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.
SeminarAchondroplasia
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
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Fibroblast growth factor receptor 3 mutations promote apoptosis but do not alter chondrocyte proliferation in thanatophoric dysplasia
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Interaction of FGF, Ihh/Pthlh, and BMP signaling integrates chondrocyte proliferation and hypertrophic differentiation
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K644E/M FGFR3 mutants activate Erk1/2 from the endoplasmic reticulum through FRS2 alpha and PLC gamma-independent pathways
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Kyphosis in achondroplasia: probably preventable
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Cervicomedullary compression in young patients with achondroplasia: value of comprehensive neurologic and respiratory evaluation
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Achondroplasia and hypochondroplasia. Comments on frequency, mutation rate, and radiological features in skull and spine
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Dwarfs in ancient Egypt
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Achondroplasia is defined by recurrent G380R mutations of FGFR3
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Health supervision for children with achondroplasia
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Recent milestones in achondroplasia research
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Epidemiological aspects of Mendelian syndromes in a Spanish population sample: I. Autosomal dominant malformation syndromes
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Birth prevalence rates of skeletal dysplasias
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Fibroblast growth factor receptor 3 mutations in achondroplasia and related forms of dwarfism
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Achondroplasia: clinical radiologic features with comment on genetic implications
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Thanatophoric dysplasia (types I and II) caused by distinct mutations in fibroblast growth factor receptor 3
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A recurrent mutation in the tyrosine kinase domain of fibroblast growth factor receptor 3 causes hypochondroplasia
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Stop codon FGFR3 mutations in thanatophoric dwarfism type 1
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Missense FGFR3 mutations create cysteine residues in thanatophoric dwarfism type I (TD1)
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Fibroblast growth factor receptor 3 and the human chondrodysplasias
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A glycine 375-to-cysteine substitution in the transmembrane domain of the fibroblast growth factor receptor-3 in a newborn with achondroplasia
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Localization of fibroblast growth factor 2 (FGF-2) protein and the receptors FGFR 1–4 in normal human seminiferous epithelium
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The observed human sperm mutation frequency cannot explain the achondroplasia paternal age effect
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