A Novel GATA3 Variant Causing Familial Hypoparathyroidism, Renal Agenesis and Sensorineural Deafness Presenting With Atypical Symptoms of Chronic Hypocalcaemia

Abstract

Introduction: Familial hypoparathyroidism is a rare cause of hypocalcaemia. We report a case of long-standing hypocalcaemia secondary to hypoparathyroidism caused by a novel GATA3 variant resulting in multiple organ involvement. Case: A 20 year old girl was referred to our bone metabolic clinic for hypocalcaemia. Her past medical history included Bechet’s disease, epilepsy and depression. She had bilateral sensorineural hearing loss and encephalitis as a child. She underwent right nephrectomy for an atrophic non-functioning kidney at the age of 16. Current medication included hydroxychloroquine, diazepam, oral calcium and cholecalciferol. It was noted that the hypocalcaemia dated back to 8 years, she denied any typical symptoms of hypocalcaemia but she did report visual and auditory hallucinations, fatigue and had low seizure threshold. She sustained recurrent fractures of her arm, elbow and wrist. Initial investigations: Corrected calcium 1.88 (2.20-2.60mmol/L), Phosphate 1.54 (0.80–1.50mmol/L), PTH 1.2 (1.6–6.9pmol/), 25-OH vitamin D 37 (50-120nmol/L). Myeloma screen, thyroid, renal and liver functions were all within the normal reference range. Other bone markers: Serum Procollagen Type 1 Amino Terminal Peptide was mildly raised at 82 (19-69ug/L), CTX 0.42 (0.1-0.5ug/L), 1,25 OH Vitamin D 29 (55-139pmol/L), 24,25-dihydroxyvitamin D was normal with normal 25:24,25 Dihyroxyvitamin D ratio at 18 normal. Bone density was in the normal range for her age. MRI of the brain was normal with no evidence of calcification. There was a family history of hypocalcemia in her estranged father. Subsequent genetic analysis showed a novel likely pathogenic GATA3 missense variant (c.961T>C p.(Cys321Arg). She was started on alfacalcidol and achieved near normocalcemia with adjusted calcium levels of 2.18nmol/L. Conclusion: Pathogenic variants in the GATA3 gene are responsible for Hypoparathyroidism-deafness-renal dysplasia (HDR) syndrome. In our patient, a novel missense variant in GATA3, p.(Cys321Arg), has been detected. This variant disrupts one of four conserved cysteine residues within a zinc-finger domain, which is involved in DNA binding and is presumed to have a deleterious effect on protein function. Patients may have longstanding asymptomatic hypocalcaemia with atypical features hence genetic testing is recommended in patient with multi-organ involvement. Alfacalcidol successfully restored calcium homeostasis in this case.