title: Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.
abstract: BACKGROUND
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Tenhola
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Geoffrey N
authors.initials: GN
authors.lastname: Hendy
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Helena
authors.initials: H
authors.lastname: Valta
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Lucie
authors.initials: L
authors.lastname: Canaff
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Bonnie S P
authors.initials: BS
authors.lastname: Lee
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Betty Y L
authors.initials: BY
authors.lastname: Wong
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Matti J
authors.initials: MJ
authors.lastname: Välimäki
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: David E C
authors.initials: DE
authors.lastname: Cole
authors.affiliation: Department of Pediatrics (S.T.), Kymenlaakso Central Hospital, Kotka and Kuopio University Hospital, 70210 Kuopio, Finland; Departments of Medicine, Physiology, and Human Genetics (G.N.H., L.C.), McGill University, and Experimental Therapeutics and Metabolism, McGill University Hospital Centre-Research Institute, Montreal, Quebec, H3H 2R9 Canada; Children's Hospital (H.V., O.M.), Helsinki University Central Hospital and University of Helsinki, 00100 Helsinki, Finland; Departments of Laboratory Medicine and Pathobiology, Medicine, and Genetics (B.S.P.L., B.Y.L.W., D.E.C.C.), University of Toronto, Toronto, Ontario M5S 2J7, Canada; Division of Endocrinology (M.J.V.), Department of Medicine, Helsinki University Central Hospital, 00029 Helsinki, Finland; Folkhälsan Institute of Genetics (O.M.), 00014 Helsinki, Finland; and Department of Molecular Medicine and Surgery (O.M.), Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, 17176 Stockholm, Sweden.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D033962:Adaptor Protein Complex 2 / Q000235:genetics*; D034002:Adaptor Protein Complex sigma Subunits / Q000235:genetics*; D000293:Adolescent; D001483:Base Sequence; D000069449:Cinacalcet; D004062:DiGeorge Syndrome / Q000150:complications / Q000188:drug therapy*; D006801:Humans; D006934:Hypercalcemia / Q000150:complications / Q000151:congenital* / Q000188:drug therapy / Q000235:genetics; D008297:Male; D020125:Mutation, Missense; D009281:Naphthalenes / Q000627:therapeutic use*; D010375:Pedigree
chemical_list: C510065:AP2S1 protein, human; D033962:Adaptor Protein Complex 2; D034002:Adaptor Protein Complex sigma Subunits; D009281:Naphthalenes; D000069449:Cinacalcet