Publications by authors named "Kazuhiro Ohkubo"

19 Publications

  • Page 1 of 1

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

Case Rep Oncol 2020 Jan-Apr;13(1):358-364. Epub 2020 Apr 2.

Department of Pediatrics, Ehime University Graduate School of Medicine, Toon, Japan.

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.
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http://dx.doi.org/10.1159/000506044DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7184839PMC
April 2020

Malignant transformation of phosphaturic mesenchymal tumor: a case report and literature review.

Clin Pediatr Endocrinol 2020 16;29(2):69-75. Epub 2020 Apr 16.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Phosphaturic mesenchymal tumor, mixed connective tissue variant (PMT-MCT) causes tumor-induced osteomalacia (TIO). Most cases follow a benign clinical course, with rare occurrences of malignant transformation. We report a case of malignant PMT-MCT and review previous malignant cases to identify predictive factors for transformation. A 13-yr-old female, who presented with hypophosphatemic rickets, elevated serum intact fibroblast growth factor 23 (FGF23) levels, and a nodule in the back, received a diagnosis of TIO because of the benign PMT histopathology. After resection of the primary tumor, regular imaging analyses did not indicate any relapse. At 17 years of age, a tumor developed in the left leg and increased in size. The resected tumor showed a histopathology of pleomorphic sarcoma positive for the mutation. Despite amputation of the affected leg, the patient died due to multiple metastases at 18 years of age. A literature review revealed that 14 out of 15 reported malignant PMT-MCT tumors occurred in adults, and found no predictive factors for malignant transformation and treatment outcome. Changes in size or number of the tumors along with intact FGF23 levels have been considered as the only sign of malignant transformation. This pediatric case report and literature review indicate the need for prolonged regular monitoring for PMT-MCT.
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http://dx.doi.org/10.1297/cpe.29.69DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160461PMC
April 2020

The expanding phenotype of hypokalemic periodic paralysis in a Japanese family with p.Val876Glu mutation in CACNA1S.

Mol Genet Genomic Med 2020 04 27;8(4):e1175. Epub 2020 Feb 27.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Hypokalemic periodic paralysis (HypoPP) is an autosomal dominant disease characterized by the episodic weakness of skeletal muscles and hypokalemia. More than half patients with HypoPP carry mutations in CACNA1S, encoding alpha-1 subunit of calcium channel. Few reports have documented the non-neuromuscular phenotypes of HypoPP.

Methods: The proband is a Japanese woman who developed HypoPP at 6 years of age. An excessive insulin secretion with the oral glucose tolerance test rationalized that she had experienced frequent attacks of paralysis on high-carbohydrate diets.

Results: Voglibose and acetazolamide effectively controlled her paralytic episodes. Her 8-year-old son and 2-year-old daughter started showing the paralytic symptoms from 4 and 2 years of age, respectively. Laboratory tests revealed high concentrations of creatinine kinase in serum and elevated renin activities in plasma of these children. The targeted sequencing confirmed that these three patients had an identical heterozygous mutation (p.V876E) in CACNA1S.

Conclusion: Our data indicate that the p.V876E mutation in CACNA1S contributes to the early onset of neuromuscular symptoms and unusual clinical phenotypes of HypoPP.
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http://dx.doi.org/10.1002/mgg3.1175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196457PMC
April 2020

Clinical Features, Molecular Genetics, and Long-Term Outcome in Congenital Chloride Diarrhea: A Nationwide Study in Japan.

J Pediatr 2019 11 30;214:151-157.e6. Epub 2019 Aug 30.

Department of Medical Biochemistry, Kurume University School of Medicine, Kurume, Japan.

Objective: To clarify clinical and genetic features of Japanese children with congenital chloride diarrhea (CCD).

Study Design: This was a multi-institutional, retrospective survey of 616 pediatric centers in Japan with identified patients with CCD between 2014 and 2018. Mutations involving SLC26A3 were detected by Sanger sequencing.

Results: Thirteen patients met all entry criteria including mutations in SLC26A3, and 14 patients satisfied clinical diagnostic criteria. Homozygous or compound heterozygous mutations in SLC26A3, including 6 novel mutations, were identified in 13 of these 14 patients (93%). The most common (detected in 7 of 13) was c.2063-1g>t. Median age at diagnosis was 1 day. Nine of the patients meeting all criteria were diagnosed as neonates (69%). Median follow-up duration was 10 years. When studied, 8 patients had <5 stools daily (62%), and all had fewer than in infancy. Only 1 patient had nephrocalcinosis, and 3 (23%) had mild chronic kidney disease. Neurodevelopment was generally good; only 1 patient required special education. Five patients (38%) received long-term sodium, potassium, and chloride supplementation.

Conclusions: Early fetal ultrasound diagnosis and prompt long-term sodium, potassium, and chloride supplementation were common management features. Genetic analysis of SLC26A3 provided definitive diagnosis of CCD. In contrast with previously reported localities, c.2063-1g>t might be a founder mutation in East Asia.
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http://dx.doi.org/10.1016/j.jpeds.2019.07.039DOI Listing
November 2019

A Child with Prostaglandin I-associated Thyrotoxicosis: Case Report

J Clin Res Pediatr Endocrinol 2019 05 16;11(2):207-210. Epub 2018 Oct 16.

Kyushu University Graduate School of Medical Sciences, Department of Pediatrics, Fukuoka, Japan

Prostaglandin I (PGI) causes hyperthyroidism, a critical complication in patients with pulmonary arterial hypertension (PAH). However, it remains unknown whether PGI may have unfavorable effects on thyroid function in children with congenital portosystemic venous shunt syndrome (CPSVS). We present a boy with CPSVS who developed PAH at seven years of age. During ongoing PGI therapy, he experienced thyrotoxicosis at 17 years of age. The literature review showed that the reported 12 patients with PAH (median 11 years of age) developed hyperthyroidism during between one and 11 years of PGI treatment. Only one patient survived the acute PAH crisis due to hyperthyroidism. These data provide evidence that prophylactic intervention for hyperthyroidism is indicated for children with CPSVS during PGI treatment.
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http://dx.doi.org/10.4274/jcrpe.galenos.2018.2018.0169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6571540PMC
May 2019

Vascular pathomechanism in acute encephalopathy with biphasic seizures and late reduced diffusion.

J Neurol Sci 2018 12 3;395:141-146. Epub 2018 Oct 3.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a childhood-onset encephalopathy, but the precise pathophysiology remains unclear. We encountered a child with Moyamoya syndrome and AESD. He exhibited left-predominant stenosis of the middle cerebral artery (MCA), and later developed broad lesions in the left hemisphere, raising the possibility that insufficient blood supply relates to formation of the lesions. To test the hypothesis, we investigated the relationship between MCA volume and lesion extent in seven AESD children without preexisting diseases. The MCA volume and lesion extent were quantified with time of flight images for construction of magnetic resonance angiography and apparent diffusion coefficient maps, respectively. Lateralization indices ([right - left]/[right + left]) of the MCA volume and lesion extent were calculated. We found that the lateralization indices were negatively correlated (r = -0.786, p = .036), that is, when the MCA volume was smaller in one side than the other side, the lesions were likely to develop more extensively in the ipsilateral side than the contralateral side. This indicates the association of insufficient blood supply with the lesions. The present study provides the first observation to suggest the involvement of vascular mechanism in AESD and has potential implications for novel therapeutic approach.
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http://dx.doi.org/10.1016/j.jns.2018.10.007DOI Listing
December 2018

A male case with CDKL5-associated encephalopathy manifesting transient methylmalonic acidemia.

Eur J Med Genet 2018 Aug 3;61(8):451-454. Epub 2018 Mar 3.

Departments of Pediatric, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Mutations in the X-linked gene CDKL5 cause early-onset epileptic encephalopathy and severe developmental delay. Because this disorder predominantly affects females, the full clinical spectrum of male patients remains elusive. We herein report a 16-year-old boy, who suffered from intractable seizures 20 days after birth. Serial electroencephalograms detected recurrent focal epileptiform discharges from age 4 months, which evolved to hypsarrhythmia later in infancy. Mass-spectrometric analyses revealed increase in urinary excretion of methylmalonic acid without perturbed concentrations of propionic acid, homocystein and methionine. Whole-exome sequencing identified a de novo, truncating mutation in CDKL5 (NM_003159.2:c.419dupA, p.Asn140Lysfs*8). Targeted sequencing excluded concomitant mutations in methylmalonic academia-associated genes. No methylmalonic acidemia has been reported in children with CDKL5 disorder. Extensive analyses on organic acid metabolism for males with CDKL5 mutations will gain more insight into their biochemical profiles in infancy.
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http://dx.doi.org/10.1016/j.ejmg.2018.03.003DOI Listing
August 2018

Effective shunt closure for pulmonary hypertension and liver dysfunction in congenital portosystemic venous shunt.

Pediatr Pulmonol 2018 04 23;53(4):505-511. Epub 2018 Jan 23.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Objective: Congenital portosystemic venous shunt (CPSVS) is a rare vascular malformation with a high risk of mortality from pulmonary arterial hypertension (PAH), but the treatment outcome of CPSVS closure remains elusive. Our aim was to investigate the clinical features and establish the optimal management of CPSVS with or without PAH.

Methods: Twenty-four patients with CPSVS treated in Kyushu University Hospital between 1990 and 2015 were enrolled in this study. The patients were divided into a PAH group (n = 9) and a non-PAH group (n = 15). Clinical characteristics and outcomes were evaluated.

Results: The first manifestation of CPSVS at diagnosis (28.5 [1-216] months) was hypergalactosemia in 13 (54%) or PAH in six (25%) patients. PAH was the cause of all three deaths. The PAH group had higher levels of serum total bile acid, manganese, and total bilirubin, along with higher pulmonary vascular resistance index (PVRI) than the non-PAH group (7.2 [5.1-38.1] vs 1.2 [0.5-3.3] unit/m , P < 0.001). Five of nine PAH patients underwent CPSVS closure at a median of 38 months (range 21-118) after PAH diagnosis. Pulmonary artery pressure improved after CPSVS closure with PAH-specific therapy, but normal range was not achieved. CPSVS closure improved the hepatic synthetic function of four PAH patients. Eigh-t of 15 non-PAH patients who received CPSVS closure did not develop PAH for a median of 34.5 months (range 6-164) after the procedure.

Conclusions: CPSVS closure with PAH-specific therapy successfully controlled PAH. Early CPSVS closure may prevent the occurrence and progression of PAH with CPSVS.
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http://dx.doi.org/10.1002/ppul.23944DOI Listing
April 2018

Reappraising newborn screening for cobalamin C disorder.

Pediatr Neonatol 2018 08 22;59(4):415-417. Epub 2017 Nov 22.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

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http://dx.doi.org/10.1016/j.pedneo.2017.11.002DOI Listing
August 2018

Sustained endocrine profiles of a girl with WAGR syndrome.

BMC Med Genet 2017 10 23;18(1):117. Epub 2017 Oct 23.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.

Background: Wilms tumor, aniridia, genitourinary anomalies and mental retardation (WAGR) syndrome is a rare genetic disorder caused by heterozygous deletions of WT1 and PAX6 at chromosome 11p13. Deletion of BDNF is known eto be associated with hyperphagia and obesity in both humans and animal models; however, neuroendocrine and epigenetic profiles of individuals with WAGR syndrome remain to be determined.

Case Presentation: We report a 5-year-old girl with the typical phenotype of WAGR syndrome. She showed profound delays in physical growth, motor and cognitive development without signs of obesity. Array comparative genome hybridization (CGH) revealed that she carried a 14.4 Mb deletion at 11p14.3p12, encompassing the WT1, PAX6 and BDNF genes. She experienced recurrent hypoglycemic episodes at 5 years of age. Insulin tolerance and hormonal loading tests showed normal hypothalamic responses to the hypoglycemic condition and other stimulations. Methylation analysis for freshly prepared DNA from peripheral lymphocytes using the pyro-sequencing-based system showed normal patterns of methylation at known imprinting control regions.

Conclusions: Children with WAGR syndrome may manifest profound delay in postnatal growth through unknown mechanisms. Epigenetic factors and growth-associated genes in WAGR syndrome remain to be characterized.
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http://dx.doi.org/10.1186/s12881-017-0477-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5654094PMC
October 2017

Comprehensive screening for monogenic diabetes in 89 Japanese children with insulin-requiring antibody-negative type 1 diabetes.

Pediatr Diabetes 2018 03 9;19(2):243-250. Epub 2017 Jun 9.

Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.

Background: Mutations in causative genes for neonatal diabetes or maturity-onset diabetes of the young have been identified in multiple patients with autoantibody-negative type 1 diabetes (T1D).

Objectives: We aimed to clarify the prevalence and phenotypic characteristics of monogenic abnormalities among 89 children with autoantibody-negative insulin-requiring T1D.

Methods: Mutations in 30 genes were screened using next-generation sequencing, and copy-number alterations of 4 major causative genes were examined using multiplex-ligation-dependent probe amplification. We compared the clinical characteristics between mutation carriers and non-carriers.

Results: We identified 11 probable pathogenic substitutions (6 in INS , 2 in HNF1A , 2 in HNF4A , and 1 in HNF1B ) in 11 cases, but no copy-number abnormalities. Only 2 mutation carriers had affected parents. De novo occurrence was confirmed for 3 mutations. The non-carrier group, but not the carrier group, was enriched with susceptible HLA alleles. Mutation carriers exhibited comparable phenotypes to those of non-carriers, except for a relatively normal body mass index (BMI) at diagnosis.

Conclusions: This study demonstrated significant genetic overlap between autoantibody-negative T1D and monogenic diabetes. Mutations in INS and HNF genes, but not those in GCK and other monogenic diabetes genes, likely play critical roles in children with insulin-requiring T1D. This study also suggests the relatively high de novo rates of INS and HNF mutations, and the etiological link between autoimmune abnormalities and T1D in the non-carrier group. Carriers of monogenic mutations show non-specific phenotypes among all T1D cases, although they are more likely to have a normal BMI at diagnosis than non-carriers.
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http://dx.doi.org/10.1111/pedi.12544DOI Listing
March 2018

Hyperinsulinemic hypoglycemia in Beckwith-Wiedemann, Sotos, and Kabuki syndromes: A nationwide survey in Japan.

Am J Med Genet A 2017 Feb 7;173(2):360-367. Epub 2016 Nov 7.

Department of Pediatrics, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Beckwith-Wiedemann syndrome (BWS) is a congenital overgrowth syndrome that is occasionally associated with hyperinsulinemic hypoglycemia (HH) in the neonatal period. Sotos syndrome (SS) and Kabuki syndrome (KS) are other malformation syndromes that may be complicated with HH, however, the detailed clinical characteristics of HH accompanied with these syndromes remain unclear. We herein conducted a nationwide questionnaire survey in Japan. We sent a primary questionnaire concerning the clinical experience for these syndromes to 347 perinatal care institutions. As a result, 222 departments or hospitals returned the questionnaires and the total numbers of BWS, SS, and KS patients were 113, 88, and 51, respectively. We sent a secondary questionnaire to 31 institutions where patients with these syndromes presented with HH during infancy. The secondary questionnaires were returned from the institutions and the numbers of patients were 16 for BWS, 9 for SS, and 3 for KS, respectively. Then, we compared the clinical characteristics of infants suffering from transient HH with and without these dysmorphic syndromes. As a result, BWS, SS, and KS patients showed significantly larger body size, lower Apgar scores, higher insulin levels at HH, and shorter durations of HH than non-dysmorphic infants with transient HH. We propose that a careful observation for the signs of HH, even if not specific to the syndromes, is important for the diagnosis of patients with BWS, SS, and KS in the postnatal period. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38011DOI Listing
February 2017

Resolution of Hydronephrosis in a Patient With Mucopolysaccharidosis Type II With Enzyme Replacement Therapy.

Urology 2017 Mar 20;101:163-165. Epub 2016 Dec 20.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan; Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Higashi-ku, Fukuoka, Japan.

Mucopolysaccharidosis type II (MPS II) is caused by deficiency of lysosomal enzyme iduronate-2-sulfatase. Insufficient activity of the enzyme results in accumulation of glycosaminoglycans leading to progressive multisystem pathologies. MPS II is less likely to be complicated by kidney and urinary tract problems. We report a boy with MPS II, who developed left hydronephrosis. His hydronephrosis improved after starting enzyme replacement therapy. It was suggested that MPS II was closely associated with the pathogenesis of hydronephrosis.
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http://dx.doi.org/10.1016/j.urology.2016.12.010DOI Listing
March 2017

Moyamoya disease susceptibility gene RNF213 links inflammatory and angiogenic signals in endothelial cells.

Sci Rep 2015 Aug 17;5:13191. Epub 2015 Aug 17.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.

Moyamoya disease (MMD) is a cerebrovascular disorder characterized by occlusive lesions of the circle of Willis. To date, both environmental and genetic factors have been implicated for pathogenesis of MMD. Allelic variations in RNF213 are known to confer the risk of MMD; however, functional roles of RNF213 remain to be largely elusive. We herein report that pro-inflammatory cytokines, IFNG and TNFA, synergistically activated transcription of RNF213 both in vitro and in vivo. Using various chemical inhibitors, we found that AKT and PKR pathways contributed to the transcriptional activation of RNF213. Transcriptome-wide analysis and subsequent validation with quantitative PCR supported that endogenous expression of cell cycle-promoting genes were significantly decreased with knockdown of RNF213 in cultured endothelial cells. Consistently, these cells showed less proliferative and less angiogenic profiles. Chemical inhibitors for AKT (LY294002) and PKR (C16) disrupted their angiogenic potentials, suggesting that RNF213 and its upstream pathways cooperatively organize the process of angiogenesis. Furthermore, RNF213 down-regulated expressions of matrix metalloproteases in endothelial cells, but not in fibroblasts or other cell types. Altogether, our data illustrate that RNF213 plays unique roles in endothelial cells for proper gene expressions in response to inflammatory signals from environments.
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http://dx.doi.org/10.1038/srep13191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4538604PMC
August 2015

Thyroid Follicular Carcinoma in a Fourteen-year-old Girl with Graves' Disease.

Clin Pediatr Endocrinol 2014 Apr 20;23(2):59-64. Epub 2014 Apr 20.

Department of Pediatrics, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan.

Here we present the case of a 14-yr-old girl who developed thyroid follicular carcinoma accompanied by Graves' disease. She was diagnosed with Graves' disease at 10 yr of age and soon achieved a euthyroid state after starting treatment. When she was 13 yr of age, her hyperthyroidism and goiter worsened despite medical therapy. Multiple nodules were found in her enlarged thyroid gland by ultrasonography. Her serum Tg level seemed within the normal range. She underwent near-total thyroidectomy for control of thyroid function. Histopathological study demonstrated that multiple oxyphilic follicular neoplasms were surrounded by the thyroid tissue compatible with Graves' disease. Capsular invasion was identified in one of the nodules, and thus the histological diagnosis was minimally invasive follicular carcinoma. She did not have signs suggesting metastasis, and has had no relapse for 18 mo after the operation. Although some previous studies showed a high prevalence of thyroid cancer with an aggressive nature in adult patients with Graves' disease, few reports about thyroid cancer accompanied by Graves' disease are available in children. The present case, however, suggests that careful investigation is needed when we detect thyroid nodules or progressive thyroid enlargement, especially in children with Graves' disease.
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http://dx.doi.org/10.1297/cpe.23.59DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4004999PMC
April 2014

Neuroendocrine phenotypes in a boy with 5q14 deletion syndrome implicate the regulatory roles of myocyte-specific enhancer factor 2C in the postnatal hypothalamus.

Eur J Med Genet 2013 Sep 5;56(9):475-83. Epub 2013 Jul 5.

Department of Pediatrics, Kyushu University Hospital, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. Electronic address:

The 5q14.3 deletion syndrome is a rare chromosomal disorder characterized by moderate to severe intellectual disability, seizures and dysmorphic features. We report a 14-year-old boy with 5q14.3 deletion syndrome who carried a heterozygous deletion of the myocyte-specific enhancer factor 2c (MEF2C) gene. In addition to the typical neurodevelopmental features of 5q14.3 deletion syndrome, he showed recurrent hypoglycemia, appetite loss and hypothermia. Hormonal loading tests using insulin, arginine and growth hormone-releasing factor revealed that growth hormone was insufficiently released into serum in response to these stimuli, thus disclosing the hypothalamic dysfunction in the present case. To uncover the biological roles of MEF2C in the hypothalamus, we studied its expression in the postnatal mouse brain. Notably, neuropeptide Y (NPY)-positive interneurons in the hypothalamic arcuate nuclei highly expressed MEF2C. In contrast, the Rett syndrome-associated protein, Methyl-CpG binding Protein 2 (MECP2) was barely expressed in these neurons. MEF2C knockdown or overexpression experiments using Neuro2a cells revealed that MEF2C activated the endogenous transcription of NPY. Conversely, siRNA-mediated knockdown of MECP2 led to derepression of the Npy gene. These data support the concept that MEF2C and MECP2 share common molecular pathways regulating the homeostatic expression of NPY in the adult hypothalamus. We propose that individuals with 5q14.3 deletion syndrome may exhibit neuroendocrine phenotypes through the functional loss of MEF2C in the postnatal hypothalamus.
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http://dx.doi.org/10.1016/j.ejmg.2013.06.009DOI Listing
September 2013

Hypothyroidism and levothyroxine-responsive liver dysfunction in a patient with ring chromosome 18 syndrome.

Thyroid 2012 Oct 4;22(10):1080-3. Epub 2012 Sep 4.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background: Ring chromosome 18 [r18] is a rare constitutional chromosomal aberration syndrome, characterized by dysmorphic face, hypoactivity, short stature, and delayed development. Autoimmune thyroiditis and immunoglobulin (Ig) A deficiency are occasionally associated with chromosome-18 deletion syndromes.

Summary: Here, we report a 2-year-old male child with r(18) syndrome and a selective IgA deficiency (<1.6 mg/dL, reference range [rr]: 20-149), who developed hypothyroidism and liver dysfunction. Thyroid function tests (thyroid-stimulating hormone [TSH]: 1031 μIU/mL, rr 0.43-4.0; free triiodothyronine: 0.52 pg/mL, rr 2.37-4.65; free thyroxine: 0.11 ng/dL, rr 1.03-2.00) and positive thyroid antibodies (anti-TSH receptor 1.7 IU/L, cut-off index [coi]: <1.0, antithyroid peroxidase 171 IU/mL, coi <0.3, and antithyroglobulin 2.8 IU/mL, coi <0.3) indicated autoimmune hypothyroidism. Elevated levels of aspartate aminotransferase (AST, 240 IU/L, rr 17-39) and alanine aminotransferase (ALT, 315 IU/L, rr 4-23), but negative antibodies against LKM and mitochondrial M2, suggested no autoimmune hepatitis. Transaminase levels became normalized after he was given levothyroxine therapy to achieve the euthyroid state, but they repeatedly became elevated when levothyroxine was inadvertently discontinued (peak AST=409 IU/L; peak ALT=390 IU/L). A maintenance dose of levothyroxine has effectively maintained the euthyroid state and normalized liver function tests despite no immunosuppressive therapy.

Conclusions: The r18 patient with autoimmune hypothyroidism and IgA deficiency suffered from idiopathic hepatitis. The liver dysfunction was associated with hypothyroidism that resolved with thyroid hormone treatment. While the former combination has been described, the latter has not. The reason for the development of hepatitis in association with hypothyroidism is unexplained. However, we postulate that it might be related, in ways that are not clear, to the deleted genes of r18.
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http://dx.doi.org/10.1089/thy.2011.0521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3462387PMC
October 2012

The signal transducer and activator of transcription 5B gene polymorphism contributes to the cholesterol metabolism in Japanese children with growth hormone deficiency.

Clin Endocrinol (Oxf) 2011 May;74(5):611-7

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Background And Aims: GH plays a significant role in the lipid metabolism. In this study, we focused on the JAK2 - signal transducer and activator of the transcription 5 (STAT5) pathway, which transmit the signals from the GH receptor, and selected the STAT5A/B gene as a candidate for the regulation of lipid metabolism in GH deficiency (GHD).

Design And Participants: The study population comprised 83 children with idiopathic GHD. The serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and the non-HDL cholesterol (non-HDL-C) levels were monitored before and at 3, 6, 9 and 12 months after starting GH treatment. The height, weight, body mass index, and serum insulin-like growth factor-I (IGF-I) level were also measured before and 12 months after starting the GH treatment. For the genetic analysis of the STAT5A/B gene, five tag SNPs were selected using the tag SNP picker programme on the homepage of the HapMap project. The evaluation of promoter activity of the -44816A/G SNP in the STAT5B gene was performed by a luciferase assay in vitro.

Results: The TC and non-HDL-C levels were gradually decreased during the GH treatment. Five tag SNPs (rs4029774, rs6503691, rs9900213, rs16967637 and rs2272087) were picked up for the STAT5A/B gene, and the genetic study demonstrated that the paediatric GHD patients who were heterozygotes or homozygotes of minor alleles of the analysed SNPs in the same block of the STAT5B gene showed significantly higher serum TC or non-HDL-C levels both before and after GH treatment for 12 months. Most of the SNPs also demonstrated significant differences among genotypes in the decreases in serum TC or non-HDL-C levels during the 12 months of GH treatment. A luciferase assay showed that the -44816A/G SNP (rs4029774) in the STAT5B gene functionally affected the expression level in vitro.

Conclusion: These results indicate that STAT5B may therefore play a role in regulating the cholesterol metabolism in children with GHD.
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http://dx.doi.org/10.1111/j.1365-2265.2011.03980.xDOI Listing
May 2011

Nephrolithiasis as an extra-intestinal presentation of pediatric inflammatory bowel disease unclassified.

J Crohns Colitis 2010 Dec 30;4(6):674-8. Epub 2010 Jun 30.

Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.

Urolithiasis is quite rare in pediatric inflammatory bowel disease (IBD) compared with the incidence at 9-18% in adult cases. The diagnosis and treatment of pediatric IBD is challenging. Indeterminate colitis (IC), originally proposed as a subgroup of fulminant IBD, has also been used for patients when the diagnosis of either UC or CD cannot be made with certainty. Such patients should be diagnosed as having "IBD unclassified" based on evidence including mucosal biopsy samples. We report herewith a 9-year-old boy with isolated colitis that reached a diagnosis of IBD unclassified. Infliximab therapy led to a successful remission after the refractory course. However, urolithiases were impacted in the urethral valves and vesico-ureteral junction. Microhematuria was noticed from the onset of colitis. Renal calculi were detected on the X-ray films during the first line treatment. Transurethrally crushed stones consisted of calcium oxalate. Renal calculi are more closely associated with CD than ulcerative colitis in adult patients for the ileal involvement. The oxalate stones and treatment response indicated a CD-like pathophysiology. Nephrolithiasis might be a rare but noticeable extra-intestinal presentation of pediatric IBD. Infliximab therapy could be an option in pediatric refractory colitis to change the critical steroid dependency.
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http://dx.doi.org/10.1016/j.crohns.2010.05.012DOI Listing
December 2010