Hypoparathyroidism, sensorineural deafness and renal disease (HDR) syndrome due to a novel GATA3 mutation p.Ala287Asp

in Endocrinology, Diabetes & Metabolism Case Reports
Authors:
Luke Vroegindewey Lake Cumberland Regional Hospital, Somerset, Kentucky, USA
Endocrinology Center of Lake Cumberland, Somerset, Kentucky, USA

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John Kim Lake Cumberland Regional Hospital, Somerset, Kentucky, USA
Endocrinology Center of Lake Cumberland, Somerset, Kentucky, USA

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Dennis J Joseph Lake Cumberland Regional Hospital, Somerset, Kentucky, USA
Endocrinology Center of Lake Cumberland, Somerset, Kentucky, USA

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Correspondence should be addressed to L Vroegindewey: lavroegindewey@liberty.edu
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Summary

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.

Learning points

  • 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.

Abstract

Summary

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.

Learning points

  • 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.

Background

HDR syndrome is an extremely rare autosomal dominant disorder caused by mutations in the GATA3 gene. It has been reported in fewer than 200 individuals worldwide (1). Also known as Barakat syndrome, it was first described in 1977 as a triad of hypoparathyroidism, sensorineural deafness and familial nephrosis (2). The term HDR syndrome (OMIM no. 146255) was coined by Hasegawa and coworkers as an acronym for the characteristic triad of hypoparathyroidism, sensorineural deafness and renal anomalies (3). Haploinsufficiency of the GATA-binding protein 3 (GATA3) gene located on chromosome 10p13–14 with autosomal dominant inheritance was eventually identified as the cause of human HDR syndrome (4). GATA-binding protein 3 is a dual-zinc finger (ZF1 and ZF2) transcription factor that recognizes A/T GATA A/G nucleotide sequences, which promote or repress genetic expression involved in the development of parathyroid glands, inner ears, kidneys, thymus and the central nervous system (5). Several mutations of the GATA3 gene have been identified, including intragenic deletion, missense, nonsense, frameshift and acceptor splice site mutations (6), yet an exact genotype–phenotype correlation has not been demonstrated. While sensorineural deafness and hypoparathyroidism are present in more than 90% of affected individuals, renal disease is less common. A wide spectrum of phenotypic variations has been described, with mortality depending on the nature and severity of renal disease. Most individuals will eventually develop all components of the triad by age 50 (7), as in our patient. We report a hitherto unreported missense GATA3 mutation with a relatively late-onset and milder phenotype of the HDR triad.

Case presentation

A 56-year-old male presented with a history of sensorineural hearing loss since childhood, diagnosed by an audiologist using broadband click stimulation. He began using hearing aids at age 50. He also reported seizures starting at age 7, for which he only began treatment with levetiracetam at age 41. His last seizure occurred at age 49, and he experiences loss of consciousness during seizures. As a child, he experienced intermittent tetany in his hands and face but was never diagnosed or treated for hypoparathyroidism. Recently, he has experienced tetany in his lower back muscles. There is no family history of hearing loss, renal issues or hypoparathyroidism among his parents or five siblings. On physical examination, the patient appeared fatigued and had bilateral sensorineural hearing loss. Chvostek’s and Trousseau’s signs were negative, and there were no signs of tetany.

Investigation

Laboratory investigations revealed hypocalcaemia, with serum ionized calcium 4.1 mg/dL (reference range (RR): 4.65–5.27 mg/dL), normal serum phosphorus 3.7 mg/dL (RR: 2.8–4.1 mg/dL), low magnesium 1.5 mg/dL (RR: 1.6–2.3 mg/dL), low parathyroid hormone level 7 pg/mL (RR: 15–65 pg/mL), creatinine 1.3 mg/dL (RR: 0.76–1.27 mg/dL), eGFR 64 (stage 2 chronic kidney disease (CKD)) and 25-hydroxy vitamin D 25.3 ng/mL (RR: 30.0–100.0 ng/mL). Urinalysis was unremarkable. Renal ultrasound showed a hypoplastic right kidney measuring 4.5 × 2.3 × 2.5 cm (Fig. 1). The left kidney had compensatory hypertrophy measuring 14.4 × 3.9 × 6.5 cm (Fig. 2).

Figure 1
Figure 1

Sagittal view of echogenic and hypoplastic right kidney.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0020

Figure 2
Figure 2

Sagittal view of enlarged left kidney.

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0020

Genetic testing involved extraction of genomic DNA specimen from the patient’s saliva. Relevant regions of DNA were captured with hybridization technology and were sequenced with Illumina’s reversible dye terminator platform NovaSeq 6000 using 150 by 150 bp paired-end reads (Illumina, USA). Sanger sequencing with polymerase chain reaction (PCR) was used to amplify necessary exons and flanking non-coding sequences. Applied Genetic Biosystems Inc. (ABI, USA) BigDye Terminator v3.1 kit cycle sequenced purified PCR products. PCR products were resolved by electrophoresis on an ABI 3730xl capillary sequencer. The copy number variant calling algorithm, which compares read depth and distribution for each target, was compared against multiple match controls. Comparing sequence variants revealed a novel heterozygous mutation in GATA3, identified as c.860C>A, resulting in a substitution of amino acids, p.Ala287Asp, indicative of a missense mutation. The variant was classified as a ‘variant of uncertain significance’ according to ACMG guidelines (8). Pathogenic variants of GATA3 mutations are catalogued in the Online Mendelian Inheritance in Man (OMIM 146255). This specific variant has not been previously reported and is absent from the large population database at http://gnomad.broadinstitute.org. Therefore, due to the lack of reported functional and genetic evidence, it was labelled as uncertain significance. In silico prediction data generated using the PolyPhen online tool for isoform 2 of GATA3 (trans-acting T-cell-specific transcription factor GATA3, UniProt ID: P23771-2) predicted the alteration p.Ala287Asp to be “probably damaging” with a score of 0.999 (sensitivity: 0.14; specificity: 0.99). The examination of sequence homologies using the UniProt database reveals significant conservation of the alanine residue at position 287 in isoform 2 of the trans-acting T-cell-specific transcription factor GATA3 (UniProt ID: P23771-2) across various vertebrate species. For instance, in Homo sapiens (human), Mus musculus (mouse) and Bos taurus (cow), the sequence alignment demonstrates a high degree of similarity, with the conserved presence (Table 1).

Table 1

Species with homologous GATA3 protein amino acid sequence.

SpeciesAmino acid sequence
Homo sapiens (human)GGSPGFGCKSRPKARSS-TGRECVNCGATSTPLWRRDGTGHYLCNACGLYHKMNGQNRP
Mus musculus (mouse)GGSPGFGCKSRPKARSS-TGRECVNCGATSTPLWRRDGTGHYLCNACGLYHKMNGQNRP
Bos taurus (cow)GGSPGFGCKSRPKARSS-TGRECVNCGATSTPLWRRDGTGHYLCNACGLYHKMNGQNRP

This conservation underscores the functional importance of this residue. In addition, the structural insight provided by the 3D model generated using UniProt and PyMol software highlights the proximity of alanine 287 to the cysteine residues critical for zinc coordination within the zinc finger domain of GATA3 (Fig. 3) (9). Given the spatial relationship between alanine 287 and the zinc-binding site, the introduction of a carboxyl group via the substitution to aspartic acid may potentially interfere with zinc binding, thus perturbing the structure and function of the zinc finger domain and, consequently, GATA3 function.

Figure 3
Figure 3

3D structure of zinc finger moiety of GATA3, highlighting aspartate at position 287 (red) and its proximity to the zinc atom (purple).

Citation: Endocrinology, Diabetes & Metabolism Case Reports 2024, 4; 10.1530/EDM-24-0020

Clinical manifestations of HDR syndrome in our patient confirm that this GATA3 mutation is pathogenic.

Treatment

The patient was treated with calcium 1200 mg orally once daily (as calcium carbonate), magnesium oxide (241.3 mg magnesium) orally once daily and calcitriol 0.5 μg orally once daily.

Outcome and follow-up

His calcium levels were found to be mid-normal at 9.6 (RR: 8.7–10.2), and energy levels improved with complete cessation of tetanic episodes. After 24 h, urinary calcium was found to be 149 mg with a goal of less than 300 mg, as hypercalciuria can cause complications such as worsening renal function or urinary stones. The patient’s renal function had not changed after treatment. The patient declined to undergo genetic testing for family members.

Discussion

HDR syndrome is a very rare disorder with variable expressivity and penetrance. While the classic triad includes hypoparathyroidism, sensorineural deafness and/or renal anomalies, patients may lack one of the components of the triad (7). It has been found that approximately 71% of patients will have the whole triad (1). Our patient had signs and symptoms of sensorineural hearing loss and tetany for most of his life but had not been fully evaluated until later in life. Our patient did have CKD stage 2, and renal ultrasound did end up showing right renal hypoplasia. Family history may not always be helpful due to variable expressivity and penetrance. Genetic anticipation has also been observed in families with HDR (1). Our case revealed HDR with a novel GATA3 mutation c.860C>A that has not been reported in the literature or genomic databases yet. The N-terminal zinc finger ZF1 (residues 263–287) helps to interact with other zinc finger proteins of different types and stabilizes DNA binding (6). Given the ‘probably damaging’ prediction by the PolyPhen software, potential interference with zinc binding observed in the 3D model and the high conservation of alanine at position 287 across sequences, this missense mutation (p.Ala287Asp) is likely pathogenic. Clinical manifestations of HDR syndrome confirm that this GATA3 mutation is pathogenic. Despite the involvement of the crucial ZF1 region of the GATA-binding protein 3, the mild phenotype in our patient confirms the lack of phenotype–genotype correlation. Our case also lends credence to the view that the severity of renal impairment (rather than genotype) is the most important contributor to the lethality of this mutation. Even though not part of the classical triad, epilepsy has been reported in other cases of HDR syndrome (7), reflecting the role of GATA3 in the development of the central nervous system (10). Hypomagnesaemia is often under-recognized in HDR syndrome, which is thought to be due to renal wasting associated with the renal involvement of the condition (11, 12). Hypocalcaemia and hypomagnesaemia could also have been a cause of our patient’s seizures as both hypocalcaemia and hypomagnesaemia increase excitability of neurons (13).

Several missense mutations of GATA3 have been reported, but this is the first case of HDR syndrome reported with this novel mutation. Clinicians who identify this rare triad of hypoparathyroidism, sensorineural deafness and renal anomalies should further investigate with genetic testing for GATA3 mutations. With fewer than 200 cases of this syndrome reported so far, further research is required to better understand why mutations that disrupt functional domains of the GATA3 protein are not associated with more severe phenotypes of the HDR syndrome.

Declaration of interest

The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Patient consent

Written informed consent was obtained from the patient/parent/guardian/relative for the publication of this case report.

Author contribution statement

LV, DJJ and JK substantially contributed to the drafting of this manuscript, including surveying the literature, identifying relevant articles and incorporating supporting comments. DJJ provided details about the patient’s clinical presentation and course of treatment.

References

  • 1

    Tao Y, Yang L, Han D, et al. A GATA3 gene mutation that causes incorrect splicing and HDR syndrome: a case study and literature review. Front Genet 2023 14 1254556. (https://doi.org/10.3389/fgene.2023.1254556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Barakat AY, D'Albora JB, Martin MM, et al. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 1977 91 6164. (https://doi.org/10.1016/s0022-3476(77)80445-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hasegawa T, Hasegawa Y, Aso T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997 73 416418. (https://doi.org/10.1002/(sici)1096-8628(19971231)73:4<416::aid-ajmg9>3.0.co;2-l)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000 406 419–. (https://doi.org/10.1038/35019088)

  • 5

    Chou J, Provot S & Werb Z GATA3 in development and cancer differentiation: cells GATA have it. J Cell Physiol 2010 222 4249. (https://doi.org/10.1002/jcp.21943)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Nesbit MA, Bowl MR, Harding B, et al. Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 2004 279 2262422634. (https://doi.org/10.1074/jbc.M401797200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Adachi M, Tachibana K, Asakura Y, et al. A novel mutation in the GATA3 gene in a family with HDR syndrome (hypoparathyroidism, sensorineural deafness and renal anomaly syndrome). J Pediatr Endocrinol Metab 2006 19 8792. (https://doi.org/10.1515/jpem.2006.19.1.87)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 17 405424. (https://doi.org/10.1038/gim.2015.30)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Varadi M, Bertoni D, Magana P, et al. AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences. Nucleic Acids Res 2024 52 D368D375. (https://doi.org/10.1093/nar/gkad1011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Pandolfi PP, Roth ME, Karis A, et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 1995 11 4044. (https://doi.org/10.1038/ng0995-40)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Alkaissi HR & Banerji MA Primary hypoparathyroidism presenting as idiopathic intracranial hypertension in a patient with Barakat syndrome. Cureus 2022 14 e24521. (https://doi.org/10.7759/cureus.24521)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Spennato U, Siegwart J, Hartmann B, et al. Barakat syndrome diagnosed decades after initial presentation. Endocrinol Diabetes Metab Case Rep 2023 2023 23-0018. (https://doi.org/10.1530/EDM-23-0018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Han P, Trinidad BJ & Shi J Hypocalcemia-induced seizure: demystifying the calcium paradox. ASN Neuro 2015 7 1759091415578050. (https://doi.org/10.1177/1759091415578050)

    • PubMed
    • Search Google Scholar
    • Export Citation

 

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  • Expand
  • Figure 1

    Sagittal view of echogenic and hypoplastic right kidney.

  • Figure 2

    Sagittal view of enlarged left kidney.

  • Figure 3

    3D structure of zinc finger moiety of GATA3, highlighting aspartate at position 287 (red) and its proximity to the zinc atom (purple).

  • 1

    Tao Y, Yang L, Han D, et al. A GATA3 gene mutation that causes incorrect splicing and HDR syndrome: a case study and literature review. Front Genet 2023 14 1254556. (https://doi.org/10.3389/fgene.2023.1254556)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 2

    Barakat AY, D'Albora JB, Martin MM, et al. Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 1977 91 6164. (https://doi.org/10.1016/s0022-3476(77)80445-9)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    Hasegawa T, Hasegawa Y, Aso T, et al. HDR syndrome (hypoparathyroidism, sensorineural deafness, renal dysplasia) associated with del(10)(p13). Am J Med Genet 1997 73 416418. (https://doi.org/10.1002/(sici)1096-8628(19971231)73:4<416::aid-ajmg9>3.0.co;2-l)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4

    Van Esch H, Groenen P, Nesbit MA, et al. GATA3 haplo-insufficiency causes human HDR syndrome. Nature 2000 406 419–. (https://doi.org/10.1038/35019088)

  • 5

    Chou J, Provot S & Werb Z GATA3 in development and cancer differentiation: cells GATA have it. J Cell Physiol 2010 222 4249. (https://doi.org/10.1002/jcp.21943)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6

    Nesbit MA, Bowl MR, Harding B, et al. Characterization of GATA3 mutations in the hypoparathyroidism, deafness, and renal dysplasia (HDR) syndrome. J Biol Chem 2004 279 2262422634. (https://doi.org/10.1074/jbc.M401797200)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7

    Adachi M, Tachibana K, Asakura Y, et al. A novel mutation in the GATA3 gene in a family with HDR syndrome (hypoparathyroidism, sensorineural deafness and renal anomaly syndrome). J Pediatr Endocrinol Metab 2006 19 8792. (https://doi.org/10.1515/jpem.2006.19.1.87)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015 17 405424. (https://doi.org/10.1038/gim.2015.30)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Varadi M, Bertoni D, Magana P, et al. AlphaFold Protein Structure Database in 2024: providing structure coverage for over 214 million protein sequences. Nucleic Acids Res 2024 52 D368D375. (https://doi.org/10.1093/nar/gkad1011)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Pandolfi PP, Roth ME, Karis A, et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat Genet 1995 11 4044. (https://doi.org/10.1038/ng0995-40)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 11

    Alkaissi HR & Banerji MA Primary hypoparathyroidism presenting as idiopathic intracranial hypertension in a patient with Barakat syndrome. Cureus 2022 14 e24521. (https://doi.org/10.7759/cureus.24521)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 12

    Spennato U, Siegwart J, Hartmann B, et al. Barakat syndrome diagnosed decades after initial presentation. Endocrinol Diabetes Metab Case Rep 2023 2023 23-0018. (https://doi.org/10.1530/EDM-23-0018)

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Han P, Trinidad BJ & Shi J Hypocalcemia-induced seizure: demystifying the calcium paradox. ASN Neuro 2015 7 1759091415578050. (https://doi.org/10.1177/1759091415578050)

    • PubMed
    • Search Google Scholar
    • Export Citation