ORPHA: 2021; DO: 0080672;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1p21.1 | Fibrochondrogenesis 1 | 228520 | Autosomal recessive | 3 | COL11A1 | 120280 |
A number sign (#) is used with this entry because of evidence that fibrochondrogenesis-1 (FBCG1) can be caused by compound heterozygous mutation in the COL11A1 gene (120280) on chromosome 1p21.
Fibrochondrogenesis is a severe, autosomal recessive, short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (summary by Tompson et al., 2010).
Genetic Heterogeneity of Fibrochondrogenesis
Fibrochondrogenesis-2 (FBCG2; 614524) is caused by mutation in the COL11A2 gene (120290) on chromosome 6p21.3.
Fibrochondrogenesis is a rare, often neonatally lethal, rhizomelic chondrodysplasia distinguished from other forms of lethal dwarfism by broad long-bone metaphyses, pear-shaped vertebral bodies, and characteristic microscopic changes of cartilage: unique interwoven fibrous septa and fibroblastic dysplasia of chondrocytes. Lazzaroni-Fossati et al. (1978) first described this disorder in an infant from an uncle-niece marriage; a previously born sib apparently was identically affected. Whitley et al. (1984) described 2 unrelated cases in full detail. Eteson et al. (1982, 1984) also detailed 2 unrelated cases, 1 Japanese and 1 Italian.
Hunt and Vujanic (1998) presented a case of fibrochondrogenesis diagnosed in a fetus of 17 weeks, the youngest patient reported to that time. The fetus showed severe micrognathia and bifid tongue, 2 manifestations not previously described.
Tompson et al. (2010) reported 3 patients, 2 of whom were sibs, with fibrochondrogenesis. The proband from one family was the first child of parents of European descent and was stillborn at 32 weeks of gestation. The proband from the second family was the second affected child born to a father of European descent and an African American mother. The pregnancy for the first affected child was terminated at 24 weeks' gestation, whereas the second affected child was born at term. Although the radiographs supported a diagnosis of fibrochondrogenesis in both affected offspring, the clinical phenotype of the second child was milder than previously reported for fibrochondrogenesis and he was 3 years of age at the time of report. He had a flat midface, prominent eyes, short stature, and short limbs, and his hands exhibited brachyclinodactyly with some soft tissue syndactyly in the web spaces. His trunk was short and narrow, he had a pectus carinatum, and he was able to breathe without assistance. He had high myopia, a left cataract, and mild to moderate hearing loss. The parents in both families had myopia or hearing loss or both.
Prenatal Diagnosis
Bankier et al. (1991) described a pair of affected twins diagnosed at 24 weeks' gestation. Details of the histologic and ultrastructural features of cartilage and bone were presented.
Leeners et al. (2004) described the prenatal detection of fibrochondrogenesis in male and female sibs resulting from a Turkish first-cousin union. The diagnosis was confirmed in both fetuses by histopathologic and radiologic findings.
Fibrochondrogenesis is an autosomal recessive disorder (Leeners et al., 2004; Tompson et al., 2010).
Among the 1,158,067 live births registered by the Spanish Collaborative Study of Congenital Malformations (ECEMC), Martinez-Frias et al. (1996) encountered a case of fibrochondrogenesis. This was supposedly the eighth reported case. The frequency in this series should be considered a minimal prevalence for live births.
Tompson et al. (2010) sequenced the COL11A1 gene (120280) in 2 unrelated patients with fibrochondrogenesis and demonstrated that each was a compound heterozygote for a loss-of-function mutation on one allele and a mutation predicting substitution for a conserved triple-helical glycine residue on the other (120280.0008-120280.0011). The parents who were carriers of a missense mutation had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele. Tompson et al. (2010) suggested that COL11A1 is a locus for mild, dominantly inherited hearing loss and that there might be phenotypic manifestations among carriers.
Bankier, A., Fortune, D., Duke, J., Sillence, D. O. Fibrochondrogenesis in male twins at 24 weeks gestation. Am. J. Med. Genet. 38: 95-98, 1991. [PubMed: 2012139] [Full Text: https://doi.org/10.1002/ajmg.1320380121]
Eteson, D. J., Adomian, G. E., Koide, T., Sugiura, Y., Calabro, A., Lungarati, S., Lachman, R. S., Rimoin, D. L. Fibrochondrogenesis: a rare short-limbed skeletal dysplasia. (Abstract) Clin. Res. 30: 133A only, 1982.
Eteson, D. J., Adomian, G. E., Ornoy, A., Koide, T., Sugiura, Y., Calabro, A., Lungarotti, S., Mastroiacovo, P., Lachman, R. S., Rimoin, D. L. Fibrochondrogenesis: radiologic and histologic studies. Am. J. Med. Genet. 19: 277-290, 1984. [PubMed: 6507479] [Full Text: https://doi.org/10.1002/ajmg.1320190210]
Hunt, N. C. A., Vujanic, G. M. Fibrochondrogenesis in a 17-week fetus: a case expanding the phenotype. Am. J. Med. Genet. 75: 326-329, 1998. [PubMed: 9475607] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19980123)75:3<326::aid-ajmg20>3.0.co;2-q]
Langer, L. O., Whitley, C. B., Gilbert, E. F., Horton, W. A., Gorlin, R. J., Opitz, J. M. Fibrochondrogenesis. (Abstract) Proc. Greenwood Genet. Center 3: 95 only, 1984.
Lazzaroni-Fossati, F., Stanescu, V., Stanescu, R., Serra, G., Magliano, P., Maroteaux, P. La fibrochondrogenese. Arch. Franc. Pediat. 35: 1096-1104, 1978. [PubMed: 749746]
Leeners, B., Funk, A., Cotarelo, C. L., Sauer, I. Two sibs with fibrochondrogenesis. Am. J. Med. Genet. 127A: 318-320, 2004. [PubMed: 15150788] [Full Text: https://doi.org/10.1002/ajmg.a.20620]
Martinez-Frias, M. L., Garcia, A., Cuevas, J., Rodriguez, J. I., Urioste, M. A new case of fibrochondrogenesis from Spain. J. Med. Genet. 33: 429-431, 1996. [PubMed: 8733059] [Full Text: https://doi.org/10.1136/jmg.33.5.429]
Tompson, S. W., Bacino, C. A., Safina, N. P., Bober, M. B., Proud, V. K., Funari, T., Wangler, M. F., Nevarez, L., Ala-Kokko, L., Wilcox, W. R., Eyre, D. R., Krakow, D., Cohn, D. H. Fibrochondrogenesis results from mutations in the COL11A1 type XI collagen gene. Am. J. Hum. Genet. 87: 708-712, 2010. [PubMed: 21035103] [Full Text: https://doi.org/10.1016/j.ajhg.2010.10.009]
Whitley, C. B., Langer, L. O., Jr., Ophoven, J., Gilbert, E. F., Gonzalez, C. H., Mammel, M., Coleman, M., Rosemberg, S., Rodriques, C. J., Sibley, R., Horton, W. A., Opitz, J. M., Gorlin, R. J. Fibrochondrogenesis: lethal, autosomal recessive chondrodysplasia with distinctive cartilage histopathology. Am. J. Med. Genet. 19: 265-275, 1984. [PubMed: 6507478] [Full Text: https://doi.org/10.1002/ajmg.1320190209]