Content Reviewers:Rishi Desai, MD, MPH
Contributors:Tanner Marshall, MS
In HBO’s adaptation of Game of Thrones, the character Tyrion Lannister is treated poorly by his father and siblings because he is born with dwarfism.
In a classic scene in the show, he says [“I’m guilty of being a dwarf! [father says: You’re not on trial for being a dwarf] Oh! Yes I am, I’ve been on trial for that my entire life].
Both Tyrion and his real-life counterpart—Peter Dinklage—have achondroplasia, an autosomal dominant genetic condition which is the most common cause of dwarfism and results from a heterozygous mutation in a gene called FGFR3, or fibroblast growth factor receptor 3, on chromosome 4, which codes for FGFR3 protein.
When FGFR3 protein binds fibroblast growth factors, or FGFs, it slows down the growth of certain bones.
The mutation causing achondroplasia is almost always the 380th amino acid, which is glycine, getting swapped out for arginine in the FGFR3 protein, and this swap causes the FGFR3 receptor to be constitutively active, which means constantly, active.
In other words, the mutation makes the receptor behave as though it’s binding an FGF even when it’s not, which sends a strong signal to inhibit bone growth.
More specifically, FGFR3 that is “always on” causes chondrocytes at the growth plate to proliferate slowly and become disorganized.
This is where bone grows without an existing cartilage matrix.
Specific long bone defects include rhizomelic, or proximal, shortening of the limbs, varus leg deformity (or, ‘knees out’), short metacarpals creating a broad hand, and short phalanges causing brachydactyly (literally meaning short fingers).
When outstretched, the fingers form a shape called a ‘trident hand,’ where the tips of fingers can’t touch each other.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "Pathophysiology of Disease: An Introduction to Clinical Medicine 8E" McGraw-Hill Education / Medical (2018)
- "CURRENT Medical Diagnosis and Treatment 2020" McGraw-Hill Education / Medical (2019)
- "Achondroplasia" The Lancet (2007)
- "Distraction Osteogenesis of the Lower Extremity in Patients With Achondroplasia/Hypochondroplasia Treated With Transplantation of Culture-Expanded Bone Marrow Cells and Platelet-Rich Plasma" Journal of Pediatric Orthopaedics (2007)
- "Achondroplasia: pathogenesis and implications for future treatment" Current Opinion in Pediatrics (2010)