Publications by authors named "Sumito Dateki"

39 Publications

Compound heterozygous variants in the gene in a Japanese girl with sitosterolemia.

Hum Genome Var 2020 14;7:25. Epub 2020 Sep 14.

Department of Pediatrics, National Hospital Organization Tokyo Medical Center, Tokyo, Japan.

Sitosterolemia is an autosomal recessive disorder that affects lipid metabolism and is characterized by elevated serum plant sterol levels, xanthomas, and accelerated atherosclerosis. In this study, we report a novel nonsense single-nucleotide variant, c.225G > A (p.Trp75*), and an East Asian population-specific missense multiple-nucleotide variant, c.1256_1257delTCinsAA (p.Ile419Lys), in the gene in a compound heterozygous state observed in a Japanese girl with sitosterolemia.
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http://dx.doi.org/10.1038/s41439-020-00112-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7490419PMC
September 2020

Screening for imprinting disorders in 58 patients with clinically diagnosed idiopathic short stature.

J Pediatr Endocrinol Metab 2020 Aug 31;33(10):1335-1339. Epub 2020 Aug 31.

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

Objectives Imprinted genes have important roles for normal growth and development. Imprinting disorders (IDs) such as Silver-Russell syndrome and Temple syndrome are rare diseases that typically cause short children born small for gestational age (SGA). However, some patients with short stature (SS) caused by IDs were born non-SGA. To date, the contribution of IDs to idiopathic short stature (ISS) has been poorly investigated. The aim of this study was to clarify the contribution of IDs to ISS. Methods We conducted methylation analysis for 10 differentially methylated regions using pyrosequencing to detect known IDs in 58 patients (31 male and 27 female children, height standard deviation score -4.2 to -2.0) carrying a clinical diagnosis of ISS. Results We identified no patient with IDs among these patients with ISS. Conclusions These results indicate that IDs are rare in patients having ISS, and that imprinted genes affect fetal growth more than postnatal growth. Because patients with IDs born non-SGA usually have clinical features characteristic of each ID, in addition to SS, the patients with ISS as a clinical diagnosis may not be associated with IDs. It is unlikely that cases clinically diagnosed with ISS are caused by IDs leading to growth failure.
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http://dx.doi.org/10.1515/jpem-2020-0198DOI Listing
August 2020

Efficacy and safety of denosumab treatment in a prepubertal patient with cherubism.

J Pediatr Endocrinol Metab 2020 Jul;33(7):963-966

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

Background Denosumab is an inhibitor of receptor activator of nuclear factor kappa-B ligand, which strongly suppresses osteoclasts. Cherubism is a rare autosomal dominant disorder characterized by symmetrical swelling of the jaws, in which the bone is replaced by a fibrous granuloma containing osteoclast-like giant cells. Case presentation We report the efficacy and safety of denosumab treatment in a prepubertal boy with progressive cherubism. The treatment consisting of eight subcutaneous denosumab injections (120 mg/dose) in 6 months not only suppressed the expansion of the osteolytic lesions but also dramatically ossified them. However, a transiently decreased growth rate and rebounded asymptomatic hypercalcemia were associated with the treatment. Conclusions The present case demonstrated the therapeutic potential of denosumab for treatment of cherubism, although adverse effects, especially those on childhood growth, remain obscure. Further studies are needed to establish a safe and effective protocol for denosumab treatment of children.
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http://dx.doi.org/10.1515/jpem-2019-0581DOI Listing
July 2020

A case of ezetimibe-effective hypercholesterolemia with a novel heterozygous variant in ABCG5.

Endocr J 2020 Nov 9;67(11):1099-1105. Epub 2020 Jul 9.

Department of Molecular Endocrinology and Metabolism, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo 113-8519, Japan.

Sitosterolemia is caused by homozygous or compound heterozygous gene mutations in either ATP-binding cassette subfamily G member 5 (ABCG5) or 8 (ABCG8). Since ABCG5 and ABCG8 play pivotal roles in the excretion of neutral sterols into feces and bile, patients with sitosterolemia present elevated levels of serum plant sterols and in some cases also hypercholesterolemia. A 48-year-old woman was referred to our hospital for hypercholesterolemia. She had been misdiagnosed with familial hypercholesterolemia at the age of 20 and her serum low-density lipoprotein cholesterol (LDL-C) levels had remained about 200-300 mg/dL at the former clinic. Although the treatment of hydroxymethylglutaryl-CoA (HMG-CoA) reductase inhibitors was ineffective, her serum LDL-C levels were normalized by ezetimibe, a cholesterol transporter inhibitor. We noticed that her serum sitosterol and campesterol levels were relatively high. Targeted analysis sequencing identified a novel heterozygous ABCG5 variant (c.203A>T; p.Ile68Asn) in the patient, whereas no mutations were found in low-density lipoprotein receptor (LDLR), proprotein convertase subtilisin/kexin type 9 (PCSK9), or Niemann-Pick C1-like intracellular cholesterol transporter 1 (NPC1L1). While sitosterolemia is a rare disease, a recent study has reported that the incidence of loss-of-function mutation in the ABCG5 or ABCG8 gene is higher than we thought at 1 in 220 individuals. The present case suggests that serum plant sterol levels should be examined and ezetimibe treatment should be considered in patients with hypercholesterolemia who are resistant to HMG-CoA reductase inhibitors.
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http://dx.doi.org/10.1507/endocrj.EJ20-0044DOI Listing
November 2020

-related disorder in a patient with a novel frameshift variant (c.3925dup).

Hum Genome Var 2019 13;6:54. Epub 2019 Dec 13.

3Departments of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Heterozygous pathogenic variants in the gene, which encodes lysine acetyltransferase 6B, have been identified in patients with congenital rare disorders, including genitopatellar syndrome and Say-Barber-Biesecker-Young-Simpson syndrome. Herein, we report another Japanese patient with a -related disorder and a novel de novo heterozygous variant in exon 18 of [c.3925dup, p.(Glu1309fs*33)], providing further evidence that truncating variants in exon 17 and in the proximal region of exon 18 are associated with genitopatellar syndrome-like phenotypes.
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http://dx.doi.org/10.1038/s41439-019-0085-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911078PMC
December 2019

Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients.

J Hum Genet 2019 Dec 17;64(12):1173-1186. Epub 2019 Sep 17.

Asahikawa-Kosei General Hospital, Hokkaido, Japan.

Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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http://dx.doi.org/10.1038/s10038-019-0667-4DOI Listing
December 2019

Identification of a homozygous frameshift variant in RFLNA in a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome.

J Hum Genet 2019 May 22;64(5):467-471. Epub 2019 Feb 22.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Spondylocarpotarsal synostosis syndrome, a rare syndromic skeletal disorder characterized by disrupted vertebral segmentation with vertebral fusion, scoliosis, short stature, and carpal/tarsal synostosis, has been associated with biallelic truncating mutations in the filamin B gene or monoallelic mutations in the myosin heavy chain 3 gene. We herein report the case of a patient with a typical phenotype of spondylocarpotarsal synostosis syndrome who had a homozygous frameshift mutation in the refilin A gene (RFLNA) [c.241delC, p.(Leu81Cysfs*111)], which encodes one of the filamin-binding proteins. Refilins, filamins, and myosins play critical roles in forming perinuclear actin caps, which change the nuclear morphology during cell migration and differentiation. The present study implies that RFLNA is an additional causative gene for spondylocarpotarsal synostosis syndrome in humans and a defect in forming actin bundles and perinuclear actin caps may be a critical mechanism for the development of spondylocarpotarsal synostosis syndrome.
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http://dx.doi.org/10.1038/s10038-019-0581-9DOI Listing
May 2019

A homozygous splice site ROBO1 mutation in a patient with a novel syndrome with combined pituitary hormone deficiency.

J Hum Genet 2019 Apr 28;64(4):341-346. Epub 2019 Jan 28.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, 852-8501, Japan.

The genetic causes of combined pituitary hormone deficiency remain elusive in most patients. Recently, incompletely penetrant heterozygous mutations in ROBO1 have been described in patients with pituitary stalk interruption syndrome. Herein, we identified a novel homozygous slice site mutation in ROBO1 (c.1342+1G>A) using a trio whole-exome sequencing strategy in a 5-year-old Japanese boy who had combined pituitary hormone deficiency, psychomotor developmental delay, severe intellectual disability, sensorineural hearing loss, strabismus, and characteristic facial features, including a broad forehead, micrognathia, and arched eyebrows. Magnetic resonance imaging delineated anterior pituitary hypoplasia, ectopic posterior pituitary, invisible pituitary stalk, thinning of the corpus callosum, and hypoplasia of the pons and midbrain. The phenotypically normal parents (first cousins) were heterozygous for the mutation. The results provide further evidence of ROBO1 being involved in the development of the pituitary gland. A recessive mutation of ROBO1 is a potential novel cause of a syndromic disorder associated with combined pituitary hormone deficiency.
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http://dx.doi.org/10.1038/s10038-019-0566-8DOI Listing
April 2019

Language delay and developmental catch-up would be a clinical feature of pseudohypoparathyroidism type 1A during childhood.

Endocr J 2019 Mar 23;66(3):215-221. Epub 2019 Jan 23.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

Pseudohypoparathyroidism type 1A (PHP1A) is characterized by resistance to multiple hormones, the Albright Hereditary Osteodystrophy phenotype, obesity, and developmental delay. Developmental delay usually appears prior to hypocalcemia due to parathyroid hormone resistance and could be a clinically important feature for early diagnosis of PHP1A. To date, however, the details have not been documented. With regard to developmental delays, we conducted a multicenter retrospective study of 22 PHP1A patients from 18 families who were diagnosed clinically or genetically from 2005 to 2015. For quantitative analysis of their development, we calculated the ratios of the milestone ages of the patients to those in normal reference data. The ratio of the ages with respect to speech development, i.e., speaking a first meaningful word (median: 1.67), was significantly higher than that for gross motor development, walking unassisted (median: 1.34). The ratio of age at stringing a two-word sentence (median: 1.32) was significantly lower than that of saying a first word (median: 1.84). Ten out of 11 (91%) patients exhibited two or three of the following clinical phenotypes: developmental delay, obesity, and hyperthyrotropinemia. These results suggest two possible clinical features of developmental delays in PHP1A patients: developmental delay is more obvious in speech acquisition than in gross motor skills, and speech delays could be attenuated during later childhood. Further, the presence of multiple of three clinical symptoms could be an important indicator to differentiate the diagnosis of PHP1A during early childhood.
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http://dx.doi.org/10.1507/endocrj.EJ18-0326DOI Listing
March 2019

Clinical characteristics of adolescent cases with Type A insulin resistance syndrome caused by heterozygous mutations in the β-subunit of the insulin receptor (INSR) gene.

J Diabetes 2019 Jan 4;11(1):46-54. Epub 2018 Jul 4.

Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.

Background: Type A insulin resistance (IR) is a rare form of severe congenital IR that is frequently caused by heterozygous mutations in the insulin receptor (INSR) gene. Although Type A IR requires appropriate intervention from the early stages of diabetes, proper diagnosis of this disease is challenging, and accumulation of cases with detailed clinical profiles and genotypes is required.

Methods: Herein we report on six peripubertal patients with clinically diagnosed Type A IR, including four patients with an identified INSR mutation. To clarify the clinical features of Type A IR due to INSR mutation, we validated the clinical characteristics of Type A IR patients with identified INSR mutations by comparing them with mutation-negative patients.

Results: Four heterozygous missense mutations within the β-subunit of INSR were detected: Gly1146Arg, Arg1158Trp, Arg1201Trp, and one novel Arg1201Pro mutation. There were no obvious differences in clinical phenotypes, except for normal lipid metabolism and autosomal dominant inheritance, between Type A IR due to INSR mutations and Type A IR due to other factors. However, our analysis revealed that the extent of growth retardation during the fetal period is correlated with the severity of insulin signaling impairment.

Conclusions: The present study details the clinical features of four patients with genetically proven Type A IR. Further accumulation of genetically proven cases and long-term treatment prognoses following early diagnosis are required to further elucidate the dynamics of this disease.
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http://dx.doi.org/10.1111/1753-0407.12797DOI Listing
January 2019

Novel compound heterozygous variants in the gene in a patient with Alazami syndrome.

Hum Genome Var 2018 29;5:18014. Epub 2018 Mar 29.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

The gene encodes a chaperone protein of the noncoding RNA 75 K, and mutations in this gene have been identified in patients with Alazami syndrome. Herein, we report another Japanese patient with Alazami syndrome and novel compound heterozygous variants in (i.e., c.370delG, p.Glu124fs*38 and c.641_667+25del involving the splice donor site of intron 8). These findings provide further evidence that biallelic LARP7 defects cause the phenotype of Alazami syndrome.
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http://dx.doi.org/10.1038/hgv.2018.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874394PMC
March 2018

A hot-spot mutation in CDC42 (p.Tyr64Cys) and novel phenotypes in the third patient with Takenouchi-Kosaki syndrome.

J Hum Genet 2018 Mar 15;63(3):387-390. Epub 2018 Jan 15.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Takenouchi-Kosaki syndrome (TKS) is a congenital malformation syndrome characterized by severe developmental delay, macrothrombocytopenia, camptodactyly, sensorineural hearing loss, and dysmorphic facial features. Recently, a heterozygous de novo mutation (p.Tyr64Cys) in the CDC42 gene, which encodes a key small GTP-binding protein of the Rho-subfamily, was identified in two unrelated patients with TKS. We herein report a third patient with TKS who had the same heterozygous CDC42 mutation. The phenotype of the patient was very similar to those of the two previously reported patients with TKS; however, she also demonstrated novel clinical manifestations, such as congenital hypothyroidism and immunological disturbance. Thus, despite the heterozygous mutation of CDC42 (p.Tyr64Cys) likely being a hot-spot mutation for TKS, its phenotype may be variable. Further studies and the accumulation of patients with CDC42 mutations are needed to clarify the phenotype in patients with TKS and the pathophysiological roles of the CDC42 mutation.
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http://dx.doi.org/10.1038/s10038-017-0396-5DOI Listing
March 2018

A novel heterozygous GLI2 mutation in a patient with congenital urethral stricture and renal hypoplasia/dysplasia leading to end-stage renal failure.

CEN Case Rep 2018 May 9;7(1):94-97. Epub 2018 Jan 9.

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

Glioblastoma 2 (GLI2) is a mediator of Sonic hedgehog signaling pathway that plays an important role in development of the central nervous system and limbs. Heterozygous GLI2 mutations have been associated with postaxial polydactyly, various pituitary dysfunction, and holoprosencephaly-like phenotype. Herein, we report a Japanese boy who presented with isolated growth hormone deficiency with ectopic posterior pituitary, postaxial polydactyly, atrioventricular septal defect, intellectual disability and dysmorphic facial features including mid-facial hypoplasia. The patient was also complicated with congenital urethral stricture with megacystis, hydronephrosis, and renal hypoplasia/dysplasia, which led to end-stage renal failure by the age of 8 years. Trio-whole-exome sequencing showed a novel de novo heterozygous frameshift mutation in GLI2 (c.3369delG, p.Met1123Ilefs*7) in the patient. This is the first report of possible association between GLI2 mutation and the phenotype of congenital anomalies of the kidney and urinary tract, and subsequent end-stage renal failure. Further studies on the urogenital phenotype in patients with GLI2 mutations may clarify a role of GLI2 in embryonic development of the urinary tract.
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http://dx.doi.org/10.1007/s13730-018-0302-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886933PMC
May 2018

mutations as a cause of familial short stature.

Authors:
Sumito Dateki

Clin Pediatr Endocrinol 2017 27;26(3):119-125. Epub 2017 Jul 27.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Aggrecan, encoded by , is a major proteoglycan component of the extracellular matrix in the growth plate and articular cartilage. Aggrecan provides the hydrated gel structure important for the load-bearing properties of joints and plays a key role in cartilage and bone morphogenesis. At least 25 pathological mutations have been identified in patients with highly variable phenotypes of syndromic or non-syndromic short stature. This review provides an overview of the current understanding of and the clinical and genetic findings concerning aggrecan-associated diseases.
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http://dx.doi.org/10.1297/cpe.26.119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5537209PMC
July 2017

Next generation sequencing-based mutation screening of 86 patients with idiopathic short stature.

Endocr J 2017 Oct 3;64(10):947-954. Epub 2017 Aug 3.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Although mutations in ACAN, FGFR3, NPR2, and SHOX typically lead to skeletal dysplasia, and mutations in GHRHR, GH1, GHR, STAT5B, IGF1, IGFALS, and IGF1R usually underlie hormonal defects of the growth hormone (GH)-insulin-like growth factor 1 (IGF1) axis, such mutations have also been identified in patients with idiopathic short stature (ISS). Of these, SHOX abnormalities are known to account for a certain percentage of ISS cases, whereas the frequency of mutations in the other 10 genes in ISS cohorts remains unknown. Here, we performed next-generation sequencing-based mutation screening of the 10 genes in 86 unrelated Japanese ISS patients without SHOX abnormalities. We searched for rare protein-altering variants. The functional significance of the identified variants was assessed by in silico analyses. Consequently, we identified 18 heterozygous rare variants in 19 patients, including four probable damaging variants in ACAN, six pathogenicity-unknown variants in FGFR3, GHRHR, GHR, and IGFALS, and eight possible benign variants. Pathogenic variants in NPR2, GH1, and IGF1 were absent from our cohort. Unlike previously reported patients with ACAN mutations, our four patients with ACAN variants manifested non-specific short stature with age-appropriate or mildly delayed bone ages, and had parents of normal stature. These results indicate that ACAN mutations can underlie ISS without characteristic skeletal features, and that such mutations are possibly associated with de novo occurrence or low penetrance. In addition, our data imply that mutations in FGFR3, NPR2, and GH-IGF1 axis genes play only limited roles in the etiology of ISS.
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http://dx.doi.org/10.1507/endocrj.EJ17-0150DOI Listing
October 2017

Novel SGCE mutation (p.Glu65*) in a Japanese family with myoclonus-dystonia.

Pediatr Int 2017 Sep 14;59(9):1018-1020. Epub 2017 Jul 14.

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

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http://dx.doi.org/10.1111/ped.13335DOI Listing
September 2017

Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver-Russell syndrome.

J Hum Genet 2017 Oct 8;62(10):919-922. Epub 2017 Jun 8.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Silver-Russell syndrome (SRS) is a congenital developmental disorder characterized by intrauterine and postnatal growth failure, craniofacial features (including a triangular shaped face and broad forehead), relative macrocephaly, protruding forehead, body asymmetry and feeding difficulties. Hypomethylation of the H19 differentially methylated region (DMR) on chromosome 11p15.5 is the most common cause of the SRS phenotype. We report the first SRS patient with hypomethylation of the H19-DMR and maternally derived 15q11.2-q13.1 duplication. Although her clinical manifestations overlapped with those of previously reported SRS cases, the patient's intellectual disability and facial dysmorphic features were inconsistent with the SRS phenotype. Methylation analyses, array comparative genomic hybridization, and a FISH analysis revealed the hypomethylation of the H19-DMR and a maternally derived interstitial 5.7 Mb duplication at 15q11.2-q13.1 encompassing the Prader-Willi/Angelman critical region in the patient. On the basis of the genetic and clinical findings in the present and previously reported cases, it is unlikely that the 15q duplication in the patient led to the development of hypomethylation of the H19-DMR and it is reasonable to consider that the characteristic phenotype in the patient was caused by the coexistence of the two (epi)genetic conditions. Further studies are needed to clarify the mechanisms leading to methylation aberrations in SRS.
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http://dx.doi.org/10.1038/jhg.2017.62DOI Listing
October 2017

Identification of a novel heterozygous mutation of the Aggrecan gene in a family with idiopathic short stature and multiple intervertebral disc herniation.

J Hum Genet 2017 Jul 23;62(7):717-721. Epub 2017 Mar 23.

Department of Pediatrics, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.

Aggrecan is a critical proteoglycan component of the extracellular matrix of the growth plates and articular cartilage and has a key role in the biophysical and biomechanical properties of cartilage. Recently, heterozygous mutations in the ACAN gene, which encodes aggrecan, have been identified in patients with short stature and accelerated bone age. We herein report another family with a heterozygous ACAN mutation associated with idiopathic short stature along with accelerated bone age and early-onset herniation of the lumbar discs at the levels of L1/2 through L5/S1. Whole-exome sequencing identified a novel heterozygous frameshift mutation in the ACAN gene (c.1744delT; p.Phe582fs*69) in all of the affected family members but not in the unaffected one, providing further evidence that ACAN haploinsufficiency causes short stature with advanced bone maturation. In addition, we advocate early-onset multiple disc herniation as a novel phenotype associated with ACAN haploinsufficiency.
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http://dx.doi.org/10.1038/jhg.2017.33DOI Listing
July 2017

[Ictal arterial spin labeling MRI findings in two cases of acute confusional migraine].

No To Hattatsu 2017 03;49(2):136-40

Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) technique that enables visualizing of cerebral blood flow without need of a contrast medium. In recent years, there have been reports from outside Japan related to ASL use in migraine attacks. We report two cases of acute confusional migraine (ACM) in children. At time of confusion, ASL imaging showed reduced blood flow: for the first patient, in both cerebral hemispheres from the occipital lobe through the parietal lobe to the temporal lobe; for the second patient, throughout the left cerebral hemisphere. T1-, T2-, diffusion-weighted images, and fluid attenuation inversion recovery (FLAIR) images indicated normal results. Subsequent ASL re-examinations for both cases showed recovery from reduced blood flow. In our view, ACM can be characterized by a reduction in blood flow not limited to the occipital lobe but across wide regions of the cerebral hemisphere. We consider ASL to be helpful in the difficult differentiation of ACM from other disturbances of consciousness, in addition to enabling repeated examinations without the risks associated with single-photon emission computed tomography (SPECT) concerning radiation exposure or with contrast MRI concerning contrast media use.
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March 2017

A case of sitosterolemia due to compound heterozygous mutations in : clinical features and treatment outcomes obtained with colestimide and ezetimibe.

Clin Pediatr Endocrinol 2017 Jan 31;26(1):17-23. Epub 2017 Jan 31.

Department of Pediatrics, Kawasaki Medical School, Okayama, Japan.

Sitosterolemia is a rare, autosomal recessively inherited disorder of lipid metabolism caused by mutations in the "ATP-binding cassette, subfamily G" member 5 and 8 proteins (encoded by the and genes, respectively), which play critical roles in the intestinal and biliary excretion of plant sterols. We report the clinical features and treatment outcomes of an 18-month-old Japanese girl with sitosterolemia, who presented with multiple linear and intertriginous xanthomas around the joint areas. Serum lipid analyses revealed elevated levels of total cholesterol (T-Chol: 866 mg/dL), low density lipoprotein-cholesterol (LDL-C: 679 mg/dL), and plant sterols (sitosterol: 24.6 mg/dL, campesterol: 19.2 mg/dL, stigmasterol: 1.8 mg/dL). Compound heterozygous mutations (p.R419H and p.R389H) were identified in . The patient was placed on a low cholesterol/low plant sterol diet and treated with colestimide (a bile acid sequestrant) and ezetimibe (an NPC1L1 inhibitor). Serum T-Chol and LDL-C levels decreased to normal within 2 mo, and plant sterol levels decreased by 30% within 4 mo. The xanthomas regressed gradually, and almost completely disappeared after 1.5 yr of treatment. No further reductions of plant sterol levels were observed. Long-term follow-up is important to verify appropriate therapeutic goals to prevent premature atherosclerosis and coronary artery disease.
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http://dx.doi.org/10.1297/cpe.26.17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5295247PMC
January 2017

Numerous intertriginous xanthomas in infant: A diagnostic clue for sitosterolemia.

J Dermatol 2016 Nov 12;43(11):1340-1344. Epub 2016 Jul 12.

Department of Dermatology, Kawasaki Medical School, Kurashiki, Japan.

Sitosterolemia is a very rare autosomal recessive lipoprotein metabolic disorder caused by homozygous or compound heterozygous mutations in one of the two adenosine triphosphate-binding cassette transporter genes, ABCG5 and ABCG8. Sitosterolemia is clinically characterized by xanthomas and atherosclerosis, arthritis, fever, hemolysis and macrothrombocytopenia even in early childhood. We described a 16-month-old girl, who had numerous yellowish-brown intertriginous xanthomas along the skin creases on the extremities with severe hypercholesterolemia and elevated plant sterol levels. Histopathologically, xanthoma showed aggregation of foam cells in the dermis with a zone of mucin deposits in the dermal papilla. Electron microscopy showed numerous membrane-bound lipid droplets and multivesicular lipid bodies in the foam cells, a round cell containing lipid droplets in the basal cell layer and abundant mucin deposits just beneath the basal lamina. Diagnosis of sitosterolemia was confirmed by DNA sequencing showing compound heterozygosity for previously reported missense mutations in exon 9 of ABCG5. Infants presenting with multiple xanthomas should be investigated for sitosterolemia, if there is no family history of dyslipidemia.
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http://dx.doi.org/10.1111/1346-8138.13511DOI Listing
November 2016

Molecular and clinical features of K -channel neonatal diabetes mellitus in Japan.

Pediatr Diabetes 2017 Nov 29;18(7):532-539. Epub 2016 Sep 29.

Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, Osaka, Japan.

Background: There are few reports pertaining to Asian patients with neonatal diabetes mellitus (NDM) caused by activating mutations in the ATP-sensitive potassium channel genes (KATP-NDM).

Objectives: To elucidate the characteristics of Japanese patients with KATP-NDM.

Methods: By the amplification and direct sequencing of all exons and exon-intron boundaries of the KCNJ11 and ABCC8 genes, 25 patients with KATP-NDM were identified from a total of 70 patients with NDM. Clinical data were collected from the medical charts.

Results: Sixteen patients had mutations in KCNJ11 and nine in ABCC8. Eight novel mutations were identified; two in KCNJ11 (V64M, R201G) and six in ABCC8 (R216C, G832C, F1176L, A1263V, I196N, T229N). Interestingly, V64M caused DEND (developmental delay, epilepsy, neonatal diabetes) syndrome in our patient, while mutation of the same residue (V64G) had been reported to cause congenital hyperinsulinism. Mutations in ABCC8 were associated with TNDM (4/9) or isolated PNDM (5/9), whereas those in KCNJ11 were associated with more severe phenotypes, including DEND (3/16), iDEND (intermediate DEND, 4/16), or isolated PNDM (6/16). Switching from insulin to glibenclamide monotherapy was successful in 87.5% of the patients. Neurological improvement was observed in two patients, one with DEND (T293N) and one with iDEND (R50P) syndrome. Three others with iDEND mutations (R201C, G53D, and V59M) remained neurologically normal at 5, 1, and 4 years of age, respectively, with early introduction of sulfonylurea.

Conclusion: Overall, clinical presentation of KATP-NDM in Japanese patients was similar to those of other populations. Early introduction of sulfonylurea appeared beneficial in ameliorating neurological symptoms.
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http://dx.doi.org/10.1111/pedi.12447DOI Listing
November 2017

Identification of 11p14.1-p15.3 deletion probably associated with short stature, relative macrocephaly, and delayed closure of the fontanelles.

Am J Med Genet A 2017 Jan 23;173(1):217-220. Epub 2016 Sep 23.

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

We herein report a de novo hemizygous 9.2-Mb interstitial deletion of chromosome 11p14.1-15.3 in a 3-year-old Japanese girl with short stature, relative macrocephaly, and delayed closure of cranial fontanelles and sutures. She did not show either any motor or mental development delay. This deletion involves 25 genes including NELL1. The loss of the Nell1 function leads to skeletal defects in the cranial vault and vertebral column, and overexpression of Nell1 causes craniosynostosis in mice. These results imply that short stature and an abnormality of membranous ossification could be explained by haploinsufficiency of NELL1 on 11p14.1-p15.3. Further studies are needed to clarify the phenotype in patients with an 11p14.1-15.3 deletion and the pathogenesis of NELL1. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.37978DOI Listing
January 2017

Genetic background of hyperphenylalaninemia in Nagasaki, Japan.

Pediatr Int 2016 May;58(5):431-3

Department of Pediatrics, Nagasaki University Hospital, Nagasaki, Japan.

Phenylketonuria (PKU) and related hyperphenylalaninemia (HPA) are caused by a deficiency in hepatic phenylalanine hydroxylase (PAH). The incidence of PKU in Nagasaki prefecture is higher than that in all parts of Japan (1/15 894 vs 1/120 000). To investigate the genetic background of patients with HPA in Nagasaki prefecture, mutation analysis was done in 14 patients with PKU or mild HPA. Homozygous or compound heterozygous PAH mutations were identified in all the patients. The spectrum of PAH mutations in the cohort was broad and similar to those in all parts of Japan and East Asian countries. R53H is the most common mutation in patients with mild HPA. The present results provide further support for genotype-phenotype correlations in patients with HPA. The high incidence of PKU in Nagasaki, the westernmost part of Japan, might be due to migration of people with PAH mutations from China and Korea, and geographic factors.
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http://dx.doi.org/10.1111/ped.12924DOI Listing
May 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

Mutation spectrum and phenotypic variation in nine patients with SOX2 abnormalities.

J Hum Genet 2014 Jun 8;59(6):353-6. Epub 2014 May 8.

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

Multiple mutations in SOX2 have been identified in patients with ocular anomalies and/or pituitary dysfunction. Here, we identified SOX2 abnormalities in nine patients. The molecular defects included one missense, one nonsense and four frameshift mutations, and three submicroscopic deletions involving SOX2. Three of the six mutations and all deletions were hitherto unreported. The breakpoints determined in one deletion were located within Alu repeats and accompanied by an overlap of 11 bp. Three of the six mutations encoded SOX2 proteins that lacked in vitro transactivation activity for the HESX1 promoter, whereas the remaining three generated proteins with ∼15-∼20% of transactivation activity. All cases manifested ocular anomalies of various severities, together with several complications including arachnoid cyst and hamartoma. There was no apparent correlation between the residual activity and clinical severity. The results indicate that molecular defects in SOX2 are highly variable and include Alu repeat-mediated genomic rearrangements. Our data provide further evidence for wide phenotypic variation of SOX2 abnormalities and the lack of genotype-phenotype correlation in patients carrying SOX2 lesions.
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http://dx.doi.org/10.1038/jhg.2014.34DOI Listing
June 2014

SLC25A13 gene analysis in citrin deficiency: sixteen novel mutations in East Asian patients, and the mutation distribution in a large pediatric cohort in China.

PLoS One 2013 19;8(9):e74544. Epub 2013 Sep 19.

Department of Pediatrics, The First Affiliated Hospital, Jinan University, Guangzhou, China.

Background: The human SLC25A13 gene encodes citrin, the liver-type mitochondrial aspartate/glutamate carrier isoform 2 (AGC2), and SLC25A13 mutations cause citrin deficiency (CD), a disease entity that encompasses different age-dependant clinical phenotypes such as Adult-onset Citrullinemia Type II (CTLN2) and Neonatal Intrahepatic Cholestasis caused by Citrin Deficiency (NICCD). The analyses of SLC25A13 gene and its protein/mRNA products remain reliable tools for the definitive diagnoses of CD patients, and so far, the SLC25A13 mutation spectrum in Chinese CD patients has not been well-characterized yet.

Methods And Results: By means of direct DNA sequencing, cDNA cloning and SNP analyses, 16 novel pathogenic mutations, including 9 missense, 4 nonsense, 1 splice-site, 1 deletion and 1 large transposal insertion IVS4ins6kb (GenBank accession number KF425758), were identified in CTLN2 or NICCD patients from China, Japan and Malaysia, respectively, making the SLC25A13 variations worldwide reach the total number of 81. A large NICCD cohort of 116 Chinese cases was also established, and the 4 high-frequency mutations contributed a much larger proportion of the mutated alleles in the patients from south China than in those from the north (χ(2) = 14.93, P<0.01), with the latitude of 30°N as the geographic dividing line in mainland China.

Conclusions: This paper further enriched the SLC25A13 variation spectrum worldwide, and formed a substantial contribution to the in-depth understanding of the genotypic feature of Chinese CD patients.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0074544PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3777997PMC
May 2014

Submicroscopic deletion involving the fibroblast growth factor receptor 1 gene in a patient with combined pituitary hormone deficiency.

Endocr J 2013 9;60(8):1013-20. Epub 2013 May 9.

Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Combined pituitary hormone deficiency (CPHD), isolated hypogonadotropic hypogonadism (IHH), Kallmann syndrome (KS), and septo-optic dysplasia (SOD) are genetically related conditions caused by abnormal development of the anterior midline in the forebrain. Although mutations in the fibroblast growth factor receptor 1 (FGFR1) gene have been implicated in the development of IHH, KS, and SOD, the relevance of FGFR1 abnormalities to CPHD remains to be elucidated. Here, we report a Japanese female patient with CPHD and FGFR1 haploinsufficiency. The patient was identified through copy-number analyses and direct sequencing of FGFR1 performed for 69 patients with CPHD. The patient presented with a combined deficiency of GH, LH and FSH, and multiple neurological abnormalities. In addition, normal TSH values along with a low free T4 level indicated the presence of central hypothyroidism. Molecular analyses identified a heterozygous ~ 8.5 Mb deletion involving 56 genes and pseudogenes. None of these genes except FGFR1 have been associated with brain development. No FGFR1 abnormalities were identified in the remaining 68 patients, although two patients carried nucleotide substitutions (p.V102I and p.S107L) that were assessed as benign polymorphism by in vitro functional assays. These results indicate a possible role of FGFR1 in anterior pituitary function and the rarity of FGFR1 abnormalities in patients with CPHD.
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http://dx.doi.org/10.1507/endocrj.ej13-0023DOI Listing
March 2014

Identification of chromosome 15q26 terminal deletion with telomere sequences and its bearing on genotype-phenotype analysis.

Endocr J 2011 14;58(3):155-9. Epub 2011 Jan 14.

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

We report a de novo heterozygous 5,013,940 bp terminal deletion of chromosome 15q26 in a 13 9/12 -year-old Japanese girl with short stature (-3.9 SD), mild mental retardation, and ventricular septal defect (VSD). This terminal deletion involved IGF1R but not NR2F2, and was associated with an addition of telomere repeat sequences (TTAGGG) at the end of the truncated chromosome. The results provide further support for the notion that terminal deletions are healed by de novo addition of telomere sequences essential for chromosome stability and DNA replication. Furthermore, while growth failure and mental retardation are primarily explained by loss of IGF1R, the occurrence of VSD might suggest the existence of a cardiac anomaly gene, other than the candidate cardiac anomaly gene NR2F2, in the deleted region.
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http://dx.doi.org/10.1507/endocrj.k10e-251DOI Listing
July 2011

Mutation and gene copy number analyses of six pituitary transcription factor genes in 71 patients with combined pituitary hormone deficiency: identification of a single patient with LHX4 deletion.

J Clin Endocrinol Metab 2010 Aug 9;95(8):4043-7. Epub 2010 Jun 9.

Department of Endocrinology and Metabolism, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan.

Context: Mutations of multiple transcription factor genes involved in pituitary development have been identified in a minor portion of patients with combined pituitary hormone deficiency (CPHD). However, copy number aberrations involving such genes have been poorly investigated in patients with CPHD.

Objective: We aimed to report the results of mutation and gene copy number analyses in patients with CPHD.

Subjects And Methods: Seventy-one Japanese patients with CPHD were examined for mutations and gene copy number aberrations affecting POU1F1, PROP1, HESX1, LHX3, LHX4, and SOX3 by PCR-direct sequencing and multiplex ligation-dependent probe amplification. When a deletion was indicated, it was further studied by fluorescence in situ hybridization, oligoarray comparative genomic hybridization, and serial sequencing for long PCR products encompassing the deletion junction.

Results: We identified a de novo heterozygous 522,009-bp deletion involving LHX4 in a patient with CPHD (GH, TSH, PRL, LH, and FSH deficiencies), anterior pituitary hypoplasia, ectopic posterior pituitary, and underdeveloped sella turcica. We also identified five novel heterozygous missense substitutions (p.V201I and p.H387P in LHX4, p.T63M and p.A322T in LHX3, and p.V53L in SOX3) that were assessed as rare variants by sequencing analyses for control subjects and available parents and by functional studies and in silico analyses.

Conclusions: The results imply the rarity of abnormalities affecting the six genes in patients with CPHD and the significance of the gene copy number analysis in such patients.
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http://dx.doi.org/10.1210/jc.2010-0150DOI Listing
August 2010