Endocrine Abstracts

Introduction: Short stature is a common cause of consultation in pediatric endocrinology. In 80% of cases, the etiology remains unknown¹ and classified as « idiopathic short stature. We report the case of a child with a heterozygote complete deletion of the IGF1 gene.

Case report: A 21 months old boy was referred in pediatric endocrinology because of his extreme short stature. The parents of Sicilian origin are not consanguineous. The father’s height is 160.8 cm (−2.3 SD) and head circumference is 54.7 cm. The mother’s height is 148.3 cm (−2.6 SD) and head circumference is 50.2 cm. The target height of our patient is 159.8 cm (−2.5 SD). He has a 9 years old brother with a normal height for his parents. The patient was born after a spontaneous normal pregnancy at 39.5 weeks by vaginal delivery. His weight was 2340 g (−2.9 SD), his length was 43 cm (−3.95 SD) and his head circumference was 32 cm (−2 SD). He had a left orchidopexy at the age of one year. This infant has a good appetite according to his parents and a correct psychomotor development. At physical examination the height is 72.7 cm (−4.2 SD), the weight is 6.9 kg (−5.6 SD) and the body mass index is 13.1 kg/m² (−3.8 SD). A microcephaly with a head circumference of 42.7 cm (−5.5 SD) is noticed. He presents a fifth finger clinodactyly and has no other dysmorphic feature. Hearing tests are normal. The physical examination is otherwise normal. The growth curve showed a failure-to-trive from the age of 4 month. Previous check-up excluded celiac disease, cystic fibrosis, cardiopathy, thyroid disturbances and other chronical disease. We are therefore in front of a small for gestational age (SGA) child with a severe failure-to-thrive and a microcephaly, in a context of a familial short stature. We suspect a defect in the GH/IGF1 axis. The IGF1 level is low (26 ng/ml) (range: 70.3–128.5 ng/ml)², the IGFPB3 level is normal and a glucagon test shows a normal response of growth hormone (GH peak at 7.4 mcg/l). The IGF1 generation test shows no increase of IGF1 after 7 days (day 0, IGF-1: 30 μg/l and day 7, IGF-1: 34 μg/l) of GH treatment (0.05 mg/kg/day GH). The diagnostic hypothesis is an anomaly of the IGF1 gene. Indeed, the cGH array shows a 12q23.1q23.3 deletion including the whole IGF1 gene. This same deletion is found in his mother, maternal grand-father (height:150 cm), maternal uncle (height:165 cm) and his son already treated with GH for SGA.

Discussion and conclusion: We report the second case of complete heterozygous IGF1 gene deletion in a young boy and his family with an autosomal dominant inheritance pattern. The IGF1-haploinsufficiency is the cause of the intra-uterine growth retardation and the short stature with microcephaly. To our knowledge, only one other case of complete heterozygote deletion of the IGF1 gene has been reported until now in the literature³. The phenotype of our patient with short stature associated to microcephaly and clinodactyly, is very similar to other patients with incomplete deletion of IGF1 gene³. The psychomotor development in our patient is normal unlike the other cases described in the literature³. The diagnostic trap is the diagnosis of familial short stature even though our patient is shorter than his target height. CGH array was helpful to confirm at the molecular level the clinical and biological diagnosis of IGF1 deficiency. This IGF1-happloinsufficiency with heterozygote complete deletion of the IGF1 gene may respond to GH therapy unlike those with homozygous complete loss of function variants in IGF1. The efficiency of GH or IGF1 treatment remains to be documented in this very short stature.

References: 1. Zahnleiter D, Uebe S, Ekici AB, et al. Rare copy number variants are a common cause of short stature. PLoS Genet. 2013;9:e1003365.

2. B. Yüksel, Serum IGF-1 and IGFBP-3 Levels in Healthy Children Between 0 and 6 Years of Age, J Clin Res Ped Endo 2011;3(2):84–88.

3. A Novel Deletion of IGF1 in a Patient With Idiopathic Short Stature Provides Insight Into IGF1 Haploinsufficiency, L. Batey and all, J Clin Endocrinol Metab, January 2014, 99(1):E153–E159.