New light shed on genetic landscape of SGA children who remain short

medwireNews: Genetic variations in genes regulating the growth plate appear to play a “central role” in the aetiology of persistent short stature among children born small for gestational age (SGA), report researchers from the Czech Republic.

Mutations in genes regulating the growth hormone–insulin-like growth factor-1 (GH–IGF-1) axis, the thyroid axis and intracellular signalling also make “substantial contributions”, write Ledjona Toni (Charles University, Prague) and colleagues in Hormone Research in Paediatrics.

They identified 176 children (53% boys) who were SGA with persistent short stature, defined as a birth length and/or birth weight below −2 standard deviations (SD) for gestational age and life-minimum height below −2.5 SD, and were treated with growth hormone.

Using a variety of testing methods, including whole-exome sequencing, targeted gene panel testing (398 growth-related genes), karyotyping, fluorescence in situ hybridization and multiplex ligation-dependent probe amplification, the researchers were able to determine the genetic aetiology of short stature in 42% of the cohort.

The most frequent pathogenic or likely pathogenic (P/LP) mutations were observed in genes affecting the growth plate, affecting 42% of the participants with known genetic aetiology.

“This finding is in line with previous studies and corresponds with the new paradigm with the growth plate playing a key role in short stature pathogenesis”, Toni et al remark.

Among the children with mutations affecting the growth plate, 23% had P/LP variants in genes responsible for components of the cartilaginous matrix (ACAN, FLNB, MATN3, various collagens), 9% had impaired paracrine regulation of chondrocytes (FGFR3, FGFR2, NPR2) and 9% had SHOX gene defects.

In addition, 16% of children with known genetic aetiology harboured P/LP gene variants affecting pituitary development or growth hormone secretion (LHX4, OTX2, PROKR2, PTCH1, POU1F1, GHSR) and/or the GH–IGF-1 and IGF-2 axes (IGFALS, IGF1R, STAT3, HMGA2).

P/LP variants involved in fundamental intracellular and intranuclear processes (CDC42, KMT2D, LMNA, NSD1, PTPN11, SRCAP, SON, SOS1, SOX9, TLK2) were detected in 16%, and those affecting the thyroid axis (TRHR, THRA) in 3%.

The investigators say that the presence of latter two variants “clearly show that pre- and postnatal growth is affected by the thyroid axis far beyond the classical hypothyroidism.”

The researchers also report that Silver-Russell syndrome was diagnosed in 16% (11p15, UPD7) of participants with known genetic aetiology, and miscellaneous chromosomal aberrations were identified in a further 7%.

Toni and co-authors conclude that their results “demonstrate a complex aetiology of short stature affecting all the three key levels of growth regulation including the endocrine system, growth plate function, and fundamental processes of intracellular regulation and signalling.”

They continue: “A conclusive genetic finding not only provides a clear explanation of the growth disorder but also enables focussing on possible associated hidden comorbidities and genetic consulting.

“In our opinion, routine genetic testing may therefore become a standard of diagnostic care in resource-rich countries for all SGA-[short stature] children after other causes of growth failure are ruled out.”

By Laura Cowen

medwireNews is an independent medical news service provided by Springer Healthcare Ltd. © 2023 Springer Healthcare Ltd, part of the Springer Nature Group

Horm Res Pediatr 2023; doi:10.1159/000530521
Martin Savage
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