fat was preserved in the cheeks, neck, and abdomen. In addition, visceral fat deposition, fatty changes in the liver, and metabolic derangements such as insulin resistance and hypertriglyceridemia were evident. These features resemble Dunnigan-type familial partial lipodystrophy, which is a rare condition caused by LMNA gene mutation. These patients shared a common medical history involving HSCT, including conditioning with total body irradiation (TBI). They also received intensive chemotherapy because of multiple metastases (n = 3), relapse (n = 3), and repetitive HSCT (n = 3). We propose HSCT as a new etiology for acquired partial lipodystrophy and recommend that patients who undergo HSCT with TBI and intensive chemotherapy early in their lives must receive careful observation for the possible development of lipodystrophy and metabolic complications.
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http://dx.doi.org/10.1292/cpe.22.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3809731PMC
October 2013

Association between graves' disease and renal coloboma syndrome: a case report.

Clin Pediatr Endocrinol 2013 Jul 1;22(3):45-51. Epub 2013 Aug 1.

Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Kanagawa, Japan ; Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.

Renal coloboma syndrome is an autosomal dominant condition characterized by renal lesions and optic nerve abnormalities. We report an 11-yr-old Japanese girl with familial renal coloboma syndrome, who also had Graves' disease. Four affected family members had a previously reported heterozygous mutation (c.76dupG, p.Val26Glyfs*28) in the PAX2 gene. We hypothesized that PAX2 mutations may increase the risk of autoimmune diseases through alterations of human β-defensin 1 expression.
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http://dx.doi.org/10.1292/cpe.22.45DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3748283PMC
July 2013

Bone marrow transplantation in Schimke immuno-osseous dysplasia.

Am J Med Genet A 2013 Oct 15;161A(10):2609-13. Epub 2013 Aug 15.

Child and Family Research Institute, Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.

Schimke immuno-osseous dysplasia (SIOD, OMIM 242900) is a rare autosomal recessive multisystem childhood disorder characterized by short stature, renal failure, T-cell immunodeficiency, and hypersensitivity to genotoxic agents. SIOD is associated with biallelic mutations in SMARCAL1 (SWI/SNF-related matrix-associated actin-dependent regulator of chromatin, subfamily a-like 1), which encodes a DNA stress response enzyme with annealing helicase activity. Two features of SIOD causing much morbidity and mortality are bone marrow failure and T-cell deficiency with the consequent opportunistic infections. To address the safety and efficacy of bone marrow transplantation (BMT) in SIOD, we reviewed the outcomes of the only five SIOD patients known to us in whom bone marrow or hematopoietic stem cell transplantation has been attempted. We find that only one patient survived the transplantation procedure and that the existing indicators of a good prognosis for bone marrow transplantation were not predictive in this small cohort. Given these observations, we also discuss some considerations for the poor outcomes.
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http://dx.doi.org/10.1002/ajmg.a.36111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3788057PMC
October 2013
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