Severe Short Stature Caused by Novel Compound Heterozygous Mutations of the Insulin-Like Growth Factor 1 Receptor (IGF1R)

Context: IGF-I, essential for normal human growth in utero and postnatally, mediates its effects through the IGF-I receptor (IGF1R). More than nine heterozygous mutations, including one compound heterozygous mutation, of the IGF1R gene have been reported in patients with varying degrees of intrauterine and postnatal growth retardation. Objective: The objective of the study was the analysis of the IGF1R gene in a short-statured patient. Patient: The male patient, with a height of -5.91 SD score (aged 20.3 yr), had consistently elevated circulating serum concentrations of IGF-I. A diagnosis of antibody-negative insulin-requiring diabetes was made at age 14 yr. His deceased sister was also severely short statured (-3.75 SD score). Results: The patient and his sister carried novel, compound heterozygous IGF1R missense mutations, E121K (exon 2) and E234K (exon 3), inherited from the mother and father, respectively. In vitro reconstitution studies demonstrated that neither the E121K nor E234K mutation affected IGF1R prepeptide expression, but levels of the proteolytically cleaved alpha- and beta-subunit were consistently low. As a consequence, each IGF1R variant exhibited significantly reduced IGF-I-induced signal transduction. Correlating to these studies, expression of functional IGF1R and the IGF-I-induced activation of the IGF1R pathway were markedly reduced in the primary dermal fibroblasts established from the patient. Conclusions: Only the second compound heterozygous IGF1R mutations to be identified, the p.E121K/E234K variant is the cause of intrauterine growth retardation and the most severe postnatal growth failure described to date in a patient with IGF1R defects. Whether the mutant IGF1R also contributes to the diabetic phenotype, however, remains to be determined. (J Clin Endocrinol Metab 97: E243-E247, 2012)