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BIRTH DEFECT RISK FACTOR SERIES: Achondroplasia

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DEFINITION

Achondroplasia is a genetic, developmental disorder of the bones and cartilage that results in short stature, lumbar lordosis (sway-back), and limited elbow extension (Brown 2003, Moutou 2003). Commonly called dwarfism, this disorder has several other associated features, including delayed motor development; however, mental retardation is not associated with this disorder (Moutou 2003). Affected individuals will also have a small foramen magnum (the large hole located in the base of the skull which allows passage of the spinal cord); this can lead to cervicomedullary compression, which may cause infants to have difficulty breathing and sleeping (Moutou 2003, Jones 1997).

ETIOLOGY

This disorder has been found to be autosomal dominant with the vast majority of the cases occurring spontaneously (Jones 1997). Achondroplastic parents have a 50% change of passing this disorder onto their children. If both parents have achondroplasia, then there is a 25% chance that the child will be homozygous for this disorder (Gooding 2002). Children who are homozygous for this disorder are much more severely affected than children who are heterozygous. The homozygous condition is almost always fatal within a few months after birth (Gooding 2002).

Approximately 80% of individuals with achrondroplasia have a mutation of fibroblast growth factor receptor 3 (FGFR3) (Su 2004, Li 2004, Brown 2003, Pehlivan 2003). This condition can be detected by genetic testing (amniocentisis or chorionic villi sampling), increased nuchal translucency on ultrasound, or using size-fractioned DNA in maternal plasma (Tonni 2005, Li 2004, Li 2002).

DEMOGRAPHIC AND REPRODUCTIVE FACTORS

Affected parents have a 50% chance of having offspring affected with this disorder, and a 25% chance of having a child that is homozygous for this disorder (Gooding 2002) but unaffected otherwise. They also have a 25% chance of having an unaffected child. The recurrence risk for this defect is dependent on whether or not the parents are affected. The recurrence risk for unaffected couples is low (Gooding 2002). One study indicated that the recurrence risk for unaffected couples that have one child with achondroplasia is 0.02% (Mettler 2000).

Advanced paternal age has been linked to this disorder in several studies (Wyrobek 2006, Kuhnert 2004, Glaser 2004, Rolf 2001,Orioli 1995). Achondroplasia has not been linked to advanced maternal age.

Paternal grandparents of children with achondroplasia tend to have higher risk for various types of cancer than do maternal grandparents, leading to a hypothesis of the existence of a "mutator" gene acting in male meiosis and in somatic, mitotic cells in both sexes which may favor also the occurrence of cancer (Stoll 2004).

It has also been suggested that achondroplasia occurs concurrently with polyhydramnios (an excess of amniotic fluid). Polyhydramnios in conjunction with achondroplasia can exacerbate the limb-shortening effect of this disorder (Latini 2002).

Achondroplasia is found in both males and females of all races/ethnicities. Prenatal diagnosis of this disorder by sonogram is not always successful (Parilla 2003).

FACTORS IN LIFESTYLE OR ENVIRONMENT

As achondroplasia is primarily a genetic disorder, there are no known teratogens for this disorder. Listed below are some common exposures that have been studied for increased risk of achondroplasia, but for which no association has been found:

  • Maternal obesity (Cedergreen 2004)
  • Maternal diabetes (Becerra 1990).
  • Living in proximity to landfills or solid waste incinerators (Harrison 2003, Cordier 2004)
  • Exposure to nitrate or chlorination byproducts in drinking water (Cedergren 2002) Marijuana and methamphetamines (Fried 2002, Jeng 2005)
  • Chemotherapy (Cardonick 2004),
  • Fluoxetine (Prozac™) (Chambers 1996)
  • Anticonvulsant drugs (Holmes 2001).
  • Antihistamine drugs (Kallen 2002).
  • Corticosteroids and calcium channel blockers (Park-Wyllie 2000, Sorensen 2001).
  • Thalidomide (Stromland 2002).

PREVALENCE

In Texas, the rate for achondroplasia is 0.32 per 10,000 live births.

REFERENCES

  • Becerra JE, Khoury MJ, Cordero JF, Erickson JD. Diabetes mellitus during pregnancy and the risks for specific birth defects: a population case-control study. Pediatrics 1990; 85:1:1-9.
  • Berkowitz GS, Obel J, Deych E, Lapinski R, Godbold J, Liu Z, Landrigan PJ, Wolff MS. Exposure to indoor pesticides during pregnancy in a multiethnic, urban cohort. Environmental Health Perspectives 2003;111:1:79-84.
  • Cardonick E, Iacobucci A. Use of chemotherapy during human pregnancy. Lancet Oncology 2004;5:283-291.
  • Cedergren MI. Maternal morbid obesity and the risk of adverse pregnancy outcome. Obstetrics and Gynecology 2004;103:2;219-224.
  • Cedergren MI, Selbing AJ, Lofman O, Kallen BAJ. Chlorination byproducts and nitrate in drinking water and risk for congenital cardiac defects. Environmental Research Section A 2002;89:124-130.
  • Chambers CD, Johnson KA, Dick LM, Felix RJ, Jones KL. Birth outcomes in pregnant women taking fluoxetine. New England Journal of Medicine 1996;335:14:1010-1015.
  • Cordier S, Chevrier C, Robert-Gnansia E, Lorente C, Brula P, Hours M. Risk of congenital anomalies in the vicinity of municipal solid waste incinerators. Occup Environ Med 2004;61:8-15.
  • Fried PA. The consequences of marijuana use during pregnancy: a review of the human literature, in Women and Cannabis: Medicine, Science, and Sociology, Haworth Integrative Healing Press, 2002.
  • Glaser RL, Jabs EW. Dear old dad: paternal age and the origin of spontaneous mutations in humans. Science of Aging, Knowledge Environment 2004:1-11.
  • Gooding HC, Boehm K, Thompson RE, Hadley D, Francomano CA, Biesecker BB. Issues surrounding prenatal genetic testing for achondroplasia. Prenatal Diagnosis 2002: 22:93-940.
  • Harrison RM. Hazardous waste landfill sites and congenital anomalies. Occup Environ Med 2003;2003:60:79-80.
  • Holmes LB, Harvey EA, Coull BA, Huntington KB, Khoshbin S, Hayes AM, Ryan LM. The teratogenicity of anticonvulsant drugs. The New England Journal of Medicine 2001:344:1132-1138.
  • Jeng W, Wong AM, Ting-A-Kee R, Wells PG. Methamphetamine-enhanced embryonic oxidative DNA damage and neurodevelopmental deficits. Free Radical Biology and Medicine 2005;29:317-326.
  • Kallen B. Use of antihistamine drugs in early pregnancy and delivery outcome. Journal of Maternal-Fetal and Neonatal Medicine 2002:11:146-152.
  • Kuhnert B, Nieschlag E. Reproductive functions of the ageing male. Hum Reprod Update. 2004 Jul-Aug;10(4):327-39. Epub 2004 Jun 10.
  • Latini G, De Felice C, Parrini S, Verrotti A, Di Maggio G, Petraglia F. Polyhydramnios: a predictor of sever growth impairment in achondroplasia. J Pediatr 2002;141:274-276.
  • Li Y, Holzgreve W, Page-Christiaens GCML, Gille JJP, Hahn S. Improved prenatal detection of a fetal point mutation for achondroplasia by the use of size-fractioned circulatory DNA in maternal plasma—case report. Prenatal Diagnosis 2004; 24:896-898.
  • Jones KL. Smith’s recognizable patterns of human malformation, fifth edition. W.B. Saunders Company, Harcourt Brace & Company, Philadelphia, 1997.
  • Mettler G, Fraser FC. Recurrance risk for sibs of children with “sporadic” achondroplasia. American Journal of Medical Genetics 2000;90:250-251.
  • Moutou C, Rongieres C, Battahar-Lebugle K, Gardes N, Phillippe C, Viville S. Preimplantation genetic diagnosis for achondroplasia: genetic and gynaecolocial limits and difficulties. Human Reproduction, 2003;18:3:509-514.
  • Park-Wyllie L, Mazzotta P, Pastuszak A, Moretti ME, Beique L, Hunnisett L, Friesen MH, Jacobson S, Kasapinovic S, Chang D, Diav-Citrin O, Chitayat D, Nulman I, Einarson TR. Birthdefects after maternal exposure to corticosteroids: prospective cohort study and meta-analysis of epidemiological studies. Teratology 2000;62:385-392.
  • Parilla BV, Leeth EA, Kambich MP, Chilis P, MacGregor SN. Antenatal detection of skeletal dysplasias. J Ultrasound Med 2003 22:255-258.
  • Pehlivan S, Ozkinay F, Okutman O, Cogulu O, Ozcan A, Cankaya T, Ulgenalp A. Achondroplasia in Turkey is defined by recurrent G380R mutation of the FGFR3 gene. Turkish Journal of Pediatrics 2003:45:99-101.
  • Rolf C, Nieschlag E. Reproductive functions, fertility and genetic risks of ageing men. Exp Clin Endocrinol Diabetes. 2001;109(2):68-74.
  • Sorensen HT, Czeizel AE, Rockenbauer M, Steffensen FH, Olsen J. The risk of limb deficiencies and other congenital abnormalities in children exposed in utero to calcium channel blockers. Acta Abstet Gynecol Scand 2001;80:397-401.
  • Stoll C, Feingold J. Do parents and grandparents of patients with achondroplasia have a higher cancer risk? Am J Med Genet A. 2004 Oct 1;130(2):165-8.
  • Stromland K, Philipson E, Gronlund MA. Offspring of male and female parents with thalidomide embryopathy: birth defects and functional anomalies. Teratology 2002;66:115-121.
  • Su YN, Lee CN, Chien CH, Hung CH, Chien YH, Chen CA. Rapid deterioration of FGFR3 mutation in achondroplasia by DHPLC system-coupling heteroduplex and fluorescence-enhanced primer-extension analysis. J Hum Genet 2004;49:399-403.
  • Tonni G, Ventura A, De Felice C. First trimester increased nuchal translucency associated with fetal achondroplasia. American Journal of Perinatology 2005;2:3:145-148.
  • Wennborg H, Magnusson LL, Bonde JP, Olsen J. Congenital malformations related to maternal exposure to specific agents in biomedical research laboratories. J Occup Environ Med. 2005;47:11-19.
  • Wyrobek AJ, Eskenazi B, Young S, Arnheim N, Tiemann-Boege I, Jabs EW, Glaser RL, Pearson FS, Evenson D. Advancing age has differential effects on DNA damage, chromatin integrity, gene mutations, and aneuploidies in sperm Proc Natl Acad Sci U S A. 2006 Jun 20;103(25):9601-6.

Please Note: The primary purpose of this report is to provide background necessary for conducting cluster investigations. It summarizes literature about risk factors associated with this defect. The strengths and limitations of each reference were not critically examined prior to inclusion in this report. Consumers and professionals using this information are advised to consult the references given for more in-depth information. 

This report is for information purposes only and is not intended to diagnose, cure, mitigate, treat, or prevent disease or other conditions and is not intended to provide a determination or assessment of the state of health. Individuals affected by this condition should consult their physician and when appropriate, seek genetic counseling.

For more information:

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512-776-7232 Fax 512-7768-7330

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Last updated February 10, 2012