Achondroplasia

Achondroplasia
Jason "Wee Man" Acuña, an actor and stunt performer with achondroplasia
Pronunciation
  • /eɪˌkɒndrəˈpleɪziə, ə-, -ˈpleɪʒiə, -ˈpleɪʒə/[1][2]
Specialty Medical genetics
Symptoms Short arms and legs, enlarged head, prominent forehead[3]
Complications Ear infections, lordosis, back pain, spinal stenosis, hydrocephalus[3]
Causes Mutation in FGFR3 gene[3]
Diagnostic method Based on symptoms, genetic testing if uncertain[4]
Differential diagnosis Hypochondroplasia, thanatophoric dysplasia, cartilage-hair hypoplasia, pseudoachondroplasia[4]
Treatment Support groups, growth hormone therapy, treatment of complications[4]
Prognosis 10 year shorter life expectancy[4]
Frequency 1 in 27,500 people[3]

Achondroplasia is a genetic disorder that results in dwarfism.[3] In those with the condition, the arms and legs are short, while the torso is typically of normal length.[3] Those affected have an average adult height of 131 centimetres (4 ft 4 in) for males and 123 centimetres (4 ft) for females.[3] Other features include an enlarged head and prominent forehead.[3] Intelligence is generally normal.[3]

Achondroplasia is due to a mutation in the fibroblast growth factor receptor 3 (FGFR3) gene.[3] In about 80% of cases this occurs as a new mutation during early development.[3] In the other cases it is inherited from one's parents in an autosomal dominant manner.[3] Those with two affected genes do not typically survive.[3] Diagnosis is generally based on symptoms, but may be supported by genetic testing if uncertain.[4]

Treatments may include support groups and growth hormone therapy.[4] Efforts to treat or prevent complications such as obesity, hydrocephalus, obstructive sleep apnea, middle ear infections, or spinal stenosis may be required.[4] Life expectancy of those affected is about 10 years less than average.[4] The condition affects about 1 in 27,500 people.[3] Rates are higher in Denmark and Latin America.[5] The shortest known adult with the condition is Jyoti Amge at 62.8 centimetres (2 ft 0.7 in).[6]

Signs and symptoms

Causes

In 80% of cases Achondroplasia is caused by a mutation in fibroblast growth factor receptor 3 (FGFR3) gene.[7] This gene is mainly responsible for making the protein, fibroblast growth factor receptor 3. This protein contributes to the production of collagen and other structural components in tissues and bones. [8]When the FGFR3 gene is mutated it interferes with how this protein interacts with growth factors leading to complications with bone production. Cartilage is not able to fully develop into bone, causing the individual to be disproportionately shorter in height.

In normal development 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. The effect is genetically dominant, with one mutant copy of the FGFR3 gene being sufficient to cause achondroplasia, while two copies of the mutant gene are invariably fatal (recessive lethal) before or shortly after birth (known as a lethal allele). A person with achondroplasia thus has a 50% chance of passing dwarfism to each of their offspring. People with achondroplasia can be born to parents that do not have the condition due to spontaneous mutation.[9]

Achondroplasia can be inherited through autosomal dominance. In couples where one partner has achondroplasia there is a 50% chance of passing the disorder onto their child every pregnancy. In situations where both parents have achondroplasia there is a 50% chance the child will have achondroplasia, 25% chance the child will not, and a 25% chance that the child will inherit the gene from both parents resulting in double dominance and leading to death.[10]

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 prevents the mutation from being passed on in females.

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

Diagnosis

Detail of Las Meninas by Diego Velázquez (1656), showing Maribarbola and Nicolasito Pertusato (right), achondroplastic dwarfs in the entourage of Infanta Margarita

Achondroplasia can be detected before birth by 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. Clinical features include megalocephaly, short limbs, prominent forehead, thoracolumbar kyphosis and mid-face hypoplasia.[11] Complications like dental malocclusion, hydrocephalus and repeated otitis media can be observed.[11] The risk of death in infancy is increased due to the likelihood of compression of the spinal cord with or without upper airway obstruction.

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, with a narrow sciatic notch and horizontal acetabular roof. [12] [13] The tubular bones are short and thick with metaphyseal cupping and flaring and irregular growth plates.[12] 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.[12] 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

There is no known cure 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 (which involve a different hormonal pathway). However, if desired, the controversial surgery of limb-lengthening will lengthen the legs and arms of someone with achondroplasia.[14]

Usually, the best results appear within the first and second year of therapy.[15] After the second year of growth hormone therapy, beneficial bone growth decreases.[16] Therefore, GH therapy is not a satisfactory long term treatment.[15]

Complications

Children

Children with achondroplasia often have less muscle tone; because of this it is common for them to have delayed walking and motor skills. It is also common for children to have bowed legs, scoliosis, lordosis, arthritis, issues with joint flexibility, breathing problems, ear infections, and crowded teeth.[17] These issues can be treated with surgery, braces, or physical therapy.

Hydrocephalus is a severe effect associated with achondroplasia in children.This condition occurs when cerebrospinal fluid is not able to flow in and out of the skull because of how the spine narrows.[18] This fluid build up is associated with an enlarged head, vomiting, lethargy, headaches, and irritability.[19] A shunt surgery is commonly performed to treat this condition, but an endoscopic third ventriculostomy can also be done.[20]

Adults

Adults with achondroplasia often face issues with obesity and sleep apnea. It is also typical for adults to suffer from numbness or tingling in their legs because of nerve compression.

Women with achondroplasia are considered higher risk pregnancies and generally have their babies delivered through C-sections to prevent complications that could occur with a natural birth. [21]

Epidemiology

Achondroplasia is one of several 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.[22] Another study at the same time found a rate of 1 per 10,000.[22]

Other animals

Based on their disproportionate dwarfism, some dog breeds traditionally have been classified as "achondroplastic". This is the case for the dachshund, basset hound, corgi and bulldog breeds.[23][24][25] 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).[26] 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.[27]

A similar form of achondroplasia was found in a litter of piglets from a phenotypically normal Danish sow. The dwarfism was inherited dominant in the offspring from this litter. The piglets were born phenotypically normal, but became more and more symptomatic as they reached maturity.[28] This involved a mutation of the protein Collagen, type X, alpha 1, encoded by the COL10A1 gene. In humans a similar mutation (G595E) has been associated with Schmid metaphyseal chondrodysplasia (SMCD), a relatively mild skeletal disorder that is also associated with dwarfism.

The now-extinct Ancon sheep was created by humans through the selective breeding of common domestic sheep with achondroplasia. The average-sized torso combined with the relatively smaller legs produced by achondroplasia was valued for making affected sheep less likely to escape without affecting the amount of wool or meat each sheep produced.[29]

Research

Gene based therapy is being studied. In June 2015, BioMarin announced positive results of their Phase 2 study, stating that 10 children experienced a mean increase of 50% in their annualized growth velocity.[30]

See also

References

  1. ↑ "Achondroplasia". Oxford Dictionaries. Oxford University Press. Retrieved 2016-01-20.
  2. ↑ "Achondroplasia". Merriam-Webster Dictionary.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 "Achondroplasia". Genetics Home Reference. May 2012. Retrieved 12 December 2017.
  4. 1 2 3 4 5 6 7 8 Pauli, RM; Adam, MP; Ardinger, HH; Pagon, RA; Wallace, SE; Bean, LJH; Mefford, HC; Stephens, K; Amemiya, A; Ledbetter, N (2012). "Achondroplasia". GeneReviews. PMID 20301331.
  5. ↑ "Achondroplasia". Genetic and Rare Diseases Information Center (GARD) – an NCATS Program. 2016. Retrieved 12 December 2017.
  6. ↑ "New world's shortest woman: It's official – Jyoti Amge from India is new record holder". Guinness World Records. 13 December 2011. Retrieved 12 December 2017.
  7. ↑ "Learning About Achondroplasia". National Human Genome Research Institute (NHGRI). Retrieved 2018-09-26.
  8. ↑ Reference, Genetics Home. "FGFR3 gene". Genetics Home Reference. Retrieved 2018-09-26.
  9. ↑ 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.
  10. ↑ "Achondroplasia". Retrieved 2018-09-26.
  11. 1 2 Beattie, R.M.; Champion, M.P., eds. (2004). Essential questions in paediatrics for MRCPCH (1st ed.). Knutsford, Cheshire: PasTest. ISBN 1-901198-99-5.
  12. 1 2 3 EL-Sobky, TA; Shawky, RM; Sakr, HM; Elsayed, SM; Elsayed, NS; Ragheb, SG; Gamal, R (15 November 2017). "A systematized approach to radiographic assessment of commonly seen genetic bone diseases in children: A pictorial review". J Musculoskelet Surg Res. doi:10.4103/jmsr.jmsr_28_17.
  13. ↑ "Achondroplasia Pelvis". Archived from the original on 2007-10-22. Retrieved 2007-11-28.
  14. ↑ 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.
  15. 1 2 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.
  16. ↑ 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.
  17. ↑ "Dwarfism". kidshealth.org. Retrieved 2018-09-26.
  18. ↑ "Achondroplasia | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Retrieved 2018-09-26.
  19. ↑ Kieffer, Sara. "Achondroplasia | Johns Hopkins Pediatric Neurosurgery". Retrieved 2018-09-26.
  20. ↑ "Hydrocephalus - Diagnosis and treatment - Mayo Clinic". www.mayoclinic.org. Retrieved 2018-09-26.
  21. ↑ Services, Department of Health & Human. "Dwarfism". Retrieved 2018-09-26.
  22. 1 2 Online Mendelian Inheritance in Man (OMIM) ACHONDROPLASIA; ACH -100800
  23. ↑ "WebMD".
  24. ↑ Jones, T.C.; Hunt, R.D. (1979). "The musculoskeletal system". In Jones, T.C.; Hunt, R.D.; Smith, H.A. Veterinary Pathology (5th ed.). Philadelphia: Lea & Febiger. pp. 1175–6. ISBN 0812107896.
  25. ↑ Willis M.B. (1989). "Inheritance of specific skeletal and structural defects". In Willis M.B. Genetics of the Dog. Great Britain: Howell Book House. pp. 119–120. ISBN 087605551X.
  26. ↑ Parker HG, VonHoldt BM, Quignon P, et al. (August 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.
  27. ↑ Braund KG, Ghosh P, Taylor TK, Larsen LH (September 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.
  28. ↑ Nielsen VH, Bendixen C, Arnbjerg J, et al. (December 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.
  29. ↑ Gidney, Louisa (May–June 1019). "Earliest Archaeological Evidence of the Ancon Mutation in Sheep from Leicester, UK". International Journal of Osteoarchaeology. John Wiley and Son. 15 (27): 318–321. doi:10.1002/oa.872. ISSN 1099-1212.
  30. ↑ "BioMarin Surges On Positive Results From Phase-2 Study Of Dwarfism Drug". NASDAQ.com. The NASDAQ OMX Group, Inc. Retrieved 23 June 2015.
Classification
External resources
  • Achondroplasia at Curlie (based on DMOZ)
  • Pauli RM (1998). "Achondroplasia". In Pagon RA, Bird TD, Dolan CR, et al. GeneReviews. Seattle WA: University of Washington, Seattle. PMID 20301331. NBK1152.
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