Skeletal Dysplasias

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% of cases 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
- Eleven FGFR3 mutations (6 missense and 5 read-throughs of the native stop codon) cause 99% of TD1
- A single FGFR3 mutation, K650E, is responsible for TD2
- 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, leading to premature differentiation of proliferative chondrocytes and premature bone maturation

Clinical Presentation

AP
- Long bones measure <5th 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 is 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 Testing

AP
- Shortening of long bones on ultrasound in late second and early third trimester
HP
- Disproportionate shortening of the long bones identified >3 years of age
TD
- First trimester – ultrasound showing increased nuchal translucency, reverse flow in ductus venosus, long-bone shortening
- Second/third trimester – ultrasound examination 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 for AP and HP

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

Tests generally appear in the order most useful for common clinical situations

Test name: Achondroplasia (FGFR3) 2 Mutations

ARUP #: 0051266

Methodology: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Use:

DNA confirmation of a clinical and radiological diagnosis of AP

Limitations:

Mutations other than c.1138G>A and c.1138G>C will not be detected

Clinical sensitivity 99%

Test name: Achondroplasia (FGFR3) 2 Mutations, Fetal

ARUP #: 0051265

Methodology: Polymerase Chain Reaction/Fluorescent Resonance Energy Transfer

Use:

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

Limitations:

Mutations other than c.1138G>A and c.1138G>C will not be detected

Clinical sensitivity 99%

Test name: Hypochondroplasia (FGFR3) 1 Mutation

ARUP #: 0051367

Methodology: Polymerase Chain Reaction/Fluorescence Monitoring

Use:

DNA confirmation of a clinical and radiological diagnosis of HP

Limitations:

Mutations in FGFR3 and other than c.1620C>A/G and c.1620>G will not be detected

Clinical sensitivity 70%

Test name: Thanatophoric Dysplasia, Types 1 & 2 (FGFR3) 13 Mutations

ARUP #: 0051506

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

DNA confirmation of a clinical and radiological diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T, c.746C>G, c.1108G>T, c.11A>T, c.1118A>G, c.2419T>G, c.2419T>A, c.2420G>T, c.2420G>C, c.2421A>T, c.2421A>C and c.2421A>G in TD1 and c.1948A>G in TD2

Limitations:

Mutations other than those targeted in FGFR3 will not be detected; specificity may be compromised by rare primer site mutations

Clinical sensitivity 99%

Test name: Thanatophoric Dysplasia, Types 1 & 2 (FGFR3) 13 Mutations, Fetal

ARUP #: 0051508

Methodology: Polymerase Chain Reaction/Fragment Analysis

Use:

DNA confirmation of a clinical and radiological diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T, c.746C>G, c.1108G>T, c.1111A>T, c.1118A>G, c.2419T>G, c.2419T>A, c.2420G>T, c.2420G>C, c.2421A>T, c.2421A>C and c.2421A>G in TD1 and c.1948A>G in TD2

Limitations:

Mutations other than those targeted in FGFR3 will not be detected; specificity may be compromised by rare primer site mutations

Clinical sensitivity 99%

General

Comprehensive Review: June 2011
Last Update: June 2011