ReviewAchondroplasia: From genotype to phenotype
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.
References (57)
- et al.
Apnea and sudden unexpected death in infants with achondroplasia
J Pediatr
(1984) - et al.
Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia
Cell
(1994) Bad bones, absent smell, selfish testes: the pleiotropic consequences of human FGF receptor mutations
Cytokine Growth Factor Rev
(2005)- et al.
Cell responses to FGFR3 signalling: growth, differentiation and apoptosis
Exp Cell Res
(2005) - et al.
Mutations in fibroblast growth-factor receptor 3 in sporadic cases of achondroplasia occur exclusively on the paternally derived chromosome
Am J Hum Genet
(1998) - et al.
Fibroblast growth factor receptor 3 mutations in epidermal nevi and associated low grade bladder tumors
J Invest Dermatol
(2007) - et al.
Hormone regulation of chondrocyte differentiation and endochondral bone formation
Mol Cell Endocrinol
(1999) - et al.
Fibroblast growth factor receptor 3 is a negative regulator of bone growth
Cell
(1996) FGF signaling in the developing endochondral skeleton
Cytokine Growth Factor Rev
(2005)- et al.
Fibroblast growth factor expression in the postnatal growth plate
Bone
(2007)
The neurological complications of achondroplasia
Brain Dev
C-type natriuretic peptide in vascular physiology and disease
Pharmacol Ther
The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans
Endocr Rev
Health supervision for children with achondroplasia
Pediatrics
A gene for achondroplasia–hypochondroplasia maps to chromosome 4p
Nat Genet
Mutations in the gene encoding fibroblast growth factor receptor-3 in achondroplasia
Nature
FGFs, their receptors, and human limb malformations: clinical and molecular correlations
Am J Med Genet
Roles of FGF signaling in skeletal development and human genetic diseases
Front Biosci
Achondroplasia is defined by recurrent G380R mutations of FGFR3
Am J Hum Genet
Clinical hypochondroplasia in a family caused by a heterozygous double mutation in FGFR3 encoding GLY380LYS
Am J Med Genet A
Novel FGFR3 mutations creating cysteine residues in the extracellular domain of the receptor cause achondroplasia or severe forms of hypochondroplasia
Eur J Hum Genet
Reproductive functions, fertility and genetic risks of ageing men
Exp Clin Endocrinol Diabetes
Developmental regulation of the growth plate
Nature
Bcl-2 lies downstream of parathyroid hormone-related peptide in a signaling pathway that regulates chondrocyte maturation during skeletal development
J Cell Biol
Indian hedgehog signaling regulates proliferation and differentiation of chondrocytes and is essential for bone formation
Genes Dev
A Lys644Glu substitution in fibroblast growth factor receptor 3 (FGFR3) causes dwarfism in mice by activation of STATs and ink4 cell cycle inhibitors
Hum Mol Genet
A mouse model for achondroplasia produced by targeting fibroblast growth factor receptor 3
Proc Natl Acad Sci U S A
Recent milestones in achondroplasia research
Am J Med Genet A
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