Three Novel <i>IGFALS</i> Gene Mutations Resulting in Total ALS and Severe Circulating IGF-I/IGFBP-3 Deficiency in Children of Different Ethnic Origins

Abstract

Background/Aims: To date, four mutations in the IGFALS gene have been reported. We now describe two children of different ethnic background with total acid-labile subunit (ALS) and severe circulating IGF-I/IGFBP-3 deficiencies resulting from three novel mutations in the IGFALS gene. Patients/Methods: Serum and DNA of patients were analyzed. Results: Case 1 is a 12-year-old boy of Mayan origin. Case 2 is a 5-year-old girl of Jewish/Eastern European (Polish, Russian, Austrian-Hungarian)/Icelandic/European (French, English) ancestry. The reported cases had moderate short stature (–2.91 and –2.14 SDS, respectively), nondetectable serum ALS and extremely low serum concentrations of IGF-I and IGFBP-3. Case 1 harbored a novel homozygous 1308_1316 dup9 mutation in a highly conserved leucine-rich repeat (LRR) 17 motif of exon 2, representing an in-frame insertion of 3 amino acids, LEL. Case 2 harbored a novel heterozygous C60S/L244F mutation in exon 2, located within a highly conserved LRR 1 and LRR 9, respectively. Conclusions: The identification of additional novel IGFALS mutations, resulting in severe IGF-I/IGFBP-3 and ALS deficiencies, supports IGFALS as a candidate gene of the GH/IGF system, implicated in the pathogenesis of primary IGF deficiency, and represents an important part of its differential diagnosis.

Impact of Heterozygosity for Acid-Labile Subunit (IGFALS) Gene Mutations on Stature: Results from the International Acid-Labile Subunit Consortium

“…Among the 16 families analyzed, parents were consanguineous in three (19%) families (2, 6, 9); in 11 (69%) families, parents were nonconsanguineous. There is no record on consanguinity in two (12%) families because children were adopted at an early age (1,7).…”

“…Only three girls (14%) were reported (3,7,10), most likely representing the common male-oriented ascertainment bias commonly observed in evaluation of short stature. Mean chronological age at diagnosis was 11.1 Ϯ 4.8 yr (range, 4.1-19.6 yr).…”

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

“…being demonstrated compared with WT subjects and an additional 1.0-1.5 S.D. in subjects with homozygous defects (31,42). The suggestion has also recently been made that heterozygous mutations of two or more growth-regulating genes may combine to induce a short stature phenotype (24).…”

“…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).…”

Human Acid-Labile Subunit Deficiency: Clinical, Endocrine and Metabolic Consequences

“…Between 10.5 and 12 years of age, a GnRH analogue was added to preserve growth potential during GH therapy. In both periods the growth response was considered insufficient, and from 12 years of age IGF-I therapy (Increlex; Tercica, Brisbane, Calif., USA) was started with the results pending [24]. Case 13 was treated with GH from 4.4 years of age onward, and the growth response appeared suboptimal [24].…”