ISSN 1662-4009 (online)

ESPE Yearbook of Paediatric Endocrinology (2021) 18 4.12 | DOI: 10.1530/ey.18.4.12

Division of Endocrinology, Nemours Alfred I. duPont Hospital for Children, Wilmington, Delaware. USA.

J Clin Endocrinol Metab. 2020;105(2):dgaa465. doi: 10.1210/clinem/dgaa465. PMID: 32685970

This study aimed to identify potential (epi)genetic causes of short stature in 20 SGA children (13 boys; 7 girls) treated with rhGH. Exome sequencing, single-nucleotide polymorphism (SNP) array (both performed in the whole cohort) and genome-wide methylation analysis (performed in a random subset of 10 children) were applied. This extended genetic approach allowed to identify pathogenic/likely pathogenic variants in 4 children: two siblings harboring variants in ELAC2 gene, a female with homozygous frameshift variant of CEP57 gene, and a male with a likely pathogenic variant of HNRHPH1 gene. SNP array analysis showed pathogenic copy number variants in 5q35.2q35.3 and 22q11.21q11.22 in two subjects. Finally, genome-wide methylation analysis detected different patterns of methylation in specific regions regulating the GNAS gene. Notably, all but one (male patient who has 5q35.2q35.3 microduplication) with genetic variants or CNVs showed a clinical picture including other features beyond shortness, such as dysmorphic features, additional anomalies and neurodevelopmental delay. 5 of the 6 children with a genetic diagnosis responded well during the first year of GH treatment.

Approximately 2.3% of all newborns are born SGA (1). Maternal, placental, and/or fetal factors may account for the small size at birth (2). Low birth size can be either the only clinical feature or be associated with other features suggestive of a specific syndrome. Albeit SGA represents a worldwide accepted indication for rhGH treatment, the efficacy is extremely variable. This variability in the response to rhGH is due to the fact that SGA is not a single diagnosis, but a definition which includes a heterogeneous group of different underlying etiologies and clinical outcomes. The accurate identification of the underlying etiology may lead to a more appropriate clinical management and genetic counseling. Genetics and epigenetics account for about 30-50% of birth weight variability (3,4), and the use of array-CGH, genome-wide methylation analysis and whole exome sequencing may allow to identify a genetic abnormality in a high proportion of SGA subjects (4). The current study confirms a thorough advanced diagnostic approach based on (epi)genetic analyses is successful in revealing new pathways responsible for short stature and may allow future better prediction of individual height responses to rhGH therapy.

Reference: 1. van der Steen M, Hokken-Koelega AC. Growth and Metabolism in Children Born Small for Gestational Age. Endocrinol Metab Clin North Am. 2016;45(2):283–94.2. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics. 2003;111(6 Pt 1):1253–61.3. Lunde A, Melve KK, Gjessing HK, Skjaerven R, Irgens LM. Genetic and environmental influences on birth weight, birth length, head circumference, and gestational age by use of population-based parent-offspring data. Am J Epidemiol. 2007;165(7):734–41.4. Stalman SE, Solanky N, Ishida M, Aleman-Charlet C, Abu-Amero S, Alders M, et al. Genetic Analyses in Small-for-Gestational-Age Newborns. J Clin Endocrinol Metab. 2018;103(3):917–25.

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