Severe Pre- and Postnatal Growth Retardation in a Child Harboring a Novel Homozygous IGF1 Gene Mutation

AC KESELMAN; ROMINA ARMANDO; DEBORA BRASLAVSKY; HAMILTON CASSINELLI; ANGEL CAMPOS BARROS; HÉCTOR JASPER; PENNISI, PATRICIA; PAULA A. SCAGLIA; NORA SANGUINETI; MARIA G BALLERINI; BÁRBARA CASALI; JULIÁN NEVADO BLANCO; CLAUDIA ARBERAS; PABLO LAPUNZINA-BADÍA; MARTIN, AYELEN; MARIANA GUTIÉRREZ; MARIA G ROPELATO; GRACIELA DEL REY; HORACIO MARIO DOMENÉ; RODOLFO A. REY; IGNACIO BERGADA

Atenas

Congreso; 57th Annual Meeting of the European Society for Paediatric Endocrinology (ESPE); 2018

European Society for Paediatric Endocrinology (ESPE)

Background: Human IGF1 gene defects are characterized byintrauterine and postnatal growth retardation, sensorineural deafness,microcephaly and intellectual disability. Seven cases havebeen reported so far, and the underlying pathophysiology has beencharacterized in only three.Objective: To describe a patient with severe short stature presentinga novel homozygous IGF1 gene mutation and its underlyingpathogenic mechanism.Case: Born from consanguineous parents at 40 weeks of gestationalage with IUGR. Birth weight was 1910 g (-3.06 SD), length38 cm (-6.3 SD), and head circumference 34 cm (-0.4 SD). Hismother and father were born with low weight (1900 g and 2500 g,respectively) and had short stature (height -1.92 SD and -2.6 SD,respectively).Results: At 3.2 years of age, the patient´s height was 74 cm(-6.15 SD), weight 6.1 kg (-5.1 SD), head circumference 41 cm(-6.05 SD). Physical examination revealed proportionate shortstature, microcephaly, and facial dysmorphism (frontal bossing,triangular face, bulbous nose, full lips, retrognathia). He also presentedbilateral sensorineural deafness, mild global developmentaldelay, and hyperactivity behavior. Basal levels of GH and IGF-Iwere variable (GH: 1.9 to 29 ng/ml; IGF-I: 47 to 206 ng/ml), andnormal-high IGFBP-3 (2.3 to 5.3 μg/ml). Karyotype was normal(46, XY). MLPA for subtelomeric regions showed a duplicationin the Xq28 region. SNP array showed multiple chromosomal regionsof homozygosity, including 12q23.2 where IGF1, a potentialcandidate gene for the patient´s phenotype, maps. IGF1 codingand known regulatory regions were analyzed by High ResolutionMelting. Fragments displaying abnormal melting pattern were sequenced.The patient was homozygous and his parents heterozygousfor a novel missense variant (NM_001111285.2: c.322T>C,p.Tyr108His). The change of a highly conserved Tyr residue(Tyr60 in the mature IGF-I peptide), was consistently predictedas pathogenic by multiple bioinformatic tools. Tyr60 has alreadybeen described to be critical for IGF-I interaction with type 1 IGFreceptor (IGF-1R). We performed in vitro studies using HEK293Tcells, that showed marked reduced phosphorylation of IGF-1R after10 minutes stimulation with serum from the patient comparedto control serum.Conclusion: This novel IGF1 mutation may result in diminishedaffinity of mutant IGF-I for its receptor, resulting in the observedclinical condition. In addition, the duplication in the Xq28region may also contribute to the patient´s clinical and dysmorphicfeatures.