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

Abstract

Background: Mutations of the IGFALS gene have been reported since 2004 in 24 patients, but only 5 of these are females. Case Report: We describe a 14.7-year-old female of a consanguineous Moroccan family with growth retardation and normal-onset but slow progression of puberty without manifest pubertal height gain. Results: At age 3.2 years, the patient's height was 85.5 cm (-2.9 SDS) and her weight 9.9 kg (-2.9 SDS) with a head circumference of 44.5 cm (-3.3 SDS). Serum IGF-I and IGFBP-3 concentrations were low with normal basal and stimulated growth hormone (GH) levels. An IGF-I generation test confirmed a lack of response to GH administration. While onset of puberty occurred at a normal age, no significant pubertal growth acceleration was observed despite progression of breast development. Sequencing of the IGFALS gene revealed a novel homozygous frameshift mutation (c.1291delT) with a stop codon (p.W431GfsX10) leading to undetectable serum levels of acid-labile subunit. Conclusion: We report the phenotype of an adolescent girl with primary IGF-I deficiency due to a novel homozygous mutation of the IGFALS gene, who presented with growth delay, normal pubertal onset with slow progression and no pubertal growth acceleration indirectly suggesting a contributing role of the circulating IGF-I pool in the pubertal growth spurt.

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

“…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). The novel mutation was a splice site, single-base deletion in exon 2, which was predicted to result in a frameshift leading to a premature stop codon and abolition of the leucine-rich repeats between amino acid residues 574-618, required for protein-protein interactions.…”

Characterization of four Latin American families confirms previous findings and reveals novel features of acid‐labile subunit deficiency

“…From the original report in 2004, at least 30 patients with complete ACLSD have been characterized . In autosomal recessive genetic diseases, patients arise usually in consanguineous families being both parents’ carriers for the same pathogenic variants.…”

“…In the present study, we have characterized ACLSD in four children presenting either short stature, normal stature but shorter than mid- From the original report in 2004, 1 at least 30 patients with complete ACLSD have been characterized. [3][4][5][6] In autosomal recessive genetic diseases, patients arise usually in consanguineous families being both parents' carriers for the same pathogenic variants. However, in ACLSD more than 40% of the patients reported were compound heterozygous for two different variants inherited from nonrelated parents.…”

“…The condition is transmitted with an autosomal recessive pattern of inheritance in both consanguineous and nonconsanguineous families . About 30 patients from diverse ethnic backgrounds have been reported worldwide . Because acid‐labile subunit (ALS) is essential for the stability of ternary complex with IGF‐I and IGFBP‐3 (or IGFBP‐5), the lack of this protein results in the absence of the 150‐kDa complex in the circulation and the instability of IGF‐I and IGFBP‐3.…”

Analysis of acid-labile subunit and its usefulness in pediatrics

“…To assess the effect of ALS gene mutations on simple heterozygosity, the International ALS Society conducted a study on family members of patients with ALS-D. They used data collected for 21 patients who were homozygotes or compound heterozygotes, and for 44 family members who were heterozygous carriers 36 or who lacked ALS gene mutations 8 . This study demonstrated a potential dose effect because homozygotes and compound heterozygotes were approximately 1.5 SDS shorter than heterozygous carriers, and, in turn, these were an average of 1 SDS shorter than individuals without mutations.…”