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The Genetic Landscape of Children Born Small for Gestational Age with Persistent Short Stature

Ledjona Toni1, Lukas Plachy1, Petra Dusatkova1

  • 1Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czechia.

Hormone Research in Paediatrics
|April 5, 2023
PubMed

Insights

Genetic factors were identified in 42% of children who remained short after being born small for gestational age. These genetic causes impact growth hormone (GH) and thyroid axes, intracellular processes, and growth plate development.

Area of Science:

  • Pediatric Endocrinology
  • Human Genetics
  • Molecular Biology

Background:

  • 10-15% of children born small for gestational age (SGA) do not experience a growth spurt and remain short (SGA-SS).
  • The genetic underpinnings of SGA-SS are largely unknown, necessitating further investigation.
  • This study focuses on a large single-center cohort to identify genetic causes of SGA-SS.

Purpose of the Study:

  • To investigate the genetic aetiologies contributing to short stature in children born small for gestational age (SGA-SS).
  • To elucidate the molecular mechanisms underlying the failure to catch up growth in a cohort of SGA-SS patients.
  • To enhance the diagnostic yield for genetic causes of SGA-SS.

Main Methods:

  • Included 176 children with SGA-SS from a cohort of 820 growth hormone-treated patients with available DNA (child and both parents).
  • Employed targeted genetic testing for suspected disorders and MS-MLPA for Silver-Russell syndrome.
  • Utilized whole-exome sequencing or a targeted gene panel for cases with unknown genetic etiology, classifying variants per ACMG guidelines.

Main Results:

  • Identified pathogenic or likely pathogenic gene variants in 74/176 (42%) of children with SGA-SS.
  • Discovered genetic variants affecting pituitary development, GH-IGF-1/IGF-2 axis, thyroid axis, cartilaginous matrix, and paracrine chondrocyte regulation.
  • Also found variants impacting intracellular processes, SHOX deficiency, Silver-Russell syndrome, and chromosomal aberrations.

Conclusions:

  • The study achieved a high diagnostic yield, revealing a complex genetic landscape for SGA-SS.
  • Highlights the critical role of the growth plate, GH-IGF-1 axis, thyroid axis, and intracellular signaling pathways in SGA-SS.
  • Provides new insights into the genetic basis of SGA-SS, aiding in diagnosis and understanding.
Abstract

Keywords:
GH-IGF-1 axisGeneticsGrowth plateShort statureSmall for gestational age

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