In our latest mini review, Ola Nilsson gives an overview of the growth plate and how defects in its function can underlie growth disorders in children.
Elongation of bones, and thus overall body dimensions, is primarily determined by longitudinal bone growth which occurs at the growth plate located at the ends of long bones and vertebrae. At the growth plates, chondrocyte proliferation, chondrocyte hypertrophy, and extracellular matrix secretion all contribute to growth plate chondrogenesis and therefore to linear growth1. The hypertrophic zone is continuously invaded by blood vessels and bone cell precursors, which remodel the newly formed cartilage into bone. The net effect is that new bone tissue is progressively created at the bottom of the growth plate, resulting in bone elongation. During foetal life, the rate of linear growth is rapid and peaks in mid-gestation at more than 100 cm per year. The growth rate then gradually declines so that at birth the growth rate is approximately 50 cm per year. In mid childhood the growth rate is approximately 5 cm per year. The decline in growth rate is briefly interrupted by the pubertal growth spurt but then continues and eventually comes to a complete stop. Growth cessation is followed by epiphyseal fusion after which the bones can no longer elongate and the child has thus reached their adult height2.
The unique structure and cellular kinetics of the growth plate are controlled by complex networks of endocrine signals and local factors. Consequently, normal growth in children requires normal concentrations of all the involved endocrine and systemic factors and also normal production and action of multiple paracrine factors and extracellular matrix molecules, as well as normal function of multiple intracellular processes required for chondrocyte proliferation, hypertrophy, and extracellular matrix production. Recent studies have identified numerous new growth plate genes that, when mutated, cause short stature or tall stature 3. Similarly, genome-wide association studies (GWAS) of normal variation of height point to an overlapping and very large network of genes important for growth. A recent finding shows that as much as 21% of the genome contributes to the genetic variability in height 4. These findings taken together form the simple concept that linear growth disorders are due to dysfunction of the very structure responsible for longitudinal bone growth, ie, the growth plate.
Growth disorders are caused by growth plate dysfunction that can result from a primary defect, that is, a disorder intrinsic to the growth plate, or a secondary defect, in which growth plates are adversely affected by a systemic disorder.
Primary defects may involve:
- Paracrine signalling systems in the growth plate
- Cartilage extracellular matrix molecules in growth plate cartilage
- Intracellular pathways in growth plate chondrocytes
In secondary disorders, growth plate chondrocytes can be adversely affected through a variety of mechanisms, including abnormalities in:
- Nutrition (often mediated by endocrine signals)
- Endocrine signalling
- Inflammatory cytokines
- Extracellular fluid (such as acidosis)
- Physical factors (such as radiation)
However, for several conditions, including many dysmorphic syndromes, constitutional delay of growth, and idiopathic short stature, the mechanism responsible for the growth plate dysfunction remains unknown.
Given the complex aetiology, evaluation of children with growth disorders requires a broad approach and should include a detailed family history, careful physical examination to identify distinctive clinical features, including body proportions, facial dysmorphism, brachydactyly, scoliosis and other skeletal findings, as well as laboratory and radiological evaluation including bone age and, in selected patients, skeletal surveys.
The evaluation should aim to determine if there is a primary or secondary growth (plate) disorder, and also if a genetic aetiology is likely, and if so, whether the condition is more likely to be monogenic or polygenic. If the growth disorder is severe and likely to be monogenic, genetic evaluation may be warranted and have the potential to identify a genetic cause in many short children even if distinct diagnostic skeletal or other syndromic features are lacking 5.