ESPE Yearbook of Paediatric Endocrinology

Brief summary: This observational study aimed at clarifying the contribution of pathogenic copy number variants (PCNVs) and candidate pathogenic variants in 86 children born small-for-gestational-age with short stature (SGA-SS).

Approximately 10% of children born SGA do not show catch-up and remain permanently short (SGA-SS) (1,2). There is increasing evidence suggesting that genetic abnormalities underlie a high proportion of SGA-SS children. In this study, 86 children born SGA and with short stature underwent a comprehensive molecular analysis consisting of methylation analysis, copy number variant evaluation, and multigene sequencing. Children with imprinting disorders, including Silver-Russel-syndrome, were excluded. The definition criteria of SGA-SS were: (A) a child with both BW and BL below the 10th percentile for the gestational age and sex and (B) a stature at 24 months of age below −2 SDS (3,4). The cohort included 20 preterm children. About 60% of patients showed no clinical features other than SGA-SS.

Pathogenic copy number variants (PCNVs) were identified in 8 patients (9.3%) in a heterozygous state. A candidate pathogenic genetic variant was identified in 11 patients (12.8%), in a heterozygous state, including one nonsense and 10 missense variants. According to the American College of Medical Genetics standards and guidelines, 5 variants were classified as pathogenic and 6 variants of unknown significance (VUS). The 5 pathogenic variants included 4 previously reported variants of Myhre syndrome (SMAD4), Noonan syndrome (PTPN11), Noonan syndrome–like disorder (CBL), Feingold syndrome (MYCN) and 1 causative variant for short stature (NPR2). Among 6 VUS, 2 were genes (GHR and IGF1R) involved in the GH/IGF-I axis, and 4 were genes (COL2A1, SHOX, ACAN, and FGFR3) involved in growth plate physiology. Interestingly, all cases were not clinically diagnosed before molecular analyses because their phenotype was not suggestive of a specific genetic disease. These results highlight the importance of performing a comprehensive genetic assessment in children born SGA with unexplained short stature.

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(3):804–810. doi: 10.1210/jc.2006-2017. 2. Houk CP, Lee PA. Early diagnosis and treatment referral of children born small for gestational age without catch-up growth are critical for optimal growth outcomes. Int J Pediatr Endocrinol. 2012;2012(1):11. doi: 10.1186/1687-9856-2012-11. 3. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P. International Small for Gestational Age Advisory Board consensus development conference statement: management of the short child born small for gestational age. Pediatrics. 2001;111:1253–1261. doi: 10.1542/peds.111.6.1253. 4. 2023 ICD-10-CM Diagnosis Code. Link: https://www.icd10data.com/ICD10CM/Codes/P00-P96/P05-P08/P05-/P05.1