ESPE Abstracts (2019) 92 RFC14.2

Deciphering Genetic Aetiology Among Children Born Small-For-Gestational-Age with Persistent Short Stature (SGA-SS): Phenotypic Characteristics at Diagnosis in a Large Single-Centre Cohort

Ledjona Toni, Lukas Plachy, Petra Kucerova, Lenka Elblova, Zdenek Sumnik, Stanislava Kolouskova, Marta Snajderova, Barbora Obermannova, Stepanka Pruhova, Jan Lebl


Department of Pediatrics, 2nd Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic


Background: SGA-SS is a heterogeneous condition defined as birth weight and/or birth length below -2SD for gestational age and postnatal height below -2.5SD, according to age-and sex-specific normative values. Despite being an indication for growth hormone (GH) therapy for 15 years, aetiology and prediction of treatment outcomes in most of SGA-SS children awaits elucidation.

Aim: To decipher genetic aetiologies among a large single-centre cohort of children born SGA and to define phenotypic characteristics at diagnosis in genetically defined subcohorts.

Patients/Methods: A single-centre cohort consists of 445 SGA-SS children (221 females; Turner syndrome was excluded) aged 1.3-27.0 years at this evaluation (median 11.8). We searched for genetic aetiology in majority of the cohort using individualised phenotype-based genetic techniques that included standard karyotyping, array comparative genomic hybridization (CGH), targeted or whole exome sequencing in selected individuals and methylation studies in phenotype of Silver-Russell syndrome (SRS).

Results: Thus far, genetic aetiology was elucidated in 60 children (33 females). Of these, 11 had a pathogenic variant of genes encoding cartilaginous matrix components (ACAN or one of genes encoding collagen structures [assigned here as COL_X]), 13 had SHOX defects, 9 had pathogenic genetic variants perturbing the GH-IGF-1 axis (GHSR, HGMA2, OTX2, STAT3, IGFALS, IGF1R), 10 had SRS, and 17 had miscellaneous single-gene or chromosomal conditions. Whereas the mid-parental height-SDS in children without known genetic aetiology (n=385) was -0.94±0.04 (mean±SEM), parents were shorter in ACAN/COL_X (-2.10±0.15; P<0.0001) and in SHOX (-1.51±0.17; P=0.01) and taller in SRS (+0.17±0.27; P<0.0001). SRS children tended to be born earlier (gestational week 36.2±1.1 vs. 38.1±0.2; P=0.06). Whereas the birth length in all subgroups was similar, birth weight-SDS was -1.96±0.04 (mean±SEM) in SGA-SS children with undetermined aetiology but lower in SRS (-2.53±0.25; P<0.05) and higher in SHOX (-1.31±0.25; P<0.01). The postnatal growth failure was more pronounced in SRS (height-SDS at start of GH therapy -3.84±0.41; P<0.05) than in SGA-SS children with undetermined aetiology (-3.06±0.06), in ACAN/COL_X (-2.97±0.14; n.s.), in SHOX (-3.02±0.25; n.s.), and in the perturbed GH-IGF-1 axis (-3.13±0.21; n.s.).

Conclusions: Subcohorts of SGA-SS children defined by genetic aetiology display specific phenotypic characteristics and differ in parental heights, gestational age, size at birth and severity of postnatal growth failure. These variables may facilitate predicting genetic background in some SGA-SS children. Nevertheless, in SGA-SS children genetic diagnosis remains a challenging task at the current level of knowledge.