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ABSTRACT

  • Achondroplasia and pseudoachondroplasia are clinically and genetically distinct phenotypes that are among the most common human disorders resulting in short stature. Both are inherited as autosomal dominant conditions. Achondroplasia, the single most common form of human dwarfism, results in most cases from one of two very specific mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Pseudoachondroplasia is caused by a variety of mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Both disorders are characterized by short-limb dwarfism, in which the affected person's arms and legs are relatively short compared to the height of the trunk. Disorders with clinical, radiographic, and molecular features in common with achondroplasia include hypochondroplasia, thanatophoric dysplasia (TD), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Similarly, pseudoachondroplasia and multiple epiphyseal dysplasia (MED) are related.

  • The clinical manifestations of achondroplasia include rhizomelic short stature, frontal bossing with midface hypoplasia, short ribs, trident hand, limited elbow extension, and hyperextensible hips and knees. Infants may have a thoracolumbar kyphosis or gibbus. Spinal stenosis is a common complication in adulthood. Less frequent complications in childhood include cervicomedullary compression secondary to a small foramen magnum, hydrocephalus, and obstructive apnea secondary to small airways. Age-specific mortality is increased in the first 4 years of life and in the fourth to fifth decades.

  • Homozygous achondroplasia is a neonatal lethal condition in which the skeletal manifestations of achondroplasia are exaggerated. Death is usually secondary to respiratory compromise or from cervical cord compression by a very small foramen magnum. In families where both parents have achondroplasia, the children are at 25 percent risk of inheriting the achondroplasia mutation from both parents, resulting in homozygous achondroplasia.

  • The phenotype of hypochondroplasia is similar to that of achondroplasia but milder in degree. The height curves overlap with those of the average population and spinal stenosis is infrequently observed. Learning disabilities may be more common among children with hypochondroplasia than among children with achondroplasia.

  • Thanatophoric dysplasia (TD), a neonatal lethal disorder, is the most severe of the FGFR3 phenotypes. Two types, designated TDI and TDII, are distinguishable on clinical and molecular grounds. The SADDAN phenotype is a recently recognized condition in the achondroplasia family of disorders.

  • Achondroplasia, hypochondroplasia, TDI, TDII, and the SADDAN phenotype are all caused by mutations in the FGFR3 gene. All are dominant phenotypes and most cases occur as a result of new mutation. Most, if not all, new mutations causing achondroplasia occur on the paternal allele.

  • The FGFRs are a family of four tyrosine kinase receptors. They have three immunoglobulin-like regions in the extracellular domain, a transmembrane domain, and a split intracellular tyrosine kinase domain. The different receptors bind fibroblast growth factors (FGFs) with variable affinity. Alternative splicing is a feature of FGFR RNA processing. The receptor monomers dimerize, in a step requiring heparin, before ligand may be bound. The dimerization process is promiscuous; any FGFR monomer may dimerize with any other.

  • FGFR3 has two splice forms depending on which ...

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