Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation

• Published in: The journal of clinical endocrinology and metabolism Vol. 100; no. 7; pp. 2515 - 2518
• Main Authors: Tenhola, Sirpa, Hendy, Geoffrey N, Valta, Helena, Canaff, Lucie, Lee, Bonnie S. P, Wong, Betty Y. L, Välimäki, Matti J, Cole, David E. C, Mäkitie, Outi
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.07.2015; Copyright by The Endocrine Society
• Subjects: Adaptor Protein Complex 2 - genetics; Adaptor Protein Complex sigma Subunits - genetics; Adolescent; Base Sequence; Cinacalcet Hydrochloride; DiGeorge Syndrome - complications; DiGeorge Syndrome - drug therapy; Humans; Hypercalcemia - complications; Hypercalcemia - congenital; Hypercalcemia - drug therapy; Hypercalcemia - genetics; Male; Medicin och hälsovetenskap; Mutation, Missense; Naphthalenes - therapeutic use; Pedigree
• ISSN: 0021-972X; 1945-7197; 1945-7197
• DOI: 10.1210/jc.2015-1518

Context: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical 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. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. Conclusions: Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.