A case of HDR syndrome with recurrent matured ovarian teratomas

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is caused by pathogenic variants in the GATA3 gene located on chromosome 10p14. Here we present a 10-year-old girl with HDR syndrome who also has oligoarticular juvenile idiopathic arthritis (JIA). The patient presented for genetics evaluation with bilateral sensorineural hearing loss, oligoarticular JIA, and a renal cyst. Trio-based exome sequencing and chromosome microarray analysis revealed a pathogenic heterozygous ~1.45 Mb deletion that included the entire GATA3 gene, consistent with a diagnosis of HDR syndrome. GATA3 is a risk locus associated with autoimmune disease, including rheumatoid arthritis; however, the link between protein-coding variants in GATA3 and autoimmune disease has not been well established. Previously, a single patient with HDR syndrome and psoriatic JIA was identified as having a frameshift variant in the GATA3 gene. These reports highlight the potential for increased susceptibility to early-onset autoimmune arthritis in HDR syndrome, expanding its phenotypic spectrum. Further studies are needed to investigate the role of pathogenic variants in the GATA3 gene in the pathogenesis of JIA and other autoimmune diseases.

HDR syndrome is a rare genetic disorder caused by mutations in the GATA3 gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we report case of a 9-month-old male with history of hydronephrosis and sensorineural deafness who presented with febrile seizures. He was found to have hypocalcemia and inappropriately normal parathyroid hormone. His neurologic and infectious workup were negative. Genetic testing revealed a nonsense mutation in the GATA3 gene, consistent with HDR syndrome. Hypocalcemia was responsive to calcium carbonate and calcitriol treatment. This case highlights hypocalcemia caused by hypoparathyroidism as a potential etiology of seizures. When hypoparathyroidism is detected with either hearing loss or renal disease, HDR syndrome should be considered, and other features of the syndrome should be investigated.

HDR syndrome is a rare genetic disease caused by variants in the GATA3 gene and is phenotypically defined by the triad of hypoparathyroidism (H), deafness (D), and renal disease (R). Renal disorders of HDR are mainly developmental abnormalities, although renal functional abnormalities can also be observed. Nephrotic syndrome or nephrotic-level proteinuria is rare in HDR syndrome. Here, we report a Chinese infant with HDR syndrome who presented with early-onset nephrotic syndrome. We suggest that variants in the GATA3 gene might be associated with nephrotic syndrome. A 9-month-old boy was hospitalized with a complaint of diarrhea. Proteinuria was detected in the patient by routine testing for 3 days. No edema, oliguria, fever or abnormal urine color were observed. Routine urinary tests at a local hospital revealed proteinuria (protein 3 +) and microscopic hematuria (red blood cells 5-10/HP). The patient was born by cesarean delivery due to placental abruption at 35 weeks + 4 days of gestation. Intrauterine growth retardation was detected beginning at 6 months of gestation. His birth weight was 1.47 kg (< P3th), length was 39 cm (< P3th), and head circumference was 28 cm (< P3th). His motor developmental milestones were obviously delayed. Clinical data were analyzed, and genetic analysis for hereditary nephrotic syndrome was performed by next-generation sequencing. The clinical data showed that the boy exhibited growth retardation, early-onset nephrotic syndrome, microscopic hematuria, sensorineural deafness, T-cell immunodeficiency and congenital heart disease. Genetic tests revealed that the boy carried a de novo hemizygous variant, c.704C>T (p.Pro235 Leu), in exon 3 of the GATA3 gene. We report an infant with HDR syndrome who presented with early-onset nephrotic syndrome in China. We suggest that variants in the GATA3 gene might be associated with infant-onset nephrotic syndrome.

We report the case of a young Emirati boy with HDR (Hypoparathyroidism, sensorineural Deafness, and Renal hypoplasia) syndrome due to the novel heterozygous deletion of two nucleotides (c.35_36delGC ) in exon 2 of the GATA3 gene. The patient developed hypocalcemia and hypomagnesemia at 3 weeks of age with high fractional excretion of magnesium, indicating renal magnesium loss. This is the first published report of hypomagnesemia in association with HDR syndrome.

HDR syndrome is an autosomal dominant disorder characterized by hypoparathyroidism (H), deafness (D), and renal dysplasia (R) caused by genetic variants of the GATA3 gene. We present the case of a 38-year-old Japanese man with HDR syndrome who exhibited hypoparathyroidism, sensorineural deafness, renal dysfunction, severe symptomatic hypocalcemia with Chvostek's and Trousseau's signs, and QT prolongation on electrocardiography. He had a family history of deafness and hypocalcemia. Genetic testing revealed a novel GATA3 gene variant at exon 2 (c.48delC), which induces a frameshift resulting in termination at codon 178, causing HDR syndrome. We summarized 45 Japanese cases of HDR syndrome with regard to the mode of onset (familial or sporadic) and the age at diagnosis. In addition, we summarized all previous cases of HDR syndrome with GATA3 gene variants. Mapping of previously reported genetic variants in HDR syndrome revealed that most missense variants were observed at exons 4 and 5 regions in the GATA3 gene. These two regions contain zinc finger domains, demonstrating their functional importance in GATA3 transcription. This review of literature provides a useful reference for diagnosing HDR syndrome and predicting the related future manifestations.

Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant genetic disease associated with mutations in the GATA3 gene, which encodes GATA3 that plays essential roles in vertebrate development. This study aimed to identify and report the pathogenic mutation in GATA3 in a Chinese family diagnosed with HDR syndrome and determine its functional impacts in vivo. The clinical features of a 25-year-old male patient with HDR syndrome and his parents were collected. GATA3 gene exome sequencing and Sanger sequencing were performed on the proband and his family, respectively. Functional analyses of GATA3 were performed using bioinformatics tools and zebrafish assays to determine pathogenicity and phenotype spectrum. A novel, heterozygous, missense mutation in exon 4 of the GATA3 gene, c.863 G > A, p.Cys288Tyr, in the proband and his mother who presented the complete HDR triad, was predicted to be deleterious by in silico tools. 3D structure modeling showed that the variant caused significant structural changes. In vivo studies using a zebrafish animal model revealed the deleterious impact of the variant on the gill buds, otoliths, and pronephros. We identified a novel missense mutation, GATA3 p.Cys288Tyr, within a family with HDR syndrome and delineated it as a loss-of-function variant in vivo. This expands the spectrum of GATA3 mutations associated with HDR syndrome in the Chinese population and mimics HDR-related changes in vivo.

Introduction: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is caused by haploinsufficient GATA3 variants. Renal disease is present in 72% of patients with HDR syndrome, with a widely variable age of onset and rate of progression. Overall prognosis is primarily dependent upon the severity of renal disease. Four patients have been previously reported to have kidney transplants due to HDR syndrome, but there are minimal data describing transplant outcomes. We describe a case of a 74-year-old male with HDR syndrome receiving a living related renal transplant lasting 27 years. Case Presentation: A 74-year-old male with genetically confirmed HDR syndrome due to a pathogenic c.608_609del (p.Gly203Glufs*100) variant in GATA3. He developed hearing loss as an adolescent and was diagnosed with end stage renal disease at age 46. He had a living donor kidney transplant at age 47 that was well tolerated until age 73, and he is now listed for a repeat transplant. Discussion: This individual previously had a clinical diagnosis of Alport syndrome, but the presence of congenital symptoms in other family members suggested an alternative diagnosis. In addition to highlighting discrepancies between Alport syndrome and HDR syndrome, this case establishes that long-term successful renal outcomes are possible in HDR syndrome. Current limited evidence suggests kidney transplantation should be readily offered to individuals with end-stage renal disease due to HDR syndrome.

HDR syndrome is a rare autosomal dominant disorder caused by mutations in the GATA3 gene and characterized by hypoparathyroidism, sensorineural deafness and renal abnormalities. Here we report a Brazilian family, from which the proband, his mother and his grandfather were diagnosed with bilateral sensorineural hearing loss. Molecular screening of the GJB2, GJB6 and MTRNR1 genes in the proband showed no alterations; however, whole exome sequencing detected a heterozygous mutation, c.1099C > T (p.Arg367*), in the GATA3 gene. Segregation analyses showed that the mother also had the mutation, but not the grandparents, hence indicating a different hearing impairment type for the grandfather. Paternity test of the mother of the proband confirmed that she has a de novo mutation. Furthermore, HDR syndrome was confirmed with new clinical evaluations showing right kidney agenesis in the proband. This is the first study reporting only deafness and renal abnormalities as symptoms of the p.Arg367* mutation in the GATA3 gene, and also the sixth HDR syndrome case in the world, and the first on the American continent. Together with other reported cases, this study highlights the variability of HDR syndrome symptoms in individuals with the p.Arg367* mutation, emphasizing the importance of molecular analyses for correct diagnosis.

BackgroundBarakat syndrome is an autosomal dominant rare genetic disease caused by haploinsufficiency of the GATA binding protein 3 (GATA3) gene. It is also known as HDR syndrome, and is characterized by varying degrees of hypoparathyroidism, sensorineural deafness and renal disease. This is the first report of a heterozygous GATA3 whole gene deletion causing HDR syndrome in a Sri Lankan family.Case presentationA 13-year-old boy with an acute febrile illness, hypocalcaemia and bilateral carpopedal spasm was referred for evaluation. A past medical history of treatment for persistent hypocalcaemic symptoms since the age of 7 months was obtained. Biochemical investigations showed persistent low serum corrected calcium levels with hyperphosphataemia, hypomagnesaemia, low parathyroid hormone levels, hypercalciuria, and low total 25-hydroxy vitamin D levels. His renal functions and renal sonography were normal. Audiometry showed bilateral moderate to severe sensorineural hearing loss. On screening, his mother was also found to have asymptomatic hypocalcaemia, hypomagnesaemia, hyperphosphataemia, hypercalciuria and low total 25-hydroxy vitamin D levels. She had impaired renal functions and chronic parenchymal changes in the renal scan. Audiometry showed bilateral profound sensorineural hearing loss. Genetic analysis using multiplex-ligation dependent probe amplification showed a reduced gene dosage for GATA3 that is consistent with a heterozygous whole gene deletion in both the child and mother.ConclusionsThis report demonstrates the wide intra-familial phenotypic variability observed in HDR syndrome and adds further to the existing scientific literature on the genotype-phenotype correlation of this syndrome. It highlights the need for HDR syndrome to be considered in the differential diagnosis of persistent hypocalcaemia with sensorineural deafness and/or renal involvement, and for appropriate genetic evaluation to be done to confirm the diagnosis.

Disclosure: S. Pan: None. W. Lin: None. G. Chen: None.Purpose: Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is a rare autosomal dominant genetic disease associated with mutations in the GATA3 gene, which encodes GATA3 that plays essential roles in vertebrate development. This study aimed to identify and report the pathogenic mutation in GATA3 in a Chinese family diagnosed with HDR syndrome and determine its functional impacts in vivo. Subjects and methods The clinical features of a 25-year-old male patient with HDR syndrome and his parents were collected. GATA3 gene exome sequencing and Sanger sequencing were performed on the proband and his family, respectively. Functional analyses of GATA3 were performed using bioinformatics tools and zebrafish assays to determine pathogenicity and phenotype spectrum. Results: A novel, heterozygous, missense mutation in exon 4 of the GATA3 gene, c.863 G > A, p.Cys288Tyr, in the proband and his mother who presented the complete HDR triad, was predicted to be deleterious by in silico tools. 3D structure modeling showed that the variant caused significant structural changes. In vivo studies using a zebrafish animal model revealed the deleterious impact of the variant on the gill buds, otoliths, and pronephros. Conclusion: We identified a novel missense mutation, GATA3 p.Cys288Tyr, within a family with HDR syndrome and delineated it as a loss-of-function variant in vivo. This expands the spectrum of GATA3 mutations associated with HDR syndrome in the Chinese population and mimics HDR-related changes in vivo.Presentation: Sunday, July 13, 2025

We report here on a girl and her father with HDR syndrome (Hypoparathyroidism, sensorineural Deafness and Renal anomaly syndrome). The proband, an 11 year-old girl, complained of periodic tetany lasting for 6 years, and also used a hearing aid because of sensorineural hearing impairment. Furthermore, she had hemimegalencephaly, and had been taking an anti-epileptic agent to treat psychomotor seizures for 6 years. Endocrine assessment showed modest hypocalcemia, hyperphosphatemia and hypophosphaturia with lower normal parathyroid hormone concentration, and she had no renal abnormalities. Her father, who was 40 years old at the time of the investigation, had sensorineural hearing impairment, a lower than normal calcium level and normal renal function. Direct sequencing after PCR amplification of genomic DNA revealed a novel insertional mutation (405insC) in the GATA3 gene of both patients. This mutation was hypothesized to disrupt dual zinc fingers as well as one transactivating domain. The present findings lend additional support to the notion that the phenotype cannot be precisely estimated from the genotype in HDR syndrome.

HDR syndrome (hypoparathyroidism, sensorineural deafness, renal abnormalities) (OMIM #146265) is a rare autosomal dominant disorder caused by mutations in the GATA-3 gene (OMIM 13120), a transcription factor coding for a protein involved in vertebrate embryonic development. More than a hundred cases with variable renal features have been described so far. Here, we report on a patient suffering from HDR syndrome with glomerular nephropathy. Hypoparathyroidism appeared early in childhood but the subsequent features of HDR occurred later in the form of bilateral sensorineural deafness and renal insufficiency associated with nephrocalcinosis. HDR was not initially diagnosed due to the appearance of a transitory cardiac involvement and atypical renal symptoms (diffuse proliferative glomerulonephritis characterized by a self-limiting nephrotic syndrome). HDR syndrome with glomerular nephropathy has not yet been reported to our knowledge. Further studies of GATA-3 are needed to explore the involvement of this transcription factor in the development of HDR in humans, particularly in the kidneys.

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.

Hypoparathyroidism, deafness and renal dysplasia (HDR) syndrome is a rare autosomal dominant disorder, secondary to mutations in the GATA-3 gene. Due to its wide range of penetrance and expressivity, the disease may not always be recognized. We herein describe clinical and genetic features of patients with HDR syndrome, highlighting diagnostic clues. Medical records of eight patients from five unrelated families exhibiting GATA-3 mutations were reviewed retrospectively, in conjunction with all previously reported cases. HDR syndrome was diagnosed in eight patients between the ages of 18 and 60 years. Sensorineural deafness was consistently diagnosed, ranging from clinical hearing loss since infancy in seven patients to deafness detected only by audiometry in adulthood in one single patient. Hypoparathyroidism was present in six patients (with hypocalcaemia and inaugural seizures in two out of six). Renal abnormalities observed in six patients were diverse and of dysplastic nature. Three patients displayed nephrotic-range proteinuria and reached end-stage renal disease (ESRD) between the ages of 19 and 61 years, whilst lesions of focal and segmental glomerulosclerosis were histologically demonstrated in one of them. Interestingly, phenotype severity differed significantly between a mother and son within one family. Five new mutations of GATA-3 were identified, including three missense mutations affecting zinc finger motifs [NM_001002295.1: c.856A>G (p.N286D) and c.1017C>G (p.C339W)] or the conserved linker region [c.896G>A (p.R299G)], and two splicing mutations (c.924+4_924+19del and c.1051-2A>G). Review of 115 previously reported cases of GATA-3 mutations showed hypoparathyroidism and deafness in 95% of patients, and renal abnormalities in only 60%. Overall, 10% of patients had reached ESRD. We herein expand the clinical and mutational spectrum of HDR syndrome, illustrating considerable inter- and intrafamilial phenotypic variability. Diagnosis of HDR should be considered in any patient with hypoparathyroidism and deafness, whether associated with renal abnormalities or not. HDR diagnosis is established through identification of a mutation in the GATA-3 gene.

HDR is a rare autosomal dominant genetic disorder characterized by the triad of hypoparathyroidism, sensorineural deafness and renal anomalies caused by haploinsufficiency loss of function of the GATA-binding protein 3 (GATA3) gene. We present a case of a 56-year-old male diagnosed with hypoparathyroidism, sensorineural deafness, renal hypoplasia and epilepsy. Genetic testing revealed a novel GATA3 heterozygous mutation c.860C>A with a predicted amino acid substitution p.Ala287Asp. This hitherto unreported missense GATA mutation was characterized by a relatively late-onset and milder phenotype of the HDR triad. GATA3 gene mutations located on chromosome 10p cause haploinsufficiency of the GATA3 protein affecting fetal development of the parathyroid glands, inner ear and renal anomalies, resulting in HDR syndrome with an autosomal dominant inheritance pattern.Also known as Barakat syndrome, it has been reported in less than 200 cases with an identified mutation, each having a varied phenotypic presentation without consistent genotypic correlation.We present a patient with HDR syndrome who tested positive for a novel mutation c.860C>A, resulting in a missense substitution of amino acids p.Ala287Asp in the GATA3 gene.Clinicians who identify this rare triad of hypoparathyroidism, sensorineural deafness and renal anomalies should further investigate with genetic testing for GATA3 mutations.