Elsevier

The Lancet

Volume 370, Issue 9582, 14–20 July 2007, Pages 162-172
The Lancet

Seminar
Achondroplasia

https://doi.org/10.1016/S0140-6736(07)61090-3Get rights and content

Summary

Achondroplasia is the most common form of short limb dwarfism in human beings, affecting more than 250 000 individuals worldwide. More than 95% of patients have the same point mutation in the gene for fibroblast growth factor receptor 3 (FGFR3) and more than 80% of these are new mutations. The mutation, which causes gain of FGFR3 function, affects many tissues, most strikingly the cartilaginous growth plate in the growing skeleton, leading to a variety of manifestations and complications. The biology of FGFR3 and the molecular and cellular consequences of the achondroplasia mutation are being elucidated, providing a more complete understanding of the disorder and a basis for future treatments targeted directly at relevant pathogenetic pathways. Furthermore, the natural history of the condition, which has been well delineated in childhood and adolescence, is being defined more fully in adults with achondroplasia; most of the serious complications can be modified favourably or prevented by anticipation and early treatment. Possible future treatments include chemical inhibition of receptor signalling, antibody blockade of receptor activation, and alteration of pathways that modulate the downstream propagation of FGFR3 signals.

Introduction

Achondroplasia (OMIM 100800) is the most common form of human dwarfism and the mutation causing it might be the most common disease-causing mutation to arise de novo in human beings.1, 2 The condition has been recognised for centuries, with examples seen in art from ancient Egypt, Greece, and Rome.3 Moreover, its name, coined about 100 years ago, implies historical knowledge of disturbed cartilage function during linear bone growth. Today we recognise that cartilage serves a template function during the process of endochondral ossification. Achondroplasia must be distinguished from other forms of disproportionate short stature, which, until recently, were all called achondroplasia.4 Indeed, the heterogeneity of disproportionate short stature only began to be appreciated and studied about 40 years ago, leading to the recognition of hundreds of specific clinical entities each with their own clinical and radiographic features, natural history, complications, and genetic basis.5, 6

The primary manifestations and medical complications of achondroplasia have received much attention over the past four decades and are now well established for childhood and adolescence.5, 7, 8, 9 By contrast, the natural history is only gradually being delineated for adults, and several new potential complications have been uncovered. Similarly, mutations of the gene for fibroblast growth factor receptor 3 (FGFR3), were discovered in achondroplasia over a decade ago.2, 10 The nature of these mutations, as well as the biology of the receptor encoded by FGFR3, and the molecular consequences of the mutations on linear bone growth are becoming better understood.11 Eventually, this knowledge will probably provide the underpinning for future treatments that will be targeted directly at the molecular disturbances caused by the FGFR3 mutations. Even though the most striking feature of achondroplasia involves cartilage growth, the achondroplasia mutation affects many systems.

This Seminar addresses the present state of knowledge about achondroplasia. We discuss the diagnosis and management of typical clinical manifestations, but we give particular attention to recent observations (eg, medical complications in adults with achondroplasia), and focus especially on the molecular pathogenesis of achondroplasia, our understanding of which continues to slowly emerge.

Section snippets

Epidemiology and genetics

The birth incidence of achondroplasia is uncertain because of the frequent inclusion of other disorders in population estimates; however, it is estimated to occur in between one in 10 000 and one in 30 000 livebirths.12, 13, 14 Achondroplasia is part of a spectrum of disorders caused by different mutations in FGFR3, which includes hypochondroplasia (OMIM 146000), severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN), and thanatophoric dysplasia, of which two types can

Pathophysiology

The distinction between genetics and pathogenesis is important. During the past decade there has been tremendous progress in mapping gene loci, identifying disease loci, and finding specific mutations. However, emphasis is now shifting from genetics as such to pathogenesis with special attention to molecular mechanisms. This section addresses what is known about the molecular biology of FGFR3 and the specific interactions and pathways that are disturbed by mutation—ie, the functional

Clinical and radiological characteristics

The clinical features of achondroplasia are so distinctive they can easily be identified clinically and radiologically at birth, as well as later in life, so that confusion about the diagnosis should not occur.17, 18, 19, 84 Nevertheless, about 20% of affected individuals are not recognised at birth.7, 8, 85 With prenatal ultrasound becoming routine in developed countries, many affected fetuses are recognised in the third trimester of pregnancy, allowing families to be prepared for the birth of

Primary and secondary skeletal complications

The complications of achondroplasia involve many organ systems, but in most instances they are the consequence of abnormal linear bone growth. Many, if not most, of these complications evolve or appear at predicted ages including during adulthood, so that they can be anticipated and often minimised or even prevented if detected and treated early.7, 8, 105, 106, 107 Indeed, guidelines for health supervision for children with achondroplasia have been developed to aid primary care physicians in

Therapies to increase stature

There have been several trials of human growth hormone treatment in children with achondroplasia, mostly using pharmacological doses comparable with those used in Turner syndrome.152, 153, 154, 155, 156, 157, 158, 159, 160 Although there has been some increase in growth rate reported, especially early in the trials, no clear long-term benefit has been established and most experts do not recommend such treatment for achondroplasia.

Surgical limb lengthening is another approach that has been used

Future directions

As the molecular pathways involved in the pathogenesis of achondroplasia and related disorders have become clearer, a number of potential therapeutic strategies have emerged. Most of these approaches have been patterned after those used to treat cancer. This might seem peculiar because the physiological disturbances are in opposite directions—ie, excessive growth in cancer versus inadequate growth in achondroplasia. However, at the molecular level, the mechanisms are quite similar—excessive

Search strategy and selection criteria

We searched PubMed and Medline for clinical and basic science articles related to achondroplasia with the key words “achondroplasia”, “chondrodysplasia”, “skeletal dysplasia”, “FGFR3”, “FGFR”, and “FGF”. We also used our own published work accumulated over many years. We paid particular attention to articles published in English since the 1950s, when achondroplasia was delineated as a distinct clinical entity.

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