A couple, both of whom have achondroplasia, ask during preconception counselling: what is the likelihood that their baby would have average stature (that is, inherit neither achondroplasia-causing allele)?

a. 0%
b. 25%
c. 50% regardless of sex
d. 60%
e. 75%

Answer: 25%

Detailed discussion for MRCP

This is a classic autosomal dominant inheritance question, but it has an important twist: both parents are affected.

Step 1: Know the genotype in achondroplasia

Achondroplasia is caused by a mutation in FGFR3 and is inherited in an autosomal dominant manner.

Most living adults with achondroplasia are heterozygous, meaning they have:

one normal allele = a
one mutated allele = A

So each affected parent is usually:

Why not AA? Because homozygous achondroplasia (AA) is classically lethal in the perinatal or early neonatal period.

So when two affected adults with achondroplasia have children, the cross is:

Aa × Aa

Step 2: Draw the Punnett square

Possible combinations:

So probabilities are:

25% AA = homozygous achondroplasia = usually lethal
50% Aa = heterozygous achondroplasia = affected living child
25% aa = unaffected, normal height

Therefore, the chance of a child of normal height is:

25%

Step 3: Why this is not 50%

Many candidates make the mistake of thinking autosomal dominant means “half the children will be unaffected.” That is true only when one parent is heterozygous affected (Aa) and the other is unaffected (aa).

But here both parents are affected:

Father = Aa
Mother = Aa

So the result becomes 1:2:1, not 1:1.

Step 4: Important clinical point

In achondroplasia:

heterozygous state (Aa) = viable and typical achondroplasia phenotype
homozygous state (AA) = severe skeletal abnormality, usually incompatible with survival beyond the neonatal period

That is why counselling in two affected parents is especially important:

25% unaffected
50% affected viable child
25% lethal homozygous child

Step 5: High-yield genetics principle

For two heterozygotes in an autosomal dominant disorder:

25% unaffected
50% heterozygous affected
25% homozygous affected

But whether the homozygous state is viable depends on the disease:

In achondroplasia, homozygous state is usually lethal
In some other AD disorders, homozygous forms may exist but are more severe

Step 6: What MRCP wants you to know about achondroplasia

Achondroplasia is the most common skeletal dysplasia causing disproportionate short stature.

Gene

FGFR3 mutation on chromosome 4
FGFR3 normally inhibits bone growth; mutation causes overactive inhibition of endochondral ossification

Inheritance

Autosomal dominant
Many cases are new mutations
Strong association with advanced paternal age

Phenotypic features

Disproportionate short stature
Rhizomelia = proximal limb shortening
Large head
Frontal bossing
Midface hypoplasia
Depressed nasal bridge
Short fingers
Trident hand
Lumbar lordosis

Complications

Foramen magnum stenosis
Hydrocephalus
Obstructive sleep apnoea
Recurrent otitis media
Spinal stenosis
Orthopaedic complications

Step 7: Exam trap

If a question asks the chance of:

an unaffected child = 25%
a living child with achondroplasia = 50%
any affected genotype = 75%
But remember: in achondroplasia, that 75% includes the 25% homozygous lethal group, so not all “affected conceptions” become surviving children.

Step 8: Subtle counselling language

When speaking to parents, it is better to distinguish between:

chance at conception
chance of a liveborn unaffected child
chance of a liveborn affected child

The standard genetics exam answer for “chance of a child of normal height” is 25%.

If phrased more precisely in real-life counselling, one may discuss the lethal homozygous group and survival implications in detail.

Step 9: Extra topper points

Why achondroplasia is disproportionate

The mutation mainly affects endochondral bone formation, so long bones are more affected than membranous bones. Hence:

limbs are short
trunk is relatively preserved
skull vault may be relatively large

Important distinction

Achondroplasia is not a disorder of growth hormone deficiency. So GH therapy is not the central issue.

Molecular mechanism

FGFR3 is a negative regulator of chondrocyte proliferation in the growth plate. Gain-of-function mutation means:

less cartilage proliferation
less longitudinal bone growth
shortened long bones

Prenatal diagnosis

Can be considered if both parents are affected:

ultrasound features
molecular testing for FGFR3 mutation

Anesthetic relevance

Patients may have:

difficult airway
cervicomedullary compression risk
spinal issues
Very useful in real clinical practice and viva discussions.

Cheat sheet

Achondroplasia inheritance: autosomal dominant
Gene: FGFR3 gain-of-function mutation
Most affected adults: heterozygous (Aa)
Homozygous achondroplasia (AA): usually lethal in perinatal/early infancy period
Cross when both parents affected: Aa × Aa
Outcomes:
- 25% aa = unaffected, normal height
- 50% Aa = affected, viable
- 25% AA = homozygous lethal
Chance of normal-height child = 25%
Chance of living affected child = 50%
Chance of affected conception overall = 75%
Key features:
- rhizomelic short stature
- frontal bossing
- midface hypoplasia
- trident hand
- lumbar lordosis
Important association: advanced paternal age
Pathophysiology: defective endochondral ossification

Flash cards

Q: What is the inheritance pattern of achondroplasia?
A: Autosomal dominant.
Explanation: A single mutant FGFR3 allele is enough to produce the phenotype.

Q: Which gene is mutated in achondroplasia?
A: FGFR3.
Explanation: FGFR3 gain-of-function suppresses normal chondrocyte proliferation at the growth plate.

Q: What is the usual genotype of a living adult with achondroplasia?
A: Heterozygous (Aa).
Explanation: The homozygous state is typically lethal, so surviving affected adults are almost always heterozygous.

Q: If both parents have achondroplasia, what cross is used?
A: Aa × Aa.
Explanation: This is the key setup for calculating risk.

Q: In Aa × Aa, what proportion of offspring are unaffected?
A: 25%.
Explanation: One in four inherit two normal alleles (aa).

Q: In Aa × Aa, what proportion are heterozygous affected?
A: 50%.
Explanation: Two of the four combinations are Aa.

Q: In Aa × Aa, what proportion are homozygous affected?
A: 25%.
Explanation: One in four inherit AA, which in achondroplasia is usually lethal.

Q: What is the chance that two parents with achondroplasia will have a child of normal height?
A: 25%.
Explanation: Only the aa genotype gives normal stature.

Q: Why is the answer not 50%?
A: Because both parents are affected heterozygotes, not one affected and one unaffected.
Explanation: Two heterozygotes produce a 1:2:1 ratio, not a 1:1 ratio.

Q: What happens in homozygous achondroplasia?
A: It is usually lethal in the perinatal or early neonatal period.
Explanation: Severe skeletal abnormalities cause incompatible survival.

Q: What type of limb shortening is typical in achondroplasia?
A: Rhizomelic shortening.
Explanation: The proximal segments of limbs are disproportionately shortened.

Q: What are classic craniofacial features of achondroplasia?
A: Frontal bossing and midface hypoplasia.
Explanation: These are highly characteristic and commonly tested.

Q: What hand appearance is classically described in achondroplasia?
A: Trident hand.
Explanation: There is separation between the fingers, giving a trident-like appearance.

Q: What parental factor is associated with sporadic achondroplasia mutations?
A: Advanced paternal age.
Explanation: New FGFR3 mutations become more common with increasing paternal age.

Q: What bone formation process is primarily disrupted in achondroplasia?
A: Endochondral ossification.
Explanation: This explains predominant involvement of long bones.

MCQs to test yourself

1. A man and woman, both with achondroplasia, seek genetic counselling before pregnancy. What is the probability that their child will be unaffected?
A. 50%
B. 75%
C. 25%
D. 0%
E. 100%

Answer: C. 25%
Explanation: Achondroplasia is autosomal dominant and affected living adults are usually heterozygous (Aa). Thus Aa × Aa gives 25% aa, 50% Aa, and 25% AA.

2. In achondroplasia, the genotype most commonly seen in surviving affected adults is:
A. AA
B. Aa
C. aa
D. XO
E. XXY

Answer: B. Aa
Explanation: Homozygous achondroplasia (AA) is usually lethal early in life, so surviving affected individuals are generally heterozygous.

3. Which of the following best explains the lethality of homozygous achondroplasia?
A. Homozygous loss of FGFR3 activity
B. Severe skeletal dysplasia due to homozygous FGFR3 gain-of-function mutation
C. Autoimmune destruction of cartilage
D. Excess collagen type I deposition
E. Defective osteoclast maturation

Answer: B. Severe skeletal dysplasia due to homozygous FGFR3 gain-of-function mutation
Explanation: Achondroplasia is caused by activating FGFR3 mutation. Homozygous inheritance produces a much more severe phenotype, usually lethal.

4. A couple in whom both partners have achondroplasia conceive. What is the chance that the fetus will be heterozygous for the mutation?
A. 25%
B. 50%
C. 75%
D. 100%
E. 12.5%

Answer: B. 50%
Explanation: Aa × Aa produces Aa in 2 out of 4 combinations.

5. Which of the following is false regarding achondroplasia?
A. It is usually inherited as an autosomal dominant trait
B. FGFR3 is the implicated gene
C. Homozygous state is generally lethal
D. It primarily affects endochondral ossification
E. It is usually inherited as an autosomal recessive trait

Answer: E. It is usually inherited as an autosomal recessive trait
Explanation: Achondroplasia is classically autosomal dominant, not recessive.

6. The most likely molecular mechanism in achondroplasia is:
A. FGFR3 loss-of-function mutation
B. Collagen type II deficiency
C. FGFR3 gain-of-function mutation
D. Elastin gene deletion
E. Defective fibrillin synthesis

Answer: C. FGFR3 gain-of-function mutation
Explanation: FGFR3 normally restrains bone growth; gain-of-function exaggerates that inhibition.

7. Which feature is most typical of achondroplasia?
A. Marfanoid habitus
B. Rhizomelic limb shortening
C. Arachnodactyly
D. Hyperextensible skin
E. Blue sclerae

Answer: B. Rhizomelic limb shortening
Explanation: Achondroplasia classically causes proximal shortening of the limbs.

8. When counselling two parents with achondroplasia, what is the probability of an affected conception overall?
A. 25%
B. 40%
C. 50%
D. 75%
E. 100%

Answer: D. 75%
Explanation: 50% are heterozygous affected and 25% are homozygous affected, giving 75% affected conceptions in total.

9. Which of the following is false about sporadic achondroplasia?
A. It may arise as a new mutation
B. Advanced paternal age is a risk factor
C. All cases are inherited from an affected parent
D. FGFR3 mutation is involved
E. It remains an autosomal dominant disorder once present

Answer: C. All cases are inherited from an affected parent
Explanation: Many cases arise de novo, so a positive parental history is not required.

10. A child is born to two parents with achondroplasia and survives infancy without features of achondroplasia. What is the most likely genotype?
A. AA
B. Aa
C. aa
D. A0
E. Mosaic FGFR3

Answer: C. aa
Explanation: A normal-height unaffected child must have inherited the normal allele from both parents.

11. Which hand abnormality is classically associated with achondroplasia?
A. Swan-neck deformity
B. Claw hand
C. Trident hand
D. Ape hand
E. Dupuytren contracture

Answer: C. Trident hand
Explanation: The fingers are short and separated in a characteristic trident configuration.

12. Which skull/facial combination is most typical of achondroplasia?
A. Microcephaly and mandibular overgrowth
B. Frontal bossing and midface hypoplasia
C. Craniosynostosis and exophthalmos
D. Micrognathia and cleft palate
E. Tall forehead with prognathism

Answer: B. Frontal bossing and midface hypoplasia
Explanation: These are classic examination features.

13. Which statement best distinguishes achondroplasia from endocrine short stature?
A. Achondroplasia causes proportionate short stature
B. Achondroplasia is due to growth hormone deficiency
C. Achondroplasia mainly affects membranous ossification
D. Achondroplasia causes disproportionate short stature from impaired endochondral ossification
E. Achondroplasia only affects girls

Answer: D. Achondroplasia causes disproportionate short stature from impaired endochondral ossification
Explanation: The long bones are especially affected, producing disproportionate short stature.

14. In a standard Punnett square for Aa × Aa, the fraction representing homozygous normal offspring is:
A. 1/2
B. 1/3
C. 1/4
D. 3/4
E. 2/3

Answer: C. 1/4
Explanation: Only one of the four possible combinations is aa.

15. Which of the following is false in achondroplasia?
A. Midface hypoplasia may occur
B. Lumbar lordosis may be seen
C. Rhizomelia is common
D. It is due to an FGFR3 mutation
E. Homozygous state is usually benign

Answer: E. Homozygous state is usually benign
Explanation: Homozygous achondroplasia is usually severe and lethal, not benign.

16. What is the chance that two parents with achondroplasia will have a viable child with achondroplasia?
A. 25%
B. 50%
C. 75%
D. 100%
E. 12.5%

Answer: B. 50%
Explanation: The viable affected group is the heterozygous Aa group, which makes up half of offspring.

17. Which parental factor is particularly associated with new achondroplasia mutations?
A. Advanced maternal age
B. Maternal smoking
C. Advanced paternal age
D. Maternal diabetes
E. Maternal folate deficiency

Answer: C. Advanced paternal age
Explanation: This is a classic epidemiological association for new FGFR3 mutations.

18. The principal developmental process impaired in achondroplasia is:
A. Neural tube closure
B. Endochondral ossification
C. Intramembranous ossification exclusively
D. Myelination
E. Osteoclast-mediated bone resorption only

Answer: B. Endochondral ossification
Explanation: This is why long bones are shortened while other structures are relatively less affected.

Summary for quick exam revision

Achondroplasia is an autosomal dominant FGFR3 gain-of-function disorder causing disproportionate short stature due to impaired endochondral ossification, with classic features including rhizomelia, frontal bossing, midface hypoplasia, trident hands, and lumbar lordosis. Surviving affected adults are usually heterozygous (Aa), so when two affected parents conceive, the cross is Aa × Aa, giving 25% unaffected normal-height offspring (aa), 50% heterozygous affected viable offspring (Aa), and 25% homozygous affected offspring (AA), which is usually lethal in the perinatal or early neonatal period. Therefore, the chance of a child of normal height is 25%, and this is one of the highest-yield inheritance patterns in MRCP genetics questions.

Short stature