Glial Cell Missing Homolog 2 Mutation Causing Severe Hypoparathyroidism: Report of Two Cases With Novel Mutations

Abstract

Abstract Hypoparathyroidism is a common encounter in endocrinology practice. A thorough search for the etiology is generally futile, and most cases are labeled as idiopathic. Familial idiopathic hypoparathyroidism is a large chunk of these idiopathic cases. Here we present 2 cases who presented with features of hypocalcemia and were eventually diagnosed with hypoparathyroidism. Our first case is that of a middle-age woman who presented with spontaneous tetany and perioral numbness. She had very low serum calcium values, low serum magnesium, hypokalemia, hypercalciuria, and undetectable parathormone levels. She was initially managed with parenteral calcium, magnesium, and oral potassium chloride, which was shifted to oral replacements once stabilized. Focused exome sequencing for causes of hypoparathyroidism and hypocalcemia revealed a frameshift mutation in glial cell missing homolog 2 (GCM2) (NM_004752.4) on chromosome 6, c737dupA variant (p. Asp246Glufs*25) located at exon 5. The second case presented is that of a 1-month-old infant presenting with hypocalcemic seizures, severe hypocalcemia, hyperphosphatemia, and low parathormone levels. The infant was stabilized with parenteral calcium and trial of subcutaneous teriparatide for further improvement. Oral calcium and calcitriol were instituted once stabilized, and teriparatide was tapered off. Focused exome sequencing revealed a homozygous mutation involving GCM2 (ENST0000379491.5) on chromosome 6, variant CM2 chr6:10876558_10877139insT located on exon1-2. Both of these mutations are novel and underscore the profound effect of GCM2 on parathyroid gland development in infants and maintenance in adults.