Publications by authors named "Tsutomu Ogata"

336 Publications

Congenital disorders of estrogen biosynthesis and action.

Best Pract Res Clin Endocrinol Metab 2021 Sep 13:101580. Epub 2021 Sep 13.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan; Department of Pediatrics, Hamamatsu Medical Center, Hamamatsu, Japan. Electronic address:

Estrogens regulate pubertal development and reproductive function in women, spermatogenesis in men, and bone turnover and metabolic conditions in individuals of both sexes. Estradiol, the major estrogen in humans, is synthesized from testosterone by the action of aromatase and exerts its effects though binding to estrogen receptors. Germline loss- and gain-of-function variants in CYP19A1, the gene encoding aromatase, lead to aromatase deficiency and aromatase excess syndrome, respectively. Germline loss-of-function variants in ESR1, the gene encoding estrogen receptor α, are known to cause of estrogen insensitivity/resistance. In addition, rare variants in ESR1 and ESR2 have been implicated in various disease phenotypes. Clinical studies on these rare endocrine disorders provided clues to understand the biological functions of estrogens in the human body. This review introduces the genetic basis, phenotypes, and current management procedures of congenital disorders in estrogen biosynthesis and action.
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http://dx.doi.org/10.1016/j.beem.2021.101580DOI Listing
September 2021

Global developmental delay, systemic dysmorphism and epilepsy in a patient with a de novo U2AF2 variant.

J Hum Genet 2021 Jun 11. Epub 2021 Jun 11.

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

U2 small nuclear RNA auxiliary factor 2 (U2AF2) is an essential pre-mRNA splicing factor in an early step of splicing. Alternative splicing plays an important role in neuronal development, and disorders of RNA processing steps are implicated in neurological disorders. Recently, the large trio whole-exome sequencing study reported U2AF2 as a novel gene significantly associated with developmental disorders: however, the clinical details of patients with U2AF2 variants were not available. Here, we report an individual with a de novo U2AF2 variant (c.445C>T, p.(Arg149Trp)) using trio-based whole-exome sequencing. This residue was positioned in the RNA recognition motif 1 which recognizes a polypyrimidine-tract splice site signal. The patient showed global developmental delay, intellectual disability, epilepsy, short stature, microcephaly, facial dysmorphism, intermittent exotropia, bilateral ptosis, muscle hypotonia and thin corpus callosum, indicating that U2AF2-related disorder could include systemic dysmorphisms, epilepsy and brain malformation along with global developmental delay.
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http://dx.doi.org/10.1038/s10038-021-00948-4DOI Listing
June 2021

Mutation Screening for 117 Patients with Kallmann Syndrome.

J Endocr Soc 2021 Jul 30;5(7):bvab056. Epub 2021 Mar 30.

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

Introduction: Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although , a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH) has previously been implicated in KS, the clinical significance of variants as the cause of KS remains uncertain.

Patients And Methods: A total of 117 patients with KS underwent mutation screening of and 14 other causative genes for KS/HH. Rare variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with variants.

Results: Sequence analysis identified 2 heterozygous variants of (c.1225G > T, p.Gly409* and c.475C > T, p.Arg159Trp) in patients 1-3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the promoter and exerted no dominant-negative effects. Patients 1-3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the 5 variant-positive individuals exhibited hypopigmentation, while 1 and 2 individuals exhibited complete and partial hearing loss, respectively.

Conclusion: These results provide evidence that haploinsufficiency accounts for a small percentage of KS cases. haploinsufficiency is likely to be associated with a broad phenotypic spectrum, which includes KS without other clinical features of WS/PCWH.
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http://dx.doi.org/10.1210/jendso/bvab056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8170842PMC
July 2021

Spontaneous intraperitoneal renal rupture with urinoma formation in the fetus.

Urol Case Rep 2021 Jul 5;37:101697. Epub 2021 May 5.

Department of Urology and Renal Transplantation, Nagasaki University Hospital, Nagasaki, Japan.

Spontaneous intraperitoneal renal rupture with urinoma formation in fetuses is an unusual condition that is caused by upper or lower urinary tract obstruction. We report the case of a neonatal male infant who presented with a spontaneous intraperitoneal right renal rupture accompanying ipsilateral ureterovesical junction obstruction (UVJO). Fetuses with UVJO accompanying contralateral multicystic dysplastic kidney should be observed carefully because of the risk of spontaneous renal rupture.
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http://dx.doi.org/10.1016/j.eucr.2021.101697DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167486PMC
July 2021

Novel ALG12 variants and hydronephrosis in siblings with impaired N-glycosylation.

Brain Dev 2021 Jun 3. Epub 2021 Jun 3.

Department of Biochemistry, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Background: ALG12-CDG is a rare autosomal recessive type I congenital disorder of glycosylation (CDG) due to pathogenic variants in ALG12 which encodes the dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase. Thirteen patients from unrelated 11 families have been reported, most of them result in broad multisystem manifestations with clinical variability. It is important to validate abnormal glycosylation to establish causal relationship.

Case Report: Here, we report two siblings with novel compound heterozygous variants in ALG12: c.443T>C, p.(Leu148Pro) and c.412_413insCGT, p.(Gln137_Phe138insSer). Both patients showed global developmental delay, microcephaly, hypotonia, failure to thrive, facial dysmorphism, skeletal malformations and coagulation abnormalities, which are common in ALG12-CDG. In addition, one of our patients showed left hydronephrosis, which is a novel clinical feature in ALG12-CDG. Brain MRI showed hypoplasia of cerebrum, brain stem and cerebellar vermis in both patients. N-glycosylation defects of trypsin digested transferrin peptides were revealed by matrix-assisted laser desorption/ionization mass spectrometry (MALDI-MS), and electrospray ionization MS verified the lack of N-glycans in transferrin.

Conclusions: The present study can add hydronephrosis to phenotypic spectrum of ALG12-CDG. Since the symptoms of ALG12-CDG are quite diverse, the combination of whole-exome sequencing and transferrin glycopeptide analysis with MS, can help diagnosis of ALG12-CDG.
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http://dx.doi.org/10.1016/j.braindev.2021.05.013DOI Listing
June 2021

ZNF445: a homozygous truncating variant in a patient with Temple syndrome and multilocus imprinting disturbance.

Clin Epigenetics 2021 May 26;13(1):119. Epub 2021 May 26.

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

Background: ZNF445, as well as ZFP57, is involved in the postfertilization methylation maintenance of multiple imprinting-associated differentially methylated regions (iDMRs). Thus, ZNF445 pathogenic variants are predicted to cause multilocus imprinting disturbances (MLIDs), as do ZFP57 pathogenic variants. In particular, the MEG3/DLK1:IG-DMR would be affected, because the postzygotic methylation imprint of the MEG3/DLK1:IG-DMR is maintained primarily by ZNF445, whereas that of most iDMRs is preserved by both ZFP57 and ZNF445 or primarily by ZFP57.

Results: We searched for a ZNF445 variant(s) in six patients with various imprinting disorders (IDs) caused by epimutations and MLIDs revealed by pyrosequencing for nine iDMRs, without a selection for the original IDs. Re-analysis of the previously obtained whole exome sequencing data identified a homozygous ZNF445 variant (NM_181489.6:c.2803C>T:p.(Gln935*)) producing a truncated protein missing two of 14 zinc finger domains in a patient with Temple syndrome and MLID. In this patient, array-based genomewide methylation analysis revealed severe hypomethylation of most CpGs at the MEG3:TSS-DMR, moderate hypomethylation of roughly two-thirds of CpGs at the H19/IGF2:IG-DMR, and mild-to-moderate hypomethylation of a few CpGs at the DIRAS3:TSS-DMR, MEST:alt-TSS-DMR, IGF2:Ex9-DMR, IGF2:alt-TSS, and GNAS-AS1:TSS-DMR. Furthermore, bisulfite sequencing analysis for the MEG3/DLK1:IG-DMR delineated a markedly hypomethylated segment (CG-A). The heterozygous parents were clinically normal and had virtually no aberrant methylation pattern.

Conclusions: We identified a ZNF445 pathogenic variant for the first time. Since ZNF445 binds to the MEG3/DLK1:IG-DMR and other iDMRs affected in this patient, the development of Temple syndrome and MLID would primarily be explained by the ZNF445 variant. Furthermore, CG-A may be the target site for ZNF445 within the MEG3/DLK1:IG-DMR.
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http://dx.doi.org/10.1186/s13148-021-01106-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157728PMC
May 2021

A patient with Silver-Russell syndrome with multilocus imprinting disturbance, and Schimke immuno-osseous dysplasia unmasked by uniparental isodisomy of chromosome 2.

J Hum Genet 2021 May 24. Epub 2021 May 24.

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

Silver-Russell syndrome (SRS) is a congenital disorder characterized by prenatal and postnatal growth failure and craniofacial features. Hypomethylation of the H19/IGF2:IG-differential methylated region (H19LOM) is observed in 50% of SRS patients, and 15% of SRS patients with H19LOM had multilocus imprinting disturbance (MLID). Schimke immuno-osseous dysplasia (SIOD), characterized by spondyloepiphyseal dysplasia and nephropathy, is an autosomal recessive disorder caused by mutations in SMARCAL1 on chromosome 2. We report a patient with typical SRS-related features, spondyloepiphyseal dysplasia, and severe nephropathy. Molecular analyses showed H19LOM, paternal uniparental isodisomy of chromosome 2 (iUPD(2)pat), and a paternally inherited homozygous frameshift variant in SMARCAL1. Genome-wide methylation analysis showed MLID in this patient, although it showed no MLID in another patient with SIOD without SRS phenotype. These results suggest that iUPD(2)pat unmasked the recessive mutation in SMARCAL1 and that the SMARCAL1 gene mutation may have no direct effect on the patient's methylation defects.
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http://dx.doi.org/10.1038/s10038-021-00937-7DOI Listing
May 2021

Parthenogenetic mosaicism: generation via second polar body retention and unmasking of a likely causative PER2 variant for hypersomnia.

Clin Epigenetics 2021 Apr 7;13(1):73. Epub 2021 Apr 7.

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

Background: Parthenogenetic mosaicism is an extremely rare condition identified only in five subjects to date. The previous studies indicate that this condition is mediated by parthenogenetic activation and is free from a specific phenotype ascribed to unmaking of a maternally inherited recessive variant in the parthenogenetic cell lineage.

Results: We examined a 28-year-old Japanese 46,XX female with Silver-Russell syndrome and idiopathic hypersomnia. The results revealed (1) predominance of maternally derived alleles for all the differentially methylated regions examined; (2) no disease-related copy-number variant; (3) two types of regions for all chromosomes, i.e., four BAF (B-allele frequency) band regions with single major microsatellite peaks of maternal origin and single minor microsatellite peaks of non-maternal (paternal) origin, and six BAF band regions with single major microsatellite peaks of maternal origin and two minor microsatellite peaks of maternal and non-maternal (paternal) origin; (4) an unmasked extremely rare PER2 variant (c.1403G>A:p.(Arg468Gln)) with high predicted pathogenicity; (5) mildly affected local structure with altered hydrogen bonds of the p.Arg468Gln-PER2 protein; and (6) nucleus-dominant subcellular distribution of the p.Arg468Gln-PER2 protein.

Conclusions: The above findings imply that the second polar body retention occurred around fertilization, resulting in the generation of the parthenogenetic cell lineage by endoreplication of a female pronucleus and the normal cell lineage by fusion of male and female pronuclei, and that the homozygous PER2 variant in the parthenogenetic cells is the likely causative factor for idiopathic hypersomnia.
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http://dx.doi.org/10.1186/s13148-021-01062-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028705PMC
April 2021

Variants Associated With X-Linked Intellectual Disability and Congenital Malformation.

Front Cell Dev Biol 2021 3;9:631428. Epub 2021 Mar 3.

Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

Background: X-linked intellectual disability (XLID), which occurs predominantly in males, is a relatively common and genetically heterogeneous disorder in which over 100 mutated genes have been reported. The gene at Xp11.23 encodes ovarian tumor deubiquitinase 5 protein, which is a deubiquitinating enzyme member of the ovarian tumor family. LINKage-specific-deubiquitylation-deficiency-induced embryonic defects (LINKED) syndrome, arising from pathogenic variants, was recently reported as a new XLID with additional congenital anomalies.

Methods: We investigated three affected males (49- and 47-year-old brothers [Individuals 1 and 2] and a 2-year-old boy [Individual 3]) from two families who showed developmental delay. Their common clinical features included developmental delay, hypotonia, short stature, and distinctive facial features, such as telecanthus and a depressed nasal bridge. Individuals 1 and 2 showed epilepsy and brain magnetic resonance imaging showed a thin corpus callosum and mild ventriculomegaly. Individual 3 showed congenital malformations, including tetralogy of Fallot, hypospadias, and bilateral cryptorchidism. To identify the genetic cause of these features, we performed whole-exome sequencing.

Results: A hemizygous missense variant, c.878A>T, p.Asn293Ile [NM_017602.4], was identified in one family with Individuals 1 and 2, and another missense variant, c.1210 C>T, p.Arg404Trp, in the other family with Individual 3, respectively. The former variant has not been registered in public databases and was predicted to be pathogenic by multiple prediction tools. The latter variant p.Arg404Trp was previously reported as a pathogenic variant, and Individual 3 showed a typical LINKED syndrome phenotype. However, Individuals 1 and 2, with the novel variant (p.Asn293Ile), showed no cardiac or genitourinary malformations.

Conclusions: Unlike previous reports of LINKED syndrome, which described early lethality with congenital cardiac anomalies, our three cases are still alive. Notably, the adult brothers with the novel missense variant have lived into their forties. This may be indicative of a milder phenotype as a possible genotype-phenotype correlation. These findings imply a possible long-term prognosis for individuals with this new XLID syndrome, and a wider phenotypic variation than initially thought.
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http://dx.doi.org/10.3389/fcell.2021.631428DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7965969PMC
March 2021

Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing.

Clin Genet 2021 07 8;100(1):40-50. Epub 2021 Mar 8.

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

Whole-exome sequencing (WES) enables identification of pathogenic variants, including copy number variants (CNVs). In this study, we performed WES in 101 Japanese patients with unexplained developmental delay (DD) or intellectual disability (ID) (63 males and 38 females), 98 of them with trio-WES. Pathogenic variants were identified in 54 cases (53.5%), including four cases with pathogenic CNVs. In one case, a pathogenic variant was identified by reanalysis of exome data; and in two cases, two molecular diagnoses were identified. Among 58 pathogenic variants, 49 variants occurred de novo in 48 patients, including two somatic variants. The accompanying autism spectrum disorder and external ear anomalies were associated with detection of pathogenic variants with odds ratios of 11.88 (95% confidence interval [CI] 2.52-56.00) and 3.46 (95% CI 1.23-9.73), respectively. These findings revealed the importance of reanalysis of WES data and detection of CNVs and somatic variants in increasing the diagnostic yield for unexplained DD/ID. In addition, genetic testing is recommended when patients suffer from the autism spectrum disorder or external ear anomalies, which potentially suggests the involvement of genetic factors associated with gene expression regulation.
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http://dx.doi.org/10.1111/cge.13951DOI Listing
July 2021

Biallelic CDK9 variants as a cause of a new multiple-malformation syndrome with retinal dystrophy mimicking the CHARGE syndrome.

J Hum Genet 2021 Feb 27. Epub 2021 Feb 27.

Department of Ophthalmology and Laboratory for Visual Science, National Center for Child Health and Development, Tokyo, Japan.

CDK9 has been considered a candidate gene involved in the CHARGE-like syndrome in a pair of cousins. We report an 8-year-old boy with a strikingly similar phenotype including facial asymmetry, microtia with preauricular tags and bilateral hearing loss, cleft lip and palate, cardiac dysrhythmia, and undescended testes. Joint contracture, no finger flexion creases, and large halluces were the same as those of a previously reported patient with homozygous CDK9 variants. The ocular phenotype included blepharophimosis, lacrimal duct obstruction, eyelid dermoids, Duane syndrome-like abduction deficit, and congenital cataracts. Optical coherence tomography and electroretinography evaluations revealed severe retinal dystrophy had developed at an early age. Trio-based whole-exome sequencing identified compound heterozygous variants in CDK9 [p.(A288T) of maternal origin and p.(R303C) of paternal origin] in the patient. Variants' kinase activities were reduced compared with wild type. We concluded that CDK9 biallelic variants cause a CHARGE-like malformation syndrome with retinal dystrophy as a distinguishing feature.
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http://dx.doi.org/10.1038/s10038-021-00909-xDOI Listing
February 2021

Primary ovarian insufficiency in a female with phosphomannomutase-2 gene (PMM2) mutations for congenital disorder of glycosylation.

Endocr J 2021 May 11;68(5):605-611. Epub 2021 Mar 11.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

Primary ovarian insufficiency (POI) is a highly heterogeneous condition, and its underlying causes remain to be clarified in a large fraction of patients. Congenital disorders of glycosylation (CDG) are multisystem diseases caused by mutations of a number of genes involved in N-glycosylation or O-glycosylation, and the most frequent form is PMM2-CDG (alias, CDG-Ia) resulting from biallelic mutations in PMM2 encoding phosphomannomutase-2 involved in N-glycosylation. Here, we examined a 46,XX Japanese female with syndromic POI accompanied by an undetectable level of serum anti-Müllerian hormone (AMH). Whole exome sequencing identified biallelic pathogenic mutations of PMM2 (a novel c.34G>C:p.(Asp12His) of maternal origin and a recurrent c.310C>G:p.(Leu104Val) of paternal origin) (NM_000303.3), and N-glycosylation studies detected asialotransferrin and disialotransferrin characteristic of PMM2-CDG, in addition to normally glycosylated tetrasialotransferrin. Clinical assessment showed cerebellar hypotrophy, which is a fairly characteristic and highly prevalent feature in PMM2-CDG, together with multiple non-specific features reported in PMM2-CDG such as characteristic face, intellectual disability, skeletal abnormalities, and low blood antithrombin III value. These results including the undetectable level of serum AMH, in conjunction with previously reported findings suggestive of the critical role of glycosylation in oocyte development and function, imply that PMM2-CDG almost invariably leads to POI primarily because of the defective oogenesis and/or oocyte-dependent early folliculogenesis rather than the compromised bioactivity of FSH/LH with defective glycosylation. Thus, it is recommended to examine PMM2 in patients with syndromic POI, especially in those with cerebellar ataxia/hypotrophy.
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http://dx.doi.org/10.1507/endocrj.EJ20-0706DOI Listing
May 2021

NDNF variants are rare in patients with congenital hypogonadotropic hypogonadism.

Hum Genome Var 2021 Feb 2;8(1). Epub 2021 Feb 2.

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

Although NDNF was recently reported as a novel causative gene for congenital hypogonadotropic hypogonadism (CHH), this conclusion has yet to be validated. In this study, we sequenced NDNF in 61 Japanese CHH patients. No variants, except for nine synonymous substitutions that appear to have no effect on splice-site recognition, were identified in NDNF coding exons or flanking intronic sequences. These results indicate the rarity of NDNF variants in CHH patients and highlight the genetic heterogeneity of CHH.
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http://dx.doi.org/10.1038/s41439-021-00137-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7854707PMC
February 2021

Long-term Effect of Aromatase Inhibition in Aromatase Excess Syndrome.

J Clin Endocrinol Metab 2021 04;106(5):1491-1500

Division of Pediatrics, Niigata University Graduate School of Medicine and Dental Science, Niigata, Japan.

Context: Aromatase excess syndrome (AEXS) is a very rare disorder characterized by prepubertal gynecomastia, bone age acceleration, and early growth arrest. Heterozygote submicroscopic rearrangements within the promotor of CYP19A1 result in overexpression of aromatase and enhanced aromatization of androgens.

Objective: The objective was to study long-term treatment effects of an aromatase inhibitor.

Methods: Data from 7 boys with AEXS were retrospectively collected. Genetic analysis revealed upstream of CYP19A1 a 165 901 bp deletion in 4 German cousins, a 198 662 bp deletion in 2 Japanese brothers, and a 387 622 bp tandem duplication in a Japanese boy.

Results: All boys developed prepubertal gynecomastia, at median 9.0 years of age (range: 7.0-11.0). Height was +1.20 standard deviation score (SDS) (-0.24 to +1.98); predicted adult height was -1.29 SDS (-3.29 to +1.09). Four boys were treated with 1.0 mg of anastrozole daily, while 3 reached adult height untreated. Treatment with anastrozole was stopped after 5.6 years (4.0-6.8). Three treated boys exceeded their prognosis by 2.4, 6.9, and 8.1 cm, while 1 untreated boy fell below the prognosis by 8.6 cm. One treated with a low dose and 2 untreated reached their prognosis. Adult heights were -0.91 SDS with anastrozole (-2.86 to -0.29) and -0.15 SDS without (-2.31 to -0.03). Distance to target height was -0.22 SDS with anastrozole (-1.72 to +0.52) and +0.54 SDS without (+0.23 to +1.30).

Conclusion: Spontaneous growth in AEXS varied, even in the same family. Our data suggest that early started, long-term inhibition by anastrozole promotes adult height in boys with AEXS.
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http://dx.doi.org/10.1210/clinem/dgab054DOI Listing
April 2021

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

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

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

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

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

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

Role of Imprinting Disorders in Short Children Born SGA and Silver-Russell Syndrome Spectrum.

J Clin Endocrinol Metab 2021 03;106(3):802-813

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

Background: (Epi)genetic disorders associated with small-for-gestational-age with short stature (SGA-SS) include imprinting disorders (IDs). Silver-Russell syndrome (SRS) is a representative ID in SGA-SS and has heterogenous (epi)genetic causes.

Subjects And Methods: To clarify the contribution of IDs to SGA-SS and the molecular and phenotypic spectrum of SRS, we recruited 269 patients with SGA-SS, consisting of 103 and 166 patients referred to us for genetic testing for SGA-SS and SRS, respectively. After excluding 20 patients with structural abnormalities detected by comparative genomic hybridization analysis using catalog array, 249 patients were classified into 3 subgroups based on the Netchine-Harbison clinical scoring system (NH-CSS), SRS diagnostic criteria. We screened various IDs by methylation analysis for differentially methylated regions (DMRs) related to known IDs. We also performed clinical analysis.

Results: These 249 patients with SGA-SS were classified into the "SRS-compatible group" (n = 148), the "non-SRS with normocephaly or relative macrocephaly at birth group" (non-SRS group) (n = 94), or the "non-SRS with relative microcephaly at birth group" (non-SRS with microcephaly group) (n = 7). The 44.6% of patients in the "SRS-compatible group," 21.3% of patients in the "non-SRS group," and 14.3% in the "non-SRS with microcephaly group" had various IDs. Loss of methylation of the H19/IGF2:intergenic-DMR and uniparental disomy chromosome 7, being major genetic causes of SRS, was detected in 30.4% of patients in the "SRS-compatible group" and in 13.8% of patients in the "non-SRS group."

Conclusion: We clarified the contribution of IDs as (epi)genetic causes of SGA-SS and the molecular and phenotypic spectrum of SRS. Various IDs constitute underlying factors for SGA-SS, including SRS.
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http://dx.doi.org/10.1210/clinem/dgaa856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7947753PMC
March 2021

Genome-wide methylation analysis in Silver-Russell syndrome, Temple syndrome, and Prader-Willi syndrome.

Clin Epigenetics 2020 10 22;12(1):159. Epub 2020 Oct 22.

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

Background: Imprinting disorders (IDs) show overlapping phenotypes, particularly in Silver-Russell syndrome (SRS), Temple syndrome (TS14), and Prader-Willi syndrome (PWS). These three IDs include fetal and postnatal growth failure, feeding difficulty, and muscular hypotonia as major clinical features. However, the mechanism that causes overlapping phenotypes has not been clarified. To investigate the presence or absence of methylation signatures associated with overlapping phenotypes, we performed genome-wide methylation analysis (GWMA).

Results: GWMA was carried out on 36 patients with three IDs (SRS [n = 16], TS14 [n = 7], PWS [n = 13]) and 11 child controls using HumanMethylation450 BeadChip including 475,000 CpG sites across the human genome. To reveal an aberrantly methylated region shared by SRS, TS14, and PWS groups, we compared genome-wide methylation data of the three groups with those of control subjects. All the identified regions were known as SRS-, TS14-, and PWS-related imprinting-associated differentially methylated regions (iDMRs), and there was no hypermethylated or hypomethylated region shared by different ID groups. To examine the methylation pattern shared by SRS, TS14, and PWS groups, we performed clustering analysis based on GWMA data. The result focusing on 620 probes at the 62 known iDMRs (except for SRS-, TS14-, and PWS-related iDMRs) classified patients into two categories: (1) category A, grossly normal methylation patterns mainly consisting of SRS group patients; and (2) category B, broad and mild hypermethylation patterns mainly consisting of TS14 and PWS group patients. However, we found no obvious relationship between these methylation patterns and phenotypes of patients.

Conclusions: GWMA in three IDs found no methylation signatures shared by SRS, TS14, and PWS groups. Although clustering analysis showed similar mild hypermethylation patterns in TS14 and PWS groups, further study is needed to clarify the effect of methylation patterns on the overlapping phenotypes.
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http://dx.doi.org/10.1186/s13148-020-00949-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583213PMC
October 2020

Identification and functional characterization of a novel mutation (p.His39Pro) causing familial thyroid hypoplasia.

Clin Pediatr Endocrinol 2020 3;29(4):173-178. Epub 2020 Oct 3.

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

Mutations in , the gene for a thyroid-specific transcription factor, causes congenital hypothyroidism (CH) with autosomal dominant inheritance. All previously detected mutations except one are located in the DNA-binding paired domain The proband, a 1-yr-old boy, was diagnosed with CH in the frame of newborn screening. He had high serum TSH level (180 mU/L) and low serum free T level (0.4 ng/dL). Ultrasonography revealed that the proband had thyroid hypoplasia. Importantly, he had a family history of CH, , his mother also had CH and hypoplasia. Next generation sequencing-based mutation screening revealed a novel heterozygous mutation (c.116A>C, p.His39Pro) that was transmitted to the proband from the mother. Expression experiments with HeLa cells confirmed that His39Pro-PAX8 exhibited defective transactivation of the promoter-luciferase reporter. In conclusion, we identified and described a novel loss-of-function mutation in a family with thyroid hypoplasia. Patients with dominantly inherited CH and no extrathyroidal abnormalities could have mutations.
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http://dx.doi.org/10.1297/cpe.29.173DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7534521PMC
October 2020

Kagami-Ogata syndrome in a patient with 46,XX,t(2;14)(q11.2;q32.2)mat disrupting MEG3.

J Hum Genet 2021 Apr 16;66(4):439-443. Epub 2020 Oct 16.

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

Kagami-Ogata syndrome (KOS14) is a rare imprinting disorder characterized by a unique constellation of phenotypes including bell-shaped small thorax with coat-hanger appearance of the ribs. We encountered an African American female infant with KOS14 phenotype and 46,XX,t(2;14)(q11.2;q32.2)mat. After excluding upd(14)pat and an epimutation (hypermethylation) and a deletion affecting the maternally derived 14q32.2 imprinted region, we performed whole-genome sequencing, revealing that the translocation was generated between noncoding region at 2q11.2 and intron 6 of MEG3 at 14q32.2. Subsequent Sanger sequencing for the fusion points showed that the chromosomal fusion on the der(2) chromosome occurred between Chr2:102,193,994 (bp) and Chr14:101,314,628 (bp) in association with an insertion of 5-bp segment of unknown origin and that on the der(14) chromosome took place between Chr14:101,314,627 (bp) and Chr2:102,193,995 (bp) in association with an insertion of 1-bp segment of unknown origin (according to GRCh37/hg19). The results, together with the previous data in patients with KOS14, imply that the MEG3 disruption by 46,XX,t(2;14)(q11.2;q32.2)mat caused silencing of all MEGs including RTL1as and resultant excessive RTL1 expression, leading to the development of KOS14. To our knowledge, while Robertsonian translocations involving chromosome 14 have been reported in KOS14, this is the first case of KOS14 caused by a chromosomal translocation involving the 14q32.2 imprinted region.
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http://dx.doi.org/10.1038/s10038-020-00858-xDOI Listing
April 2021

Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development.

Sci Rep 2020 10 15;10(1):17375. Epub 2020 Oct 15.

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

Although splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons. Here, we report an MAP3K1 splice variant identified in two siblings with 46,XY disorder of sex development. The patients carried a maternally derived c.2254C>T variant. The variant was initially recognized as a nonsense substitution leading to nonsense-mediated mRNA decay (p.Gln752Ter); however, RT-PCR for lymphoblastoid cell lines showed that this variant created a new splice donor site and caused 39 amino acid deletion (p.Gln752_Arg790del). All transcripts from the variant allele appeared to undergo altered splicing. The two patients exhibited undermasculinized genitalia with and without hypergonadotropism. Testosterone enanthate injections and dihydrotestosterone ointment applications yielded only slight increase in their penile length. Dihydrotestosterone-induced APOD transactivation was less significant in patients' genital skin fibroblasts compared with that in control samples. This study provides an example of nonsense-associated altered splicing, in which a highly potent exonic splice site was created. Furthermore, our data, in conjunction with the previous data indicating the association between MAP3K1 and androgen receptor signaling, imply that the combination of testicular dysgenesis and androgen insensitivity may be a unique phenotype of MAP3K1 abnormalities.
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http://dx.doi.org/10.1038/s41598-020-74405-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7567082PMC
October 2020

TSC1 intragenic deletion transmitted from a mosaic father to two siblings with cardiac rhabdomyomas: Identification of two aberrant transcripts.

Eur J Med Genet 2020 Nov 2;63(11):104060. Epub 2020 Sep 2.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan. Electronic address:

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by non-cancerous tumors in multiple organs including the brain, kidney, lung, heart, and skin. We encountered a Japanese family consisting of two siblings (a four-year-old boy and a one-year-old girl) with multiple cardiac rhabdomyomas conveying a high risk of TSC and apparently unaffected sibling (a two-year-old girl) and parents. Whole exome sequencing and application of Integrative Genomic Viewer revealed an identical intragenic TSC1 deletion with the breakpoints on intron 15 and exon 19 in the affected siblings, but not in the apparently unaffected sibling and parents. Subsequently, PCR-based analyses were performed using primers flanking the deletion, showing that the deletion was also present in the father and that the deletion occurred between chr9:135,777,038 (bp) and chr9:135,780,540 (bp) in association with a one bp overlap. Furthermore, RT-PCR analyses were carried out using lymphoblastoid cell lines, revealing a major in-frame insertion/deletion transcript produced by aberrant splicing using a cryptic ″ag″ splice acceptor motif at intron 15 (r.1998_2438delinsTTCATTAGGTGG) and a minor frameshift transcript generated by aberrant splicing between exon 15 and exon 20 (r.1998_2502del, p.Lys666Asnfs*15) in the affected siblings. These findings imply that the intragenic deletion producing two aberrant transcripts was generated as a somatic pathogenic variant involving the germline in the father and was transmitted to the affected siblings.
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http://dx.doi.org/10.1016/j.ejmg.2020.104060DOI Listing
November 2020

Insulin resistant diabetes mellitus in SHORT syndrome: case report and literature review.

Endocr J 2021 Jan 3;68(1):111-117. Epub 2020 Sep 3.

Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu 431-3192, Japan.

SHORT syndrome is a rare developmental disorder frequently associated with growth failure and insulin resistant diabetes mellitus (IRDM). Since GH has a diabetogenic effect, GH therapy has been regarded as a contraindication. We observed a Brazilian girl with SHORT syndrome who received GH therapy from 4 6/12 years of age for SGA short stature. GH dosage was increased from 0.23 to 0.36 mg/kg/week, but statural response to GH therapy remained poor. Her blood HbA1c level, though it remained 5.5-6.0% in childhood, began to elevate with puberty and increased to 9.2% at 10 6/12 years of age, despite the discontinuation of GH therapy at 9 11/12 years of age. Laboratory studies indicated antibody-negative IRDM. She was treated with metformin and canagliflozin (a sodium glucose co-transporter 2 (SGLT2) inhibitor), which ameliorated overt diurnal hyperglycemia and mild nocturnal hypoglycemia and reduced her blood HbA1c around 7%. Whole exome sequencing revealed a de novo heterozygous pathogenic variant (c.1945C>T:p.(Arg649Trp)) in PIK3R1 known as the sole causative gene for SHORT syndrome. Subsequent literature review for patients with molecularly confirmed SHORT syndrome revealed the development of IRDM in 10 of 15 GH-untreated patients aged ≥12 years but in none of three GH-treated and six GH-untreated patients aged ≤10 years. These findings imply a critical role of pubertal development and/or advanced age rather than GH therapy in the development of IRDM, and a usefulness of SGLT2 inhibitor in the treatment of IRDM.
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http://dx.doi.org/10.1507/endocrj.EJ20-0291DOI Listing
January 2021

Human Spermatogenesis Tolerates Massive Size Reduction of the Pseudoautosomal Region.

Genome Biol Evol 2020 11;12(11):1961-1964

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

Mammalian male meiosis requires homologous recombination between the X and Y chromosomes. In humans, such recombination occurs exclusively in the short arm pseudoautosomal region (PAR1) of 2.699 Mb in size. Although it is known that complete deletion of PAR1 causes spermatogenic arrest, no studies have addressed to what extent male meiosis tolerates PAR1 size reduction. Here, we report two families in which PAR1 partial deletions were transmitted from fathers to their offspring. Cytogenetic analyses revealed that a ∼400-kb segment at the centromeric end of PAR1, which accounts for only 14.8% of normal PAR1 and 0.26% and 0.68% of the X and Y chromosomes, respectively, is sufficient to mediate sex chromosomal recombination during spermatogenesis. These results highlight the extreme recombinogenic activity of human PAR1. Our data, in conjunction with previous findings from animal studies, indicate that the minimal size requirement of mammalian PARs to maintain male fertility is fairly small.
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http://dx.doi.org/10.1093/gbe/evaa168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7608489PMC
November 2020

Assisted reproductive technology represents a possible risk factor for development of epimutation-mediated imprinting disorders for mothers aged ≥ 30 years.

Clin Epigenetics 2020 07 22;12(1):111. Epub 2020 Jul 22.

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

Backgrounds: The proportion of assisted reproductive technology (ART)-conceived livebirths of patients with imprinting disorders (IDs) is higher than that of the general population. Whether this is due to ART or confounding effects of advanced parental age was not investigated. We examined the association of ART and parental ages at childbirth for the development of eight epimutation-mediated imprinting disorders (epi-IDs).

Results: We enrolled 136 patients with epi-IDs and obtained general population ART data from the Japanese robust nationwide registry. We compared the proportion of ART-conceived livebirths and maternal childbearing ages between patients with epi-IDs and the general population. The proportion of ART-conceived livebirths in patients with epi-IDs was higher than that in mothers aged ≥ 30 years, the age group in which more than 90% of ART procedures performed. The maternal childbearing ages of patients with epi-IDs were widely distributed from 19 to 45 (median: 32) within the approximate 2.5th to 97.5th percentiles of maternal childbearing ages of the general population. In addition, we compared the proportion of ART-conceived livebirths and parental ages at childbirth across patients with eight epi-IDs. We demonstrated that more than 90% of ART-conceived patients with epi-IDs were found in Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) patients, and parental ages were almost consistent in patients with eight epi-IDs, except Prader-Willi syndrome.

Conclusions: According to the prerequisite that most of the ART procedures in Japan are performed on mothers aged ≥ 30 years, ART can be a risk factor for the development of epi-IDs, particularly SRS and BWS, for mothers aged ≥ 30 years.
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http://dx.doi.org/10.1186/s13148-020-00900-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7374921PMC
July 2020

Rare variant of the epigenetic regulator SMCHD1 in a patient with pituitary hormone deficiency.

Sci Rep 2020 07 3;10(1):10985. Epub 2020 Jul 3.

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

Isolated hypogonadotropic hypogonadism (IHH), combined pituitary hormone deficiency (CPHD), and septo-optic dysplasia (SOD) constitute a disease spectrum whose etiology remains largely unknown. This study aimed to clarify whether mutations in SMCHD1, an epigenetic regulator gene, might underlie this disease spectrum. SMCHD1 is a causative gene for Bosma arhinia microphthalmia syndrome characterized by arhinia, microphthalmia and IHH. We performed mutation screening of SMCHD1 in patients with etiology-unknown IHH (n = 31) or CPHD (n = 43, 19 of whom also satisfied the SOD diagnostic criteria). Rare variants were subjected to in silico analyses and classified according to the American College of Medical Genetics and Genomics guidelines. Consequently, a rare likely pathogenic variant, p.Asp398Asn, was identified in one patient. The patient with p.Asp398Asn exhibited CPHD, optic nerve hypoplasia, and a thin retinal nerve fiber layer, and therefore satisfied the criteria of SOD. This patient showed a relatively low DNA methylation level of the 52 SMCHD1-target CpG sites at the D4Z4 locus. Exome sequencing for the patient excluded additional variants in other IHH/CPHD-causative genes. In vitro assays suggested functional impairment of the p.Asp398Asn variant. These results provide the first indication that SMCHD1 mutations represent a rare genetic cause of the HH-related disease spectrum.
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http://dx.doi.org/10.1038/s41598-020-67715-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335161PMC
July 2020

Treatment approaches for congenital transverse limb deficiency: Data analysis from an epidemiological national survey in Japan.

J Orthop Sci 2021 Jul 26;26(4):650-654. Epub 2020 Jun 26.

Department of Rehabilitation Medicine, The University of Tokyo Hospital, Tokyo, Japan. Electronic address:

Background: Congenital limb deficiency is a rare anomaly that impairs limb function. Transverse deficiency accounts for approximately half of congenital limb deficiency cases. In Japan, there have been no detailed data of clinical features, especially treatment approaches, of this disorder. The present study aimed to investigate the status of treatment approaches of congenital transverse limb deficiency in Japan.

Methods: From the national epidemiological survey of congenital limb deficiency undertaken in Japan in 2016, all the data of 200 patients with congenital transverse limb deficiencies were extracted. These data were analysed to reveal the treatment approaches of congenital transverse limb deficiency and its basic clinical features.

Results: Surgical treatments and prosthetic or orthotic intervention had been implemented or planned for about one-quarter of patients, respectively. In the upper limb deficiencies, prosthetic or orthotic intervention was likely chosen in cases of deficiency at the metacarpal or proximal to metacarpal level. Surgical treatment was chosen only in cases of deficiency at the carpal or distal to carpal level. Although the number of patients with transverse lower limb deficiencies was small, prosthetic or orthotic intervention was likely chosen in proximal deficiencies, and surgical treatment was likely chosen in distal deficiencies.

Conclusions: Herein, we revealed the status of treatment approaches for congenital transverse limb deficiency in Japan. Approximately half of the patients had no history of-and no plans for-surgical, prosthetic, or orthotic interventions. Further treatment advances may enable patients with congenital limb deficiencies to increase their participation in daily activities.

Study Design: Cross-sectional survey.
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http://dx.doi.org/10.1016/j.jos.2020.05.008DOI Listing
July 2021

Coffin-Lowry syndrome in a girl with 46,XX,t(X;11)(p22;p15)dn: Identification of disruption by whole genome sequencing.

Clin Case Rep 2020 Jun 6;8(6):1076-1080. Epub 2020 Apr 6.

Department of Pediatrics Hamamatsu University School of Medicine Hamamatsu Japan.

We report a Japanese girl with Coffin-Lowry syndrome phenotype such as hypertelorism, hypodontia, and tapering fingers and 46,XX,t(X;11)(p22;p15)dn. Whole genome sequencing revealed disruption by the translocation, and X-inactivation analysis indicated preferential inactivation of the normal X chromosome. The results explain the development of an X-linked disease in this girl.
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http://dx.doi.org/10.1002/ccr3.2826DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7303873PMC
June 2020

Loss of imprinting of the human-specific imprinted gene causes prenatal growth retardation and dysmorphic features: implications for phenotypic overlap with Silver-Russell syndrome.

J Med Genet 2021 Jun 23;58(6):427-432. Epub 2020 Jun 23.

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

Background: , encoding a zinc-finger protein, is the human-specific maternally expressed imprinted gene located on 16p13.3. The parent-of-origin expression of is regulated by the :TSS-DMR, of which only the paternal allele acquires methylation during postimplantation period. Overexpression of may contribute to some of the phenotypes associated with maternal uniparental disomy of chromosome 16 (UPD(16)mat), and some patients with UPD(16)mat presenting with Silver-Russell syndrome (SRS) phenotype have recently been reported.

Methods: A 6-year-old boy presented with prenatal growth restriction, macrocephaly at birth, forehead protrusion in infancy and clinodactyly of the fifth finger. Methylation, expression, microsatellite marker, single nucleotide polymorphism array and trio whole-exome sequencing analyses were conducted.

Results: Isolated hypomethylation of the :TSS-DMR and subsequent loss of imprinting and overexpression of were confirmed in the patient. Epigenetic alterations, such as UPD including UPD(16)mat and other methylation defects, were excluded. Pathogenic sequence or copy number variants affecting his phenotypes were not identified, indicating that primary epimutation occurred postzygotically.

Conclusion: We report the first case of isolated imprinting defect, showing phenotypic overlap with SRS despite not satisfying the clinical SRS criteria. A novel imprinting disorder entity involving the imprinted domain can be speculated.
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http://dx.doi.org/10.1136/jmedgenet-2020-107019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8142457PMC
June 2021

Contribution of gene mutations to Silver-Russell syndrome phenotype: multigene sequencing analysis in 92 etiology-unknown patients.

Clin Epigenetics 2020 06 16;12(1):86. Epub 2020 Jun 16.

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

Background: Silver-Russell syndrome (SRS) is characterized by growth failure and dysmorphic features. Major (epi)genetic causes of SRS are loss of methylation on chromosome 11p15 (11p15 LOM) and maternal uniparental disomy of chromosome 7 (upd(7)mat). However, IGF2, CDKN1C, HMGA2, and PLAG1 mutations infrequently cause SRS. In addition, other imprinting disturbances, pathogenic copy number variations (PCNVs), and monogenic disorders sometimes lead to SRS phenotype. This study aimed to clarify the frequency and clinical features of the patients with gene mutations among etiology-unknown patients with SRS phenotype.

Results: Multigene sequencing was performed in 92 out of 336 patients referred to us for genetic testing for SRS. The clinical features of the patients were evaluated based on the Netchine-Harbison clinical scoring system. None of the patients showed 11p15 LOM, upd(7)mat, abnormal methylation levels for six differentially methylated regions (DMRs), namely, PLAGL1:alt-TSS-DMR on chromosome 6, KCNQ1OT1:TSS-DMR on chromosome 11, MEG3/DLK1:IG-DMR on chromosome 14, MEG3:TSS-DMR on chromosome 14, SNURF:TSS-DMR on chromosome 15, and GNAS A/B:TSS-DMR on chromosome 20, PCNVs, or maternal uniparental disomy of chromosome 16. Using next-generation sequencing and Sanger sequencing, we screened four SRS-causative genes and 406 genes related to growth failure and/or skeletal dysplasia. We identified four pathogenic or likely pathogenic variants in responsible genes for SRS (4.3%: IGF2 in two patients, CDKN1C, and PLAG1), and five pathogenic variants in causative genes for known genetic syndromes presenting with growth failure (5.4%: IGF1R abnormality (IGF1R), SHORT syndrome (PIK3R1), Floating-Harbor syndrome (SRCAP), Pitt-Hopkins syndrome (TCF4), and Noonan syndrome (PTPN11)). Functional analysis indicated the pathogenicity of the CDKN1C variant. The variants we detected in CDKN1C and PLAG1 were the second and third variants leading to SRS, respectively. Our patients with CDKN1C and PLAG1 variants showed similar phenotypes to previously reported patients. Furthermore, our data confirmed IGF1R abnormality, SHORT syndrome, and Floating-Harbor syndrome are differential diagnoses of SRS because of the shared phenotypes among these syndromes and SRS. On the other hand, the patients with pathogenic variants in causative genes for Pitt-Hopkins syndrome and Noonan syndrome were atypical of these syndromes and showed partial clinical features of SRS.

Conclusions: We identified nine patients (9.8%) with pathogenic or likely pathogenic variants out of 92 etiology-unknown patients with SRS phenotype. This study expands the molecular spectrum of SRS phenotype.
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http://dx.doi.org/10.1186/s13148-020-00865-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7298762PMC
June 2020

Long-term efficacy and safety of two doses of Norditropin (somatropin) in Noonan syndrome: a 4-year randomized, double-blind, multicenter trial in Japanese patients.

Endocr J 2020 Aug 9;67(8):803-818. Epub 2020 May 9.

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

This 4-year randomized, double-blind, multicenter trial (NCT01927861) investigated the long-term efficacy and safety of Norditropin (NN-220; somatropin) in Japanese children with short stature due to Noonan syndrome. Pre-pubertal children with Noonan syndrome were randomized 1:1 to receive 0.033 mg/kg/day (n = 25, mean age 6.57 years) or 0.066 mg/kg/day (n = 26, mean age 6.06 years) GH. Height standard deviation score (SDS) change after 208 weeks from baseline was evaluated using an analysis of covariance model. Height SDS improved from -3.24 at baseline with a significantly greater increase (estimated mean [95% confidence interval]) with 0.066 vs. 0.033 mg/kg/day GH (1.84 [1.58; 2.10] vs. 0.85 [0.59; 1.12]; estimated mean difference 0.99 [0.62; 1.36]; p < 0.0001). The majority of treatment-emergent adverse events (TEAEs) were non-serious, mild and assessed as unlikely treatment-related. TEAE rates and frequencies of serious TEAEs were similar between groups. Three patients receiving 0.066 mg/kg/day were withdrawn; two due to TEAEs at days 1,041 and 1,289. Mean insulin-like growth factor-I SDS increased from -1.71 to -0.75 (0.033 mg/kg/day) and 0.57 (0.066 mg/kg/day) (statistically significant difference). In both groups, there were only minor glycosylated hemoglobin changes, similar oral glucose tolerance test insulin response increases and no clinically relevant changes in oral glucose tolerance test blood glucose, vital signs, electrocardiogram or transthoracic echocardiography. In conclusion, treatment with 0.033 and 0.066 mg/kg/day GH for 208 weeks improved height SDS in Japanese children with short stature due to Noonan syndrome with a significantly greater increase with 0.066 vs. 0.033 mg/kg/day GH and was well tolerated, with no new safety concerns.
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http://dx.doi.org/10.1507/endocrj.EJ19-0371DOI Listing
August 2020
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