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Achondroplasia

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Achondroplasia
SpecialtyMedical genetics Edit this on Wikidata
Detail of Las Meninas by Diego Velázquez (1656), showing Maribarbola and Nicolasito Pertusato (right), achondroplastic dwarfs in the entourage of Infanta Margarita

Achondroplasia (/[invalid input: 'icon']əˌkɒndr[invalid input: 'ɵ']ˈpleɪziə/) is a common cause of dwarfism. It occurs as a sporadic mutation in approximately 75% of cases (associated with advanced paternal age) or may be inherited as an autosomal dominant genetic disorder.

People with achondroplasia have short stature, with an average adult height of 131 centimeters (51.5 inches) [4 ft 3.5 in] for males and 123 centimeters (48.4 inches) [4 ft 0.4 in] for females. Achondroplastic adults are known to be as short as 62.8 cm (24.7 inches) [2 ft 0.7 in]. The disorder itself is caused by a change in the DNA for fibroblast growth factor receptor 3 (FGFR3), which causes an abnormality of cartilage formation. If both parents of a child have achondroplasia, and both parents pass on the mutant gene, then it is very unlikely that the homozygous child will live past a few months of its life. The prevalence is approximately 1 in 25,000.[1]

Causes

In normal figures, FGFR3 has a negative regulatory effect on bone growth. In achondroplasia, the mutated form of the receptor is constitutively active and this leads to severely shortened bones.

People with achondroplasia have one normal copy of the FGFR3 gene and one mutant copy. Two copies of the mutant gene are invariably fatal before or shortly after birth. Only one copy of the gene has to be present for the condition to occur. Therefore, a person with achondroplasia has a 50% chance of passing on the gene to his or her offspring, meaning that there will be a 50% chance that each child will have achondroplasia. Since it is fatal to have two copies (homozygous), if two people with achondroplasia have a child, there is a 25% chance of the child dying shortly after birth, a 50% chance the child will have achondroplasia, and a 25% chance the child will have an average phenotype. People with achondroplasia can be born to parents that do not have the condition. This is the result of a new mutation.[2]

New gene mutations leading to achondroplasia are associated with increasing paternal age[3] (over 35 years old). Studies have demonstrated that new gene mutations for achondroplasia are exclusively inherited from the father and occur during spermatogenesis; it is theorized that oogenesis has some regulatory mechanism that hinders the mutation from originally occurring in females (although females are still readily able to inherit and pass on the mutant allele). More than 99% of achondroplasia is caused by two different mutations in the FGFR3. In about 98% of cases, a G to A point mutation at nucleotide 1138 of the FGFR3 gene causes a glycine to arginine substitution (Bellus et al. 1995, Shiang et al. 1994, Rousseau et al. 1996). About 1% of cases are caused by a G to C point mutation at nucleotide 1138. The mutant gene was discovered by John Wasmuth and his colleagues in 1994.

There are two other syndromes with a genetic basis similar to achondroplasia: hypochondroplasia and thanatophoric dysplasia.

Diagnosis

Achondroplasia can be detected before birth by the use of prenatal ultrasound. A DNA test can be performed before birth to detect homozygosity, wherein two copies of the mutant gene are inherited, a lethal condition leading to stillbirths.

Radiologic findings

A skeletal survey is useful to confirm the diagnosis of achondroplasia. The skull is large, with a narrow foramen magnum, and relatively small skull base. The vertebral bodies are short and flattened with relatively large intervertebral disk height, and there is congenitally narrowed spinal canal. The iliac wings are small and squared,[4] with a narrow sciatic notch and horizontal acetabular roof. The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates. Fibular overgrowth is present. The hand is broad with short metacarpals and phalanges, and a trident configuration. The ribs are short with cupped anterior ends. If the radiographic features are not classic, a search for a different diagnosis should be entertained. Because of the extremely deformed bone structure, people with achondroplasia are often "double jointed".

The diagnosis can be made by fetal ultrasound by progressive discordance between the femur length and biparietal diameter by age. The trident hand configuration can be seen if the fingers are fully extended.

Another distinct characteristic of the syndrome is thoracolumbar gibbus in infancy.

Treatment

At present, there is no known treatment for achondroplasia, even though the cause of the mutation in the growth factor receptor has been found.

Although used by those without achondroplasia to aid in growth, human growth hormone does not help people with achondroplasia. However, if desired, the controversial surgery of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.[5]

Usually, the best results appear within the first and second year of therapy.[6] After the second year of GH therapy, beneficial bone growth decreases.[7] Therefore, GH therapy is not a satisfactory long term treatment.[6]

Gene based therapy is on the horizon. The USA based company BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) recently announced the initiation of a Phase 1 study in healthy volunteers for BMN-111, an analog of C-type Natriuretic Peptide (CNP), for the treatment of achondroplasia.

Latest research and related efforts are tracked by the non-profit Growing Stronger.

Epidemiology

Achondroplasia is one of 19 congenital conditions with similar presentations, such as osteogenesis imperfecta, multiple epiphyseal dysplasia tarda, achondrogenesis, osteopetrosis, and thanatophoric dysplasia. This makes estimates of prevalence difficult, with changing and subjective diagnostic criteria over time. One detailed and long-running study in the Netherlands found that the prevalence determined at birth was only 1.3 per 100,000 live births.[8] However, another study at the same time found a rate of 1 per 10,000.[8]

In other species

Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic." This is the case for the dachshund, basset hound, and bulldog breeds, to mention a few.[9][10] Data from whole genome association studies in short-limbed dogs reveal a strong association of this trait with a retro-gene coding for fibroblast growth factor 4 FGF4.[11] Therefore, it seems unlikely that dogs and humans are achondroplastic for the same reasons. However, histological studies in some achondroplastic dog breeds have shown altered cell patterns in cartilage that are very similar to those observed in humans exhibiting achondroplasia.[12]

A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. The dwarfism was inherted dominant in the offspring from this litter. The mutants were born phenotypically normal but became more and more invalid as they reached maturity.[13]

See also

References

  1. ^ Wynn J, King TM, Gambello MJ, Waller DK, Hecht JT (2007). "Mortality in achondroplasia study: A 42-year follow-up". Am. J. Med. Genet. A. 143 (21): 2502–11. doi:10.1002/ajmg.a.31919. PMID 17879967.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ^ Richette P, Bardin T, Stheneur C (2007). "Achondroplasia: From genotype to phenotype". Joint Bone Spine. 75 (2): 125–30. doi:10.1016/j.jbspin.2007.06.007. PMID 17950653.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Dakouane Giudicelli M, Serazin V, Le Sciellour CR, Albert M, Selva J, Giudicelli Y (2007). "Increased achondroplasia mutation frequency with advanced age and evidence for G1138A mosaicism in human testis biopsies". Fertil Steril. 89 (6): 1651–6. doi:10.1016/j.fertnstert.2007.04.037. PMID 17706214.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ "Achondroplasia Pelvis". Archived from the original on 2007-10-22. Retrieved 2007-11-28.
  5. ^ Kitoh H, Kitakoji T, Tsuchiya H, Katoh M, Ishiguro N (2007). "Distraction osteogenesis of the lower extremity in patients that have achondroplasia/hypochondroplasia treated with transplantation of culture-expanded bone marrow cells and platelet-rich plasma". J Pediatr Orthop. 27 (6): 629–34. doi:10.1097/BPO.0b013e318093f523. PMID 17717461.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ a b Vajo, Z; Francomano, CA; Wilkin, DJ (2000). "The molecular and genetic basis of fibroblast growth factor receptor 3 disorders: the achondroplasia family of skeletal dysplasias, Muenke craniosynostosis, and Crouzon syndrome with acanthosis nigricans". Endocrine Reviews. 21 (1): 23–39. doi:10.1210/er.21.1.23. PMID 10696568.
  7. ^ Aviezer, D; Golembo, M; Yayon, A (2003). "Fibroblast growth factor receptor-3 as a therapeutic target for Achondroplasia--genetic short limbed dwarfism". Current drug targets. 4 (5): 353–65. doi:10.2174/1389450033490993. PMID 12816345.
  8. ^ a b Online Mendelian Inheritance in Man (OMIM): ACHONDROPLASIA; ACH - 100800
  9. ^ Jones, T.C.; Hunt, R.D.; (1979). "The musculoskeletal system". In Jones, T.C.; Hunt, R.D.; Smith, H.A. (ed.). Veterinary Pathology (5th ed.). Philadelphia: Lea & Febiger. pp. 1175–6. ISBN 0812107896.{{cite book}}: CS1 maint: extra punctuation (link) CS1 maint: multiple names: authors list (link)
  10. ^ Willis M.B. (1989). "Inheritance of specific skeletal and structural defects". In Willis M.B. (ed.). Genetics of the Dog. Great Britain: Howell Book House. pp. 119–120. ISBN 087605551X.
  11. ^ Parker HG, VonHoldt BM, Quignon P; et al. (2009). "An expressed fgf4 retrogene is associated with breed-defining chondrodysplasia in domestic dogs". Science. 325 (5943): 995–8. doi:10.1126/science.1173275. PMC 2748762. PMID 19608863. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  12. ^ Braund KG, Ghosh P, Taylor TK, Larsen LH (1975). "Morphological studies of the canine intervertebral disc. The assignment of the beagle to the achondroplastic classification". Res. Vet. Sci. 19 (2): 167–72. PMID 1166121. {{cite journal}}: Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
  13. ^ Nielsen VH, Bendixen C, Arnbjerg J; et al. (2000). "Abnormal growth plate function in pigs carrying a dominant mutation in type X collagen". Mamm. Genome. 11 (12): 1087–92. doi:10.1007/s003350010212. PMID 11130976. {{cite journal}}: Explicit use of et al. in: |author= (help); Unknown parameter |month= ignored (help)CS1 maint: multiple names: authors list (link)
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