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Achondroplasia

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Genetics

Genetics

Population genetics
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Down syndrome (Trisomy 21)
Edwards syndrome (Trisomy 18)
Patau syndrome (Trisomy 13)
Fragile X syndrome
Huntington disease
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Friedreich ataxia
Turner syndrome
Klinefelter syndrome
Prader-Willi syndrome
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Beckwith-Wiedemann syndrome
Cri du chat syndrome
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Alagille syndrome (NORD)
Achondroplasia
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Lesch-Nyhan syndrome
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Wiskott-Aldrich syndrome
Mitochondrial myopathy
Autosomal trisomies: Pathology review
Muscular dystrophies and mitochondrial myopathies: Pathology review
Miscellaneous genetic disorders: Pathology review

Assessments
Achondroplasia

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High Yield Notes
4 pages
Flashcards

Achondroplasia

12 flashcards
Questions

USMLE® Step 1 style questions USMLE

5 questions

USMLE® Step 2 style questions USMLE

5 questions
Preview

A 32-year-old man and his wife come to a prenatal counseling appointment inquiring about the possibility of pregnancy. Both members of the couple have achondroplasia. They want to know what the chances are that they will have a viable infant that will survive past a few months of life. Which of the following is most likely correct?

Transcript

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.

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.

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.