Addendum

Autopsy records from the Women and Infants' Hospital from January 1974 through January 1994 were reviewed to identify cardiac malformations in the presence of skeletal dysplasia. Of 24 cases of lethal fetal or neonatal osteochondrodysplasias, 4 were given diagnoses in which disorders of type II collagen are regarded as causative. These 4 were categorized in the spondyloepiphyseal dysplasia (SED) spectrum of disorders; specifically two patients with hypochondrogenesis and two with spondyloepiphyseal dysplasia congenita were identified. Defects in cardiac septation were noted in the 2 patients with hypochondrogenesis. No cardiovascular abnormalities were present in the remaining cases, which included thanatophoric dysplasia, osteogenesis imperfecta, and asphyxiating thoracic dystrophy. Although cardiovascular malformations have been described in other types of osteochondrodysplasias, e.g., short rib polydactyly syndrome type II and chondroectodermal (Ellis van Creveld) dysplasia, congenital heart disease has not been described in hypochondrogenesis. Type II collagen, which has been found to be abnormal in some patients with hypochondrogenesis, is considered to have a limited tissue distribution, and has not been detected as yet in human myocardium. The findings presented here suggest that type II collagen may function in human cardiogenesis. © 1995 Wiley-Liss, Inc.     

The clinical features of spondyloepiphyseal dysplasia congenita resulting from the substitution of glycine 997 by serine in the alpha 1(II) chain of type II collagen.

The features of a child with spondyloepiphyseal dysplasia congenita resulting from a mutation in one COL2A1 allele were studied. The child was heterozygous for a G to A transition in exon 48 that resulted in the substitution of glycine 997 by serine in the triple helical domain of alpha 1(II) chains of type II collagen. Her longitudinal growth was close to the mean growth curve for children with this chondrodysplasia. Expression of the mutation by chondrocytes would account for the abnormal growth and development of the bones of the limbs and spine. Early expression of the mutation by epithelial cells and later expression by chondrocytes of the developing craniofacial structures would also account for her complex pattern of craniofacial anomalies. The findings in this study confirm that mutations of exon 48 of the COL2A1 gene, that alter the normal Gly-X-Y triplet structure of the corresponding region of alpha 1(II) chains of type II collagen, produce the spondyloepiphyseal dysplasia congenita phenotype.     

Structural and segregation analysis of the type II collagen gene (COL2A1) in some heritable chondrodysplasias.

Seventy-seven persons with a variety of heritable chondrodysplasias were screened for gross rearrangements of the structural gene encoding the major cartilage collagen, collagen II. None was found. Segregation of the locus (COL2A1) was studied in 19 pedigrees using three restriction site dimorphisms (shown by PvuII, HindIII, and BamHI) and a length polymorphism as linkage markers. Discordant segregation between COL2A1 and the mutant locus was seen in pedigrees with multiple epiphyseal dysplasia, autosomal recessive spondyloepiphyseal dysplasia tarda, hypochondroplasia, pseudoachondroplasia, diaphyseal aclasis, and trichorhinophalangeal syndrome. One pedigree with diastrophic dysplasia was weakly concordant. Autosomal dominant spondyloepiphyseal dysplasia tarda and metaphyseal chondrodysplasia (type Schmid) were not informative. We conclude that mutations of the collagen II gene are not a common feature of the heritable chondrodysplasias. Since the chondrocyte binding protein, chondrocalcin, is also encoded at COL2A1 our conclusions apply equally to this gene.     

Two novel mutations confirm FGD1 is responsible for the Aarskog syndrome

The Aarskog syndrome or facio-genital dysplasia (FGDY, MIM No. 305400) is an X-linked condition characterized by short stature, macrocephaly, facial, genital and skeletal anomalies. It is caused by mutation of the FGD1 gene mapped to the Xp11.21 region. To date, only one point mutation has been reported in an affected family, consisting of the insertion of an additional guanine residue at nucleotide 2122 of exon 7, which causes premature translational termination. We now report the finding of two novel FGD1 mutations, a missense mutation in a family of Italian origin and a deletion of 3 exons in a sporadic case from Germany. These mutations confirm the role of FGD1 as the gene responsible for the Aarskog syndrome.     

Vitreoretinopathy with phalangeal epiphyseal dysplasia,a type II collagenopathy resulting from a novel mutation in the C-propeptide region of the molecule

A large family with dominantly inherited rhegmatogenous retinal detachment, premature arthropathy, and development of phalangeal epiphyseal dysplasia, resulting in brachydactyly was linked to COL2A1, the gene encoding proalpha1(II) collagen. Mutational analysis of the gene by exon sequencing identified a novel mutation in the C-propeptide region of the molecule. The glycine to aspartic acid change occurred in a region that is highly conserved in all fibrillar collagen molecules. The resulting phenotype does not fit easily into pre-existing subgroups of the type II collagenopathies, which includes spondyloepiphyseal dysplasia, and the Kniest, Strudwick, and Stickler dysplasias.     

Somatic mosaicism and the phenotypic expression of COL2A1 mutations

Mutations in COL2A1, the gene for type II-collagen, can result in a wide variety of phenotypes depending upon the nature of the mutation. Dominant negative mutations tend to result in severe and often lethal skeletal dysplasias such as achondrogenesis type 2, Kniest dysplasia, and spondyloepiphyseal dysplasia congenita. Stickler syndrome, a condition characterized by ophthalmological and orofacial features, deafness and arthritis, usually, but not exclusively, results from haploinsufficiency. Overlapping features of all these disorders can also be seen in the same family. Rare reports have demonstrated that phenotypic variability can be explained in some families by somatic mosaicism. Here, we describe five further examples of somatic mosaicism of COL2A1 mutations illustrating the importance of detailed clinical evaluation and molecular testing even in clinically normal parents of affected individuals.     

Spondyloepiphyseal dysplasia in a Cape Town family: linkage with the gene for type II collagen (COL2A1).

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED.     

Spondyloepiphyseal dysplasia in a cape town family: Linkage with the gene for type II collagen (COL2A1)

A moderately severe form of autosomal dominant (AD) spondyloepiphyseal dysplasia (SED) has been documented in 14 individuals in 3 generations of a family in Cape Town, South Africa. Affected persons had a short trunk; radiographic investigations indicated that skeletal involvement was worst in the hips and spine. Linkage studies with restriction fragment length polymorphisms (RFLPs) associated with the COL2A1 gene and the phenotype yielded a maximal LOD score of 4.51 at theta = 0.00. This result suggests that the structural locus for type II collagen is primarily involved in the pathogenesis of this form of SED. © 1992 Wiley-Liss, Inc.     

Report of five novel and one recurrent COL2A1 mutations with analysis of genotype-phenotype correlation in patients with a lethal type II collagen disorder

Achondrogenesis II-hypochondrogenesis and severe spondyloepiphyseal dysplasia congenita (SEDC) are lethal forms of dwarfism caused by dominant mutations in the type II collagen gene (COL2A1). To identify the underlying defect in seven cases with this group of conditions, we used the combined strategy of cartilage protein analysis and COL2A1 mutation analysis. Overmodified type II collagen and the presence of type I collagen was found in the cartilage matrix of all seven cases. Five patients were heterozygous for a nucleotide change that predicted a glycine substitution in the triple helical domain (G313S, G517V, G571A, G910C, G943S). In all five cases, analysis of cartilage type II collagen suggested incorporation of the abnormal alpha1(II) chain in the extracellular collagen trimers. The G943S mutation has been reported previously in another unrelated patient with a strikingly similar phenotype, illustrating the possible specific effect of the mutation. The radiographically less severely affected patient was heterozygous for a 4 bp deletion in the splice donor site of intron 35, likely to result in aberrant splicing. One case was shown to be heterozygous for a single nucleotide change predicted to result in a T1191N substitution in the carboxy-propeptide of the proalpha1(II) collagen chain. Study of the clinical, radiographic, and morphological features of the seven cases supports evidence for a phenotypic continuum between achondrogenesis II-hypochondrogenesis and lethal SEDC and suggests a relationship between the amount of type I collagen in the cartilage and the severity of the phenotype.     

Atypical skeletal changes in otopalatodigital syndrome type II: Phenotypic overlap among otopalatodigital syndrome type II,boomerang dysplasia,atelosteogenesis type I and type III,and lethal male phenotype of Melnick-Needles syndrome

We report on 2 cases of otopalatodigital syndrome type II (OPD II) with atypical skeletal changes, overlapping those of boomerang dysplasia, atelosteogenesis type I (AO I) and type III (AO III), and the lethal male phenotype of Melnick-Needles syndrome. One patient exhibited strikingly broad, bowed femora, which resembled those of boomerang dysplasia. The other patient possessed conspicuous undertubulation of the long bones, defective ossification of the spine, and severe undermineralization of the calvaria, which may have caused diagnostic confusion with AO I, AO III, and the lethal male phenotype of Melnick-Needles syndrome. OPD II is transmitted as an X-linked recessive trait, whereas AO I, AO III, and boomerang dysplasia are considered to result from a new dominant mutation, and Melnick-Needles syndrome is inherited as an X-linked dominant trait. Accordingly, differential diagnosis is mandatory to provide the affected families with adequate genetic counseling. Awareness of these skeletal changes in OPD II will prevent the misdiagnosis of this entity as other disorders. Furthermore, the phenotypic overlap among these disorders may expand the entities that constitute the OPD-Larsen dysplasia family proposed by Spranger [1985]. Am. J. Med. Genet. 73:132–138, 1997. © 1997 Wiley-Liss, Inc.     

Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3

We describe a family with progressive skeletal dysplasia and severe spinal involvement, short stature, premature arthrosis and joint contractures diagnosed as spondyloepiphyseal dysplasia Omani type. Mutation analysis in CHST3 , the gene encoding for the chondroitin 6- O -sulfotransferase-1 (C6ST-1), revealed a homozygous missense mutation (T141M) in exon 3 in all three affected members of the family. Using recombinant C6ST-1, we showed that the identified missense mutation results in a reduction of C6ST-1 activity to 24–29% of the wild type protein. In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.     

Stickler-like syndrome due to a dominant negative mutation in the COL2A1 gene

The type II collagenopathies include a wide spectrum of phenotypes ranging from mild spondylo epiphyseal dysplasia (SED) to severe achondrogenesis/ hypochondrogenesis. Several attempts have been made at providing phenotype-genotype correlations in this group of disorders. In this report we discuss a South African family in which four members have a phenotype resembling Stickler syndrome type 1. Ocular problems and conductive deafness predominate, while skeletal changes resemble those of a mild form of multiple epiphyseal dysplasia (MED). In distinction to the classical form of Stickler syndrome, the affected persons have stubby digits. DNA analysis of the exons of the COL2A1 gene documented a C-T transversion in exon 39, resulting in an Arg704Cys substitution in the triple helical domain of the type II collagen peptide; this nontermination mutation may be indicative of further heterogeneity in the Stickler group of disorders or of a new syndrome amongst the type II collagenopathies. Am. J. Med. Genet. 80:6–11, 1998. © 1998 Wiley-Liss, Inc.     

The cartilage collagens: a review of their structure, organization, and role in the pathogenesis of experimental arthritis in animals and in human rheumatic disease

This contribution reviews the structure and organization of collagen molecules found in cartilage and the roles that they may play in rheumatic diseases. Cartilage is unique in its physical properties and molecular composition, and contains sufficient amounts of types II, IX, X, and XI collagen to deem these molecules as ”cartilage-specific.” The vitreous body of the eye, a ”cartilagelike” tissue is also rich in the same collagens but is type X deficient. Types VI and XII collagen are present in cartilage as well as noncartilaginous tissues. Types II, IX, and XI collagen are organized into matrix fibrils, where type II constitutes the bulk of the fibril, type XI regulates fibril size, and type IX facilitates fibril interaction with proteoglycan macromolecules. Genetic defects in these collagens can produce mild to severe developmental abnormalities, including spondyloepiphyseal dysplasia often accompanied by an accelerated form of osteoarthritis. Sensitization with collagen can produce experimental rheumatic diseases. Type II collagen induces an erosive polyarthritis in certain strains of rats, mice, and higher primates which can resemble rheumatoid arthritis and relapsing polychondritis. Type XI collagen is arthritogenic in rats but not mice; type IX induces autoimmunity in both species but not arthritis. Arthritis is initiated by complement fixing antibodies that bind to type II collagen in autologous cartilage, and the production of these antibodies is MHC restricted and T cell dependent. It is unclear whether T cells alone can induce arthritis, although they probably help sustain it. Mapping and characterizing the of T cell epitopes on type II collagen has resulted in the synthesis of small homolog and substituted peptides of type II collagen which suppress arthritis in an antigen-specific manner by a variety of routes, including mucosal. Moreover, collagen-induced arthritis has proven a valuable model to study the contribution of cytokines and other biological agents in the pathogenesis of joint injury and how they might be used to develop new therapies. Collagen autoimmunity has been implicated in the pathogenesis rheumatoid arthritis and polychondritis. Circulating antibodies to type II collagen are found in both diseases. Antibodies to types IX and XI collagen are also present in rheumatoid sera but are less prevalent. Rheumatoid cartilage and synovium contain antibodies to type II collagen at a prevalence far greater than serum, suggesting an intra-articular antigen-driven immune process. Although effective in animal models, attempts to treat rheumatoid arthritis with orally administered type II collagen have proven elusive. Different approaches using newer formulations and selected or modified oligopeptides remain to be tested and could prove effective in the treatment of the human rheumatic diseases. Received: 16 April 1997 / Accepted: 15 January 1998     

Variable expression in a dominantly inherited skeletal dysplasia with similarities to brachydactyly E and spondyloepiphyseal- spondyloperipheral dysplasia

Variable expression and penetrance of dominantly inherited disorders present problems in diagnosis and counseling. The variation in clinical findings within a family with an autosomal dominant skeletal dysplasia is presented. In some members only shortened metacarpals were found, as seen in classic Brachydactyly E. Others presented with more severe and generalized skeletal involvement, such as is found in some of the spondyloepiphyseal dysplasias. This family may represent the true spectrum of Brachydactyly E; they may be affected with a specific spondyloepiphyseal dysplasia; or they may represent a new syndrome. The authors favor the first possibility and feel that this family serves to emphasize the importance of examining all affected members in a kindred with an autosomal dominant disease.     

Greig cephalopolysyndactyly syndrome with dysgenesis of the corpus callosum in a Bedouin family

We report on the first known Bedouin family with Greig cephalopolysyndactyly syndrome (MIM 175700). The index patient and his father shared pre- and postaxial polysyndactyly, mild mental retardation, and corpus callosum dysgenesis. Their phenotypic findings were compared with reported cases of both Greig cephalopolysyndactyly (GCPS) and acrocallosal syndromes. This family represents the second report of the rare occurrence of dysgenesis of the corpus callosum in GCPS. © 1996 Wiley-Liss, Inc.     

Autosomal dominant spondylarthropathy due to a type II procollagen gene(COL2A1) point mutation

Osteoarthrosis represents a very common disease with heterogeneous etiology. In some pedigrees linkage of the condition with the type II collagen gene (COL2A1) has been established, but information on the underlying gene defect is still incomplete as only one mutation causing this phenotype has been identified. We analyzed the COL2A1 gene in a 27-year-old woman and her 47-year-old mother presenting with severe premature osteoarthrosis and X-ray signs compatible with mild spondyloepiphyseal dysplasia. Examination of the complete gene in both patients was done by amplification of all 54 exons, screening of the PCR products by SSCP-analysis, and subsequent sequencing. In mother and daughter a G to A transition at the 5′-end of exon 21 was detected, leading to a substitution of serine for glycine at position 274 of the triple helical domain. The mutation was not present in unaffected family members or in healthy control individuals. The autosomal dominant spondylarthropathies may represent the less severe entities of the clinical spectrum of type II collagenopathies. © 1994 Wiley-Liss, Inc.     

Spondyloepiphyseal dysplasia, mild autosomal dominant type is not due to primary defects of type II collagen

A mild autosomal dominant form of spondyloepiphyseal dysplasia (SED) is present in several generations of a South African family of English stock. This phenotype differs from that of any other previously described. Although type II collagen defects have been found in some families with SED congenita, the phenotype in our family showed discordant segregation with COL2A1 gene associated restriction fragment length polymorphisms (RFLPs), the markers for the structural locus of type II collagen. It is evident that the SED group of disorders is heterogeneous.     

Lys650Met substitution in the tyrosine kinase domain of the fibroblast growth factor receptor gene causes thanatophoric dysplasia Type I. Mutations in brief no. 199. Online

Thanatophoric dysplasia (TD) is one of the most common neonatal lethal skeletal dysplasias with micromelic shortening of the limbs, relative macrocephaly, flat vertebral bodies and a narrow thorax. TD has been divided into two types, type I (TD1) and II (TD2), based on clinical, radiological, histological, and molecular criteria. We identified a A to T heterozygous base subsitution at position 1949 predicted to cause a Lys650Met substitution in a term infant with TD1. This mutation has been previously described in one case of TD1 and three cases of severe achondroplasia with acanthosis nigricans and mental retardation. Interestingly, all cases with the Lys650Met mutation have the same unusual curvature of the tibia and/or fibula.