Elsevier

Archives de Pédiatrie

Volume 28, Issue 8, Supplement 1, February 2022, Pages 28/8S27-28/8S32
Archives de Pédiatrie

Review articles
Exploring the genetic causes of isolated short stature. What has happened to idiopathic short stature?

https://doi.org/10.1016/S0929-693X(22)00040-9Get rights and content

ABSTRACT

Statural growth is underpinned by development of the growth plate during the process of endochondral ossification, which is strongly regulated by numerous local factors (intracellular, paracrine and extracellular matrix factors) and systemic factors (nutrition, hormones, proinflammatory cytokines and extracellular fluids). This explains why growth retardation can be associated with numerous pathologies, particularly genetic syndromes, hormonal or inflammatory conditions, or gastrointestinal disorders having a nutritional impact. However, in most cases (80%), no specific aetiology is found after clinical investigation and conventional additional tests have been carried out. In such cases, “idiopathic” short stature is diagnosed, which includes patients presenting with constitutional delay of growth and development and familial short stature, but also patients with very subtle constitutional skeletal dysplasia which are not easily identifiable. In recent years, new methods of genetic investigation (e.g. gene panels, exome or genome sequencing) have made it possible to identify many genetic variants associated with apparently isolated short stature. Indeed, it is still difficult to estimate the proportion of patients presenting with idiopathic short stature for which a molecular diagnosis of monogenic conditions could be made. This estimate varies hugely depending on the thoroughness of the clinical, laboratory and radiological assessments performed prior to molecular analysis, since retrospective analysis of positive cases usually reveals subtle signs of underlying syndromes or rare skeletal disorders. Molecular diagnosis in children is important to be able to offer genetic counselling and to organise patient management. Moreover, improved understanding of the molecular basis of these cases of short stature opens up numerous possibilities for more specific treatments targeting the growth plate.

© 2022 French Society of Pediatrics. Published by Elsevier Masson SAS. All rights reserved.

Introduction

Statural growth is underpinned by development of the growth plate during the process of endochondral ossification, which is strongly regulated by numerous local factors (intracellular, paracrine and extracellular matrix factors) and systemic factors (nutrition, hormones, proinflammatory cytokines and extracellular fluids). This explains why growth retardation can be associated with numerous pathologies, particularly genetic syndromes, hormonal or inflammatory conditions, or gastrointestinal disorders having a nutritional impact. However, in most cases (80%), no specific aetiology is found after clinical investigation and conventional additional tests have been carried out. In such cases, “idiopathic” short stature is diagnosed, which includes patients presenting with constitutional delay of growth and development and familial short stature, but also patients with very subtle signs of skeletal dysplasia which are not easily identifiable [1]. In recent years, new methods of genetic investigation (e.g. gene panels, exome or genome sequencing) have made it possible to identify many genetic variants associated with apparently isolated short stature. Improved understanding of the molecular basis of these cases of short stature opens up numerous possibilities for more specific treatments targeting the growth plate.

Section snippets

The growth plate – a central player in growth

Over the last thirty years, the somatotropic axis, essentially consisting of growth hormone (GH) and its mediator, insulin-like growth factor 1 (IGF-1), was considered the principal regulator of growth in childhood. Classification of growth disorders was therefore mainly centred on the GH/IGF-1 axis. Historically, this position can be explained by discovery of the role of the somatotropic axis in growth, the ability to measure circulating levels of GH and IGF-1 and, above all, hormone

The growth plate and endochondral ossification

In children, linear growth of the long bones is determined by the process of endochondral ossification at the growth plate level (Figure 1) [3]. During this process, the cells of the growth plate (chondrocytes), derived from mesenchymal stem cells, go through a series of proliferation and differentiation phases. First, the chondrocytes divide rapidly to form columns of cells in the proliferative zone. Then, these chondrocytes undergo hypertrophic differentiation, characterised by increases in

Genetic determinants of short stature

Genetic factors play a predominant role in statural growth, as underscored by the high degree of heritability of height (> 80%). Investigation of genetic determinants by genome-wide association studies (GWAS) has enabled over 600 common genetic variants (with allele frequencies > 1%) to be identified, distributed across 400 regions of the genome [5]. The impact of each of these common variants on height is weak (around 1 to 4 mm). Other studies have shown that rare variants (frequency < 1%)

When should a genetic cause be considered in a case of isolated short stature?

Retrospective clinical and radiological examinations of children presenting with idiopathic short stature associated with a genetic abnormality usually uncover clinical or radiological abnormalities in most cases. It is important, therefore, to define the phenotype of these patients as precisely as possible.

First of all, in the clinical history, one should look for a family history of short stature and/or consanguinity which could point to a genetically transmitted condition. The co-existence

Review of the literature on gene panel or exome/genome analyses

It is estimated that a molecular diagnosis could be made in at least 25% of children presenting with short stature. This estimate will vary depending on the thoroughness of the clinical, laboratory and radiological assessments performed prior to molecular analysis, since retrospective analysis of positive idiopathic short stature cases usually reveals subtle signs of underlying syndromes or genetic skeletal disorders. Molecular diagnosis in children is important to be able to offer genetic

Conclusions and new therapeutic prospects

Over the last few years, progress in genetic investigation techniques has led to a better understanding of the molecular basis of short stature linked to abnormalities of endochondral ossification. Improved understanding of the pathophysiological basis of these cases of short stature opens up the prospect of more specific treatments.

Until recently, treatment with recombinant human GH was the only therapeutic option available for short stature in children. Logically, this treatment was offered

Declaration of Competing Interest

C. Amouroux declares competing interest by being involved in clinical trials as main investigator, coordinator or main experimenter for Ipsen; by being invited as speaker to congresses by Pfizer and Kyowa Kirin and by being invited to congresses with expenses paid by Pfizer, Kyowa Kirin and Sandoz.

M. Willems, M. Barat-Houari and JP. Salles have no competing interest to report regarding this article.

T. Edouard declares competing interest by receiving research support from Novo Nordisk, Pfizer,

Authorship

All authors have made substantial contributions to all of the following: (1) conception and content of the article, (2) drafting the article or revising it critically for important intellectual content, (3) final approval of the version to be submitted.

Acknowledgements

This article is part of a supplement entitled Pediatric growth hormone deficiency published with institutional support from Pfizer.

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