ESPE Abstracts (2018) 89 P-P1-143

aCentro de Investigaciones Endocrinológicas ‘Dr. César Bergadá’ (CEDIE) CONICET – FEI – División de Endocrinología, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; bServicio de Genética, Hospital de Niños Ricardo Gutiérrez, Buenos Aires, Argentina; cINGEMM, IdiPAZ, Hospital Universitario La Paz, Madrid & CIBERER (U753), ISCIII, Madrid, Spain

Background: Human IGF1 gene defects are characterized by intrauterine and postnatal growth retardation, sensorineural deafness, microcephaly and intellectual disability. Seven cases have been reported so far, and the underlying pathophysiology has been characterized in only three.

Objective: To describe a patient with severe short stature presenting a novel homozygous IGF1 gene mutation and its underlying pathogenic mechanism.

Case: Born from consanguineous parents at 40 weeks of gestational age with IUGR. Birth weight was 1910 g (−3.06 SD), length 38 cm (−6.3 SD), and head circumference 34 cm (−0.4 SD). His mother 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 short stature, microcephaly, and facial dysmorphism (frontal bossing, triangular face, bulbous nose, full lips, retrognathia). He also presented bilateral sensorineural deafness, mild global developmental delay, and hyperactivity behavior. Basal levels of GH and IGF-I were variable (GH: 1.9 to 29 ng/ml; IGF-I: 47 to 206 ng/ml), and normal-high IGFBP-3 (2.3 to 5.3 μg/ml). Karyotype was normal (46, XY). MLPA for subtelomeric regions showed a duplication in the Xq28 region. SNP array showed multiple chromosomal regions of homozygosity, including 12q23.2 where IGF1, a potential candidate gene for the patient’s phenotype, maps. IGF1 coding and known regulatory regions were analyzed by High Resolution Melting. Fragments displaying abnormal melting pattern were sequenced. The patient was homozygous and his parents heterozygous for 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 predicted as pathogenic by multiple bioinformatic tools. Tyr60 has already been described to be critical for IGF-I interaction with type 1 IGF receptor (IGF-1R). We performed in vitro studies using HEK293T cells, that showed marked reduced phosphorylation of IGF-1R after 10 minutes stimulation with serum from the patient compared to control serum.

Conclusion: This novel IGF1 mutation may result in diminished affinity of mutant IGF-I for its receptor, resulting in the observed clinical condition. In addition, the duplication in the Xq28 region may also contribute to the patient’s clinical and dysmorphic features.

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