Hypoparathyroidism-Sensorineural Hearing Loss-Renal Dysplasia syndrome (HDR syndrome), also known as Barakat syndrome, is a rare autosomal dominant genetic disorder (1). HDR syndrome is primarily characterized by hypocalcemia-induced increased neuromuscular excitability, such as non-febrile seizures, muscle spasms, and myalgia (2). It is associated with hearing loss and abnormal kidney structure or function, caused by mutations in the GATA3 gene located on chromosome 10p14 (3, 4). The GATA3 gene belongs to the dual zinc finger transcription factor family and consists of 6 exons that encode 444 amino acids, including 2 transactivation domains and 2 zinc finger domains (5). This gene plays a crucial role in embryonic development in vertebrates and is expressed in the developing parathyroid gland, inner ear, and kidneys (6). The incidence of HDR syndrome is still clear, with limited reports on the clinical phenotype and genotype of HDR syndrome patients in China. In this case, the patient had a novel heterozygous mutation in the GATA3 gene, C.800G>T (p.C267F), which has not been reported before. Pathogenic analysis suggests that this mutation can lead to amino acid changes and is considered pathogenic. Therefore, this study aims to investigate the clinical features and genotypes of HDR syndrome, providing a foundation for accurate diagnosis and improving our understanding of the syndrome. This research will contribute to early screening and diagnosis, reducing misdiagnosis and missed diagnoses.

HDR syndrome is a rare autosomal dominant disorder, with GATA3 currently being the only known gene associated with HDR syndrome. Haploinsufficiency of GATA3 is considered a potential cause of HDR syndrome (7). The diagnosis of HDR syndrome is typically based on the identification of clinical symptoms, and the detection of haploinsufficiency or submicroscopic deletions on chromosome 10p14 through DNA analysis can help confirm the diagnosis (8).

The clinical manifestations of patients with HDR syndrome are heterogeneous, even among individuals with the same mutation (9). Studies have shown that only 53.7% of patients exhibit the full HDR triad, while the remaining patients display only two or one of the characteristics (2). Sensorineural hearing loss is often the initial manifestation of HDR syndrome and is typically present at birth. The severity of hearing impairment varies but tends to worsen with age (10). GATA3 plays a crucial role in the development of the cochlear anterior sensory domain and spiral ganglion neurons during embryogenesis, affecting all hair cells and supporting cells in the cochlea. This defect can persist from early infancy to adulthood (11). Despite the fact that this patient passed the hearing screening at birth and showed no abnormal electrophysiological changes in the bilateral ABR test, due to the infant’s young age (9 months), a pure tone audiometry (PTA) test could not be fully conducted. Therefore, continuous follow-up and monitoring are still necessary. Hypoparathyroidism manifests as symptomatic or asymptomatic hypocalcemia, including sensory abnormalities, tetany of hands and feet, hand and foot convulsions, seizures, and other symptoms (12, 13). In this case, the patient’s initial diagnosis of hypoparathyroidism was based on the observation of bilateral thumb adduction and palm rigidity, accompanied by rigidity in the right lower limb. These symptoms were alleviated after calcium supplementation. Additionally, the child’s PTH levels remained persistently below the normal range. Previous studies in heterozygous GATA3 gene knockout mice have shown smaller parathyroid glands. Additionally, low calcium-induced hypocalcemia with low vitamin D intake does not increase parathyroid proliferation or PTH secretion (14). These findings align with the observed hypocalcemia and low PTH levels in our clinical observations.

The severity of renal involvement in HDR syndrome can vary, ranging from no renal abnormalities to various conditions such as renal dysplasia, hypoplasia, cystic kidneys, and bladder-ureter reflux. In some cases, patients may progress to late-stage chronic kidney disease, necessitating renal replacement therapy (15). Studies have shown that the prognosis of HDR syndrome depends on the nature and severity of renal disease, with renal developmental abnormalities typically associated with a poorer prognosis (16).In this case, no renal abnormalities were detected in the patient, potentially due to their young age and the kidneys still being in the developmental process without exhibiting apparent abnormalities. However, it is crucial not to relax the monitoring of these clinical symptoms. Ikeuchi et al. (17) reported a case of an HDR patient who initially presented with primary hypoparathyroidism and right sensorineural hearing loss in the neonatal period, but no renal abnormalities were observed at that time. It was not until the patient reached 11 years old that right renal hypoplasia was discovered, despite the absence of evident clinical symptoms. In addition to the typical triad, previous literature has also reported other symptoms, including congenital heart defects, biliary atresia, pituitary hypofunction, genital anomalies, and diabetes (18–22).Therefore, comprehensive evaluation and regular follow-up are essential for managing patients with HDR syndrome to detect and address any potential complications.

The GATA3 protein comprises two N-terminal transactivation domains (TA1, TA2) and two C-terminal zinc finger domains (ZnF1, ZnF2). ZnF2 specifically recognizes and binds to the N-(A/T)GATA(T/G)-C sequence in DNA. ZnF1 stabilizes the binding of ZnF2 to DNA and interacts with various zinc finger proteins (23, 24). Lemos et al. compiled and analyzed data from 124 reported HDR syndrome families (including 177 patients), summarizing the GATA3 gene mutations found within these families. These mutations included 40% frameshift mutations, 23% missense mutations, 14% nonsense mutations, 6% splice site mutations, 1% in-frame deletions or insertions, 15% whole-gene deletions, and 1% gene duplications. There were no apparent mutation hotspots across the entire GATA3 gene, but missense mutations clustered within or near the ZnF1 or ZnF2 domains of the GATA3 gene (2). In this study, p.C267F is a missense mutation where the polar neutral amino acid cysteine is changed to the non-polar hydrophobic amino acid phenylalanine, located within ZnF1, resulting in a decrease in the affinity of the DNA binding site. This site has not been reported before and has important clinical significance for enriching the mutation spectrum of HDR genes.

Symptomatic management is typically the main approach for treating HDR syndrome. The treatment goal for patients with hypoparathyroidism is to alleviate symptoms and maintain serum calcium levels within the normal low range. However, it is important to note that patients with hypoparathyroidism have reduced renal reabsorption of calcium due to low levels of PTH, which makes them more susceptible to hypercalciuria compared to individuals without the condition. Furthermore, HDR syndrome patients have an inherent risk of kidney disease. Therefore, close monitoring and follow-up are necessary, and measures should be taken to prevent iatrogenic kidney stone formation (25, 26). For hearing impairment, the use of conventional hearing aids or cochlear implants can help restore hearing. Early diagnosis and intervention for hearing impairment are crucial (27). Genetic counseling is particularly important for autosomal dominant genetic disorders like HDR syndrome. It is recommended to seek early evaluation by clinical geneticists. Additionally, attention should be given to newborn hearing screening, prenatal ultrasound examinations, and early identification of hearing or renal defects to provide important opportunities for screening, diagnosis, guidance for reproductive choices, and early intervention.

The analysis of this case’s diagnosis and treatment process offers valuable insights for the clinical management of HDR syndrome. Clinicians should exercise caution when diagnosing HDR syndrome in young patients presenting with hypoparathyroidism, but without evident kidney or hearing symptoms. Early evaluation by clinical geneticists is recommended for autosomal dominant genetic disorders, and emphasis should be placed on newborn hearing screening and continuous monitoring of kidney development. Furthermore, the identification of the novel GATA3 gene variant c.800G>T (p.C267F) in this case contributes to the enrichment of the genetic database.