Endocrine Abstracts

Section 1: Case history: A 10-year-old girl presented with significant postnatal growth failure. Her birth weight was normal (–0.15SDS) but poor growth was observed from a few months of age. She had no other symptoms. On examination, height was –3.4SDS and head circumference –1.6SDS. She had no dysmorphic features and normal development. Section 2: Investigations: Baseline serum analyses were unremarkable. Karyotype was normal (46XX). Bone age was delayed by 2.5 years. A high peak GH was observed on glucagon stimulation (17.1 mcg/l). Baseline IGF-I levels were low/normal (144 micrograms/l; –1.3SDS) and responded poorly (increase <15) following IGF-I generation testing, suggesting GH resistance. Section 3: Results and treatment: RhIGF-I was commenced, and she was assessed for genetic defects in the GH-IGF-1 axis. After 6 months of rhIGF-I therapy (120 micrograms/kg BD), IGF-I levels were exceptionally high (1,044 micrograms/l; +5.9SDS). Height velocity improved from 3.6 cm/year to 6.5 cm/year. Assessment on our unique short stature gene panel identified a novel heterozygous IGFI variant (102813333C>T, c.356G>A, p.R119H) which was exceedingly rare (gnoMAD frequency 0.004%) and predicted damaging by SIFT (CADD score 32). The p.R119H variant changes an arginine to histidine. R119, the first amino acid of the IGF-I E domain, is the most critical amino acid for binding furin, an enzyme essential for cleaving pro-IGF-I to mature IGF-I (E domain removal). R119 is highly conserved across species. We hypothesise this variant impairs pro-IGF-I cleavage, reducing available mature circulating IGF-I. Pro-IGF-1 is likely to be less biologically active than mature IGF-I, resulting in postnatal growth failure and GH resistance. Functional work is ongoing. Section 4: Conclusions and points for discussion: Pathogenic IGF1 mutations are extremely rare with 5 autosomal recessive mutations, one IGF1 copy number variant and two heterozygous frameshift mutations reported associated with growth failure. Heterozygous missense IGF1 mutations have not been previously described. We report the first missense variant identified at the furin cleavage site, predicted to prevent the conversion of pro-IGF-I to mature IGF-I. Since the standard ELISA IGF-I assay cannot distinguish mature IGF-I from pro-IGF-I, the proportion of each IGF-I form in the circulation is unknown. A skewing to increased pro-IGF-I may impact IGF-I function as the functional roles of pro-IGF-I and the E domain are poorly understood. We are currently assessing whether IGF-I p.R119H competitively inhibits mature IGF-I from binding IGF1R and thus act in a dominant negative manner. Characterisation of this naturally-occurring novel mutation will fundamentally enhance our understanding of IGF-I regulation/growth physiology.