Achondroplasia

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