Achondroplasia

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Introduction0:00–0:30

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.

Physiology0:30–1:00

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.

Pathology1:00–2:20

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.
So, because of this it mostly affects endochondral bone formation, which is the process of bone forming right on previously-laid-down cartilage matrix, which causes the bone to elongate.
With the mutation though, this elongation is inhibited, which means long bones like the humerus and phalanges are affected.
Alright so the mutation affects endochondral bone formation, but bones that are products of intramembranous bone formation are way less affected.
This is where bone grows without an existing cartilage matrix. This includes flat bones like the skull and ribs.
Also an intramembranous process is appositional growth, which is the process of widening of long bones, so that happens pretty normally too.

Symptoms2:20–3:14

The result of shortened long bones is dwarfism with disproportionate short stature, where the limbs are short while the trunk and head size is largely preserved.
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. Flat bone defects, on the other hand, although less pronounced, do exist, and can include large head size, frontal bossing, flattened nasal bridge, a narrow foramen magnum, and spinal lordosis.
Although there are a lot of changes to the skeleton, a person’s other organs, intelligence, lifespan, and fertility are all normal.

Diagnosis3:14–4:47

Long bone shortening is often pronounced enough that achondroplasia can be diagnosed by prenatal ultrasound. The ratio of skull width (or biparietal diameter) to femur length in this case is higher than normal.
Also a DNA test can confirm the diagnosis either before or after birth. A skeletal survey, which is just a series of x-rays that capture much or all of the skeleton, can also confirm the diagnosis.
Alternatively, though, it can suggest that a person might have another skeletal dysplasia, which is a blanket term for disorders of skeletal development, of which there are hundreds of types in addition to achondroplasia.
Achondroplasia, though, is actually the most common skeletal dysplasia. This is because of an incredibly high new mutation rate.
New, or de novo, mutations come from the father, and get more frequent with increased paternal age, since sperm progenitor cells have more and more time to acquire mutations.
Now, with achondroplasia remember that it’s a heterozygous mutation, meaning they have one copy of the FGFR3 gene with the mutation, but the other copy’s normal.
What if both mom and dad have achondroplasia, and they happen to both contribute an FGFR3 mutation to the child? Well this results in homozygous achondroplasia, an extremely severe form of the disease that is lethal before or shortly after birth.
On the other hand, though, what happens if neither parent transmits their FGFR3 mutation? Well if that happens then the child won’t have achondroplasia.

Treatment4:47–4:58

Alright so what about treatment? Well unfortunately for people with achondroplasia, there isn’t any generally accepted way to increase height at the present time.

Review4:58–5:28

Alright so as a quick recap, achondroplasia is an autosomal dominant genetic disorder involving a FGFR3 mutation, FGFR3’s a receptor that inhibits bone growth, and the mutation causes it to be “always on”, so people with this develop dwarfism with disproportionate short limbs and other skeletal abnormalities.
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