Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations

• Published in: European journal of endocrinology Vol. 168; no. 1; pp. K1 - K7
• Main Authors: Gannagé-Yared, Marie-Hélène, Klammt, Jürgen, Chouery, Eliane, Corbani, Sandra, Mégarbané, Hala, Abou Ghoch, Joelle, Choucair, Nancy, Pfäffle, Roland, Mégarbané, André
• Format: Journal Article
• Language: English
• Published: Bristol BioScientifica 01.01.2013
• Subjects: Abnormalities, Multiple - genetics; Adolescent; Biological and medical sciences; Case Report; Child, Preschool; Endocrinopathies; Failure to Thrive - genetics; Female; Fetal Growth Retardation - genetics; Fundamental and applied biological sciences. Psychology; Heterozygote; Homozygote; Humans; Insulin Resistance - genetics; Intellectual Disability - genetics; Medical sciences; Models, Molecular; Receptor, IGF Type 1 - genetics; Vertebrates: endocrinology; Human; Congenital; Patient; Insulin like growth factor 1; Homozygosity; Postnatal development; Congenital disease; Gene; Malformation; Genetics; Mutation; Severe; Failure; Endocrinology
• DOI: 10.1530/EJE-12-0701
• ISSN: 0804-4643

BackgroundHeterozygous mutations in the IGF1 receptor (IGF1R) gene lead to partial resistance to IGF1 and contribute to intrauterine growth retardation (IUGR) with postnatal growth failure. To date, homozygous mutations of this receptor have not been described.SubjectA 13.5-year-old girl born from healthy first-cousin parents presented with severe IUGR and persistent short stature. Mild intellectual impairment, dysmorphic features, acanthosis nigricans, and cardiac malformations were also present.MethodsAuxological and endocrinological profiles were measured. All coding regions of the IGF1R gene including intron boundaries were amplified and directly sequenced. Functional characterization was performed by immunoblotting using patient's fibroblasts.ResultsIGF1 level was elevated at 950 ng/ml (+7 s.d.). Fasting glucose level was normal associated with high insulin levels at baseline and during an oral glucose tolerance test. Fasting triglyceride levels were elevated. Sequencing of the IGF1R gene led to the identification of a homozygous variation in exon 2: c.119G>T (p.Arg10Leu). As a consequence, IGF1-dependent receptor autophosphorylation and downstream signaling were reduced in patient's fibroblasts. Both parents were heterozygous for the mutation.ConclusionThe homozygous mutation of the IGF1R is associated with severe IUGR, dysmorphic features, and insulin resistance, while both parents were asymptomatic heterozygous carriers of the same mutation.