Acid-labile subunit deficiency and growth failure: description of two novel cases

• <i>Background/Aims:</i> Mutations in the acid-labile subunit (ALS) gene <i>(IGFALS)</i> 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 <i>IGFALS</i> mutations. <i>Methods:</i> The growth hormone receptor gene <i>(GHR)</i> and <i>IGFALS</i> were analyzed by direct sequencing. Ternary complex formation was studied by size exclusion chromatography. <i>Results:</i> 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 <i>GHR</i>. Patient 1 was homozygous for the <i>IGFALS</i> 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. <i>Conclusion:</i> Screening of the <i>IGFALS</i> is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.

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