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Achondrogenesis Achondrogenesis Authors: Doctors Laurence Faivre1 and Valérie Cormier-Daire Creation Date: July 2001 Update: May 2003 Scientific Editor: Doctor Valérie Cormier-Daire 1Consultation de génétique, CHU Hôpital d'Enfants, 10 Boulevard Maréchal de Lattre de Tassigny BP 7908, 21079 Dijon Cedex, France. [email protected] Abstract Keywords Disease name and synonyms Prevalence Diagnosis criteria / Definition Clinical description Differential diagnosis Diagnostic methods Etiology Genetic counseling Antenatal diagnosis Management including treatment Unresolved questions References Abstract Achondrogenesis is a lethal disorder characterized by deficient endochondral ossification, abdomen with disproportionately large cranium, and anasarca. Radiological features are characteristic, with virtual absence of ossification of the vertebral column, sacrum and pelvic bones. There are 2 types of achondrogenesis, and differentiation between those types is possible through clinical and radiological andhistological studies. Type I achondrogenesis is of autosomal recessive inheritance with the subtype IB caused by mutations in the diastrophic dysplasia sulfate transporter DTDST gene, and type II achondrogenesis caused by de novo dominant mutations in the collagen type II-1 COL2A1 gene. Keywords endochondral ossification deficiency, lethol disorder, anasarca, absence of ossification in vertebral column, DTDST gene, COL2A1 gene Disease name and synonyms Diagnosis criteria / Definition According to the current classification, there are Association of: 2 types of achondrogenesis: • short-limbed dwarfism with short trunk, prominent abdomen with anasarca, and Achondrogenesis type I: disproportionately large cranium; IA: achondrogenesis Houston-Harris type • virtual absence of ossification of the IB: achondrogenesis Fraccaro type vertebral column, sacrum and pelvic bones at radiological examination; Achondrogenesis type II: • lethal condition with death in utero or during achondrogenesis Langer-Saldino type the early neonatal period chondrogenesis imperfecta • new dominant mutations within the collagen Prevalence type 2 alpha1 gene COL2A1 in type II It remains unknown. achondrogenesis, and autosomal recessive inheritance in type I achondrogenesis with Faivre, L; Cormier-Daire, V.; Achondrogenesis. Orphanet encyclopedia, May 2003. http://www.orpha.net.fr/data/patho/GB/uk-achondro.pdf 1 mutations in the diastrophi dysplasia sulfate In thanatophoric dysplasia, the limbs are longer, transporte gene DTDST in type IB and the shape of the thorax is narrow but achondrogenesis elongated. The short rib-polydactyly syndromes resembles thanatophoric dysplasia and are Clinical description usually associated with hexadactyly. Achondrogenesis is characterized by: • short-limbed dwarfism with short trunk, Diagnostic methods narrow thorax, prominent abdomen, and Diagnosis depends upon the clinical and the disproportionately large cranium; pathognomonic radiographic findings. • limbs sometimes resemble flippers, and an Histological findings can be helpful, with the articular crease at the hip or shoulder can be study of sulfate incorporation into cultured present; fibroblasts or chondrocytes for type IB. Molecular • anasarca or fat appearance is given by the studies of COL2A1 or DTDST can be performed abundance of soft tissue relative to the short depending on the subtype of achondrogenesis. skeleton; X-ray findings include: • characteristic craniofacial features include • the tubular bones are the most markedly prominent forehead, flat face, short nose affected, and are much shorter in type I than with anteverted nostrils, long philtrum, type II. Femors and humeri are usually micrognathia, short neck; shortened to a degree where no major axis • inconsistent clinical features include heart can be recognized. As some metaphyseal defects, umbilical or inguinal hernias, spurring occurs, these bones end up polydactyly in type II achondrogenesis. resembling thorn apples. The tibias and fibulas are similarly misshapen, and the Differential diagnosis fibulas are not ossified in subjects with very The main problem in establishing the diagnosis early manifestations. In most cases, the ulna is to differentiate the type of achondrogenesis. is amorphous. The carpals and phalanges Different features are helpful to accurately are usually very poorly ossified and can diagnose the type: rarely be identified; • the mode of inheritance; • the iliac bones are smaller than usual and • clinical features: the distinction between the only their upper half is ossified in type I, different types of achondrogenesis is difficult often in an irregular fashion. The ischium is on clinical grounds. Hands are almost not ossified or only minimally; normal in type II, whereas in types IA and IB, • disproportion between the skull of almost they are obviously shortened. Other minor normal size and the hypoplastic skeleton is criteria can be mentioned: compared to type noticeable. The skull can be slightly less I, type II achondrogenesis is characterized ossified than expected for gestational age. by fewer stillbirths, longer survival, longer • the vertebral bodies are usually not ossified, gestational period, larger size of baby, longer at most, rudimentary calcification is seen in limbs; the central part. The vertebral lateral • X-ray features: ribs tend to be thin in type IA pedicles are generally ossified. Ribs are achondrogenesis, with multiple fractures; short. • histological features: round, vacuolated chondrocytes with inclusion bodies in type IA Etiology achondrogenesis, collagenous rings around • Type II achondrogenesis is caused by a the chondrocytes in type IB dominant mutation in the COL2A1 gene. achondrogenesis, with the characteristic Collagen II is also called cartilage collagen. image of sulfate incorporation into cultured Various types of chondrodysplasia are fibroblasts or chondrocytes. In type II allelic, including spondyloepiphyseal achondrogenesis, cartilage in all sites has an dysplasia congenital type, Strudwick type abnormal gelatinous texture and translucent and Namaqualand type; osteoarthritis with appearance, with no detection of collagen mild chondrodysplasia; spondyloepiphyseal type II. dysplasia with precocious osteoarthritis; • Molecular studies Stickler syndrome; Kniest dysplasia; The differential diagnosis includes other types of Wagner's syndrome, and lethal osteochondrodysplasia, mainly lethal hypochondrogenesis. osteogenesis imperfecta, thanatophoric • Type IB achondrogenesis is caused by dysplasia and the short ribpolydactyly recessive mutations in the DTDST gene, syndromes. In osteogenesis imperfecta, the skull which encodes the diastrophic dysplasia is soft, the sclerae blue and the bones bowed sulfate transporter. but clearly not as short as in achondrogenesis. Faivre, L; Cormier-Daire, V.; Achondrogenesis. Orphanet encyclopedia, May 2003. http://www.orpha.net.fr/data/patho/GB/uk-achondro.pdf 2 Genetic counseling Unresolved questions Since type II achondrogenesis is caused by de The gene responsible for type IA novo dominant mutation, the risk of having achondrogenesis has not been identified yet. another affected child is low for a couple who had a first affected child because of the low risk References of gonadal mosaicism. Because type I Borochowitz Z, Lachman R, Adomian GE, et al. achondrogenesis is an autosomal recessive Achondrogenesis type I: delineation of further disorder, the risk of having another affected child heterogeneity and identification of two distinct is 25% for a couple who had a first child with this subgroups. J Pediatr 1988; 112: 23-31. condition. Genetic counseling must rely on Borochowitz Z, Ornoy A, Lachman R, et al. differentiation between type I and type II Achondrogenesis II-hypochondrogenesis: achondrogenesis. variability versus heterogeneity. Am J Med Genet 1986; 24: 273-288. Antenatal diagnosis Chen H, Lui CT, Yang SS. Achondrogenesis: a A recurrence of the disease can be suspected by review with special consideration of the observation of short femora as early as achondrogenesis type II (Langer-Saldino). Am J gestational week 13 to 14 by experienced Med Genet 1981; 10: 379-384. sonographers if a first child was born with Godfrey M, Keene DR, Blank E, et al. Type II Achondrogenesis. Other ultrasound signs may achondrogenesis: morphologic and be nuchal oedema, reduced rump length, poor immunohistopathologic studies. Am J Hum ossification of the vertebral bodies and of the Genet 1988; 43: 894-903. limb bones, and polyhydramnios. Chorionic villi Mortier GR, Wilkin DJ, Wilcox WR, et al. A sampling can be proposed in early pregnancies radiographic, morphologic, biochemical and if a mutation in DTDST have been found. molecular analysis of a case of achondrogenesis Molecular prenatal diagnosis is not indicated in type II resulting from substitution for a glycine type II achondrogenesis because of the very low residue in a type II collagen trimer. Hum Mol recurrence risk and the early ultrasound prenatal Genet 1995; 4: 285-288. diagnosis. Analysis of sulfate incorporation in Superti-Furga A. Syndrome of the month: chorionic villi might theoretically be used for achondrogenesis type IB. J Med Genet 1996; prenatal diagnosis but experience is lacking. 33:957-61 Superti-Furga A, Hastbacka J, Wilcox WR, et Management including treatment al. Achondrogenesis type IB is caused by No treatment can be proposed for this lethal mutations in the diastrophic dysplasia sulfate disorder. transporter gene. Nat Genet 1996; 12: 100-102. Faivre, L; Cormier-Daire, V.; Achondrogenesis. Orphanet encyclopedia, May 2003. http://www.orpha.net.fr/data/patho/GB/uk-achondro.pdf 3 .
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