IMPE Abstracts

Introduction: Acid-labile subunit (ALS) forms ternary complexes with insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) being essential for normal circulating IGF-1 levels. The IGFALS gene encodes the ALS and loss-of-function variants in IGFALS cause ALS deficiency, which has a prevalence < 1/1.000.000. These patients generally present with moderate short stature, extraordinarily low serum levels of IGF-I and IGFBP-3 that remain abnormally low upon growth hormone stimulation. We describe a patient with a homozygous pathogenic variant in IGFALS and short stature.

Case Report: A 10.5 year-old girl, daughter of non-consanguineous parents, born at term with adequate birth weight, was monitored from 11 months of age due to short stature, presenting values within -2.3 (+/-0.4) standard deviation score (SDS) with normal growth velocity. Peak growth hormone (GH) response to GH stimulation was normal (6.27ng/ml), with low circulating IGF-1 concentration and extremely low IGFBP-3 levels. On physical examination, she had bilateral clinodactyly of 5^th phalanx, low-set and rotated ears, short neck, hypoplasia of incisors and spaced nipples, with 46 XX karyotype. A sequencing analysis of the IGFALS gene was performed, revealing a homozygous, missense variant: NM_004970.3:c.827A>G, (NP_004961.1:p.(Asn276Ser), classified as pathogenic according to ACMG criteria (PM2_supp, PS3, PM3_strong, PP3_supp). Her mother was a heterozygous carrier. Mother’s height was 154 cm (SDS-1,09). No clinical information of the father was available. Treatment with levothyroxine (12.5mg/day) was indicated, as a result of subclinical hypothyroidism, whereas treatment with rhGH was not initiated due to the lack of response reported in clinical evidence. Currently, the patient presents a height of 124 cm (SDS -1.87), growth rate of 5 cm/ year, Tanner breast stage 2 and Tanner pubic hair stage 1.

Conclusion: We describe the clinical characteristics of a female patient with complete ALS deficiency, with initiation of puberty at a normal age. It is essential to reinforce the importance of screening IGFALS gene in children with mild growth failure and a biochemical phenotype resembling GH resistance. It has already been described that rhGH treatment does not accelerate growth or increase height SDS in patients with homozygous IGFALS gene mutations.