Diabetes Mellitus in a Japanese Girl with HDR Syndrome and GATA3 Mutation

Muroya, Koji; Mochizuki, Takahiro; Fukami, Maki; Iso, Manami; Fujita, Keisuke; Itakura, Mitsuo; Ogata, Tsutomu

doi:10.1507/endocrj.k09e-313

Cited by 13 publications

(7 citation statements)

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“…A previously reported Japanese patient with a similar frameshift mutation in exon 6 of the GATA3 gene (c.1200_1201delCA; p.H400fsX506) characteristically showed insulin dependent diabetes with a more severe renal anomaly compared to our patient [ 20 ]. In addition to these phenotypic differences, the variant in our patient was different from most other reported GATA3 frameshift mutations.…”

Section: Discussionsupporting

confidence: 51%

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report

Yang

Kim

et al. 2017

BMC Med Genet

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BackgroundHypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome, also known as Barakat syndrome, is a rare genetic disorder with high phenotypic heterogeneity caused by haploinsufficiency of the GATA3 gene on chromosome 10p14-p15. For these reasons, the diagnosis of HDR syndrome is challenging and requires a high index of suspicion as well as genetic analysis.Case presentationA 14-month-old boy, with sensorineural hearing loss in both ears, showed typical radiological features of X-linked stapes gusher on preoperative temporal bone computed tomography (CT) for cochlear implantations. Then after his discharge from hospital, he suffered a hypocalcemic seizure and we discovered a renal cyst during investigation of hypocalcemia. He was finally diagnosed with HDR syndrome by clinical findings, which were confirmed by molecular genetic testing. Direct sequencing of the GATA3 gene showed a heterozygous 2-bp deletion (c.1201_1202delAT), which is predicted to cause a frameshift of the reading frame (p.Met401Valfs*106).ConclusionsTo our knowledge, this is the first case of HDR syndrome with a novel de novo variant mimicking a congenital X-linked stapes gusher syndrome. Novel mutations and the diversity of clinical manifestations expand the genotypic and phenotypic spectrum of HDR syndrome.Diagnosis of HDR syndrome is still challenging, but clinicians should consider it in their differential diagnosis for children with a wide range of clinical manifestations including hypocalcemia induced seizures and deafness. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations.Electronic supplementary materialThe online version of this article (10.1186/s12881-017-0484-6) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 51%

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report

Yang

Kim

et al. 2017

BMC Med Genet

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“…In an extensive review of the literature, we found 173 reported patients. In this report, we review these patients and an additional seven patients observed by the authors (A. Y. Barakat, personal communication, 2017) for a total of 180 patients (Adachi, Tachibana, Asakura, & Tsuchiya, ; Aksoylar et al, ; Ali et al, ; Al‐Shibli, Al Attrach, & Willems, ; Bahceci, Salgur, Tutuncuoglu, Yilmaz, & Oruk, ; Barakat, D'Albora, Martin, & Jose, ; Beetz et al, ; Belge et al, ; Bernandini et al, ; Bilous et al, ; Boysan et al, ; Chen et al, ; Chenouard et al, ; Cheon, Kim, & Yoo, ; Chiu, Chen, Chao, Yann, & Tsai, ; Chu et al, ; Civan et al, ; Doneray, Usui, Kaya, & Dönmez, ; Ferdoush, Mutanabbi, Talukder, Al Helal, & Kawser, ; Fernández et al, ; Ferraris et al, ; Fujimoto et al, ; Fukami et al, ; Gaynor et al, ; Gomes et al, ; Goodwin, Hawley, & Miller, ; Hameed et al, ; Hasegawa et al, ; Hernández et al, ; Higuchi et al, ; Kamezaki et al, ; Kato, Wada, Numata, & Kakizaki, ; Kim et al, ; Kostoglou‐Athanassiou, Stephanopoulos, Karfi, & Athanassiou, ; Lichtner et al, ; Maleki, Bashardoust, Alamdri, & Tavosi, ; Maloo ; Meena, Maloo, Samar, Ruhela, & Saini, ; Melis et al, ; Mino et al, ; Moldovan, Carvalho, Jorge, & Medeira, ; Muroya et al, ; Muroya et al, ; Mutlu, Kırmızıbekmez, Nakamura, Fukami, & Hatun, ; Nakamura et al, ; Nanba et al, ; Nesbit et al, ; Ni & Htet, ; Ohta et al, ; Pollak‐Hainz, Bartsch, Zechner, & Keilmann, ; Ranjbar‐Omrani, Zamiri, Sabayan, & Mohammadzadeh, ; Rodriguez Benitez et al, ; Sau, Chat...…”

Section: History Of the Syndromementioning

confidence: 99%

“…Similar to most phenotypic syndromes, several additional features have been described in association with the syndrome. Among others, hypergonadotropic hypogonadism, polycystic ovaries, congenital heart disease, facial abnormalities, cerebral infarctions, retinitis pigmentosa, basal ganglia calcifications, severe cognitive disability, and autism (Adachi et al, ; Al‐Shibli et al, ; Civan et al, ; Hasegawa et al, ; Hernández et al, ; Kato et al, ; Lichtner et al, ; Meena et al, ; Muroya et al, ; Nesbit et al, ; Taslipinar et al, ; van der Wees et al, ; Verri et al, ; Zahirieh et al, ). Neuropsychological and behavioral abnormalities have been observed in patients with basal ganglia calcification, often present in primary “H.” These calcifications may lead to changes in the fronto‐limbic basal ganglia causing neurological and psychiatric disorders including impaired cognitive function, psychosocial dysfunction, and depression, especially in adult patients (Al‐Shibli et al, ; Civan et al, ; Nanba et al, ).…”

Section: Clinical Characteristicsmentioning

confidence: 99%

Barakat syndrome revisited

Barakat

Raygada

Rennert

2018

American J of Med Genetics Pt A

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Barakat syndrome also known as HDR syndrome (Online Mendelian Inheritance in Man [OMIM] 146255), was first described by Barakat et al. in . It is a rare genetic disorder characterized by the triad of hypoparathyroidism "H," sensorineural deafness "D," and renal disease "R." The defect is caused by deletions in chromosome 10p14 or mutations in the GATA3 gene. Although the syndrome has been phenotypically defined by this triad the literature identifies cases with different components with, or without GATA3 defects making the definition of the syndrome confusing. We analyzed 180 cases and attempted to define the phenotype of the syndrome and suggest guidelines for diagnosis. We suggest that the diagnosis could be confirmed in patients who have all three components, and in those who have two components with a positive family history. GATA3 testing is optional to establish the diagnosis in these patients. The syndrome should be considered in patients with isolated "D" where other causes of "D" have been excluded and those with isolated "R," especially if there is family history of any of these components. In these instances, confirmatory GATA3 testing is indicated to confirm the diagnosis. In patients with nonsurgical "H," where "D" and "R" have been conclusively ruled out GATA3 studies are not needed as none of these patients were shown to be GATA3 haploinsufficient. Only 64.4% of patients in our review had "HDR." Some findings might have not been recognized or may could have appeared later in life, but it is evident that this syndrome is genotypically heterogeneous.

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“…Patients with rare defects in the gene encoding GATA3 have hypoparathyroidism, sensorineural deafness, and renal disease (HDR) (MIM 146255) resulting from decreased GATA3 function [10]. In one case report, a pediatric HDR patient also developed type I diabetes [11]. The studied GATA3 mutations result in loss of function [12, 13], with one missense mutant in a DNA-binding domain causing a dominant negative [14].…”

Section: Introductionmentioning

confidence: 99%

Juvenile idiopathic arthritis associated with a mutation in GATA3

Patrick

Wang²,

Brokamp

et al. 2019

Arthritis Res Ther

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Background GATA3 is a transcription factor that is important during development and plays a role in differentiation and activity of immune cells, particularly T cells. Abnormal T cell function is found in autoimmune arthritis. We present the first known case of autoimmune arthritis associated with a novel GATA3 mutation. Methods Whole exome sequencing of the proband was performed on a clinical basis. Peripheral blood mononuclear cells (PBMCs) were collected from the proband, healthy sibling, and parent. cDNA prepared from RNA was analyzed with polymerase chain reaction and Sanger sequencing. Intracellular proteins were assessed by immunoblot of PBMC homogenates. GATA3 in vitro activity was measured in HeLa cell cultures expressing a mammalian expression vector containing GATA3 or mutants generated by site-directed mutagenesis. GATA3 transcriptional activity was examined using a luciferase reporter assay system. T helper cell ex vivo function was evaluated by stimulating PBMCs to differentiate into effector T cells along Th0, Th1, Th2, and Th17 lineages, and re-stimulating effector cells to secrete cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay. Results The proband is the first known case of autoimmune arthritis associated with a mutation in GATA3 . The proband M401VfsX106 protein is expressed and has a dominant negative function on GATA3 transcriptional activity. The proband PBMCs have markedly increased differentiation along the Th1 and Th17 pathways, with decreased differentiation along the Th2 pathway. Unexpectedly, Th0 cells from the proband express high levels of IFNγ. Conclusions Our research presents the first known case of autoimmune arthritis associated with a mutation in GATA3 . This work expands the phenotypic spectrum of GATA3 mutations. It reveals the novel insight that decreased and altered GATA3 activity coincides with autoimmune arthritis. This work suggests that modulation of GATA3 may be a therapeutic approach for patients with autoimmune arthritis. Electronic supplementary material The online version of this article (10.1186/s13075-019-1946-3) contains supplementary material, which is available to authorized users.

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Diabetes Mellitus in a Japanese Girl with HDR Syndrome and GATA3 Mutation

Cited by 13 publications

References 13 publications

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report

HDR syndrome with a novel mutation in GATA3 mimicking a congenital X-linked stapes gusher: a case report

Barakat syndrome revisited

Juvenile idiopathic arthritis associated with a mutation in GATA3

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