SUN-760 - Double Gene Defects in A Young Woman with Severe Hypoparathyroidism

Introduction:

Congenital hypocalcemia is rare and typically due to single gene mutations affecting parathyroid development, regulation of parathyroid function, or parathyroid hormone (PTH) itself. It is very rare to have two genetic syndromes contributing to calcium (Ca) dysregulation concomitantly. This patient has both autosomal dominant hypocalcemia type 1 (ADH1) and Wilson Disease, highlighting diagnostic complexity and nuances of management.

Case:

A 26-year-old woman presented for evaluation of chronic hypocalcemia. She was diagnosed with hypoparathyroidism at 5 days old following seizures. Despite treatment with Ca carbonate (1000 mg twice daily), calcitriol (0.5 mcg twice daily), vitamin D3 (2000 IU daily), and magnesium (400 mg 3 times daily), she had frequent “brain fog,” muscle cramps, headaches, and tremors. Past medical history included depression and post-traumatic stress disorder. Family history is negative for endocrine or hepatic disorders. On exam, she had normal hearing, height, skin, nails, and no skeletal anomalies. Labs showed levels of serum Ca from 5.5 to 8.0 mg/dL, phosphorus 4.8 to 6.0 mg/dL, PTH < 3 ng/L, and 24-hour urine Ca 123 mg. Initial 25 OH vitamin D was 17 ng/dL; 1,25 OH vitamin D was 53 pg/mL. Ceruloplasmin and copper levels were mildly decreased with normal liver function. Brain MRI revealed extensive intracranial calcifications and renal ultrasound showed medullary nephrocalcinosis. Genetic testing identified a heterozygous activating CASR mutation (c.385T>C, p.Cys129Arg) consistent with ADH1, and homozygous ATP7B mutation (c.3859G>A, p.Gly1287Ser), consistent with Wilson disease. She transitioned to palopegteriparatide with marked symptom improvement and more stable serum Ca.

Discussion:

Activating CASR mutations in ADH1 lead to low PTH levels, hypocalcemia, and hyperphosphatemia. Many affected individuals have hypercalciuria despite low serum Ca levels. This increases risk of nephrocalcinosis and chronic kidney disease, exacerbated by treatment with Ca and calcitriol. Co-existence of Wilson disease, which predisposes to copper accumulation leading to atrophy and destruction of parathyroid glands, further compromises PTH secretion. This case, detected by broad genetic screening, represents the only known reported co-occurrence of ADH1 and Wilson disease. The presence of two genetic etiologies for hypoparathyroidism may explain the severity of hypocalcemia and symptoms in this patient. Two intracellular pathways disturbing parathyroid function may have accelerated development of complications like nephrocalcinosis and brain calcification. Treatment with palopegteriparatide led to improved symptoms and quality of life with reduced Ca and calcitriol intake, which may lower risks of renal complications from hypoparathyroidism.

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