Hypoparathyroidism with Sensorineural Deafness and Renal Dysplasia (HDR Syndrome) Diagnosed in an Adult Patient

Introduction:
HDR syndrome, also known as Barakat syndrome, is a rare autosomal dominant disorder manifesting as the triad of hypoparathyroidism, hearing loss, and renal dysplasia. The condition is caused by haploinsufficiency for the GATA3 gene on chromosome 10p14 and usually diagnosed in childhood or adolescence. We present a case of HDR syndrome diagnosed in an adult patient.

Case Description:
A 29-year-old female was referred for management of hypoparathyroidism. She was diagnosed with moderate sensorineural hearing loss at age three years and found to be hypocalcemic (6.4 mg/dL, 8.4-10.4 mg/dL) with low PTH level (6 pg/mL,12-88 pg/mL) during a seizure at age 11 years. Supplemental calcium and calcitriol were started for management of hypoparathyroidism, and no additional seizures occurred. A 1.6 cm simple cyst in the upper pole of the left kidney was detected by renal ultrasound, and evaluation of renal function was notable for Stage 2 CKD (creatinine 1.2 mg/dL, GFR 63 mL/min/1.73m2). There was no family history of hypoparathyroidism, hearing loss, or renal disorders. Genetic testing confirmed the patient is heterozygous for frameshift duplication variant NM_001002295.2(GATA3)c.431dupG. The duplication creates a frameshift at amino acid 145 and introduces a premature stop codon 159 amino acids downstream (p.His145Profs*159).

Discussion:
Since publication of the first two patients in 1977, nearly 200 cases of HDR syndrome have been diagnosed. In 2000, deletion-mapping identified mutations in GATA3, a zinc finger transcription factor important in embryonic development of parathyroid glands, the auditory nervous system, and kidneys, as the etiology of HDR syndrome. This patient’s mutation has been reported in three other cases of HDR syndrome and is pathogenic due to either a truncated protein with loss of function or nonsense-mediated RNA decay. Early onset sensorineural hearing loss is the most common manifestation of HDR syndrome (96.7% of patients) followed closely by hypoparathyroidism (93.3%) and renal disease (72.2%). Approximately 40% of patients have congenital kidney anomalies, and many develop renal function abnormalities (e.g., hematuria or proteinuria) and chronic kidney disease.  Onset of HDR may occur at any age, though the patient’s history indicates childhood onset.  This case illustrates the importance of adult endocrinologists having knowledge of the syndromic presentation of endocrinopathies as diagnosis may be missed in childhood. In addition to appropriate management of hypoparathyroidism and hearing loss, patient’s with HDR syndrome require careful lifelong surveillance of renal function and genetic counseling.