title: A new heterozygous mutation (L338N) in the human Gsalpha (GNAS1) gene as a cause for congenital hypothyroidism in Albright's hereditary osteodystrophy.
abstract: OBJECTIVE
  To identify the molecular defect by which psychomotor retardation is caused in two brothers with congenital hypothyroidism who received adequate treatment with l-thyroxine.
  
  
  METHODS
  A six-year-old boy presented with psychomotor retardation and congenital primary hypothyroidism (CH). The patient had a normal blood thyrotrophin (TSH) level on neonatal screening, but low total serum thyroxine and triiodothyronine concentrations prompting thyroid hormone substitution shortly after birth. Nevertheless, psychomotor development was retarded and the patient underwent further investigation. Typical features of Albright's hereditary osteodystrophy (AHO) such as round face, obesity, and shortened 1st, 4th and 5th metacarpals were found.
  
  
  RESULTS
  Further investigation confirmed AHO with pseudohypoparathyroidism (PHP) type Ia. The boy had a mild resistance to parathyroid hormone and a reduced adenylyl cyclase stimulating protein (Gsalpha) activity in erythrocytes. DNA analysis detected a new heterozygous mutation (L338N) in the Gsalpha protein (GNAS1) gene. This mutation was also present in the patient's brother who had similar features and was also treated with thyroid hormone because of CH, and in the phenotypically normal-looking mother who had a normal calcium metabolism but a reduced Gsalpha protein activity in erythrocytes suggestive of pseudopseudohypoparathyroidism.
  
  
  CONCLUSIONS
  In patients with CH, in whom the neurological outcome is poor even under adequate thyroid hormone substitution, PHP Ia may be suspected, especially when symptoms of AHO are present.
authors.affiliation: Children's Hospital, Johannes Gutenberg-University, Langenbeckstrasse 1, D-55101 Mainz, Germany. pohlenz@mail.uni-mainz.de
authors.forename: Joachim
authors.initials: J
authors.lastname: Pohlenz
authors.forename: Wiebke
authors.initials: W
authors.lastname: Ahrens
authors.forename: Olaf
authors.initials: O
authors.lastname: Hiort
mesh_terms: D002118:Calcium / Q000378:metabolism; D002648:Child; D004910:Erythrocyte Membrane / Q000737:chemistry; D005359:Fibrous Dysplasia, Polyostotic / Q000175:diagnosis / Q000235:genetics*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000097:blood / Q000235:genetics*; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics*; D008297:Male; D008663:Metacarpus / Q000002:abnormalities; D009154:Mutation; D010375:Pedigree; D011596:Psychomotor Disorders / Q000235:genetics*; D017422:Sequence Analysis, DNA; D013972:Thyrotropin / Q000097:blood; D013974:Thyroxine / Q000097:blood; D014284:Triiodothyronine / Q000097:blood
chemical_list: D014284:Triiodothyronine; D013972:Thyrotropin; D019205:GTP-Binding Protein alpha Subunits, Gs; D013974:Thyroxine; D002118:Calcium