SAT-743 HDR Syndrome: Phenotypic Variations and Autoimmune Manifestations Within One Kindred

Abstract Disclosure: A.A. Alraddadi: None. D.S. Ali: None. A.A. Khan: Takeda, Ascendis, Amolyt, Amgen Inc, Alexion,Calcilytix. Background: HDR syndrome or Barakat syndrome is a rare autosomal dominant disorder caused by pathogenic variants in GATA3 gene. HDR syndrome is characterized by a triad of Hypoparathyroidism (HypoPT), Deafness, and Renal anomalies, with emerging evidence suggesting autoimmune manifestations due to the role of GATA3 in immune regulation. This case series presents three familial cases (a mother and her two daughters) who share a pathogenic GATA3 deletion, focusing on phenotypic variability. Methods: We conducted a retrospective chart review of 180 patients with HypoPT registered at our Canadian tertiary referral center. Three patients had a confirmed molecular diagnosis of HDR syndrome. Their clinical, laboratory, and genetic data were reviewed and are presented. Results: (Case Presentations) • Case 1 (Daughter, HDR): A 22-year-old female was diagnosed with sensorineural hearing loss at birth. She developed HypoPT at age 14, with symptoms of muscle cramping, numbness, and seizures. Renal and pelvic ultrasound revealed a septate uterus, a right dysplastic kidney, and a solitary left kidney. DNA analysis at age 11 confirmed a GATA3 (10p14 deletion). Laboratory findings included low serum ionized calcium (iCa) (1.06 mmol/L; normal range (NR): 1.15-1.32 mmol/L), low PTH (1.1 pmol/L; NR: 1.6-6.9 pmol/L), and high phosphorus (1.73 mmol/L; NR: 0.8-1.45 mmol/L). She was diagnosed with hypothyroidism at age 11, with features of Hashimoto’s thyroiditis. She also has bronchial asthma, which may have an autoimmune component. • Case 2 (Daughter, DR): A 24-year-old female was diagnosed with congenital deafness at birth. Genetic testing at age 13 confirmed GATA3 deletion. Renal imaging revealed a small right kidney and a left 5 mm parapelvic cyst. Parathyroid function was normal. Autoimmune conditions included systemic lupus erythematosus (SLE) and scleroderma, confirmed by positive ANA, anticentromere, and anti-Scl-70 antibodies. • Case 3 (Mother, DR): A 44-year-old female with congenital deafness was diagnosed with HDR syndrome at age of 33 after her daughters’ diagnoses and has the same GATA3 deletion. Renal imaging revealed bilateral renal cysts. Parathyroid function was normal (iCa 1.16 mmol/L, PTH 4.1 pmol/L, phosphorus 1.14 mmol/L). Autoimmune conditions included SLE and celiac disease. Conclusion: This kindred demonstrates phenotypic variability of HDR syndrome despite sharing the same GATA3 variant. While sensorineural hearing loss and renal anomalies were consistent features, HypoPT manifested only in the youngest daughter. Significant autoimmune manifestations in both mother and elder daughter support the involvement of GATA3 in immune regulation. These findings highlight the complex genotype-phenotype relationship in HDR syndrome and the need for comprehensive clinical surveillance to understand the natural history of the disease better. Presentation: Saturday, July 12, 2025