Elsevier

Joint Bone Spine

Volume 75, Issue 2, March 2008, Pages 125-130
Joint Bone Spine

Review
Achondroplasia: From genotype to phenotype

https://doi.org/10.1016/j.jbspin.2007.06.007Get rights and content

Abstract

This review focuses on the rheumatological features of achondroplasia, which is the most common skeletal dysplasia and the most frequent cause of short-limbed dwarfism. It is inherited in an autosomal dominant manner but results in the majority of cases of de novo mutations. The disease is related to a mutation in the fibroblast growth factor receptor-3 (FGFR3) gene encoding one member of the FGFR subfamily of tyrosine kinase receptors, which results in constitutive activation of the receptor. Biochemical studies of FGFR3 combined with experiments in knock-out mice have demonstrated that FGFR3 is a negative regulator of chondrocytes proliferation and differentiation in growth plate. This mutation induces a disturbance of endochondral bone formation. The diagnosis of achondroplasia is based on typical clinical and radiological features including short stature, macrocephaly with frontal bossing, midface hypoplasia and rhizomelic shortening of the limbs. The most common rheumatological complications of achondroplasia are medullar and radicular compressions due to spinal stenosis and deformities of the lower limbs. Current treatment and future therapies are discussed.

Introduction

Achondroplasia is the most common hereditary form of dwarfism with an incidence rate between 1/15,000 and 1/40,000 live births. It is a fully penetrant autosomal dominant disorder and the majority of cases are the result of a de novo mutation [1]. The phenotype of achondroplasia is related to a disturbance in endochondral bone formation, due to a mutation in the fibroblast growth factor receptor-3 (FGFR3). Consequently, affected individuals exhibit short stature and often present with neurological and skeletal complications, which can be encountered in rheumatological practice. Most individuals with achondroplasia have normal intelligence. Although serious problems may arise during infancy, they affect only 5–10% of infants with achondroplasia [2]. Unexpected death occurs in approximately 2–5% of all infants with achondroplasia [3]. Children affected with achondroplasia commonly have otitis media and bowing of the lower legs. Less commonly, infants and children may have serious health consequences related to hydrocephalus, craniocervical junction compression, upper-airway obstruction, or thoracolumbar kyphosis [2]. The most common complication occurring in adulthood is related to lumbosacral spinal stenosis with compression of the spinal cord or nerve roots. This review focuses on the rheumatological aspects of this skeletal genetic disease [2].

Section snippets

Genetics of achondroplasia

The gene for achondroplasia was assigned in 1994 by linkage analysis to 4p16.3 [4]. Within few months, causative mutations in the fibroblast growth factor receptor-3 (FGFR3) were identified by the candidate gene approach independently by Shiang et al. and by Rousseau et al. [5], [6]. The four FGFs receptors (FGFRs1–4) are members of the tyrosine kinase receptor family. They bind with variable affinity a polypeptide family that is composed of at least 18 members: the fibroblast growth factors

Effects of FGFR3 mutations on endochondral bone formation

The phenotype observed in achondroplasia is the consequence of severe disturbances in endochondral bone growth induced by abnormal activity of FGFR3.

General characteristics

The characteristic features of achondroplasia include a disproportionate short stature with rhizomelic shortening, trident hands, enlarged head, depressed nasal bridge and prominent forehead. The patient's short stature is evident during childhood and afterwards, during adulthood. Medium adult heights are 131 ± 5.6 cm for males and 124 ± 5.9 cm for females [28]. The facial features include a large head with prominent forehead. The midface is often small with a flat nasal bridge, narrow nasal passage

Radiological aspect

Achondroplasia is characterized by shortening and thickening of the long bones with metaphyseal flaring and cupping [40]. The phalanges are short, broad, and cupped. The iliac bones are short and rectangular with narrow sacroiliac notches and short, wide pubic and ischial bones. Variation in the configuration of the acetabulum include horizontal and notched acetabular roof. There are bullet-shaped vertebral bodies with posterior scalloping and narrowing of lumbar interpedicular distances (Fig. 3

Current and future treatments of achondroplasia

Mortality rate in patients with achondroplasia is higher than in the general population, particularly during childhood. The cause of this increased mortality rate in adulthood is poorly known, whereas that in young children is attributable to severe cervicomedullary compression [43], [44]. The American Academy of Pediatrics Committee on Genetics outlined recommendations for management of children with achondroplasia. Follow-up of these patients should be performed by a practitioner with

Prenatal diagnosis and genetic counselling

Patients with achondroplasia have normal mental and sexual development. Gynaecological problems like infertility, menorrhagia, dysmenorrhoea, and early menopause may be more common in these patients [55]. There are few data regarding obstetric behaviour in achondroplastic females in literature. However, pre-eclampsia, polyhydramnios, prematurity and fetal wastage have been reported [55]. There is an increased neonatal mortality due to hydrocephalus and thoracic cage abnormality. Achondroplasia

Conclusions

The knowledge on the molecular pathogenesis of achondroplasia has made considerable progress over the last few years and has highlighted the role of FGFR3 in the regulation of the growth plate development. Multidisciplinary follow-up and management are important for patients with achondroplasia. Rheumatologists should be aware of the skeletal complications in these patients as lumbar spine stenosis and nerve root compressions are frequently encountered in adults with achondroplasia.

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