1Achondroplasia
Section snippets
Epidemiology
The birth incidence of achondroplasia is estimated to be between one in 10 000 and one in 30 0002, 3, 4, 5, affecting more than 250 000 individuals worldwide. It is one of the most common types of non-lethal skeletal chondrodysplasia. Earlier ascertainments of frequency were probably overestimates because, before involvement of the FGFR3 gene was identified, achondroplasia was often confused with various other chondrodysplasias.1 There is no racial predisposition. With prenatal ultrasound
Clinical and radiological description: natural history
Features of achondroplasia are so distinctive that they can easily be identified both clinically and radiologically. DNA testing for FGFR3 mutation is not systematically useful for diagnosis.
During pregnancy, the diagnosis of achondroplasia may be suspected in the third trimester by abnormal ultrasound findings, namely foreshortening of the limbs (<3rd percentile), increased biparietal diameter (>95th percentile) and low nasal bridge.7, 8 This can lead to intra-uterine imaging. Antenatal
Differential diagnosis
Achondroplasia belongs to a group of short-stature osteochondrodysplasias that have some clinical features in common, such as postnatal dwarfism, micromelia, short hands and narrow thorax. However, the other entities, namely Ellis-van Creveld syndrome, metatropic dysplasia, diastrophic dysplasia, thoracic dystrophy of Jeune, pseudoachondroplasia, various spondyloepiphyseal and spondylo-metaphyseal dysplasia, can be easily excluded on the bases of their major clinical and radiological features.
Complications and management
In achondroplasia, complications are consequences of the abnormal linear bone growth. Many appear at predicted ages including adulthood. They can often be minimized if detected early. Indeed, guidelines for patients with achondroplasia have been developed in several countries*11, *14, *15, *16 to aid physicians in such preventive care. Regular follow-up by a trained multidisciplinary team may be essential to prevent or treat early neurological and respiratory complications, which arise
Genetics
Achondroplasia is an autosomal-dominant disorder with essentially complete penetrance. More than 85% of patients are born from unaffected parents and harbour new mutations. The mutation rate is estimated to be between 1.4 × 10−5 ± 0.5 and 1.93 × 10−5 ± 0.43.2, 35
The achondroplasia locus was mapped to chromosome 4p16.3 in 199436, 37, and a recurrent heterozygous mutation of FGFR3 was identified soon after.*38, 39, 40 Almost all patients with achondroplasia have the same amino acid substitution in the
FGFR3
FGFR3 belongs to the fibroblast growth factor receptor family. The four FGFR (1–4) members share a common organization comprising three extracellular immunoglobin-like loops (Ig I–III), one hydrophobic transmembrane domain and two cytoplasmic tyrosine kinase subdomains TK1 and TK2, responsible for the catalytic activity.57 Binding of fibroblast growth factor (FGF) ligands in the presence of cell-surface heparan sulphate proteoglycans induces receptor dimerization and transautophosphorylation of
Therapeutic strategies
Human growth hormone therapy in children with achondroplasia has been proposed through several trials, with pharmacological doses comparable to those used in Turner syndrome.62, 63, 64 Long-term results are not conclusive; an increased growth rate was reported in some of the earliest trials. Consequently, this treatment is not recommended worldwide for achondroplasia.
Limb lengthening is often discussed, using several surgical and orthopaedic appliances. Expected lengthening is important (5–10 cm
Acknowledgements
This work was supported by the GIS-Maladies Rares 2002. The authors wish to thank the Association des Personnes de Petite Taille for their collaboration.
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