Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 254061001; ORPHA: 93296, 93297, 932; DO: 0080056;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 12q13.11 | Achondrogenesis, type II or hypochondrogenesis | 200610 | Autosomal dominant | 3 | COL2A1 | 120140 |
A number sign (#) is used with this entry because of evidence that achondrogenesis type II (ACG2) is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.
For a general phenotypic description and a discussion of genetic heterogeneity of achondrogenesis, see ACG1A (200600).
Achondrogenesis type II (ACG2) is characterized by severe micromelic dwarfism with small chest and prominent abdomen, incomplete ossification of the vertebral bodies, and disorganization of the costochondral junction. ACG2 is an autosomal dominant trait occurring mostly as new mutations. However, somatic and germline mosaicism have been reported (summary by Comstock et al., 2010).
Spranger et al. (1974) distinguished 2 forms of achondrogenesis, which they called types I and II. Type I was subdivided into type IA (200600) and IB (600972). In type I, the ribs tend to be thin, often with multiple fractures. This finding led Harris et al. (1972) to refer to it as pseudoachondrogenesis with fractures. Indeed, it might be confused with the broad-bone form of osteogenesis imperfecta (166210). Type II achondrogenesis is characterized by virtual absence of ossification in the vertebral column, sacrum and pubic bones. Saldino (1971) reported on this form. In both forms the trunk is short with prominent abdomen and hydropic appearance. Micromelia is striking. In both, death occurs in utero or the early neonatal period.
Chen et al. (1981) reported 2 cases and reviewed reported cases in extenso. As compared with type I, the cases of type II, or Langer-Saldino type, showed fewer stillbirths, longer survival, longer gestational period, larger size of baby, longer limbs, and characteristic craniofacial features (prominent forehead, flat face, micrognathia).
Spranger (1985) introduced the concept of 'bone dysplasia families' as exemplified by the similar pattern of radiographically demonstrated skeletal abnormalities, called dysostosis multiplex, produced by a variety of lysosomal storage diseases. The concept postulates that the developing skeleton reacts in a stereotypic fashion to heterogeneous disturbances of a single metabolic pathway. Spranger (1985) defined one such family as consisting of type II achondrogenesis, hypochondrogenesis, and spondyloepiphyseal dysplasia congenita, the 3 disorders constituting a spectrum of decreasing severity. This family of disorders may be etiologically more intimately related than are the various conditions that produce dysostosis multiplex, since there is evidence of abnormality of type II collagen in SED congenita (Murray and Rimoin, 1988).
Hypochondrogenesis (Hendrickx et al., 1983) may bear the same relationship to achondrogenesis that hypochondroplasia does to achondroplasia, i.e., it may be an allelic variant. Stanescu et al. (1977) described 3 cases and introduced the term hypochondrogenesis. Borochowitz et al. (1986) favored the view that hypochondrogenesis and achondrogenesis of the Langer-Saldino type are part of the spectrum of severity of the same disorder. Maroteaux et al. (1991) reiterated the view that hypochondrogenesis is an allelic form of the Langer-Saldino type of achondrogenesis, a conclusion that is probably supported by the finding of abnormalities of type II collagen in these cases.
Superti-Furga (1996) suggested that hypochondrogenesis should be considered separately from achondrogenesis type II because the phenotype can be much milder. As in achondrogenesis type II, all cases represent de novo autosomal dominant mutations in the COL2A1 gene.
In a case of lethal short-limbed dwarfism, Eyre et al. (1986) found that the cartilage in all sites had an abnormal gelatinous texture and translucent appearance. No type II collagen was detected at any site; type I was the predominant collagen present. However, cartilage-specific proteoglycans appeared to be abundant. Eyre et al. (1986) suggested that chondrogenesis imperfecta might be a satisfactory designation.
Horton et al. (1987) studied growth cartilage in 7 cases of what they designated achondrogenesis type II. The normal architecture of the epiphyseal and growth plate cartilage was replaced by morphologically heterogeneous tissue. Some areas were composed of vascular canals surrounded by extensive fibrous tissue and enlarged cells that had the appearance and histochemical characteristics of hypertrophic chondrocytes. Other areas contained a mixture of cells ranging from small to enlarged chondrocytes. Extracellular matrix in the latter area was more abundant than in the former and had characteristics of both precartilage mesenchymal matrix and typical cartilage matrix; it contained types I and II collagen and other constituents. Peptide mapping of cyanogen bromide cartilage collagen peptides revealed the presence of types I and II collagen. These observations might indicate a defect in the biosynthesis of type II collagen or in chondrocyte differentiation.
Godfrey et al. (1988) described the clinical, radiographic, histologic, and ultrastructural abnormalities in a mild case of type II achondrogenesis-hypochondrogenesis fitting the classification criteria of Whitley-Gorlin prototype IV (Whitley and Gorlin, 1983). Immunohistochemical studies using a monoclonal antibody against type II collagen showed intense staining of small, rounded-to-oval structures within chondrocytes, strongly suggesting intracellular accumulation of this collagen type, probably in the distended cisternae of the rough endoplasmic reticulum observed in all chondrocytes by electron-microscopic studies. These observations raised the possibility of an abnormal type II collagen produced by, and accumulating within, chondrocytes. Godfrey and Hollister (1988) presented evidence that the patient they studied was heterozygous for an abnormal pro-alpha-1 (II) chain which impaired the assembly and/or folding of type II collagen.
Feshchenko et al. (1989) described absence of type II collagen and a quantitative and qualitative change in proteoglycans in hyaline cartilage of the ribs and knee joint in a stillborn female with type II achondrogenesis. As they pointed out, studies in both parents would help in connection with the question of whether this represented homozygosity for a mutation located in the COL2A1 gene.
Potocki et al. (1995) reported defects in cardiac septation in 2 infants with hypochondrogenesis. One infant had a complete AV canal defect. The second had a secundum type atrial septal defect. Potocki et al. (1995) raised the question whether type II collagen may function in human cardiogenesis even though it is not detected in myocardium.
Rittler and Orioli (1995) described postaxial polydactyly of the feet in a severely affected newborn with achondrogenesis type II. The possibility that it represented a contiguous gene syndrome due to a deletion on chromosome 12 was raised.
Faivre et al. (2004) reported the recurrence of achondrogenesis type II in 2 successive pregnancies of a healthy, nonconsanguineous young couple. In the second fetus a G316D mutation in the COL2A1 gene (120140.0038) was detected. A heterozygous mutation was not found in either parent. Faivre et al. (2004) concluded that recurrence was due to germline mosaicism in 1 parent.
Forzano et al. (2007) reported another family with recurrence of achondrogenesis type II in 3 fetuses. Genetic analysis provided proof of somatic mosaicism for a COL2A1 mutation in the father (G346V; 120140.0053).
Comstock et al. (2010) reported another family in which 2 fetuses had achondrogenesis type II. Molecular analysis confirmed a heterozygous mutation in the COL2A1 gene in the second affected fetus, but molecular studies could not be completed on the first fetus. Neither parent was affected, although the father reportedly was born with clubfoot. The parents had 6 healthy term gestations and 1 spontaneous first-trimester loss. Overall, the findings suggested germline mosaicism, which increased the recurrence risk from background risk in this family.
In the patient with type II achondrogenesis-hypochondrogenesis reported by Godfrey and Hollister (1988), Vissing et al. (1989) demonstrated heterozygosity for a missense mutation in the COL2A1 gene (120140.0002).
In an infant with a severe form of skeletal dysplasia who required continuous respiratory support until his death at 3 months of age, Bogaert et al. (1992) demonstrated a missense mutation in the COL2A1 gene (120140.0009).
Mortier et al. (1995) described a missense mutation in the COL2A1 gene (120140.0022) resulting in achondrogenesis type II.
Early editions of OMIM had designated type II achondrogenesis as type IB and had incorrectly cataloged it as an autosomal recessive disorder.
Achondrogenesis Types III and IV
On radiologic grounds, Whitley and Gorlin (1983) identified 4 subtypes of achondrogenesis. Their achondrogenesis type I was the Parenti-Fraccaro type, called type I in other classifications; however, they divided the classic type II (Langer-Saldino type) into 3 types called II, III, and IV. They introduced the 'femoral cylinder index,' or CI(femur): length/width. Their types I and II have the same CI(femur), namely 1.0 to 2.8, and both have crenated ilia and stellate long bones, but multiple rib fractures, characteristic of type I, are not found in type II. Type III has unfractured ribs, halberd ilia, mushroom-stem long bones, and a CI(femur) of 2.8 to 4.9. Type IV has unfractured ribs, sculpted ilia, well-developed long bones, and a CI(femur) of 4.9 to 8.0. Whitley and Gorlin (1983) suggested that 'achondrogenesis type IV...should be considered synonymous with hypochondrogenesis until there are sufficient criteria to distinguish the suspected genetic heterogeneity.' In a survey of lethal osteochondrodysplasias in the county of Fyn (Funen), Denmark, Andersen (1989) identified new cases of type III achondrogenesis.
Superti-Furga (1996) stated that the radiologic classification devised by Whitley and Gorlin (1983) did not prove helpful and was abandoned.
On histologic grounds, the bulldog calf appears to be an authentic model of the Langer-Saldino type of achondrogenesis. Abnormalities of type II collagen were demonstrated by Sanford et al. (1989), although no abnormality of the COL2A1 gene or its mRNA transcripts could be demonstrated.
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Bogaert, R., Tiller, G. E., Weis, M. A., Gruber, H. E., Rimoin, D. L., Cohn, D. H., Eyre, D. R. An amino acid substitution (gly853-to-glu) in the collagen alpha-1(II) chain produces hypochondrogenesis. J. Biol. Chem. 267: 22522-22526, 1992. [PubMed: 1429602]
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Comstock, J. M., Putnam, A. R., Sangle, N., Lowichik, A., Rose, N. C., Opitz, J. M. Recurrence of achondrogenesis type 2 in sibs: additional evidence for germline mosaicism. Am. J. Med. Genet. 152A: 1822-1824, 2010. [PubMed: 20583175] [Full Text: https://doi.org/10.1002/ajmg.a.33463]
Eyre, D. R., Upton, M. P., Shapiro, F. D., Wilkinson, R. H., Vawter, G. F. Nonexpression of cartilage type II collagen in a case of Langer-Saldino achondrogenesis. Am. J. Hum. Genet. 39: 52-67, 1986. [PubMed: 3752081]
Faivre, L., Le Merrer, M., Douvier, S., Laurent, N., Thauvin-Robinet, C., Rousseau, T., Vereecke, I., Sagot, P., Delezoide, A.-L., Coucke, P., Mortier, G. Recurrence of achondrogenesis type II within the same family: evidence for germline mosaicism. Am. J. Med. Genet. 126A: 308-312, 2004. [PubMed: 15054848] [Full Text: https://doi.org/10.1002/ajmg.a.20597]
Feshchenko, S. P., Rebrin, I. A., Sokolnik, V. P., Sher, B. M., Sokolov, B. P., Kalinin, V. N., Lazjuk, G. I. The absence of type II collagen and changes in proteoglycan structure of hyaline cartilage in a case of Langer-Saldino achondrogenesis. Hum. Genet. 82: 49-54, 1989. [PubMed: 2714779] [Full Text: https://doi.org/10.1007/BF00288271]
Forzano, F., Lituania, M., Viassolo, V., Superti-Furga, A., Wildhardt, G., Zabel, B., Faravelli, F. A familial case of achondrogenesis type II caused by a dominant COL2A1 mutation and 'patchy' expression in the mosaic father. Am. J. Med. Genet. 143A: 2815-2820, 2007. [PubMed: 17994563] [Full Text: https://doi.org/10.1002/ajmg.a.32047]
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