Skeletal Dysplasias

Diagnosis

Indications for Testing

• Achondroplasia (AP)
  • Shortening of long bones on ultrasound in late second and early third trimester
• Hypochondroplasia (HP)
  • Disproportionate shortening of the long bones identified >3 years of age
• Thanatophoric dysplasia (TD)
  • First trimester – ultrasound showing increased nuchal translucency, reverse flow in ductus venosus, long-bone shortening
  • Second/third trimester – ultrasound revealing limb shortening <5^th percentile, recognizable by 18 weeks gestation; platyspondyly, ventriculomegaly, narrow chest cavity with short ribs, polyhydramnios, bowed femurs (TD1), cloverleaf skull (TD2), well-ossified spine and skull
  • Postnatal – clinical exam consistent with TD

Laboratory Testing

• AP and HP – DNA testing for FGFR3 mutation
• TD – DNA testing for FGFR3 mutation panel is diagnostic for TD when combined with clinical examination or prenatal ultrasound

Other testing – AP

• Ultrasound of brain, especially if large fontanel, to rule out mild hydrocephaly related to small foramen magnum
• Diagnose obstructive sleep apnea
• Orthopedic neurologic evaluation of spinal stenosis and kyphosis

Differential Diagnosis

• Achondrogenesis types 1A, 1B, and 2
• Camptomelic dysplasia
• Osteogenesis imperfecta type II
• Platyspondylic lethal skeletal dysplasia
• Severe achondroplasia with developmental delay and acanthosis nigricans
• Short rib polydactyly syndromes
• Homozygous achondroplasia
• Asphyxiating thoracic dystrophy
• Dyssegmental dysplasia

Clinical Background

Achondroplasia (AP), hypochondroplasia (HP), and thanatophoric dysplasia types 1 and 2 (TD1 and TD2) are among the most common skeletal dysplasias. They are associated with abnormalities of the skeleton and are among the more than 350 osteochondrodysplasias.

Epidemiology

• Incidence (live births worldwide)
  • AP – 1/25,000-40,000
  • HP – 1/15,000-40,000
  • TD – 1/20,000
• Sex – M:F, equal

Inheritance

• Autosomal dominant
  • AP – 80% arise from de novo mutations
  • TD – >99% arise from de novo mutations
• Penetrance – 100%
• Caused by FGFR3 gene mutations
  • AP – 99% result from substitution of an adenine or cytosine for guanine at nucleotide position 1138 in the FGFR3 gene
  • HP – 70% of cases result from substitution of an adenine or guanine for cytosine at nucleotide position 1620 in the FGFR3 gene
  • TD
    • TD1 – 99% caused by 11 FGFR3 mutations (6 missense and 5 read-throughs of the native stop codon)
    • TD2 – single FGFR3 mutation, K650E, is responsible
    • Recurrence risk for parents of one affected child is not increased over the general population

Pathophysiology

• All mutations result in gain of FGFR3 function capable of initiating intracellular signal pathways in the absence of ligand binding
• Leads to premature differentiation of proliferative chondrocytes and premature bone maturation

Clinical Presentation

• AP
  • Long bones measure <5^th percentile by the third trimester of pregnancy
  • Large head with frontal bossing, midface hypoplasia
  • Trident appearance of hands; pronounced lumbar lordosis
  • Mean adult height 48 inches (females) and 52 inches (males)
  • Normal intelligence
  • Complications include sleep apnea
  • Short eustachian tubes may lead to frequent middle ear infections and conductive hearing loss
• HP
  • Short stature – postnatal onset, usually evident by 3 years
  • Lack of facial dysmorphism but macrocephaly common
  • Short, broad hands and feet; lumbar lordosis
  • Adult height ranges from 47-60 inches
  • 10% have mental deficiency
• TD
  • Shortened long bones with onset early in the second trimester of pregnancy
  • Typically lethal in neonatal period – brain stem compression and pulmonary hypoplasia
  • Micromelia, narrow thorax with short ribs
  • Facial malformations – prominent forehead, low nasal bridge, proptotic eyes
  • Rare survivors have severe developmental delay, hearing loss, seizures  
  • TD1 – typically has bent femurs and, rarely, cloverleaf skull
  • TD2 – typically has straight femurs and cloverleaf skull

Treatment

• AP – avoid obesity
• HP – bowing of the lower limbs may merit surgical straightening
• TD – supportive

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory