ESPE Abstracts (2014) 82 P-D-2-2-470

Severe Short Stature due to a Heterozygous igf1r Mutation With a Good Response to rhgh Therapy: a Family Study

Victoria Borrás-Péreza, Monica Fernández-Canciob,c, Ana Gómez-Núñezd,e, M Catalá-Puigbóa, Laura Audíb,c & Angel Campos-Barrosd,e

aPediatric Endocrinologym, Hospital General de Granollers, Barcelona, Spain; bPediatric Endocrinology, Hospital Vall d’Hebron, Barcelona, Spain; cVHIR; CIBERER (U712), Autonomous University, Barcelona, Spain; dHospital Universitario La Paz; INGEMM, IdiPAZ, UAM, Madrid, Spain; eCIBERER (U753), ISCIII, Madrid, Spain

Background: IGF1 resistance syndrome (IGF1RS) is characterized by intrauterine and postnatal growth deficit with normal or supranormal IGF1 levels. Additional features may include intellectual deficit, microcephaly, and dysmorphisms. IGF1RS may be caused by genomic or genetic defects affecting the IGF1R locus (15q26.3).

Objective and hypotheses: Case report: a girl born at 36.5 weeks, BW 1.935 g (−3.2 SDS), length 41 cm (−4.4 SDS) and cephalic perimeter (CP) 29 cm (−5.2 SDS), was examined at 3.5 years for developmental delay, BA: 2.5 years, BW 10.5 kg (−2.4 SDS), height 87.4 cm (−3.0 SDS), CP 46.5 cm (−2.5 SDS), and mild psychomotor retardation. Maternal grandparents were consanguineous. Hormonal tests: IGF1 95.4 ng/ml (−0.8 SDS), IGFBP3 3 μg/ml (0.51 SDS), and GH test peak: 2.9 ng/ml (glucagon).

Method: Molecular studies: Mutation screening of GHR, IGF1R, and IGFALS by HRM and DNA sequencing in the proband and relatives.

Results: A heterozygous point mutation in IGF1R exon 10, c.2155C>T, was detected in the proband. The mutation causes the substitution of a highly conserved residue, p.Arg719Cys, located in the IGF1R fibronectin type III and tyrosine-protein kinase intracellular domains. The mutation was maternally transmitted. Evolution: rhGH treatment (0.04 mg/kg per day) was initiated at age 4.7 years. A good clinical response was observed after 1.5 years (growth velocity 10 cm/year; +4.7 SDS), with no BA progression and IGF1 254 ng/ml (+1.6 SDS).

Conclusion: We present a family case of partial IGF1 resistance due to a novel heterozygous IGF1R mutation with good response to rhGH treatment. Mutation analysis of IGF1R is recommended if proportional short stature coexists with IUGR, microcephaly, and intellectual delay, especially if there is evidence of familial clustering. Evaluation of the response to rhGH therapy seems an adequate option to improve growth rate.

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