Updated: 3/11/2020

Achondroplasia

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Snapshot
  • A 10-year-old boy is brought to the pediatric endocrinologist due to short stature. The mother reports that her son is not as tall as his classmates, and this is causing him stress. On physical exam, there is macrocephaly with frontal bossing, shortening of the arms and legs, and lumbar lordosis. Arrangements are made for genetic molecular testing.
Introduction
  • Clinical definition
    • a congenital skeletal dysplasia that results in shortened extremities and macrocephaly
      • also known as dwarfism
  • Etiology
    • autosomal dominant gain-of-function mutation in fibroblast growth factor receptor (FGFR3)
  • Pathogenesis 
    • constitutively active FGFR3 activity impairs chondrocyte proliferation and differentiation
      • this in turn leads to
        • impaired long bone formation (via endochondrial ossification)
        • enlarged head relative to limbs (via membranous ossification)
  • Associated findings
    • most common cause of dwarfism
    • normal life span, intelligence, and reproduction
Presentation
  • Symptoms
    • asymptomatic
  • Physical exam
    • macrocephaly
    • frontal bossing
    • shortening of arms and legs
      • proximal/rhizomelic segments are more notable
    • lumbar lordosis
    • kyphoscholiosis
Treatment
  • Conservative
    • monitoring, preventing, and addressing complications
      • e.g., leg bowing is managed with physical therapy
Differential Diagnosis
  • Cleidocranial dysplasia 
    • key distinguishing factors
      • due to mutation in RUNX2 (autosomal dominant or de novo) 
        • cranial abnormalities (delayed suture or fontanelle closure, brachycephaly, mandibular prognathism, and hypertelorism)
        • dental anomalies (supernumerary teeth, malocclusion, delayed loss of primary teeth, and delayed eruption of permanent teeth)
        • missing or underdeveloped clavicles
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Questions (6)
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(M1.MK.17.4722) A 3-year-old male is brought in to his pediatrician by his mother because she is concerned that he is not growing appropriately. Physical examination is notable for frontal bossing and shortened upper and lower extremities. His axial skeleton appears normal. He is at the 7th percentile for height and 95th percentile for head circumference. He demonstrates normal intelligence and is able to speak in three-word sentences. He first sat up without support at twelve months and started walking at 24 months. Genetic analysis reveals an activating mutation in a growth factor receptor. Which of the following physiologic processes is most likely disrupted in this patient’s condition? Tested Concept

QID: 108535
1

Intramembranous ossification

11%

(32/282)

2

Osteoblast maturation

10%

(28/282)

3

Endochondral ossification

63%

(177/282)

4

Production of type I collagen

10%

(27/282)

5

Bone resorption

4%

(10/282)

M 1 C

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(M1.MK.15.72) A young boy presents to your office for evaluation. He is not growing as quickly as his twin brother (Figure A). Genetic testing reveals a mutation in the fibroblast growth factor receptor gene.

What is the most likely mode of inheritance?

Tested Concept

QID: 106538
FIGURES:
1

Autosomal dominant

79%

(99/126)

2

Autosomal recessive

13%

(17/126)

3

X-linked recessive

2%

(3/126)

4

X-linked dominant

2%

(3/126)

5

Mitochondrial

2%

(2/126)

M 1 D

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(M1.MK.15.27) A 9-month-old female infant is brought in by her mother to the pediatrician because she is concerned that her daughter is not growing normally. On physical exam, the head circumference is 95th percentile and the height is 5th percentile. The child has disproportionate growth such that both the upper and lower extremities show a rhizomelic pattern of shortening, but the axial skeleton appears to be normal. The child appears to have normal intelligence, but has delayed motor milestones; specifically, she is not able to roll or sit up by herself. Which of the following best describes the mode of inheritance for this disorder? Tested Concept

QID: 107010
1

Autosomal recessive

21%

(30/146)

2

Autosomal dominant

57%

(83/146)

3

X-linked recessive

8%

(11/146)

4

X-linked dominant

5%

(7/146)

5

Mitochondrial pattern of inheritance

8%

(12/146)

M 1 D

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