1. Background

• the fibroblast growth factor receptor-3 gene (FGFR3 gene) is a transmembrane receptor comprised of three domains:
  • an extracellular ligand-binding domain consisting of three immunoglobulin-like (sub)domains
  • a transmembrane domain
  • an intracellular cytoplasmic domain consisting of two tyrosine kinase (sub)domains
• a mutation in the FGFR3 gene as the cause of Thanatophoric Dysplasia was first reported by two groups - Tavormina, P. et al., Nature Genetics 9:321-328 (1995); Rousseau, F. et. al., Nature Genetics 10:11-12 (1995).
• there are several disorders which arise from mutations within the FGFR3 gene:

  1. Chrondrodysplastic Disorders

  • Achondroplasia
  • Hypochondroplasia
  • Thanatophoric Dysplasia - Types I and II

  2. Nonchondrodysplastic Disorders

  • Crouzon Syndrome (with acanthosis nigricans)
  • Pfeiffer-like Craniosynostosis Syndrome

1. Type I

• cysteine replaces several amino acids within two separate regions in the extracellular domain of the FGFR3 receptor -> inhibition of linear bone growth
• another mutation has been identified where the STOP codon is removed producing a protein predicted to be 141 amino acids longer than the normal protein -> mutation of the intracellular domain of the FGFR3 receptor -> inhibition of linear bone growth

2. Type II

• lysine to glutamic acid substitution at nucleotide 650 (Lys650Glu) -> mutation of one of the intracellular tyrosine kinase (sub)domains of the FGFR3 receptor -> inhibition of linear bone growth

1. Musculoskeletal Manifestations

2. Respiratory Manifestations

• hypoplasia -> neonatal asphyxia

3. Neurological Manifestations

• infantile hypotonia
• lack of primitive reflexes

4. Others

• head - macrocephaly with frontal bossing, depressed nasal bridge, proturbant eyes

1. Imaging Studies

1. Supportive

• respiratory distress

2. Prognosis

• lethal at or shortly after birth

1. Horton, W.A., Current Opinions in Pediatrics, 9:437-442 (1997).