Clinical Background
Achondroplasia (AP), hypochondroplasia (HP), and thanatophoric dysplasia (TD) are among the most common skeletal dysplasias.
Epidemiology
- Incidence
- Achondroplasia - 1/15,000-1/20,000 live births
- Hypochondroplasia - 1/15,000-1/40,000 live births
- Thanatophoric dysplasia - 1/6,500-20,000 live births
- Sex - equal distribution
Inheritance
- Autosomal dominant, mostly de novo mutations in TD, with 100% penetrance
- Cause - fibroblast growth factor receptor 3 (FGFR3) gene mutations
- AP
- 99% of cases result from substitution of A or C nucleotide for G at 1138 in the FGFR3 gene
- HP
- 70% of cases result from substitution of A or G nucleotide for C at 1620 in the FGFR3 gene
- TD
- Eleven FGFR3 mutations (6 missense and 5 read-throughs of the native stop codon) cause 99% of TDI
- A single FGFR3 mutation, K650E, is responsible for TDII
- Recurrence risk in offspring - for phenotypically normal parents with a previously affected pregnancy, the recurrence risk 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
- All have a large head; shortening of long bones and/or short stature
- AP
- Shortened long bones fall below the 5th percentile by the third trimester of pregnancy
- Frontal bossing, midface hypoplasia
- Trident appearance of hands; pronounced lumbar lordosis
- Mean adult height 48-52 inches for female and males respectively
- Normal intelligence
- HP
- Short stature of postnatal onset, usually evident by 3 years of age
- Lack of facial dysmorphism
- Adult height ranges from 47 to 60 inches
- Ten percent have mental deficiency
- TD
- Shortened long bones with onset in the early second trimester of pregnancy
- Typically lethal in neonatal period from brain stem compression and pulmonary hypoplasia
- Micromelia, narrow thorax with short ribs
- Facial features: prominent forehead, low nasal bridge, proptotic eyes
- Rare survivors all have mental deficiency
- Type I usually has bent femurs
- Type II typically has straight femurs and a cloverleaf skull
Treatment
- TD - Supportive
- HP - Bowing of the lower limbs may merit surgical straightening
- AP
- Ultrasound of brain, especially if large fontanel, to rule out mild hydrocephaly relating to small foramen magnum
- Diagnose obstructed sleep apnea
- Orthopedic neurologic evaluation of spinal stenosis and kyphosis
- Be aware that short eustachian tubes may lead to frequent middle ear infections and conductive hearing loss
- Avoid obesity
Diagnosis
Diagnosis
- Indications for TD testing
- First trimester - ultrasound showing increased nuchal translucency, reverse flow in ductus venosus, long-bone shortening
- Second/third trimester - ultrasound examination revealing limb shortening below 5th percentile, recognizable by 20 weeks gestation; platyspondyly, ventriculomegaly, narrow chest cavity with short ribs, polyhydramnios, bowed femurs (type 1), cloverleaf skull (in type II), well-ossified spine and skull
- Postnatal - clinical exam consistent with TD
- Based on clinical examination or prenatal ultrasound
- Genetic testing for FGFR3 mutation panel is diagnostic for TD when combined with clinical examination or prenatal ultrasound
Differential Diagnosis
- Achondrogenesis dysplasia types I and II
- Camptomelic dysplasia
- Osteogenesis imperfecta type II
- Platyspondylic lethal skeletal dysplasia
- Severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN)
- Short rib polydactyly syndromes
Tests generally appear in the order most useful for common clinical situations
| Test name: Thanatophoric Dysplasia, Types I and II (FGFR3) 13 Mutations
|
| ARUP #: 0051506 |
| Methodology: Polymerase Chain Reaction/Fragment Analysis
|
| Use: Mutations tested: 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 TDI and c.1948A>G in TDII |
| Limitations: Mutations other than those targeted in FGFR3 will not be detected; specificity may be compromised by rare primer site mutations; clinical and analytic sensitivity is 99% |
| Test name: Thanatophoric Dysplasia, Types 1 & 2 (FGFR3) 13 Mutations, Fetal
|
| ARUP #: 0051508 |
| Methodology: Polymerase Chain Reaction/Fragment Analysis
|
| Use: Mutations tested: 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 TDI and c.1948A>G in TDII |
| Limitations: Mutations other than those targeted in FGFR3 will not be detected; specificity may be compromised by rare primer site mutations; clinical and analytic sensitivity is 99% |
| Test name: Hypochondroplasia
|
| ARUP #: 0051367 |
| Methodology: Polymerase Chain Reaction/Fluorescence Monitoring
|
| Use: Mutation tested: c.1620C>A/G |
| Limitations: Mutations other than c.1620C>A/G will not be detected; clinical sensitivity is 70% and analytic sensitivity is 99% |
| Test name: Achondroplasia Mutation
|
| ARUP #: 0051266 |
| Methodology: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer
|
| Use: Mutations tested: c.1138G>A, c.1138G>C |
| Limitations: Mutations other than c.1138G>A and c.1138G>C will not be detected; clinical and analytic sensitivity is 99% |
| Test name: Achondroplasia Mutation, Fetal
|
| ARUP #: 0051265 |
| Methodology: Polymerase Chain Reaction/Fluorescent Resonance Energy Transfer
|
| Use: Mutations tested: c.1138G>A, c.1138G>C |
| Limitations: Mutations other than c.1138G>A and c.1138G>C will not be detected; clinical and analytic sensitivity is 99% |
References
General References
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Medical Reviewers
Lyon, Elaine, Ph.D. Medical Director, Molecular Genetics at ARUP Laboratories; Associate Professor, Pathology, University of Utah
Mao, Rong , M.D. Co-Medical Director, Molecular Genetics at ARUP Laboratories; Assistant Professor, Pathology, University of Utah
Comprehensive Review: May 2008
Last Update: May 2008
