ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Clin Endocrinol Metab. 2019;104:2023–2030.

A child born with birth weight and/or birth length less than 2 SDS below the mean for gestational age is defined as SGA [1]. This definition implies that rather than a specific diagnostic group, SGA children are a heterogenous population with different etiologies, growth patterns and metabolic outcomes. Most SGA children experience postnatal catch-up growth leading to the achievement of a normal stature within the first 2 years of age. Approximately 10% remain permanently below the third centile and those with a more severe growth impairment are considered candidates for GH therapy. A broad range of causes underlie SGA birth, as fetal growth is regulated by maternal, placental and fetal factors [2]. The recent use of next generation sequencing (NGS) in SGA children with severe short stature has permitted to discover novel genetic causes of intrauterine growth impairment. These genetic variants are involved in the physiology of IGF system, cartilage growth plate, cartilage extracellular matrix and paracrine factors.

In this study, a cohort of 55 short SGA subjects was assessed by whole-exome sequencing (WES) or targeted gene panel sequencing. Eight (15%) heterozygous pathogenic or likely pathogenic variants were identified. All these variants involved genes associated with growth disorders such as growth plate genes (Indian hedgehog, HH; Natriuretic peptide receptor 2, NPR2; Short stature homeobox, SHOX; Aggrecan, ACAN) and RAS/MAPK pathway genes (Neurofibromin 1, NF1 and Protein-tyrosine phosphatase nonreceptor-type 11, PTPN11). Seven patients were SGA only for birth length, and one patient was SGA for both length and weight. Six of the patients with pathogenic variants had a family history of short stature, but none had a phenotype suggestive of the detected genetic variant. The identification of molecular etiologies is important for: a) providing the diagnosis to the patients and parents, b) driving genetic counselling, c) leading to the right therapeutic strategy and d) for the advancement of science.

References: 1. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab 2007;92:804–810.

2. Finken MJJ, van der Steen M, Smeets CCJ, Walenkamp MJE, de Bruin C, Hokken-Koelega ACS, Wit JM. Children Born Small for Gestational Age: Differential Diagnosis, Molecular Genetic Evaluation, and Implications. Endocr Rev 2018;39:851–894.