title: Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure.
abstract: BACKGROUND
  Primary IGF deficiency (IGFD) describes the condition in which serum concentrations of IGF-I are low in the face of normal to elevated GH production. Because IGF-I, which circulates as part of a ternary complex with IGF binding protein (IGFBP)-3 and acid-labile subunit (ALS), mediates the growth-promoting effects of GH, IGFD is associated with severe growth failure in humans.
  
  
  OBJECTIVE
  We investigated a case of IGFD in which serum IGF-I and IGFBP-3 were abnormally low, yet growth failure was modest (-2.1 sd score at 15.5 yr of age).
  
  
  RESULTS
  The young male subject, from a consanguineous pedigree, had a postnatal growth profile consistently below the third percentile. The subject had a normal fasting GH level of 3.7 muU/ml and normal serum GH binding protein level (1258 pmol/liter; normal range 431-1892 pmol/liter), but serum IGF-I and IGFBP-3 were profoundly reduced (-5.8 and -7.2 sd score, respectively, at age 12.3 yr), even through puberty. A novel homozygous missense mutation was subsequently identified in the ALS gene, which resulted in severe deficiency of serum ALS (undetectable).
  
  
  CONCLUSIONS
  ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.
authors.affiliation: Department of Pediatrics, Oregon Health and Science University, 3181 Southwest Sam Jackson Park Road, Portland, Oregon 97239-3098, USA. hwav@ohsu.edu
authors.forename: Vivian
authors.initials: V
authors.lastname: Hwa
authors.forename: Gabriele
authors.initials: G
authors.lastname: Haeusler
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Pratt
authors.forename: Brian M
authors.initials: BM
authors.lastname: Little
authors.forename: Herwig
authors.initials: H
authors.lastname: Frisch
authors.forename: Dieter
authors.initials: D
authors.lastname: Koller
authors.forename: Ron G
authors.initials: RG
authors.lastname: Rosenfeld
mesh_terms: D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D018076:DNA, Complementary / Q000235:genetics; D005347:Fibroblasts / Q000378:metabolism; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D019382:Human Growth Hormone / Q000097:blood; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000172:deficiency; D007334:Insulin-Like Growth Factor I / Q000172:deficiency; D008024:Ligands; D008297:Male; D020125:Mutation, Missense / Q000235:genetics* / Q000502:physiology*; D011627:Puberty / Q000502:physiology; D012867:Skin / Q000166:cytology; D013002:Somatomedins / Q000172:deficiency*
chemical_list: D002352:Carrier Proteins; D018076:DNA, Complementary; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; D008024:Ligands; D013002:Somatomedins; C075944:insulin-like growth factor binding protein, acid labile subunit; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I