Cinacalcet treatment in an adolescent with concurrent 22q11.2 deletion syndrome and familial hypocalciuric hypercalcemia Type 3 caused by AP2S1 mutation

Abstract

Context:The22q11.2 deletionsyndrome(DS) isacommonmultipleanomalysyndromeinwhichtypical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. Case Description: Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. FurtherDNAanalysis of adaptor protein-2 subunit (AP2S1) showed a heterozygous missense mutation c.44G-T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. Conclusions:Hypercalcemiainourpatientwith22q11.2DScouldbeexplainedbythedenovomutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.