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 <5th 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

  • Molecular testing
    • FGFR3 mutations – specific mutations associated with specific diseases; presence of mutation confirms diagnosis
      • AP – c.1138G>A, c.1138G>C
      • HP – c.1620C>A, c.1620C>G
      • TD
        • TD 1 – multiple (at least 13)
          • Missense and read-throughs of native stop codon cause TD1
        • TD2 – K650E mutation responsible for TD2

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
    • HP – 1/15,000-40,000
    • TD – 1/20,000-50,000
  • Sex – M:F, equal

Inheritance

  • Autosomal dominant
    • AP – 80% arise from de novo mutations
    • TD – most cases 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
      • 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
    • Regulation of bone growth is disrupted
  • Leads to premature differentiation of proliferative chondrocytes and premature bone maturation

Clinical Presentation

  • AP
    • May be lethal in prenatal period if homozygous or compound heterozygous mutations are present
    • Short extremities due to rhizomelic shortening
    • Short stature
    • Short/broad hands and feet; trident hands
    • Mild joint laxity/hypotonia
    • Lumbar lordosis
    • Macrocephaly – increased risk for intracranial bleeding during vaginal delivery
    • Facial findings
      • Frontal bossing
      • Midface hypoplasia
    • 7% risk of death due to brain stem compression from foramen magnum and spinal canal stenosis
  • HP
    • Nonlethal; extreme clinical variability makes diagnosis before 3 years difficult
    • Skeletal findings and medical complications are similar but less severe than achondroplasia
    • Rhizomelic or mesomelic shortening of long bones
    • Short stature
    • Short/broad hands and feet; trident hands
    • Mild joint laxity
    • Lumbar lordosis
    • Macrocephaly
    • Facial abnormalities
      • Frontal bossing
      • Midface hypoplasia
    • Developmental delay
  • TD
    • Lethal neonatal skeletal dysplasia for most individuals
      • Death typically occurs due to respiratory insufficiency in first hours/days of birth
    • 2 types
      • Type 1 has bent femurs with no skull deformity
      • Type 2 always has straight femurs and cloverleaf skull deformity
    • Rhizomelic shortening of the extremities
    • Redundant skin folds on limbs
    • Short ribs/narrow thorax
    • Hypotonia
    • Lumbar lordosis
    • Macrocephaly
    • Facial abnormalities
      • Frontal bossing
      • Flat facies
      • Low nasal bridge
      • Proptotic eyes
    • In survivors (rare)
      • Require long-term ventilatory support
      • Ventriculomegaly
      • Bilateral hearing loss
      • Kyphosis
      • Severe developmental delay

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
Test Name and Number Recommended Use Limitations Follow Up
Achondroplasia (FGFR3) 2 Mutations 0051266
Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Confirm clinical diagnosis of AP

Tests for c.1138G>A and c.1138G>C mutations

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations

 
Achondroplasia (FGFR3) 2 Mutations, Fetal 0051265
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Establish DNA diagnosis in at-risk fetuses or those with consistent ultrasonographic features of AP

Tests for c.1138G>A and c.1138G>C mutations

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations

 
Hypochondroplasia (FGFR3) 2 Mutations 0051367
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm clinical and/or radiological diagnosis of HP

Tests for c.1620C>A/G

Clinical sensitivity 70%

Rare diagnostic errors may occur due to primer-site mutations

 
Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations 0051506
Method: Polymerase Chain Reaction/Fragment Analysis

Confirm clinical diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T (p.R248C), c.746C>G (p.S249C), c.1108G>T (p.G370C), c.1111A>T (p.S371C), c.1118A>G (p.Y373C), c.1948A>G (p.K650E), c.2419T>G (p. X807G), , c.2419T>A (p.X807R), c.2420G>C (p.X807S), c.2420G>T (p.X807L), c.2421A>T (p.X807C), c.2421A>C (p.X807C), and c.2421A>G (p.X807W)

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations  
Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations, Fetal 0051508
Method: Polymerase Chain Reaction/Fragment Analysis

Confirm clinical diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T (p.R248C), c.746C>G (p.S249C), c.1108G>T (p.G370C), c.1111A>T (p.S371C), c.1118A>G (p.Y373C), c.1948A>G (p.K650E), c.2419T>G (p. X807G), , c.2419T>A (p.X807R), c.2420G>C (p.X807S), c.2420G>T (p.X807L), c.2421A>T (p.X807C), c.2421A>C (p.X807C), and c.2421A>G (p.X807W)

Clinical sensitivity 99%

Specificity may be compromised by rare primer-site mutations