2024 Volume 71 Issue 11 Pages 1077-1086
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, deafness, and renal dysplasia (HDR) syndrome (OMIM #146255), also known as Barakat syndrome, is an autosomal-dominant hereditary disorder. This syndrome is characterized by the triad of hypoparathyroidism (H), sensorineural deafness (D), and renal dysplasia (R) [1, 2]. HDR syndrome is caused by a haploinsufficiency of the GATA3 gene located on chromosome 10p14-p15. GATA binding protein 3 (GATA3) is a transcription factor involved in the embryonic development of several tissues, such as the kidney, parathyroid gland, inner ear, thymus, central nervous system, ovary, testis, and adipose tissues [3, 4]. In addition, patients with HDR syndrome exhibit a triad of phenotypes, as well as hypogonadotropic hypogonadism, polycystic ovaries, abnormal Mullerian duct structures, and cognitive disabilities [5, 6]. The GATA3 protein contains two zinc finger domains that bind to the (A/T)GATA(A/G) consensus motif on the target DNA [7].
We herein present the case of a Japanese family with a novel GATA3 variant at exon 2 (c.48delC) causing HDR syndrome. This variant induces frameshift, resulting in an altered reading frame and a premature stop at codon 178.
To date, more than 100 GATA3 variants related to HDR syndrome have been reported. We summarized the reported Japanese cases of HDR syndrome with regard to the mode of onset and the age at diagnosis. Furthermore, we summarized the previously reported GATA3 variants in patients with HDR syndrome and mapped the sites of the genetic abnormalities. This case report and review of literature will serve as a useful reference for diagnosing HDR syndrome and predicting future symptoms.
Written informed consent for genetic analysis and publication was obtained from the patient and his family. This report was approved by the ethics committee of Iwate Medical University (COA no. HG2019-010). All clinical investigations were conducted in accordance with the principles of the Declaration of Helsinki.
Genetic analysisVariant analysis in hereditary hypoparathyroidism-related genes (e.g., CASR, GNA11, GCM2, TBX1, TBX2, NEBL, CHD7, SEMA3E, GATA3, TBCE, FAM111A, PTH, SOX3, AIRE, NLRP5, HADHA, HADHB, ACADM, DHCR7, CLDN16, CLDN19, TRPM6) was performed using a next-generation sequencer in Kazusa DNA laboratory. For Sanger sequencing, DNA was extracted from the blood samples using QIAamp® DNA Blood Maxi Kit (QIAGEN, Hilden, Germany). The following oligonucleotides were used for GATA3: exon 2, forward 5'-CCTTTGCTCACCTTTGCTTCC-3' and reverse 5'-CCCTGACCGAGTTTCCGTAG-3'. The sequencing results were analyzed using an ABI PRISM 3100 Genetic analyzer (Applied Biosystems) and compared with the published GATA3 sequence (accession no. NM_000475). The impact of identified variant was assessed by the American College of Medical Genetics and Genomics (ACMG) classification using Franklin online platform (https://franklin.genoox.com – Franklin by genoox).
Review of literatureA literature search for GATA3 variant data in patients with HDR syndrome was conducted using PubMed until December 2023.
Statistical analysesAll the data are presented as means ± SD. Statistical significance was defined as p < 0.05 determined by one-way ANOVA for all data obtained in review of literature.
A 38-year-old Japanese man was transported by an ambulance and admitted to our hospital due to nausea, impaired consciousness, and hypocalcemia-induced tetany. The medical history revealed that he was born at 39 weeks weighing 2,200 g. He was diagnosed with moderate bilateral hearing loss at 4 years of age and required a hearing aid. His mother and grandmother also had moderate bilateral hearing loss from childhood (Fig. 1A). As he had a mild intellectual delay and cognitive impairment, he received special language training in junior high school. He underwent bilateral cataract surgery at 38 years of age.
(A) Pedigree of the patient with deafness. Individuals with hearing loss are noted by filled symbols. The proband is indicated with an arrow. (B) Carpopedal spasm (Trousseau sign) was observed with hypocalcemia. (C) Image of brain CT showed bilaterally symmetrical calcification in the basal ganglia, thalamus, and white matter of cerebellar hemispheres. (D) The prolonged QT interval returned to normal after activated vitamin D treatment.
On admission, the height and body weight were 160.5 cm and 55.0 kg, respectively, and the body mass index (BMI) was 21.4 kg/m2. The patient had bilateral congenital palpebral ptosis. Physical examination revealed numbness and tetany in the limbs, with positive Chvostek’s and Trousseau’s signs (Fig. 1B). Brain computed tomography (CT) revealed marked bilateral and symmetrical calcifications in the basal ganglia, thalamus, and cerebellar white matter (Fig. 1C).
Biochemical investigations revealed severely low serum corrected calcium (cCa) levels with hyperphosphatemia (Table 1). The serum intact parathyroid hormone (PTH) level was relatively low compared with the low serum calcium concentrations, indicating hypoparathyroidism. The electrocardiogram demonstrated a prolonged QT interval, which was attributed to hypocalcemia (Fig. 1D). Cervical echography revealed no apparent abnormalities in and around the thyroid glands.
| Component | Result | Reference range | |
|---|---|---|---|
| Biochemistry | TP (g/dL) | 6.0 | 6.6–8.1 |
| Albumin (g/dL) | 3.6 | 4.1–5.1 | |
| Na (mEq/L) | 138 | 138–145 | |
| K (mEq/L) | 3.3 | 3.6–4.8 | |
| Cl (mEq/L) | 97 | 101–108 | |
| Ca (mg/dL) | 4.4 | 8.8–10.1 | |
| P (mg/dL) | 6.6 | 2.7–4.6 | |
| Mg (mg/dL) | 1.8 | 1.8–2.3 | |
| AST (U/L) | 28 | 13–30 | |
| ALT (U/L) | 15 | 10–42 | |
| LDH (U/L) | 556 | 124–222 | |
| ALP (U/L) | 74 | 38–113 | |
| γGTP (U/L) | 12 | 13–64 | |
| ChE (U/L) | 203 | 240–486 | |
| T-Bil (mg/dL) | 0.8 | 0.4–1.5 | |
| AMY (U/L) | 92 | 44–132 | |
| CK (U/L) | 1,562 | 59–248 | |
| BUN (mg/dL) | 30.0 | 8–20 | |
| CRE (mg/dL) | 1.77 | 0.65–1.07 | |
| eGFR (mL/min/1.73 m2) | 36.6 | >90 | |
| UA (mg/dL) | 7.3 | 3.7–7.8 | |
| T-cho (mg/dL) | 130 | 142–248 | |
| TG (mg/dL) | 78 | 40–234 | |
| Glucose (mg/dL) | 106 | 73–109 | |
| HbA1c (%) | 5.6 | 4.9–6.0 | |
| Intact-PTH (pg/mL) | 13 | 10.3–65.9 | |
| Whole PTH (pg/mL) | 4.6 | 8.3–38.7 | |
| PTHrP (pmol/L) | <1.0 | 0–1.1 | |
| Calcitonin (pg/mL) | <0.5 | 0–9.52 | |
| 1.25-(OH)2 Vit.D3 (pg/mL) | 48.3 | 20–60 | |
| 25(OH) Vit.D (ng/mL) | 4.1 | >30 | |
| TRACP-5b (mU/dL) | 877 | 170–590 | |
| Bone ALP (μg/L) | 10.8 | 3.7–20.9 | |
| Blood count | WBC (×103/μL) | 8.39 | 3.3–8.6 |
| RBC (×106/μL) | 3.52 | 4.35–5.55 | |
| Hb (g/dL) | 11.4 | 13.7–16.8 | |
| Ht (%) | 32.5 | 40.7–50.1 | |
| MCV (fL) | 89.0 | 83.6–98.2 | |
| MCH (pg) | 30.1 | 27.5–33.2 | |
| MCHC (%) | 33.9 | 31.7–35.3 | |
| PLT (×103/μL) | 318 | 158–348 | |
| Urine | Protein | — | |
| Glucose | — | ||
| RBC | — | ||
| Ketone | — | ||
| Na (mEq/L) | 26 | ||
| K (mEq/L) | 10.1 | ||
| Cl (mEq/L) | 18 | ||
| Ca (mg/dL) | 2.3 | ||
| P (mg/dL) | 45.8 | ||
| CRE (mg/dL) | 141.2 | ||
| Urinary NAG (U/L) | 6.4 | 0.9–6.2 |
The results in bold are outside the limits of the normal value.
Abbreviations: TP: total protein, Na: sodium, K: potassium, Cl: chloride, Ca: calcium, P: phosphate, Mg: magnesium, AST: aspartate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, ALP: alkaline phosphatase, γGTP: gamma-glutamyl transpeptidase, ChE: cholinesterase, T-bil: total bilirubin, AMY: amylase, CK: creatine kinase, BUN: blood urea nitrogen, CRE: creatinine, eGFR: estimated glomerular filtration rate, UA: uric acid, T-chol: total cholesterol, TG: triglyceride, HbA1c: glycated hemoglobin, PTH: parathyroid hormone, PTHrP: parathyroid hormone-related protein, Vit: vitamin, TRACP-5b: tartrate-resistant acid phosphatase 5b, WBC: white blood cells, RBC: red blood cells, Hb: hemoglobin, Ht: hematocrit, MCV: mean corpuscular volume, MCH: mean corpuscular hemoglobin, MCHC: mean corpuscular hemoglobin concentration, PLT: platelets, NAG: N-acetyl-β-glucosaminidase
After hospitalization, the patient was intravenously administered 10 mg of calcium gluconate. Subsequently, he was initiated with the oral administration of 1α, 25-dihydroxy vitamin D3 (calcitriol: an initial dose of 0.5 μg/day to a maintenance dose of 0.75 μg/day). With oral activated vitamin D treatment, the serum-corrected calcium level increased to 7.9 mg/dL and remained within the normal range. His symptoms, such as carpal spasm, positive Chvostek’s and Trousseau’s signs, and a prolonged QT interval, were normalized (Fig. 1D). Although abdominal CT detected no apparent morphological abnormalities in the kidneys, his renal function was compromised. The serum levels of blood urea nitrogen (BUN) and creatinine (Cre) were 30.0 mg/dL and 1.77 mg/dL, respectively. The urinalysis results were negative for proteins (Table 1).
The genetic analysisAfter informed consent for genetic analysis was obtained from the patient and his family members, we performed a genetic analysis of all coding exons (exon 2–6) of GATA3 gene (GenBank accession number NM_001002295) using next-generation sequencing (NGS) and Sanger sequencing. We identified a novel heterozygous nucleotide deletion in exon 2 of the GATA3 gene (c.48delC) (Fig. 2A and 2B). This variant has not been reported previously. While his father had no pathological genetic variants in the GATA3 gene, his mother had the same deletion variant in the GATA3 gene (Fig. 2C). As this deletion variant is predicted to cause a frameshift that results in a premature stop at codon 178, it is considered pathogenic. According to the ACMG classification, this variant was evaluated as likely pathogenic by the Franklin online platform.
(A) Sequence readings generated by NGS were visualized with Integrative Genomics Viewer. The red arrow indicates the 48th codon in the GATA3 gene is missing in the heterozygous state. (B) Sequence results of the GATA3 gene in patient revealed the identification of a deletion variant c.48del (p.Ala 17ProfsTer178). (C) Direct sequencing revealed no variants in the patient’s father, but the mother had a heterozygous c.48del (p.Ala 17ProfsTer178) variant in the GATA3 gene.
We collected and summarized the data from 45 Japanese cases with HDR syndrome [8-27]. Cases with insufficient information were excluded from the study. The incidence of reported Japanese cases was approximately half familial and half sporadic (Fig. 3A). In addition, the average ages at which patients were diagnosed with hypoparathyroidism, hearing loss, and renal defects/disorders were 16.7, 9.8, and 17.0 years, respectively (Fig. 3B). Further genotype-phenotype analysis revealed that each triad was diagnosed at a later age in carriers with missense variants than with other variants (Fig. 3C).
(A) Number of familial and sporadic cases of HDR syndrome. (B) Box plots analysis for the age at diagnosis of triads in Japanese cases of HDR syndrome. (C) Box plots analysis for the age at diagnosis of triads in Japanese cases of HDR syndrome, comparing missense variants and other variants (deletion variant, nonsense variant, insertion variant, splicing variant, and gross deletion variant). There were no in-frame variants among deletion and insertion variants. * p < 0.05 between missense variants and other variants.
The GATA3 gene comprises six exons distributed over 20 kb of DNA and encodes a 444 amino-acid protein [28]. To date, more than 100 gene variants in the GATA3 gene have been reported, including deletion, nonsense, missense, insertion, splicing, and gross deletion variants. As shown in Fig. 4, we have summarized and mapped previously reported GATA3 variants in HDR syndrome. Notably, the splice variants were located only in exon 5 region. Furthermore, most missense variants are located at two apparent hotspots in exons 4 and 5, which encode two zinc finger domains (ZnF1 and ZnF2) in GATA3 [3]. These findings suggest that these zinc finger domains are critical for GATA3 transcription, serving as crucial sites for the onset of HDR syndrome.
The untranslated and coding regions are indicated by gray and white boxes, respectively. The GATA3 gene encodes two zinc finger domains (the N-terminal zinc finger (ZnF1) and the C-terminal zinc finger (ZnF2)). The gross deletion variants are shown in the bottom panel.
HDR syndrome is an autosomal dominant genetic disease caused by the haploinsufficiency of GATA3 located on chromosome 10p14-p15 [3]. The onset and severity of triads in HDR syndrome varies among patients with GATA3 variants. Even among patients with the same genetic abnormalities, the degree of renal dysfunction can vary significantly, as observed within the same family [8, 9, 31, 49]. In addition, the frequencies of each phenotypic triad of HDR syndrome increase with age [83, 88]. Our data review also revealed that deafness was more likely to be diagnosed at an early age. In addition, our analysis of HDR syndrome in Japanese patients revealed that familial and sporadic genetic forms were present in approximately half of the cases. Furthermore, our comparison of previously reported HDR syndromes in Japanese patients revealed that carriers of missense variant exhibited a slower onset of triads than those with other variants.
In the present case, sequence analysis revealed a novel heterozygous deletion variant in GATA3 in exon 2 (c.48delC) that resulted in a premature stop at codon 178, leading to the loss of two zinc finger domains. In previous reports, GATA3 variants in exon 2 were limited to deletion, nonsense, and insertion variants, all of which impeded immediate GATA3 transcription. In these cases, a well-known phenomenon called nonsense-mediated decay (NMD) due to premature stop codons may have occurred and triggered the symptoms [89]. In contrast, most missense variants were found in exons 4 and 5 (Fig. 4), clearly demonstrating the importance of the two zinc finger regions of the GATA3 protein. These two zinc fingers are crucial for GATA3 transcription. The N-terminal finger (ZnF1) functions to stabilize DNA binding and interacts with other proteins, whereas the C-terminal zinc finger (ZnF2) binds to DNA [49]. Therefore, even a minor substitution of amino acids in these two zinc finger regions could impair the DNA-binding ability of GATA3.
In the present case, his blood tests indicated renal dysfunction, although no apparent morphological abnormalities of either kidney were observed on abdominal CT. Renal anomalies are also heterogeneous, with variable penetrance, including renal hypo/dysplasia, aplasia, cystic kidney disease, pelvic calyceal deformity, and vesicoureteral reflux [58]. In addition, variability of renal defects/disorders in the manifestations of HDR syndrome can appear even within the same family. On the other hand, renal anomalies are absent in some cases [24, 31].
In the inner ear, GATA3 is expressed during the developmental stage in inner hair cells, outer hair cells, and various supporting cells [90, 91]. Hearing loss, usually bilateral [88, 92], is a plausible initial symptom of HDR syndrome that progresses with age [5, 17, 83]. Bilateral palpebral ptosis and cataracts were observed. These features are putative phenotypes associated with the HDR syndrome [31]. The clinical features other than the triad, such as bilateral cataracts, calcifications of the basal ganglia, diffuse goiter, hemimegaloencephaly with seizures, malformations in the genital tract, and mental retardation, have been occasionally described in patients carrying intragenic variants of GATA3 [10, 93]. Some of these symptoms may be considered as a consequence of the calcium-phosphorus derangement.
From the previously reported genotype-phenotype correlations, it was clarified that the variant type and the position of variant in GATA3 gene are crucial for the resulting clinical phenotypes. Therefore, the diagnosis of genetic variants is indispensable for clinical manifestations. For hypoparathyroidism, activated vitamin D supplements with monitoring of serum and urine calcium levels are recommended to prevent the formation of iatrogenic renal and urinary system stones and calcium deposition in the soft tissue. The therapeutic target level of cCa should be around lower limit of reference range to suppress the progression of chronic kidney disease [94]. Therefore, early diagnosis of HDR syndrome is crucial to provide timely intervention, genetic counseling, and prevention of emergencies caused by severe hypocalcemia and irreversible complications.
We identified a Japanese familial case of a novel deletion variant of GATA3 in an HDR syndrome. He exhibited the triad of HDR syndromes with variable phenotypes, such as cataracts, bilateral ptosis, and intellectual disability. In addition, we summarized the characteristics of Japanese cases of HDR syndrome and mapped the intragenic GATA3 variants previously reported in the literature.
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YI is a member of Endocrine Journal’s Editorial Board.
We thank S. Tamura for the technical support.
YH, TS, AC, EY, HK, HC, TO, NT, and YT took care of the patient and collected the patient’s information. YH and YI wrote the manuscript. YH performed genetic analyses. YH, KN, and YI contributed to the discussions. All the authors have read and agreed to the published version of the manuscript.
