title: Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.
abstract: OBJECTIVE
  Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through α11 (Gα11) and αq (Gαq) subunits. Heterozygous activating mutations in GNA11, the gene encoding Gα11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11.
  
  
  METHODS
  A three-generation family with seven members (3 adults, 4 children) presenting with ADH.
  
  
  METHODS
  Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed.
  
  
  RESULTS
  Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children).
  
  
  CONCLUSIONS
  The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for Gα11 signaling besides calcium regulation.
authors.affiliation: Department of PediatricsKymenlaakso Central Hospital, Kotka, Finland Department of PediatricsKuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Sirpa
authors.initials: S
authors.lastname: Tenhola
authors.affiliation: Department of PediatricsKuopio University Hospital and University of Eastern Finland, Kuopio, Finland.
authors.forename: Raimo
authors.initials: R
authors.lastname: Voutilainen
authors.affiliation: Endocrine UnitMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Monica
authors.initials: M
authors.lastname: Reyes
authors.affiliation: Department of RadiologyHUS Medical Imaging Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
authors.forename: Sanna
authors.initials: S
authors.lastname: Toiviainen-Salo
authors.affiliation: Endocrine UnitMassachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.affiliation: Children's HospitalUniversity of Helsinki and Helsinki University Hospital, Helsinki, Finland Folkhälsan Institute of GeneticsHelsinki, Finland Department of Molecular Medicine and SurgeryKarolinska Institutet and Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden outi.makitie@helsinki.fi.
authors.forename: Outi
authors.initials: O
authors.lastname: Mäkitie
mesh_terms: D000328:Adult; D002114:Calcinosis / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D002118:Calcium / Q000097:blood; D002648:Child; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D006801:Humans; D053565:Hypercalciuria / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D006996:Hypocalcemia / Q000097:blood / Q000000981:diagnostic imaging / Q000235:genetics*; D007011:Hypoparathyroidism / Q000097:blood / Q000151:congenital* / Q000000981:diagnostic imaging / Q000235:genetics; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D010375:Pedigree; D014057:Tomography, X-Ray Computed
chemical_list: C554062:GNA11 protein, human; D044385:GTP-Binding Protein alpha Subunits; D002118:Calcium