Acid-Labile Subunit Deficiency and Growth Failure: Description of Two Novel Cases

Abstract

Background/Aims: 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. Conclusion: Screening of the IGFALS is important in children with short stature associated with low serum IGF-I, IGFBP-3 and ALS.

A Novel Homozygous Mutation of the <b><i>IGFALS</i></b> Gene in a Female Adolescent: Indirect Evidence for a Contributing Role of the Circulating IGF-I Pool in the Pubertal Growth Spurt

“…Our patient was born small for gestational age, but this could be coincidental since only 7 other patients were born small for gestational age, while 6 previously reported patients had a birth length and/or birth weight appropriate for their gestational age [6,7,8,9,10,11,12,13,14,15,16,17]. …”

“…Since the initial case described in 2004, about 20 patients, mostly males, with ALS deficiency have been reported in the literature [6,7,8,9,10,11,12,13,14,15,16,17]. We now report the genotype and phenotype of a 6th girl with ALS deficiency of a consanguineous family due to a novel homozygous mutation.…”

“…Patients with ALS deficiency originate from different ethnicities belonging to the different continents of the world and from consanguineous as well as nonconsanguineous families [4,6,7,8,9,10,11,12,13,14,15,16,17]. Our patient is the second subject of Arab origin.…”

“…While insulin resistance has been described in humans with ALS deficiency, it is absent in mice at least in the basal state [3,4]. Since the initial report in 2004, only 24 patients (19 males) with 17 different homozygous or compound heterozygous mutations of the IGFALS gene have been reported [6,7,8,9,10,11,12,13,14,15,16,17]. Therefore, some aspects of the phenotype remain poorly described or controversial.…”

Genetic characterisation of a cohort of children clinically labelled as GH or IGF1 insensitive: diagnostic value of serum IGF1 and height at presentation

“…3B). Two had a previously described homozygous IGFALS mutation c.401TOA (31,32), and one had a novel c.1291delT mutation. The individual with a novel mutation has been recently published as a case report (33).…”