Clinical and biochemical response to rhGH treatment in children with Idiopathic Short Stature (ISS): Impact of heterozygous variants in the IGFALS gene

ROPELATO MG

CABA

Congreso; XXVI Annual Meeting SLEP; 2016

Sociedad Latinoamericana de Endocrinología Pediátrica

Background: Acid-labile subunit (ALS) is crucial to stabilize IGF-I in circulating ternary complexes. Complete ALS deficiency is characterized by short stature, severe reduction of serum IGF-I and IGFBP-3 levels and poor response to rhGH treatment. Less information is available on the response to rhGH treatment in children heterozygous carriers for IGFALS gene variants. Aim:Evaluate auxological and biochemical responses to one year of rhGH treatment in short children either homozygous wildtype (WT) or heterozygous carriers (HC) for non-synonymous IGFALS variants. Patients: Short children (height ≤ ?2.5 SDS) presenting normal stimulated GH levels (GH max ≥4.7 ng/ml) were recruited. Six patients (5 boys, aged 6.7 ± 2.2) had heterozygous IGFALS gene variants: 4 probably pathogenic by in silico or in vitro assessment: p.E35Gfs*17 (n = 2), p.G506R (n = 1), p.H128R (n = 1), and 2 probfrom DS who died at month 19, with CH mutation: p.Arg1027*in exon 17 and c.3529+5G>A affecting the splicing. 4) 11 year old RMS boy showed a CH mutation in exon 14: p.[Arg926Trp]; [Arg914Cys]. 5) 15 year old girl with RMS with CH mutation in exons 4&19: p.[Arg372Gln]; [Asp1177Asn]. In all cases both parents carried one of the two alterations observed in the children. All parents were healthy, with normal fasting glucose and glucose tolerance test. Patients 1&2 with SD, presented mutations in the extracellular domain of the INSR (α subunits, encoded by exons 1?11) that normally affect the number of mature receptors or their affinity for binding insulin. Otherwise, missense mutations in the tyrosine kinase domain (β subunit, encoded by exons 12?22), are commonly associated with a milder impairment of insulin binding, as in our RMS patients 4&5. Although patient 3, presented a nonsense and splice site mutations, both located in β subunit, these alterations totally disrupt INSR function. Conclusions:There is considerable clinical heterogeneity in cases presenting severe insulin resistance. However, phenotype can be correlated with the severity of the observed mutations in the INSR gene.