研究者詳細 - 鳴海　覚志

論文 - 鳴海　覚志

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Single-Exon Deletions of ZNRF3 Exon 2 Cause Congenital Adrenal Hypoplasia

Amano N., Narumi S., Aizu K., Miyazawa M., Okamura K., Ohashi H., Katsumata N., Ishii T., Hasegawa T.

Journal of Clinical Endocrinology and Metabolism 109 （ 3 ） 641 - 648 2024年03月

ISSN 0021972X

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition characterized by the inability of the adrenal cortex to produce sufficient steroid hormones. E3 ubiquitin protein ligase zinc and ring finger 3 (ZNRF3) is a negative regulator of Wnt/β-catenin signaling. R-spondin 1 (RSPO1) enhances Wnt/β-catenin signaling via binding and removal of ZNRF3 from the cell surface. Objective: This work aimed to explore a novel genetic form of PAI. Methods: We analyzed 9 patients with childhood-onset PAI of biochemically and genetically unknown etiology using array comparative genomic hybridization. To examine the functionality of the identified single-exon deletions of ZNRF3 exon 2, we performed three-dimensional (3D) structure modeling and in vitro functional studies. Results: We identified various-sized single-exon deletions encompassing ZNRF3 exon 2 in 3 patients who showed neonatal-onset adrenal hypoplasia with glucocorticoid and mineralocorticoid deficiencies. Reverse-transcriptase polymerase chain reaction (RT-PCR) analysis showed that the 3 distinct single-exon deletions were commonly transcribed into a 126-nucleotide deleted mRNA and translated into 42-amino acid deleted protein (ΔEx2-ZNRF3). Based on 3D structure modeling, we predicted that interaction between ZNRF3 and RSPO1 would be disturbed in ΔEx2-ZNRF3, suggesting loss of RSPO1-dependent activation of Wnt/β-catenin signaling. Cell-based functional assays with the TCF-LEF reporter showed that RSPO1-dependent activation of Wnt/β-catenin signaling was attenuated in cells expressing ΔEx2-ZNRF3 as compared with those expressing wild-type ZNRF3. Conclusion: We provided genetic evidence linking deletions encompassing ZNRF3 exon 2 and congenital adrenal hypoplasia, which might be related to constitutive inactivation of Wnt/β-catenin signaling by ΔEx2-ZNRF3.

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Prolongation of the Menstrual Cycle after Receipt of the Primary Series and Booster Doses of mRNA Coronavirus Disease 2019 (COVID-19) Vaccination

Hosoya S., Piedvache A., Nakamura A., Nasu R., Hine M., Itoi S., Yokomizo R., Umezawa A., Hiraike O., Koga K., Osuga Y., Narumi S., Morisaki N.

Obstetrics and Gynecology 143 （ 2 ） 284 - 293 2024年02月

ISSN 00297844

OBJECTIVE:To quantitatively evaluate the effect of a booster vaccination dose against coronavirus disease 2019 (COVID-19) on menstrual cycle in a large-scale retrospective cohort study using a menstrual cycle tracking smartphone application (app).METHODS:Prospectively or retrospectively recorded data, including the start and finish dates of menstrual cycles, were collected with the app. Detailed data on vaccinations, side effects, and participants' characteristics were retrospectively collected from a questionnaire on the app. For each COVID-19 vaccination shot (first, second, and third), within-individual changes in menstrual cycle length up to the fourth postvaccination cycle were evaluated.RESULTS:Among the 7,376 and 6,873 participants who had the first and second COVID-19 vaccine doses in different menstrual cycles, respectively, menstrual cycles immediately after the vaccination (first postvaccination cycles) were an average of 0.22 days (95% CI, 0.06-0.39) and 0.37 days (95% CI, 0.20-0.54) longer than the prevaccination cycle. In contrast, among the 1,672 participants who received the first and second doses in the same cycle, the first postvaccination cycle was an average of 4.21 days (95% CI, 3.69-4.72) longer. The second to fourth postvaccination cycles returned to the level of the prevaccination cycle. However, among the 4,768 participants who had the third COVID-19 vaccine dose, the menstrual cycle immediately after the vaccination was an average of 1.20 days (95% CI, 1.00-1.40) longer, with prolongation of cycles of 0.27 days (95% CI, 0.10-0.44) to 0.41 days (95% CI, 0.22-0.59) persisting from the second to the fourth postvaccination cycle.CONCLUSION:The booster shot against COVID-19 may have a greater and longer-lasting effect on menstrual cycles than the primary-series shots. Although the effect size was small, evidence on the side effects of immunization on menstruation should be accumulated.

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A thyroid adenoma in a pubertal male with thyroxine-binding globulin deficiency

Kim H., Naiki Y., Iwahashi-Odano M., Narumi S., Ito K., Ishiguro A.

Clinical Pediatric Endocrinology （Clinical Pediatric Endocrinology） 33 （ 1 ） 23 - 26 2024年01月

ISSN 09185739

Complete deficiency of thyroxin-binding globulin (TBG-CD) is not commonly associated with clinical symptoms, and little is known about thyroid tumors associated with TBG-CD. We present a case report of an asymptomatic follicular adenoma that spontaneously shrank in a patient with TBG-CD. A previously healthy 13-yr-old male presented with a diffusely swollen thyroid gland. Thyroid function tests revealed low total thyroxin and TBG concentrations, indicating a TBG deficiency. Ultrasonography revealed a mildly swollen thyroid gland with a nodule (14 × 12 × 19 mm) in the left lobe. Genetic analysis of peripheral blood revealed a previously reported SERPINA7 variant, which resulted in complete loss of TBG function. The nodule was identified as a follicular adenoma using fine-needle aspiration. Subsequently, the adenoma shrank without treatment. This pubertal case suggests that careful observation with ultrasonography is warranted for follicular adenoma in patients with TBG deficiency and that treatment may not be required.

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Usefulness of a mobile airwayscope with a monitor in examination of the external genitalia of a 483 g female neonate

Hiraizumi T., Sato T., Kobayashi H., Arimitsu T., Narumi S., Ishii T., Hasegawa T.

Pediatrics International （Wiley） 66 （ 1 ） e15759 2024年01月

ISSN 13288067

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Concurrent THRB and DUOX2 variants in a patient detected via newborn screening for congenital hypothyroidism: a case of resistance to thyroid hormone

Hatano M., Tanase-Nakao K., Uehara E., Iwano R., Muroya K., Narumi S.

Clinical Pediatric Endocrinology 33 （ 2 ） 94 - 100 2024年

ISSN 09185739

Most patients with resistance to thyroid hormone (RTH) test negative in newborn screening (NBS) for congenital hypothyroidism (CH). Here, we present a case of RTH diagnosed through NBS. The patient presented to us after her NBS for CH revealed high TSH (23.4 µIU/mL) and free T4 (FT4) (5.40 ng/dL) levels. Apart from tachycardia, she exhibited no other manifestations related to excess or deficiency of thyroid hormones. A confirmatory test replicated the findings, showing elevated serum TSH levels (35.7 µIU/mL) along with high FT4 levels (5.84 ng/ dL). Ultrasonography showed marked thyroid gland enlargement (> +4 SD). Targeted next-generation sequencing of genes associated with genetic thyroid disorders revealed a previously reported THRB variant, p.Gly345Cys. Unexpectedly, two biallelic DUOX2 variants (p.His678Arg and p.Arg1334Trp) were also detected. At her last visit, no significant issues were observed with neurological development, growth, bone maturation, or gastrointestinal symptoms related to thyroid function at the age of 1 year, without treatment for RTH and CH. During follow-up, the TSH and FT4 levels gradually decreased. In conclusion, we report a patient with simultaneous RTH and DUOX2 defects, demonstrating the value of conducting a comprehensive analysis of multiple genes associated with thyroid diseases to better comprehend the pathogenesis in patients with atypical thyroid-related phenotypes.

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Impact of COVID-19 on paediatric care in Japan: Analysis of national health insurance claims data

Ohnishi T., Kinoshita M., Narumi S.

Acta Paediatrica, International Journal of Paediatrics 2024年

ISSN 08035253

Aim: To quantify the impact of the COVID-19 pandemic on paediatric care use compared to adult care and identify affected subdomains. Methods: Data from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) for six fiscal years (FY2016-2021) were analysed. Pre-pandemic (FY2016-FY2019) and pandemic years (FY2020, FY2021) were compared to delineate changes in medical services for paediatric and adult patients. Virtually all individuals who received medical care in Japan during this period were included. Results: In FY2019, healthcare utilisation by the paediatric population (under 15 years) accounted for 24% of 245 million first outpatient visits, 7% of 1.2 billion follow-up visits, and 2.6% of 297 million patient-days hospitalisations. In FY2020, outpatient visits of those aged 0–4 years decreased by 44% (first visit) and 24% (follow-up visit) compared to FY2019, and hospitalisations decreased by 47%, with the largest declines observed in community medical institutions across all age groups. Conclusion: The COVID-19 pandemic led to a substantial reduction in paediatric healthcare utilisation in Japan, varying by age and type of care. These findings may inform the rational allocation of healthcare resources during public health emergencies.

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DHX37 Variant Is One of the Common Genetic Causes in Japanese Patients with Testicular Regression Syndrome/Partial Gonadal Dysgenesis without Müllerian Derivatives

Shimura K., Ichihashi Y., Nakano S., Sato T., Hamajima T., Numasawa K., Narumi S., Hasegawa T., Ishii T.

Hormone Research in Paediatrics （S. Karger AG） 98 （ 2 ） 1 - 8 2024年

ISSN 16632818

Introduction: The testicular regression syndrome (TRS) is a form of differences of sex development (DSD) in which the testes differentiate and function during early embryonic development, but subsequently regress. The clinical phenotype of TRS often overlaps with that of partial gonadal dysgenesis (PGD). Previous studies have demonstrated a causal association between TRS/ PGD and heterozygous missense variants of DHX37. Methods: We enrolled 11 Japanese 46,XY individuals (from 10 families) with TRS/PGD who exhibited undetected or hypoplastic testes, Möllerian duct regression, and low serum testosterone or anti-Möllerian hormone levels. The subjects underwent targeted sequencing of 36 known causative genes for DSD, PCR-based Sanger sequencing of DHX37, or whole-exome sequencing. Results: Previously described pathogenic variants or novel nonsense variants (SRY, NR5A1, and DMRT1) were observed in four out of 10 families. Additionally, we identified two heterozygous rare variants of DHX37 in four families: A previously reported pathogenic variant (c.923G>A, p.Arg308Gln) in three and a novel likely pathogenic variant (c.1882A>C, p.Thr628Pro) in one. The external genitalia of patients with the DHX37 variants varied from female-Type to male-Type without micropenis. Eighty percent of Japanese patients with TRS/PGD had monogenic disorders including DHX37 variant being the most commonly identified (40%). The external or internal genital phenotype of TRS/PGD overlaps between DHX37 variant carriers and others. Conclusions: DHX37 variant is one of the common genetic causes in Japanese patients with TRS/PGD without Möllerian derivatives. Genetic test is helpful in detecting DHX37-related TRS/PGD because of the phenotypic diversity of the external genitalia in this disorder.

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Deciphering the mystery of CHNG3

Narumi S.

Annals of Pediatric Endocrinology and Metabolism 29 （ 5 ） 279 - 283 2024年

ISSN 22871012

Congenital hypothyroidism (CH), characterized by insufficient thyroid hormone production due to abnormalities in the hypothalamic-pituitary-thyroid axis, is the most common congenital endocrine disorder. We previously conducted comprehensive genetic screening of 102 patients with permanent CH born in Kanagawa Prefecture, Japan and identified mutations in several genes in 19 CH patients, including defects in genes encoding dual oxidase 2, thyroglobulin, thyrotropin receptor, thyroid peroxidase, and paired-box 8. Despite these findings, approximately 80% of cases remain unexplained. CH pedigrees unexplained by known genetic forms of CH have been reported in the literature and registered as congenital hypothyroidism, nongoitrous, 3 (CHNG3; %609893) in Online Mendelian Inheritance in Man. We also identified a Japanese pedigree of CH that was compatible with CHNG3. However, the exact genetic cause of CHNG3 was not revealed by standard analysis methods such as exome sequencing and array comparative genomic hybridization. We therefore took a combined approach and analyzed a total of 11 undiagnosed CH pedigrees by whole genome sequencing to analyze a 3-Mb linkage region, and found a disease-causing variant affecting a TTTG microsatellite in a noncoding region on chromosome 15. Further analysis revealed that 13.9% of 989 Japanese CH patients had abnormalities involving the TTTG microsatellite, with a substantial proportion (41.5%) of familial CH cases carrying these mutations. Identification of the genetic cause of CHNG3 provides new insights into the pathogenesis of CH, and highlights the need for continued exploration of noncoding genomic regions in Mendelian disorders of unknown etiology.

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Congenital Hypothyroidism with Thyroid in situ: A Case Report with NKX2-1 and DUOX2 Hypomorphic Variants

Uehara E., Hori N., Tanase-Nakao K., Akiba K., Sueoka H., Matsubara K., Narumi S.

Hormone Research in Paediatrics 1 - 7 2024年

ISSN 16632818

Introduction: NK2 homeobox 1 (NKX2-1) encodes a transcription factor, NKX2-1, that is expressed in the thyroid gland, lung, and brain. Dual oxidase 2 (DUOX2) encodes an enzyme which generates hydrogen peroxide and is involved in the thyroid hormone synthesis. Cases of congenital hypothyroidism (CH) with dyshormonogenesis showing two or more genetic variants are increasingly reported. We describe the first case of transient dyshormonogenesis who had experimentally verified a loss-of-function NKX2-1 variant and DUOX2 variants. Case Presentation: The proband was a 15-year-old female patient with CH who was diagnosed in the frame of newborn screening for CH. She had a mildly elevated serum TSH level (14.56 mU/L), a low free thyroxine level (0.87 ng/dL), and a high thyroglobulin (Tg) level (>800 ng/mL). Ultrasonography revealed goiter. She was followed clinically without levothyroxine treatment and showed normal growth and development. She had slightly high Tg levels throughout the clinical course. Next-generation sequencing-based genetic analysis revealed that the patient was heterozygous for an NKX2-1 variant (p.Ile228Ser), a nonsense DUOX2 variant (p.[Lys530∗His678Arg]), and a functional DUOX2 polymorphism (p.His678Arg). NKX2-1 p.Ile228Ser showed about 50% reduced residual activity on the Tg promoter. Conclusion: A partial loss-of-function NKX2-1 variant with a monoallelic nonsense DUOX2 variant and a DUOX2 functional polymorphism can cause transient CH with high serum Tg levels.

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Siblings of neonatal hyperbilirubinemia with UGT1A1 double missense variants

Kubota Y., Sato T., Matsuyama M., Maruo Y., Narumi S., Ishii T., Hasegawa T.

Clinical Pediatric Endocrinology （Japanese Society for Pediatric Endocrinology） 33 （ 3 ） 195 - 198 2024年

ISSN 09185739

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A Small-for-Gestational-Age Infant with MIRAGE Syndrome Who Developed Heat Stroke and Rhabdomyolysis due to Severe Temperature Instability

Saito K., Nakagawa R., Narumi S., Ohashi H., Ishiguro A., Kabe K.

Neonatology （Neonatology） 120 （ 3 ） 390 - 394 2023年07月

ISSN 16617800

MIRAGE syndrome is characterized by myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy. This report describes heat stroke and rhabdomyolysis caused by anhidrosis as a symptom of MIRAGE syndrome in a small-for-gestational-age (SGA) female neonate born at 32 weeks of gestation (birth weight, 911 g [-3.8 SD]). She developed severe temperature instability with anhidrosis, growth failure, mild developmental delay, hypothyroidism, and intractable enteropathy. On day 156, her temperature reached 42.0°C; her fever persisted for 2 h with prolonged irritability. Her serum creatine kinase level increased to a peak value of 12,716 (normal range, 43-321) IU/L. The clinical feature was diagnosed as rhabdomyolysis caused by heat stroke, which resulted from physical exertion with anhidrosis. Her SAMD9 variant was c.2945G>A, p. (Arg982His). Neonatologists should be aware of MIRAGE syndrome as a differential diagnosis of SGA with temperature instability.

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Differential toxicity and localization of arginine-rich C9ORF72 dipeptide repeat proteins depend on de-clustering of positive charges

Miyagi T., Ueda K., Sugimoto M., Yagi T., Ito D., Yamazaki R., Narumi S., Hayamizu Y., Uji-i H., Kuroda M., Kanekura K.

iScience （iScience） 26 （ 6 ） 106957 - 106957 2023年06月

ISSN 2589-0042

Arginine-rich dipeptide repeat proteins (R-DPRs), poly(PR) and poly(GR), translated from the hexanucleotide repeat expansion in the amyotrophic lateral sclerosis (ALS)-causative C9ORF72 gene, contribute significantly to pathogenesis of ALS. Although both R-DPRs share many similarities, there are critical differences in their subcellular localization, phase separation, and toxicity mechanisms. We analyzed localization, protein-protein interactions, and phase separation of R-DPR variants and found that sufficient segregation of arginine charges is necessary for nucleolar distribution. Proline not only efficiently separated the charges, but also allowed for weak, but highly multivalent binding. In contrast, because of its high flexibility, glycine cannot fully separate the charges, and poly(GR) behaves similarly to the contiguous arginines, being trapped in the cytoplasm. We conclude that the amino acid that spaces the arginine charges determines the strength and multivalency of the binding, leading to differences in localization and toxicity mechanisms.

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Adult Thyroid Outcomes of Congenital Hypothyroidism

Sugisawa C., Narumi S., Tanase-Nakao K., Hoshiyama A., Suzuki N., Ohye H., Fukushita M., Matsumoto M., Yoshihara A., Watanabe N., Sugino K., Hishinuma A., Noh J.Y., Katoh R., Taniyama M., Ito K.

Thyroid （Thyroid） 33 （ 5 ） 556 - 565 2023年05月

ISSN 10507256

Background: More than 40 years have passed since the introduction of newborn screening (NBS) for congenital hypothyroidism (CH), and many early diagnosed patients have reached adulthood. Their thyroid morphology and function have been little studied. This cross-sectional, observational study was conducted to characterize the thyroid morphology and function of adult CH patients diagnosed in the framework of NBS for CH. Methods: A total of 103 adult CH patients born after 1979 were enrolled at Ito Hospital, Tokyo, Japan, and were classified into Goiter, Normal gland, and Dysgenesis groups based on ultrasonographic findings. For 60 patients, genetic analysis was performed. Thyroid function test results and the proportion of patients with thyroid nodules were compared among the three groups and between 56 female CH patients and 168 non-CH women matched for thyrotropin levels. Results: A significantly low serum free triiodothyronine/free thyroxine ratio (0.22) was observed in the Dysgenesis group. Thyroid nodules were detected in 14.3% (8/56) of female CH patients, more frequently than in non-CH women. Thyroid nodules were detected most frequently in the Goiter group (71%, 10/14). Genetic defects were identified in 89% (8/9) of patients belonging to the Goiter group, including thyroglobulin defect (33%, 3/9), thyroid peroxidase defect (33%, 3/9), and dual oxidase 2 defect (22%, 2/9). Conclusions: Our results suggest that adults with thyroid dysgenesis on levothyroxine replacement therapy have relative triiodothyronine deficiency. Most adults with goitrous CH have genetic dyshormonogenesis. They are at high risk of developing thyroid nodules. Our findings support the current guideline recommendation that CH patients with dyshormonogenesis should undergo periodic thyroid ultrasonography.

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Cord Blood Transplantation in 2 Infants Presenting Monosomy 7 Clonal Hematopoiesis: SAMD9 / SAMD9L Germline Mutation

Hirai M., Yagasaki H., Kanezawa K., Ueno M., Shimozawa K., Imai K., Morio T., Kato M., Gocho Y., Narumi S., Ebihara Y., Morioka I.

Journal of Pediatric Hematology/Oncology （Journal of Pediatric Hematology/Oncology） 45 （ 2 ） E290 - E293 2023年03月

ISSN 10774114

Recently, germline mutations in SAMD9 and SAMD9L were increasingly found in children with monosomy 7. We report the outcomes in 2 infants with the SAMD9/SAMD9L variant, who presented with anemia and thrombocytopenia (patient 1), and neutropenia and nonsymptomatic white-matter-encephalopathy (patient 2). Both patients received cord blood transplantation and experienced critical post-cord blood transplantation adverse events; patients 1 and 2 developed fulminant engraftment syndrome and life-threatening graft-versus-host disease, respectively. Of note, selective loss of chromosome 7 in bone marrow-derived CD34+ cells was inferred.

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若年者バセドウ病のMMI単独治療、MMI+KI併用治療の有効性と安全性に関する多施設共同観察研究(後ろ向きコホート研究)の現状報告

大江秀美, 南谷幹史, 宇野希世子, 金子徹治, 荒田尚子, 長谷川奉延, 伊藤順庸, 猪俣弘明, 内野眞也, 鬼形和道, 佐藤浩一, 杉原茂孝, 長崎啓祐, 鳴海覚志, 長谷川行洋, 原田正平, 深田修司, 久門真子, 御前隆, 横谷進, 吉村弘, 金城さおり, 春名英典, 松下理恵, 宮田市郎, 三善陽子, 虫本雄一, 堀川玲子, 室谷浩二, 日本甲状腺学会小児甲状腺疾患診療委員会

日本内分泌学会雑誌（(一社)日本内分泌学会） 98 （ 5 ） 1277 - 1277 2023年03月

ISSN 0029-0661

POU1F1/Pou1f1 c.143-83A > G Variant Disrupts the Branch Site in Pre-mRNA and Leads to Dwarfism

Akiba K., Hasegawa Y., Katoh-Fukui Y., Terao M., Takada S., Hasegawa T., Fukami M., Narumi S.

Endocrinology (United States) （Endocrinology (United States)） 164 （ 2 ） 2023年02月

査読有り, ISSN 00137227

POU Class 1 Homeobox1 (POU1F1/Pou1f1) is a well-established pituitary-specific transcription factor, and causes, when mutated, combined pituitary hormone deficiency in humans and mice. POU1F1/Pou1f1 has 2 isoforms: the alpha and beta isoforms. Recently, pathogenic variants in the unique coding region of the beta isoform (beta domain) and the intron near the exon-intron boundary for the beta domain were reported, although their functional consequences remain obscure. In this study, we generated mice carrying the Pou1f1 c.143-83A>G substitution that recapitulates the human intronic variant near the exon-intron boundary for the beta domain. Homozygous mice showed postnatal growth failure, with an average body weight that was 35% of wild-type littermates at 12 weeks, which was accompanied by anterior pituitary hypoplasia and deficiency of circulating insulin-like growth factor 1 and thyroxine. The results of RNA-seq analysis of the pituitary gland were consistent with reduction of somatotrophs, and this was confirmed immunohistochemically. Reverse transcription polymerase chain reaction of pituitary Pou1f1 mRNA showed abnormal splicing in homozygous mice, with a decrease in the alpha isoform, an increase in the beta isoform, and the emergence of the exon-skipped transcript. We further characterized artificial variants in or near the beta domain, which were candidate positions of the branch site in pre-mRNA, using cultured cell-basis analysis and found that only c.143-83A>G produced transcripts similar to the mice model. Our report is the first to show that the c.143-83A>G variant leads to splicing disruption and causes morphological and functional abnormalities in the pituitary gland. Furthermore, our mice will contribute understanding the role of POU1F1/Pou1f1 transcripts in pituitary development.

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女児鼠径ヘルニアを契機に診断された46,XY DSD症例の臨床遺伝学的検討

木村妙, 小田野めぐみ, 齋藤真希, 鳴海覚志, 長谷川奉延, 宮田市郎, 大石公彦

日本小児科学会雑誌（(公社)日本小児科学会） 127 （ 2 ） 199 - 199 2023年02月

ISSN 0001-6543

Graves' disease as an emerging complication of MIRAGE syndrome

Wada T., Mitani-Konno M., Tanase-Nakao K., Etani Y., Narumi S., Hasegawa Y., Kawai M.

Pediatrics International （Pediatrics International） 65 （ 1 ） e15678 2023年01月

ISSN 13288067

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Congenital anaemia associated with loss-of-function variants in DNA polymerase epsilon 1

Takeuchi I., Tanase-Nakao K., Ogawa A., Sugawara T., Migita O., Kashima M., Yamazaki T., Iguchi A., Naiki Y., Uchiyama T., Tamaoki J., Maeda H., Shimizu H., Kawai T., Taniguchi K., Hirata H., Kobayashi M., Matsumoto K., Naruse K., Hata K., Akutsu H., Kato T., Narumi S., Arai K., Ishiguro A.

Journal of Medical Genetics （Journal of Medical Genetics） 61 （ 3 ） 239 - 243 2023年

ISSN 00222593

DNA polymerase epsilon (Pol ϵ), a component of the core replisome, is involved in DNA replication. Although genetic defects of Pol ϵ have been reported to cause immunodeficiency syndromes, its role in haematopoiesis remains unknown. Here, we identified compound heterozygous variants (p.[Asp1131fs];[Thr1891del]) in POLE, encoding Pol ϵ catalytic subunit A (POLE1), in siblings with a syndromic form of severe congenital transfusion-dependent anaemia. In contrast to Diamond-Blackfan anaemia, marked reticulocytopenia or marked erythroid hypoplasia was not found. Their bone marrow aspirates during infancy revealed erythroid dysplasia with strongly positive TP53 in immunostaining. Repetitive examinations demonstrated trilineage myelodysplasia within 2 years from birth. They had short stature and facial dysmorphism. HEK293 cell-based expression experiments and analyses of patient-derived induced pluripotent stem cells (iPSCs) disclosed a reduced mRNA level of Asp1131fs-POLE1 and defective nuclear translocation of Thr1891del-POLE1. Analysis of iPSCs showed compensatory mRNA upregulation of the other replisome components and increase of the TP53 protein, both suggesting dysfunction of the replisome. We created Pole-knockout medaka fish and found that heterozygous fishes were viable, but with decreased RBCs. Our observations expand the phenotypic spectrum of the Pol ϵ defect in humans, additionally providing unique evidence linking Pol ϵ to haematopoiesis.

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A case of syndromic congenital hypothyroidism with a 15.2 Mb interstitial deletion on 2q12.3q14.2 involving PAX8

Iwahashi-Odano M., Kitamura M., Narumi S.

Clinical Pediatric Endocrinology （Clinical Pediatric Endocrinology） 32 （ 1 ） 65 - 71 2023年

ISSN 09185739

Paired box 8 (PAX8) mutations are an established genetic cause of congenital hypothyroidism (CH). The majority of these mutations are found in the protein-coding exons of the gene. The proband, a 3-yr-old girl, had tetralogy of Fallot and polydactyly soon after birth. She was diagnosed with CH in the newborn screening for CH. She had a high serum TSH level (239 mU/L) and low free T4 level (0.7 ng/dL). Ultrasonography revealed thyroid hypoplasia. We performed array comparative genomic hybridization because the patient exhibited a variety of symptoms across multiple organ systems. The analysis revealed a novel heterozygous deletion that spanned a 15.2 Mb region in 2q12.3q14.3 (GRCh37; chr2:109,568,260–124,779,449). There were 71 protein-coding genes in this region, including two genes (PAX8 and GLI2) associated with congenital endocrine disorders. The common clinical features of the two previously reported patients with a total PAX8 deletion and our case were CH, short stature and intellectual disability, but the severity of hypothyroidism and other clinical features were variable. In conclusion, we describe a syndromic CH patient with a novel 2q12.3q14.3 deletion involving PAX8. Patients with CH, whose unifying diagnosis is not obvious, could have a genomic deletion involving PAX8.

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