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Homozygous and heterozygous expression of a novel mutation of the Acid-Labile Subunit

H Duyvenvoorde, Paediatrics, Leiden University Medical Center, Leiden, Netherlands
M Kempers, Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
M Twicker, Vascular Medicine, AMC, Amsterdam, Netherlands
J Doorn, Metabolic and Endocrine Diseases, University Medical Center Utrecht, Utrecht, Netherlands
W Gerver, Paediatrics, University Medical Center Maastricht, Maastricht, Netherlands
K Noordam, Paediatrics, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands
M Losekoot, Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
M Karperien, Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, Netherlands
J Wit, Paediatrics, Leiden University Medical Center, Leiden, Netherlands
A Hermus, Endocrinology, Radboud University Nijmegen Medical Center, Nijmegen, Netherlands

Correspondence: Hermine Duyvenvoorde, Email: H.A.van_Duyvenvoorde{at}lumc.nl

Abstract

Context: Acid-labile subunit (ALS) deficiency due to homozygous inactivation of the ALS gene (IGFALS) is associated with moderate short stature, and in few cases pubertal delay. The clinical expression of heterozygosity is unknown.

Objective: To investigate the clinical, laboratory and radiological features of homozygous and heterozygous carriers of a novel mutation in the ALS gene in comparison to non-carriers.

Subjects: Three short Kurdish brothers and their relatives.

Results: The index cases presented with short stature, microcephaly, low circulating IGF-I and IGFBP-3 and undetectable ALS levels. Two were known with a low bone mineral density, and one of them had suffered from 2 fractures. We found a novel homozygous ALS gene mutation resulting in a premature stopcodon (c.1490dupT, p.Leu497PhefsX40). The IGF-I, IGFBP-3 and ALS 150 kDa ternary complex was absent and ALS proteins in serum were not detected with Western blot. IGFPB-1 and -2 were low and there was a mild insulin resistance. Five heterozygous carriers tended to have a lower height and head circumference than five non-carriers, and had low plasma ALS and IGFBP-3 levels. Bone mineral (apparent) density was low in 2 out of 3 homozygous carriers, but also in 4 out of 9 relatives.

Conclusions: The clinical presentation of homozygous ALS mutations may besides short stature include microcephaly. Heterozygous carriers may have less statural and head growth, suggestive for a gene-dosage effect.