Cookies on this website

We use cookies to ensure that we give you the best experience on our website. If you click 'Accept all cookies' we'll assume that you are happy to receive all cookies and you won't see this message again. If you click 'Reject all non-essential cookies' only necessary cookies providing core functionality such as security, network management, and accessibility will be enabled. Click 'Find out more' for information on how to change your cookie settings.

CONTEXT: Acid labile subunit (ALS) deficiency, caused by IGFALS mutations, is a subtype of primary IGF-I deficiency (PIGFD) and has been associated with insulin resistance (IR) and osteopenia. Whether patients respond to recombinant human IGF-I (rhIGF-I) is unknown. OBJECTIVE AND DESIGN: This study determined the 14-hour pharmacokinetic response of free and total IGF-I and IGF binding protein 3 (IGFBP-3) to a single sc dose of rhIGF-I (120 μg/kg) in four ALS-deficient patients, compared with severe PIGFD, moderate PIGFD, and controls. Intravenous glucose tolerance tests, fasting blood levels, dual-energy X-ray absorptiometry, peripheral quantitative computed tomography, and metacarpal radiogrammetry were performed in the four patients and 12 heterozygous family members. RESULTS: IGF-I and IGFBP-3 increased above baseline (P < .05) for 2.5 hours, returning to baseline 7 hours after rhIGF-I injection. Mean (SD) IGF-I Z-score increased by 2.49 (0.90), whereas IGFBP-3 Z-score increased by 0.57 (0.10) only. IGF-I elimination rates in ALS deficiency were similar, but the IGF-I increment was lower than those for severe PIGFD. Significant gene dosage effects were found for all IGF-I peptides, height, forearm muscle size, and metacarpal width. Bone analysis showed that ALS deficiency creates a phenotype of slender bones with normal size-corrected density. Abnormal glucose handling and IR was found in three of four patients and 6 of 12 carriers. CONCLUSIONS: These gene dosage effects demonstrate that one functional IGFALS allele is insufficient to maintain normal ALS levels, endocrine IGF-I action, full growth potential, muscle size, and periosteal expansion. Similar gene dosage effects may exist for parameters of IR. Despite similar IGF-I elimination compared with severe PIGFD, ALS-deficient patients cannot mount a similar response. Alternative ways of rhIGF-I administration should be sought.

Original publication




Journal article


J Clin Endocrinol Metab

Publication Date





E703 - E712


Adult, Blood Glucose, Body Composition, Bone Density, Bone Development, Carrier Proteins, Child, Child, Preschool, Cross-Sectional Studies, Gene Dosage, Glycoproteins, Humans, Insulin-Like Growth Factor I, Middle Aged, Recombinant Proteins, Young Adult