HDR Syndrome Research Articles

Hypoparathyroidism, Sensorineural deafness and renal disease (Barakat syndrome) caused by a reduced gene dosage in GATA3: a case report and review of literature

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.

SUN-522 Hypoparathyroidism: When to Suspect Barakat Syndrome: A Case Report

Background There are several causes of hypoparathyroidism among the least common are the genetic causes. Barakat syndrome also known as HDR syndrome is a rare genetic disorder characterized by the triad of hypoparathyroidism “H,” neurosensorial deafness “D,” and renal disease “R.” This is caused by deletions in chromosome 10p14 or mutations in the GATA3 gene. GATA3 is a transcription factor that is involved in the embryonic development of the parathyroid glands, kidneys, inner ears, thymus, and central nervous system. Other associations have been describe such as congenital heart disease, facial abnormalities, cerebral infarctions, retinitis pigmentosa, basal ganglia calcifications, severe cognitive disability, and autism.(1) Clinical Case A 52-year-old man was admitted to our hospital, he has a history of bilateral neurosensorial deafness, detected five years ago. He referred muscle spasms, paresthesias since two years ago, and a convulsive episode cause by severe hypocalcemia. The patient has no history of neck surgery or radiation exposure that could have led to hypoparathyroidism. Laboratories showed low serum calcium and low parathyroid hormone: Calcium 5.9 mg/dl (8.5-10.5), PTH 7.4pg/ml (15-65), phosphorus 5.2 mg/dl (2.5-4.9) and creatinine 1.03 mg/dl, magnesium 2.02 mg/dl 25-Hydroxycholecalciferol(25-OH-D3) 31.75ng/ml (50-70ng/ml), TSH 3.4 uUI/ml (0.27 - 4.20). At the physical exam he had micrognathia, cleft palate and narrow nose root. Because he exhibited both neurosensorial deafness and hypoparathyroidism, HDR syndrome was suspected, we search for other abnormalities. Ultrasound (US) was performed were we find left renal agenesis, which was confirmed by computed tomography. Cerebral magnetic resonance shown bilateral and symmetric calcifications in putamen, caudate nucleus and thalamus. After treatment with calcium and vitamin D has not presented a new episode of severe hypocalcemia. Conclusions To our knowledge, this is the first case of HDR syndrome reported in Peru, with typical features of the syndrome. It is important to search renal malformations in patients with hypoparathyroidism because we could be facing HDR syndrome. Our patient fulfills diagnostic criteria but requires genetic study for confirmation which is not performed in our country. The early recognition of the HDR syndrome is crucial, not only for genetic counselling but also to offer a more precise prognosis and elective therapy for prevention of hypocalcemic seizures, and avoid hyperphosphatemia complications. We hope that this case will contribute to further understanding and studies of HDR-associated GATA3 mutations. Reference 1.Barakat syndrome revisited. Amin J. Barakat. Am J Med Genet. 2018;1-8

SUN-521 Intracranial Calcifications Outside the Basal Ganglia at Presentation of Barakat Syndrome

Hypoparathyroidism-sensorineural Deafness-Renal dysgenesis (HDR, or Barakat) syndrome is an uncommon cause of hypoparathyroidism, representing fewer than 200 documented cases in the literature worldwide. Individuals with HDR have variable penetrance and a range of phenotypes. While basal ganglia calcifications are known to occur with chronic hypoparathyroidism, they are less common in children and intracranial calcifications outside the basal ganglia, to our knowledge, have not been documented in HDR syndrome. Case presentation: A 10 year-old boy with a history of sensorineural deafness and attention deficit hyperactivity disorder presented after a new-onset seizure during a basketball game. His initial total serum calcium level of 5.9 mg/dl with an albumin level of 4.4 mg/dl, serum phosphorus was 7.0 mg/dl, and normal creatinine for age. PTH level was 2 pg/ml. He was started on calcitriol and calcium supplementation. There was no prior personal nor family history of hypocalcemia, nephrolithiasis, deafness nor renal problems. A head CT showed calcifications in the basal ganglia as well as at the temporal and frontoparietal gray-white matter junction and thalamus. Parathyroid antibody testing was negative. Subsequent genetic analysis of the GATA3 gene indicated heterozygosity for c.790T>C causing a missense mutation (p.Cys264Arg), that has been reported to cause HDR due to altered DNA binding affinity of the zinc finger component of GATA3. On renal ultrasound kidneys were in the 8th-13th percentile for size, raising the possibility of mild hypoplasia. Post-treatment urine Calcium-to-Creatinine ratio was 0.105. We describe a case of HDR in childhood who presented with seizures and very rare pediatric finding of calcifications in the basal ganglia as well as additional intracranial calcification in the thalamus and temporal and frontoparietal gray-white matter junction, which to our knowledge have not previously been described with HDR Syndrome. This case highlights important features of this disorder including severe intracranial calcifications and morphologic renal anomalies. HDR patients are at high risk for renal impairment, which is a key prognostic factor. Thus, careful monitoring of renal function, avoidance of nephrotoxins and of excessive calciuria during hypoparathyroidism management are necessary.

Auditory Evaluation in a Patient with HDR Syndrome

Auditory Evaluation in a Patient with HDR Syndrome

A Unique Genomic Variant of HDR Syndrome in Newborn

HDR syndrome (also known as Barakat syndrome) is a rare genetic disorder due to deletions/mutations on specific regions of zinc-finger transcription factor (GATA3) gene. A male preterm infant presented with multiple dysmorphic features characterized by small for gestational age, hypognathia and facial abnormalities. Investigations revealed hypocalcemia and low parathyroid hormone levels and bilateral sensorineural deafness. Chromosomal microarray analysis revealed a combination of deletion on chromosome 10p (10p15.3p14) with loss of GATA3 gene and duplication of chromosome 20p (20p13p12.3) as a result of unbalanced 10:20 translocation. Detecting this syndrome at neonatal age is very important because it allows early intervention to minimize future clinical problems.

Mutant GATA3 Actively Promotes the Growth of Normal and Malignant Mammary Cells.

GATA3, a transcription factor expressed in luminal breast epithelial cells, is required for mammary gland development. Heterozygous GATA3 mutations occur in up to 15% of estrogen receptor (ER)-positive breast tumors and have been proposed to be null alleles resulting in haploinsufficiency; however, the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Transgenic mice, 3D cultures and xenografts were used to examine the effect of mutant GATA3 expression on mammary cell proliferation. Mutant GATA3 accelerated tumor growth of ZR751 cell xenografts and promoted precocious lobuloalveolar development in transgenic mouse mammary glands. GATA3 mutations, recently observed in breast cancer, encode active transcription factors, which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of ER-positive breast cancer cell lines.

Microcephaly, Deafness, and Renal Dysplasia: A Case of Barakat Syndrome

Background: Barakat syndrome is a rare autosomal dominant disorder characterized by hypoparathyroidism, sensorineural deafness, and renal disease, collectively known as HDR syndrome. This disease is caused by the mutation of GATA3 gene located on chromosome 10p15. GATA3 is involved in the embryonic development of kidneys, inner ears, parathyroid glands, and central nervous systems.Case report: Herein, we presented a 20-month-old female with seizure and microcephaly, congenital left kidney dysplasia, hypoparathyroidism, and bilateral sensorineural deafness. Her laboratory tests were consistent with hypoparathyroidism, and the chromosomal study revealed a deletion in chromosome 10. The patient was diagnosed as a case of Barakat syndrome based on her clinical and laboratory tests. The microarray-based comparative genomic hybridization study of the patient was compatible with the monosomy of 10p15.3p13 and trisomy of 12p13.33p13.33.Conclusion: It is important to be aware of rare inherited conditions like Barakat syndrome (HDR syndrome) in a patient with abnormal presentations, such as seizure, neurodevelopmental delay, kidney defects associated with hearing loss, and clinical abnormalities associated with hypoparathyroidism.

Barakat syndrome revisited.

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.

A rare case of deafness and renal abnormalities in HDR syndrome caused by a de novo mutation in the GATA3 gene.

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.

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

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.

Clinical Auditory Phenotypes Associated with GATA3 Gene Mutations in Familial Hypoparathyroidism-deafness-renal Dysplasia Syndrome.

Background:Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome is an autosomal dominant disorder primarily caused by haploinsufficiency of GATA binding protein 3 (GATA3) gene mutations, and hearing loss is the most frequent phenotypic feature. This study aimed at identifying the causative gene mutation for a three-generation Chinese family with HDR syndrome and analyzing auditory phenotypes in all familial HDR syndrome cases.Methods:Three affected family members underwent otologic examinations, biochemistry tests, and other clinical evaluations. Targeted genes capture combining next-generation sequencing was performed within the family. Sanger sequencing was used to confirm the causative mutation. The auditory phenotypes of all reported familial HDR syndrome cases analyzed were provided.Results:In Chinese family 7121, a heterozygous nonsense mutation c.826C>T (p.R276*) was identified in GATA3. All the three affected members suffered from sensorineural deafness and hypocalcemia; however, renal dysplasia only appeared in the youngest patient. Furthermore, an overview of thirty HDR syndrome families with corresponding GATA3 mutations revealed that hearing impairment occurred earlier in the younger generation in at least nine familial cases (30%) and two thirds of them were found to carry premature stop mutations.Conclusions:This study highlights the phenotypic heterogeneity of HDR and points to a possible genetic anticipation in patients with HDR, which needs to be further investigated.

Abstract P1-08-02: Mutant GATA3 actively promotes the growth of normal and malignant mammary cells

Abstract GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen receptor positive tumors, suggesting a more aggressive phenotype. These mutants have been proposed to be null alleles resulting in haploinsufficiency, however the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Based on this disparity, we propose that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. Here we focus on the GATA3 mutants which lack the second zinc finger which is responsible for GATA motif binding. Expression of these mutants accelerated xenograft tumor growth by ZR751 cells, and transgenic expression in mouse mammary glands promoted precocious lobuloalveolar development. We have used integrated gene expression and ChIP-Seq profiling to demonstrate that these zinc-finger deleted proteins retain the ability to associate with the genome by tethering to complexes associated with FOXA1 and AP-2gamma recognition motifs, where they modulate the expression of adjacent genes. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for active transcription factors which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines. Citation Format: Kenny PA, Chandiramani N, Lofgren KA. Mutant GATA3 actively promotes the growth of normal and malignant mammary cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-08-02.

Novel splice site mutation in GATA3 in a patient with HDR syndrome.

Novel splice site mutation in GATA3 in a patient with HDR syndrome.

Abstract 1991: Mutant GATA3 actively promotes the growth of normal and malignant mammary cells

Abstract GATA3 is a transcription factor expressed in luminal breast epithelial cells and is required for mammary gland development. Analysis of TCGA data reveals that somatic heterozygous mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors, and that these tumors are diagnosed a median of eight years earlier than other estrogen receptor positive tumors, suggesting a more aggressive phenotype. These mutants have been proposed to be null alleles resulting in haploinsufficiency, however the mutation spectrum of GATA3 in breast cancer is in sharp contrast to that found in HDR syndrome, a true GATA3 haploinsufficiency disease. Based on this disparity, we propose that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. Here we focus on the GATA3 mutants which lack the second zinc finger which is responsible for GATA motif binding. Expression of these mutants accelerated xenograft tumor growth by ZR751 cells, and transgenic expression in mouse mammary glands promoted precocious lobuloalveolar development. We have used integrated gene expression and ChIP-Seq profiling to demonstrate that these zinc-finger deleted proteins retain the ability to associate with the genome by tethering to complexes associated with FOXA1 and AP-2gamma recognition motifs, where they modulate the expression of adjacent genes. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for active transcription factors which elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines. Citation Format: Natasha Chandiramani, Esther Peterson, Paraic A. Kenny. Mutant GATA3 actively promotes the growth of normal and malignant mammary cells. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1991.

Interstitial 10p deletion derived from a maternal ins(16;10)(q22;p13p15.2): Report of the first familial case of 10p monosomy affecting to two familial members of different generations

Monosomy 10p is a rare chromosomal disorder with a prevalence <1/1,000,000, in which a terminal or interstitial distal region of chromosome 10 is deleted resulting in a variable phenotype depending on the size of the deletion. Two main phenotypes have been defined depending on the location of the deletion: HDR syndrome (Hypoparathyroidism, sensorineural Deafness, and Renal disease), and DGS2 (DiGeorge syndrome type 2). The vast majority of cases reported so far have resulted from de novo events. Here, we present the first familial presentation of this contiguous gene deletion syndrome, affecting two family members in different generations: a child and his maternal uncle. In both cases, the deletion was due to a malsegregation of a maternal balanced rearrangement, ins(16;10)(q22;p13p15.2). The identification and characterization of this rearrangement was possible using a combination of different genetic analyses such as karyotype, MLPA, FISH, and array CGH. We underline the importance of the present results in terms of genetic and reproductive counseling for the carriers of the balanced rearrangement within the family, and demonstrate again the utility of expanding the genetic studies to the relatives of the affected patients.

An Uncommon Presentation of HDR Syndrome: Distal Renal Tubular Acidosis in a Patient with Sjögren’s Syndrome

An Uncommon Presentation of HDR Syndrome: Distal Renal Tubular Acidosis in a Patient with Sjögren’s Syndrome

Abstract 4197: Mutant GATA3 drives precocious lobuloalveolar mammary development and promotes the growth of estrogen receptor positive xenograft tumors

Abstract The GATA3 transcription factor is expressed in luminal breast epithelial cells and is required for mammary gland development. Recent reports indicate that somatic mutations in GATA3 occur in up to 15% of estrogen receptor positive breast tumors. Our analysis of these published data demonstrates that the human breast tumors with GATA3 mutations are diagnosed 7 years earlier than other ER+ tumors, suggesting that these are more aggressive tumors. Previously, these mutations were proposed to be null alleles that resulted in haploinsufficiency for GATA3 in breast cancer, however this interpretation currently lacks experimental support. We report that the mutation spectrum of GATA3 in breast cancer is in sharp contrast to HDR syndrome, a true GATA3 haploinsufficiency disease. In breast cancer, there is a striking enrichment of GATA3 mutations in exons 5 and 6 (amino acids 294-444) which encode the second of two DNA binding zinc fingers and the C-terminal amino acids. The absence of whole gene deletions or additional 5′ mutations in the open-reading frame, frequently found in HDR syndrome, suggests that there is a selective pressure to mutate and retain a portion of the GATA3 in breast cancer. We hypothesize that these GATA3 mutations do not result in null alleles but instead encode proteins with residual or neomorphic functions which actively contribute to breast cancer progression. We have generated transgenic mice that express mammary-specific GATA3-336fs. Non-parous pubertal transgenic mice exhibit pronounced lobuloalveolar development compared to estrous-matched wildtype littermates. This indicates that expression of mutant GATA3 protein promotes aberrant mammary epithelial cell proliferation. We are currently testing the effect of mutant GATA3 on the kinetics of mammary tumorigenesis by crossing these mice with models of mammary cancer harboring mutant P53 and mutant PI3K. We have generated ZR751 luminal breast cancer cell lines that stably express the hotspot GATA3 mutations that affect codons 309, 336 and 409. When xenografted into the mammary fat pads of nude mice, cells with GATA3-309* and GATA3-336fs have a growth advantage, while GATA3-409fs had slightly slower growth than the parental line. Genome wide ChIP-Seq analysis shows that GATA3-409fs has a similar binding profile to wildtype GATA3, with a significant enrichment at the GATA binding motif. The GATA3-309* and GATA3-336fs mutants bind fewer sites in the genome and are highly enriched at non-GATA motifs indicating an alternate mechanism of DNA binding for target gene regulation. These data support a model in which the GATA3 mutations recently observed in breast cancer encode for dominantly-acting transcription factors. These mutations elicit proliferative phenotypes in normal mammary epithelium and promote the growth of estrogen receptor positive breast cancer cell lines. Citation Format: Natasha Chandiramani, Esther A. Peterson, Eric H. Jung, E. Charles Jenkins, Paraic A. Kenny. Mutant GATA3 drives precocious lobuloalveolar mammary development and promotes the growth of estrogen receptor positive xenograft tumors. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4197. doi:10.1158/1538-7445.AM2015-4197

Identification of a novel GATA3 mutation in a deaf Taiwanese family by massively parallel sequencing

Recent studies have confirmed the utility of massively parallel sequencing (MPS) in addressing genetically heterogeneous hereditary hearing impairment. By applying a MPS diagnostic panel targeting 129 known deafness genes, we identified a novel frameshift GATA3 mutation, c.149delT (p.Phe51LeufsX144), in a hearing-impaired family compatible with autosomal dominant inheritance. The GATA3 haploinsufficiency is thought to be associated with the hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome. The pathogenicity of GATA3 c.149delT was supported by its absence in the 5400 NHLBI exomes, 1000 Genomes, and the 100 normal hearing controls of the present study; the co-segregation of c.149delT heterozygosity with hearing impairment in 9 affected members of the family; as well as the nonsense-mediated mRNA decay of the mutant allele in in vitro functional studies. The phenotypes in this family appeared relatively mild, as most affected members presented no signs of hypoparathyroidism or renal abnormalities, including the proband. To our knowledge, this is the first report of genetic diagnosis of HDR syndrome before the clinical diagnosis. Genetic examination for multiple deafness genes with MPS might be helpful in identifying certain types of syndromic hearing loss such as HDR syndrome, contributing to earlier diagnosis and treatment of the affected individuals.

A novel mutation in GATA3 gene in HDR syndrome

A novel mutation in GATA3 gene in HDR syndrome

Audiometric Characteristics of a Dutch Family with a New Mutation in GATA3 Causing HDR Syndrome

We present the case of a Dutch family with a new mutation (c523_528dup) in GATA3 causing HDR syndrome. HDR syndrome is characterised by hypoparathyroidism, deafness and renal defects. In this study, we describe the audiometric characteristics of 5 patients from this family. Their hearing impairment was congenital, bilateral and symmetric. Audiograms showed mild-to-moderate hearing impairment with a flat audiogram configuration. Higher frequencies tended to be affected more strongly. Cross-sectional analyses showed no progression, and a mean audiogram was established. Psychophysical measurements in 3 HDR patients - including speech reception in noise, loudness scaling, gap detection and difference limen for frequency - were obtained to assess hearing function in greater detail. Overall, the results of the psychophysical measurements indicated characteristics of outer hair cell loss. CT scanning showed no anomalies in 3 of the HDR patients. Although 2 patients displayed vestibular symptoms, no anomalies in the vestibular system were found by vestibulo-ocular examination. Our results are in agreement with the theory that outer hair cell malfunctioning can play a major role in HDR syndrome.