Spondyloepiphyseal Dysplasia Congenita

A number sign (#) is used with this entry because SED congenita is caused by heterozygous mutation in the COL2A1 gene (120140) on chromosome 12q13.

Description

Spondyloepiphyseal dysplasia congenita is an autosomal dominant chondrodysplasia characterized by disproportionate short stature (short trunk), abnormal epiphyses, and flattened vertebral bodies. Skeletal features are manifested at birth and evolve with time. Other features include myopia and/or retinal degeneration with retinal detachment and cleft palate (summary by Anderson et al., 1990).

Clinical Features

Spranger and Wiedemann (1966, 1966) suggested the designation spondyloepiphyseal dysplasia congenita for a disorder affecting particularly the vertebrae and juxtatruncal epiphyses. Four of 6 patients had progressive myopia. Three persons (mother and 2 sons) were affected in 1 family. They collected 14 cases from the literature.

Bach et al. (1967) reported an isolated case. Platyspondyly, short limbs, and cleft palate were evident at birth. Other malformations included myopia, hypoplasia of abdominal musculature, abdominal and inguinal hernias, and mental retardation. Detachment of the retina occurs in some patients even without significant myopia.

Roaf et al. (1967) reported 4 sporadic cases. Severe myopia in particular was a serious problem in the cases reported by Fraser et al. (1969). Mother and 2 children were affected in 1 of their families.

Spranger and Langer (1970) reported 20 cases. In the affected newborn, x-rays showed lack of ossification of the os pubis, distal femoral and proximal tibial epiphyses, talus and calcaneus, and flattening of vertebral bodies.

Yang et al. (1980) demonstrated PAS-positive cytoplasmic inclusions in chondrocytes after diastase digestion to eliminate glycogen. Ultrastructural examination showed the inclusions to be accumulations of fine, granular material in dilated cisterns of rough endoplasmic reticulum. Inclusions have been found also in achondrogenesis (200600), one type of short rib-polydactyly syndrome (263520), one form of pseudoachondroplastic dysplasia (177170), and Kniest syndrome (156550). The presence of type II ('cartilage') collagen in the vitreous of the eye pointed to mutation in the COL2A1 gene as the possible basis of SED congenita. Furthermore, in connection with the deafness present in some cases (Roaf et al., 1967), the experiments of Yoo et al. (1983), demonstrating induction of sensorineural hearing loss and vestibular dysfunction in rats by a mechanism of autoimmunity to type II collagen, were noteworthy. Bilateral progressive sensorineural hearing loss has been thought to have an autoimmune etiology in some patients. Helfgott et al. (1991) reported that the presence of antibodies to type II collagen might be predictive of corticosteroid responsiveness in such patients. Sutjita et al. (1992) reviewed the difficulties with the interpretation of studies like that of Helfgott et al. (1991).

In a series of 17 patients with SED congenita, Wynne-Davies and Hall (1982) delineated 2 clinical types. There was wide clinical and radiologic variability in each with overlap between them, but 12 had very short stature and grossly disorganized hips with severe coxa vara, whereas the remaining 5 patients were less severely affected with height only a little below the third percentile and only mild coxa vara. Both groups could be diagnosed at birth but not distinguished until after the age of 3 or 4 years when the hip and height differences became evident. Both forms may be autosomal dominant; all cases were sporadic except for a concordant twin-pair, presumably monozygotic.

Hamidi-Toosi and Maumenee (1982) studied the ocular features of 18 cases. In 7 there was nonprogressive myopia of 5.00 or more diopters. In 6 of these 7, vitreoretinal degeneration was found and vitreous syneresis was present in all patients. Retinal detachment was found in none, contrary to the reports of a frequency as high as 50%.

In an infant with SED congenita who died at age 5 months after an anoxic episode, Murray et al. (1985) found in the eye that the collagen of the vitreous had a smaller-than-normal fiber diameter. Furthermore, the vitreous had central liquefaction, was detached in multiple areas, and was exerting traction on the retina. The internal limiting membrane of the retina was thin throughout and displayed many areas of discontinuity. The findings were considered consistent with a defect of type II collagen and with an increased risk of retinal detachment in this disorder. Reconciliation with the findings of Hamidi-Toosi and Maumenee (1982)--no retinal detachment in 18 cases--was difficult.

Murray and Rimoin (1985) found abnormal mobility of type II collagen cyanogen bromide peptides in cases of SED and SEMD, including cases of SED congenita and SEMD Strudwick (184250). They suggested that the abnormal mobility of multiple peptides may be the consequence of excessive posttranslational modification which in turn results from impediments in formation of the collagen helix by a variety of defects.

Murray and Rimoin (1988) demonstrated abnormal type II collagen in SED congenita.

Givon et al. (1999) described a 35-year-old mother and her 6-year-old daughter with SED congenita and a consistent finding of pseudarthrosis-like lesions in the middiaphysis of both humeri. The mother had minimal symptoms that resolved spontaneously and the child had no symptoms related to these lesions. In the mother the lesion had undergone complete remodeling. This finding, which Givon et al. (1999) concluded is a manifestation of SED congenita, resolves through bone remodeling with time.

Terhal et al. (2015) reviewed the clinical and radiologic features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphseal dysplasia congenita or a related phenotype.

Inheritance

Fraser and Friedmann (1967) observed dominant inheritance (his case M 13).

Harrod et al. (1984) evaluated 2 unrelated infants for short stature at age 14 and 27 months, respectively, and found clinical and radiographic features consistent with SED congenita. Both pairs of parents were healthy and not consanguineous. Both families were counseled for a new autosomal dominant mutation, but both had a second affected child. The parents in both families were in their twenties. Is this experience indicative of an autosomal recessive genocopy or is it explained by some other mechanism such as gonadal mosaicism? Spranger and Langer (1974) had noted the possible existence of a recessive form of SED congenita.

Lee et al. (1989) and Tiller et al. (1989, 1990) confirmed autosomal dominant inheritance of SED congenita.

Mapping

In a 4-generation family, Goldberg et al. (1989) and Anderson et al. (1990) confirmed absolute linkage of SEDC and COL2A1 on chromosome 12q.

Molecular Genetics

In a sporadic case of SED congenita, Lumadue et al. (1988) found changes in the COL2A1 gene consistent with deletion or insertion 5-prime to exon 39.

Lee et al. (1989) identified an abnormal restriction pattern in the COL2A1 gene in an affected member of a family with SED congenita. Analysis of selected genomic fragments, amplified by the polymerase chain reaction (PCR), demonstrated that all affected family members carried the same single-exon deletion in heterozygous state (120140.0001). As a consequence of the mutation, nearly 90% of the assembled type II collagen homotrimers might be expected to contain one or more procollagen subunits harboring an interstitial deletion of 36 amino acids in the triple helical domain.

In a new mutation case of SED congenita, Tiller et al. (1989, 1990) found evidence of a 45-bp tandem duplication in exon 48 of the COL2A1 gene (120140.0004), adding 5 Gly-X-Y triplets to the COOH terminus of the gene.

In a 4-year-old girl with clinical and radiographic features typical of SED congenita, Chan et al. (1993) identified heterozygosity for a missense mutation (R789C; 120140.0014) in the COL2A1 gene.

Gunthard et al. (1995) described the case of an infant thought to represent double heterozygosity for SEDC and achondroplasia (100800). The mother had the first condition, probably due to a new mutation, and the father had achondroplasia also due to a new mutation. Ultrasound examinations during gestation showed a normal femur length up to the twenty-fourth week. At 28 weeks of gestation, the femur length was 3.8 cm (normal range 4.0 to 6.5 cm). The child was delivered by elective cesarean section at 37 weeks. The newborn showed large head, short neck, bell-shaped thorax, protruding abdomen, and short limbs. There was a prominent forehead with hypoplastic midface, depressed nasal bridge, and cleft palate. 2D-echocardiography showed signs of pulmonary hypertension with right ventricular hypertrophy. The child died at the age of 1 year with pneumonia which led to right heart failure. Radiologic signs were in part those of achondroplasia and in part those of SEDC. The absence of ossification of the epiphyses at the knees and the short tubular bones were signs of both. A decrease in the interpedicular distance from the upper to lower lumbar spine, usually appearing at 6 months of age in achondroplasia, was not seen. Ischial notch hypoplasia and trident hand deformity were less pronounced than usually seen in achondroplasia. The hypoplasia of the dens was not as pronounced as usually seen in SEDC. Lung hypoplasia was also a major complication in the ACH/SEDC double heterozygote reported by Young et al. (1992).

Unger et al. (2001) reported a child with double heterozygosity for pseudoachondroplasia (177170) and spondyloepiphyseal dysplasia congenita. The child inherited pseudoachondroplasia from his mother and spondyloepiphyseal dysplasia congenita from his father. Mutations in the COMP gene (600310.0014) and the COL2A1 gene (120140.0035) were confirmed by molecular analysis. The child had clinical and radiographic findings that were more severe than those in either disorder alone.

Genotype/Phenotype Correlations

Murray et al. (1989) found that almost all the patients they studied with spondyloepiphyseal dysplasias or spondyloepimetaphyseal dysplasias showed abnormally slow electrophoretic mobility of type II collagen. Peptides near the amino terminus were almost always altered, while the mobility of peptides close to the carboxyl terminus were normal in all but the severely affected cases. Amino acid analysis indicated that the abnormal collagens had a higher ratio of hydroxylysine to lysine than did control collagen, suggesting that overmodification may be involved in the altered mobility. The results were considered consistent with a defect in the collagen helix that resulted in overmodification of the molecule from that point toward the amino terminus. Murray et al. (1989) proposed that some forms of SED and SEMD are associated with abnormalities in type II collagen that result in delayed helix formation and consequent overmodification of the collagen. Cases of SED fit into a continuous spectrum of clinical severity that correlated positively with both the extent of overmodification and the proximity of the defect to the carboxyl terminus.

Animal Model

Donahue et al. (2003) identified a naturally occurring arg1147-to-cys mutation in exon 48 of the Col2a1 gene in mice. The mutation was considered analogous to the arg789-to-cys mutation in the COL2A1 gene (R789C; 120140.0016), which had been described in 2 unrelated patients with SEDC (Chan et al. (1993, 1995)). Homozygous Sedc mice were identified at birth by their small size and short trunk. Adults had shortened noses, dysplastic vertebrae, femora, and tibias, plus retinoschisis and hearing loss.