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

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

Cuzco

Congreso; Latin American Pediatric Endocrinology Society (SLEP) 27th Annual Meeting; 2018

Objective: Human IGF1 gene defects have been reported inseven cases. We describe a patient with severe short stature presentinga novel homozygous IGF1 gene mutation and its functionalcharacterization.Case: Patient born from consanguineous parents at 40 weeksof gestational age with IUGR. His birth weight was 1910 g (?3.06SD), length 38 cm (?6.3 SD), and head circumference 34 cm (?0.4SD). His mother and father were born with low weight (1900 g and2500 g, respectively) and had short adult height (?1.92 SD and ?2.6SD, 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 and retrognathia). He alsopresented bilateral sensorineural deafness, mild global developmentaldelay, and hyperactivity behavior. Basal levels of GH andIGF-I were variable (GH: 1.9 to 29 ng/ml; IGF-I: 47 to 206 ng/ml),and IGFBP-3 levels were normal-high (2.3 to 5.3 μg/ml). Karyotypewas normal (46, XY). SNP array showed multiple chromosomalhomozygosity regions, including 12q23.2 where IGF1 maps.The patient was homozygous and his parents heterozygous for anovel missense variant (NM_001111285.2: c.322T>C, p.Tyr108His). The change of a highly conserved Tyr residue (Tyr60in the mature IGF-I peptide), was predicted as pathogenic by multiplebioinformatic tools. Tyr60 has been described to be criticalfor IGF-I interaction with type 1 IGF receptor. In vitro studies usingpatient?s serum to stimulate HEK293T cells, showed a markedreduction of IGF-1R phosphorylation compared to control serum.Conclusion: In summary, we report a novel IGF1 variant associatedwith familial short stature. Our preliminary functionalstudies suggest that this mutation may result in a diminished IGF-1 bioactivity, explaining the observed clinical condition