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NORD is very grateful to John M. Opitz, MD, Dsci, Professor of Pediatrics (Medical Genetics), Human Genetics, Pathology and Obstetrics and Gynecology, University of Utah School of Medicine, for assistance in the preparation of this report.
Achondrogenesis is a group of rare disorders characterized by extreme short-limb dwarfism, abnormal development of ribs and other skeletal abnormalities. The health problems associated with these conditions are life-threatening and most affected infants die before birth, are stillborn or die shortly after birth of respiratory failure. Achondrogenesis type IA and type IB, are autosomal recessive genetic conditions. Achondrogenesis type II is an autosomal dominant genetic condition.
Achondrogenesis is characterized by premature birth, abnormal accumulation of fluid in the body (hydrops fetalis), a head this is normal in shape but may be unusually soft, and a short neck and trunk. In addition, affected individuals have extremely short limbs and ribs, vertebrae and other bones of the skeleton are not properly developed. In infants born with this disorder the abdomen is prominent. Other abnormalities are incomplete closure of the roof of the mouth (cleft palate), corneal clouding, ear deformities and underdeveloped testicles and rectum. The disorder is often life-threatening either before birth or shortly after birth.
Achondrogenesis type IA (Houston-Harris type) is characterized by short trunk and limbs, short ribs prone to fractures, and soft skull bones. Bone formation is abnormal in the spine and pelvis.
Achondrogenesis type IB (Fraccaro type) is characterized by short trunk and limbs, narrow chest, and prominent abdomen. Affected infants may have a protrusion around the belly-button (umbilical hernia), or near the groin (inguinal hernia), and have short fingers and toes with feet turned inward.
Achondrogenesis type II (Langer-Saldino type) is characterized by a narrow chest, abnormally small or short bones in the arms and/or legs (micromelia), thin ribs, underdeveloped lungs, prominent forehead, small chin and cleft palate. Bone formation is abnormal in the spine and pelvis. Abnormal accumulation of fluid may occur (hydrops fetalis) and the abdomen may be enlarged.
Achondrogenesis type IA and type IB, are autosomal recessive genetic conditions. Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, the person is a carrier for the disease but usually will not show symptoms. The risk for two carrier parents to have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
All individuals carry several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than non-consanguineous parents to carry the same abnormal gene, which increases the risk to have children with a rare recessive genetic disorder.
Achondrogenesis type 1A is caused by mutations in the TRIP11 gene. Achondrogenesis type 1B is caused by mutations in the SLC26A2 gene. These two genes are required for the efficient cellular transport of certain cartilage proteins needed to build skeleton and other tissues.
Achondrogenesis type II follows autosomal dominant genetic condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. Most cases of achondrogenesis type 2 are caused by a new mutation in the COL2A1 gene. Sibs have been reported to be affected and this is most likely due to the presence of more than one cell line in the egg or sperm from a parent (germline mosaicism).
The prevalence of achondrogenesis type IA and type IB is unknown. Achondrogenesis type II occurs in approximately 1/40,000-1/60,000 newborns.
Kniest dysplasia is one of several forms of dwarfism that is caused by a change (mutation) in the COL2A1 gene. This gene is involved in the production of a particular protein that forms type 2 collagen, which is essential for the normal development of bones and other connective tissue. Changes in the composition of type 2 collagen lead to abnormal skeletal growth and, thus, to a variety of dwarfing conditions known as skeletal dysplasias. Some of the signs and symptoms of Kniest dysplasia, such as short stature, enlarged knees, and cleft palate, are usually present at birth. Other characteristics may not appear for two or three years. (For more information on this disorder, choose "Kniest" as your search term in the Rare Disease Database.)
Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is characterized by bowing and angular shape of the long bones of the legs, especially the tibiae; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females. (For more information on this disorder, choose "campomelic" as your search term in the Rare Disease Database.)
Hypophosphatasia is an inborn metabolic disorder of the bones characterized by skeletal defects resembling those of rickets. The symptoms result from a failure of bone mineral to be deposited in young, uncalcified bone (osteoid), and in the cartilage at the end of the long bones (epiphyses) during early years. The activity of the enzyme alkaline phosphatase in blood serum and bone cells is lower than normal. Urinary excretion and blood plasma concentrations of phosphoethanolamine and inorganic pyrophosphate are abnormally high. Unlike other forms of rickets, Hypophosphatasia does not respond to treatment with vitamin D. (For more information on this disorder, choose "hypophosphatasia" as your search term in the Rare Disease Database.)
Thanatophoric dysplasia is another form of dwarfism. It is characterized by an enlarged head, short bones in the arms and legs, small, short ribs and flattened vertebrae. There is an abnormally large amount of amniotic fluid and very little fetal movement before birth.
Short-rib-polydactyly syndrome is a form of short-limb dwarfism. The infant has cleft lip and palate, deformed ears, and a narrow chest with short ribs. The kidneys are often deformed as are the sex organs. There may be brain malformations and an absence of a gallbladder. This disorder is often life-threatening as a result of insufficient lung development.
Achondrogenesis is diagnosed by physical features, X-ray findings and examination of tissue samples under a microscope (histology). Biochemical tests and molecular genetic tests can be used to confirm the diagnosis.
Prenatal diagnosis of achondrogenesis by ultrasound is possible after 14-15 weeks gestation. Prenatal diagnosis by chorionic villus sampling (10-12 weeks gestation) or amniocentesis (15-18 weeks gestation) is possible if the specific gene mutations have been identified in a family member.
Treatment of achondrogenesis is symptomatic and supportive. Genetic counseling is recommended for families with an affected child.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
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For information about clinical trials sponsored by private sources, contact:
Contacts for additional information about achondrogenesis:
John M. Opitz, MD, DSci
Professor of Pediatrics (Medical Genetics), Human Genetics
Pathology and Obstetrics and Gynecology
University of Utah School of Medicine
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Aigner T, Niederhagen M, Zaucke F, et al. Achondrogenesis type IA (Houston-Harris): a still-unresolved molecular phenotype. Pediatr Dev Pathol. 2007;10(4):328-34.
Kapur RP. Achondrogenesis. Pediatr Dev Pathol. 2007;10(4);253-5.
Superti-Furga A and Unger S. Nosology and classification of genetic skeletal disorders: 2006 revision. Am J Med Genet A. 2006;143A: 1-
Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat 2001:18(1):82
Superti-Furga A, Bonafe L, and Rimoin DL. Molecular-pathogenetic classification of genetic disorders of the skeleton. Am J Med Genet. 2001;106:282-93.
Korkko J, Cohn DH, Ala-Kokko L, et al. Widely distributed mutations in the COL2A1 gene produce achondrogenesis type II/hypochondrogenesis. Am J Med Genet. 2000;92(2):95-100.
Superti-Furga A, Hastbacka J, Wilcox WR, et al. Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene. Nat Genet. 1996;12:100-2.
FROM THE INTERNET
Bonafe L, Ballhausen D, and Superti-Furga A. (Updated 9/22/09). Achondrogenesis Type 1b. In: GeneReviews at Gentests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Acessed 8/10.
McKusick VA, ed. Online Mendelian Inheritance in Man (OMIM); http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=200600, Last Update:1/25/10, Accessed 8/10; http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=600972, Last Update:1/25/10, Accessed 8/10; http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=200610, Last Update:5/20/10, Accessed 8/10.
Report last updated: 2010/08/31 00:00:00 GMT+0