Acid-labile subunit deficiency and growth failure: description of two novel cases.
OBJECTIVE
Mutations in the acid-labile subunit (ALS) gene (IGFALS) have been associated with circulating insulin-like growth factor I (IGF-I) deficiency and short stature. Whether severe pubertal delay is also part of the phenotype remains controversial due to the small number of cases reported. We report 2 children with a history of growth failure due to novel IGFALS mutations.


METHODS
The growth hormone receptor gene (GHR) and IGFALS were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography.


RESULTS
Two boys of 13.3 and 10.6 years, with pubertal stages 2 and 1, had mild short stature (-3.2 and -2.8 SDS, respectively) and a biochemical profile suggestive of growth hormone resistance. No defects were identified in the GHR. Patient 1 was homozygous for the IGFALS missense mutation P73L. Patient 2 was a compound heterozygote for the missense mutation L134Q and a novel GGC to AG substitution at position 546-548 (546-548delGGCinsAG). The latter causes a frameshift and the appearance of a premature stop codon. Size exclusion chromatography showed no peaks corresponding to ternary and binary complexes in either patient.


CONCLUSIONS
Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.
David
A
A
Centre for Endocrinology, Queen Mary University of London, Barts and the London School of Medicine and Dentistry, London, UK.
Rose
S J
SJ
Miraki-Moud
F
F
Metherell
L A
LA
Savage
M O
MO
Clark
A J L
AJ
Camacho-Hübner
C
C
D000293:Adolescent; D002352:Carrier Proteins / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D016368:Frameshift Mutation; D006023:Glycoproteins / Q000172:deficiency* / Q000235:genetics*; D006130:Growth Disorders / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000097:blood; D008297:Male; D020125:Mutation, Missense
D002352:Carrier Proteins; D006023:Glycoproteins; D018972:Insulin-Like Growth Factor Binding Protein 3; C075944:insulin-like growth factor binding protein, acid labile subunit
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