Achondrogenesis was first described in 1936 by Parenti (1936). Lethal cases of osteogenesis imperfecta have been known since Vrolik’s (1849) description. Achondroplasia (formerly chondrodystrophy) was the only other diagnosis for all other dwarfed newborns until thanatophoric dysplasia was recognized as a separate entity (Maroteaux et al., 1967).

The lethal osteochondrodysplasias.

Fibrochondrogenesis is a severe, autosomal-recessive, short-limbed skeletal dysplasia. In a single case of fibrochondrogenesis, whole-genome SNP genotyping identified unknown ancestral consanguinity by detecting three autozygous regions. Because of the predominantly skeletal nature of the phenotype, the 389 genes localized to the autozygous intervals were prioritized for mutation analysis by correlation of their expression with known cartilage-selective genes via the UCLA Gene Expression Tool, UGET. The gene encoding the α1 chain of type XI collagen (COL11A1) was the only cartilage-selective gene among the three candidate intervals. Sequence analysis of COL11A1 in two genetically independent fibrochondrogenesis cases 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. The parents who were carriers of missense mutations had myopia. Early-onset hearing loss was noted in both parents who carried a loss-of-function allele, suggesting COL11A1 as a locus for mild, dominantly inherited hearing loss. These findings identify COL11A1 as a locus for fibrochondrogenesis and indicate that there might be phenotypic manifestations among carriers.

https://www.cell.com/ajhg/pdf/S0002-9297(10)00525-2.pdf

Fibrochondrogenesis Results from Mutations in the COL11A1 Type XI Collagen Gene

The skeletal dysplasias.

Chondroosseous tissue from six infants with infantile hypophosphatasia and six control infants were studied by light, transmission, and scanning electron microscopy. Alkaline phosphatase histochemical reaction of the growth plate was studied in two infants and was greatly reduced when compared to two control infants. Hypertrophic chondrocytes were increased in number with persisting cartilage islets in the metaphysis. In five of the six cases studied, chondrocytes and intercartilagenous intercellular chondroid matrix appeared ultrastructurally normal. Matrix vesicle distribution was similar to that of control subjects, but they were associated with few mineral crystals. In two infants, the matrix vesicles were alkaline phosphatase nonreactive. In the calcifying zone of the growth plate and in the newly formed metaphyseal trabecular bone, cartilagenous calcospherites often were small and the orientation of crystals was nonradial when compared to that of control infants. The mineralization of diaphyseal bone appeared normal. It seems that matrix vesicles are present in hypophosphatasia and that the impaired mineralization of cartilage is due primarily to the deficiency of alkaline phosphatase. In spite of the lack of alkaline phosphatase, secondary mineralization of bone which is not mediated by matrix vesicles was normal.

Histologic and ultrastructural studies on the mineralization process in hypophosphatasia.

Akawi NA, Al-Gazali L, Ali BR. Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations.



Fibrochondrogenesis is documented to be a neonatally lethal rare recessively inherited disorder characterized by short-limbed skeletal dysplasia. Here we report two patients from two unrelated consanguineous Emirati families who have unexpectedly survived till the ages of 3 and 6 years. These patients show additional symptoms which include developmental delay, profound sensory–neural deafness, severe myopia and progressive severe skeletal abnormalities. Linkage of fibrochondrogenesis in the Emirati families to chromosome 1 has been established using homozygosity mapping confirming recent findings by Tompson et al. in 2010. Screening of the COL11A1 gene revealed two null homozygous mutations [c.4084C>T (p.R1362X) and c.3708+437T>G] in the aforementioned two families. The c.4084C>T mutation is predicted to introduce a stop codon at position Arg1362, whereas the c.3708+437T>G mutation causes the activation of an intronic pseudoexon between exons 48 and 49. This resulted in the insertion of 50 nucleotides into the mRNA. The carriers of these mutations display ocular defects with normal hearing. In conclusion, our data shall improve the overall understanding of fibrochondrogenesis especially in surviving homozygous patients and, at least partly, explain the phenotypic variability associated with COL11A1 gene mutations.

Clinical and molecular analysis of UAE fibrochondrogenesis patients expands the phenotype and reveals two COL11A1 homozygous null mutations.

Fibrochondrogenesis is a distinct, neonatally lethal, short-limb skeletal dysplasia which was first described in a single patient in 1978. We report the radiographic and morphologic studies of 2 additional unrelated stillborn infants with fibrochondrogenesis. This syndrome has distinct radiographic and chondro-osseous morphologic defects different from those seen in the other known skeletal dysplasias. The long bones are short and dumbbell-shaped with metaphyseal flare. The spine is platyspondylic with superior-inferior clefting defects, and the ribs are short and distally cupped. The growth-plate cartilage is grossly disorganized and has a densely fibrous collagenous matrix when examined by light and electron microscopy. Light, transmission, and scanning electron microscopy shows diaphyseal and metaphyseal trabecular bone to be normal.

Serena Lungarotti

Papers

Fibrochondrogenesis: radiologic and histologic studies.