Spondyloepimetaphyseal Dysplasia Research Articles

Novel amino acid substitution in the Y‐position of collagen type II causes spondyloepimetaphyseal dysplasia congenita

We report on monozygotic twins with short stature and severe spondyloepimetaphyseal dysplasia congenita (SEMDC) from the Polish population. Phenotype of the twin girls resembles spondyloepiphyseal dysplasia congenita Spranger-Wiedemann (SEDC-SW), but shortening of the stature is more severe and the cranioface is normal. The distinctive radiographic features, in spite of similarity to SEDC-SW, indicate different spinal and, notably, severe metaphyseal involvement. Molecular analysis of the COL2A1 gene revealed an A to G transition at nucleotide +79 of exon 41 that converted the codon for arginine at amino acid 792 to a codon for glycine (Arg792Gly). The twins were heterozygous for the mutation and neither parent had this change. The Arg792Gly substitution is located at the Y-position of Gly-X-Y triplet, and it is likely that this substitution decreased the thermal stability of the triple helix and may affect fibril growth by replacement of an arginine residue, which is important for a conformation of the triple helix.

Degenerative knee joint disease in mice lacking 3′-phosphoadenosine 5′-phosphosulfate synthetase 2 (Papss2) activity: a putative model of human PAPSS2 deficiency-associated arthrosis

Murine brachymorphism (bm) results from an autosomal recessive mutation of the Papss2 gene that encodes 3'-phosphoadenosine 5'-phosphosulfate synthetase 2, one of the principal enzymes required for the sulfation of extracellular matrix molecules in cartilage and other tissues. A spondyloepimetaphyseal dysplasia has been identified in Pakistani kindred having a mutation of PAPSS2. In addition to skeletal malformations that include short stature evident at birth due to limb shortening, brachydactyly, and kyphoscoliosis, affected individuals demonstrate premature onset degenerative joint disease. We investigated whether loss of Papss2 activity would similarly lead to degenerative joint disease in mice. Mice carrying the bm mutation on a C57BL/6 background were obtained from the Jackson Laboratory. Limbs were analyzed by micro-computed tomography (microCT) and histology. At 12 months of age both male and female bm mice exhibited severe degenerative knee joint disease, with cartilage damage being primarily evident in the patello-femoral and medial compartments. Control 12-14-month-old C57BL/6 mice, in contrast, only occasionally demonstrated minimal cartilage damage. muCT imaging of bm limbs revealed shortened diaphyses associated with flared metaphyses in the proximal elements of both fore and hind limbs. Additionally, the bm hind limbs demonstrated extensive structural alterations, characterized by distortion of the patello-femoral groove, and prominent bowing of both tibia and fibula. The bm mutant, which develops severe articular cartilage lesions of the knee joint by approximately 12 months of age, represents a novel example of murine degenerative joint disease, possibly representing a model of human PAPSS2 deficiency-associated arthrosis.

Le syndrome de Dyggve-Melchior-Clausen : à propos d'une observation

Dyggve-Melchior-Clausen syndrome (DMCS) is a rare skeletal disorder, characterised by a spondyloepimetaphyseal dysplasia. DMCS associates progressive nanism and mental retardation with variable severity. Radiological features include spondyloepimetaphyseal dysplasia, platyspondyly and small iliac wings with lacy iliac crest. We report a case of DMCS in a nine-year-old child.

Exclusion of the dymeclin and PAPSS2 genes in a novel form of spondyloepimetaphyseal dysplasia and mental retardation

Spondyloepimetaphyseal dysplasias (SEMD) represent a heterogeneous group of conditions composed of at least 15 well-defined entities. The classification is based on clinical, radiological and molecular findings. Among them, several conditions also include a mental retardation (MR) syndrome, namely Wolcott-Rallison syndrome, Dyggve-Melchior-Clausen syndrome (DMC) and lysosomal storage disorders. Here, we report on a novel form of SEMD with MR in two Pakistani sisters born to first-cousin parents. SEMD, MR, microcephaly, ataxia, facial dysmorphism and hirsutism of back and legs were noted in the two children. Skeletal findings included flat vertebral bodies with irregular vertebral plates, irregular and flared metaphyses with vertical striations, small and irregular epiphyses, small carpal bones and narrow iliac wings without lacy pelvis iliac crest. Similarities with DMC prompted us to test and eventually exclude the DMC gene, dymeclin, by direct sequencing. Similarly, we excluded the PAPSS2 gene (3'-alpha phosphoadenosine 5'-phosphosulphate synthase 2) responsible for SEMD Pakistani type. The combination of features observed in the two sisters does not fit with any previously reported SEMD and represents therefore a novel form of autosomal recessive SEMD with MR.

Distinctive new form of spondyloepimetaphyseal dysplasia with severe metaphyseal changes similar to Jansen metaphyseal chondrodysplasia

We report a boy with a unique, "new" form of spondyloepimetaphyseal dysplasia. The conspicuous features of the spinal changes were the delay in ossification of the cervical spine and posterior elements of the thoraco-lumbar spine. The vertebral bodies were of abnormal shape but of normal size and well ossified. The hallmark of epiphyseal changes was markedly delayed ossification (bone age). The severely disturbed metaphyseal ossification was similar to Jansen metaphyseal dysplasia. This pattern of changes has not yet been described in spondyloepimetaphyseal dysplasia.

A dominantly inherited spondylometaphyseal dysplasia with “corner fractures” and congenital scoliosis

Spondylometaphyseal dysplasia (SMD) is a term applied to a varied group of skeletal dysplasias that principally involve the spine and the metaphyses of long bones. SMD Sutcliffe or "Corner Fracture" type is characterized by short stature, developmental coxa vara, fragmented appearance of the metaphyses ("corner fractures"), abnormally shaped vertebrae, odontoid hypoplasia, and dominant inheritance. We report a family with a dominantly inherited SMD with "corner fractures" and severe, congenital scoliosis but neither coxa vara nor odontoid abnormalities. This could either represent phenotypic variability in SMD-"Corner Fracture" type, or be a new, dominantly inherited SMD. The presence of severe, congenital scoliosis and short stature is present in all members of this family, and not typically seen in SMD-"Corner Fracture" type, supporting our hypothesis that this might represent a new, dominantly inherited SMD.

Altered endochondral bone development in matrix metalloproteinase 13-deficient mice.

The assembly and degradation of extracellular matrix (ECM) molecules are crucial processes during bone development. In this study, we show that ECM remodeling is a critical rate-limiting step in endochondral bone formation. Matrix metalloproteinase (MMP) 13 (collagenase 3) is poised to play a crucial role in bone formation and remodeling because of its expression both in terminal hypertrophic chondrocytes in the growth plate and in osteoblasts. Moreover, a mutation in the human MMP13 gene causes the Missouri variant of spondyloepimetaphyseal dysplasia. Inactivation of Mmp13 in mice through homologous recombination led to abnormal skeletal growth plate development. Chondrocytes differentiated normally but their exit from the growth plate was delayed. The severity of the Mmp13- null growth plate phenotype increased until about 5 weeks and completely resolved by 12 weeks of age. Mmp13-null mice had increased trabecular bone, which persisted for months. Conditional inactivation of Mmp13 in chondrocytes and osteoblasts showed that increases in trabecular bone occur independently of the improper cartilage ECM degradation caused by Mmp13 deficiency in late hypertrophic chondrocytes. Our studies identified the two major components of the cartilage ECM, collagen type II and aggrecan, as in vivo substrates for MMP13. We found that degradation of cartilage collagen and aggrecan is a coordinated process in which MMP13 works synergistically with MMP9. Mice lacking both MMP13 and MMP9 had severely impaired endochondral bone, characterized by diminished ECM remodeling, prolonged chondrocyte survival, delayed vascular recruitment and defective trabecular bone formation (resulting in drastically shortened bones). These data support the hypothesis that proper ECM remodeling is the dominant rate-limiting process for programmed cell death, angiogenesis and osteoblast recruitment during normal skeletal morphogenesis.

Chicken Collagen X Regulatory Sequences Restrict Transgene Expression to Hypertrophic Cartilage in Mice

Collagen X is produced by hypertrophic cartilage undergoing endochondral ossification. Transgenic mice expressing defective collagen X under the control of 4.7- or 1.6-kb chicken collagen X regulatory sequences yielded skeleto-hematopoietic defects (Jacenko O, LuValle P, Olsen BR: Spondylometaphyseal dysplasia in mice carrying a dominant-negative mutation in a matrix protein specific for cartilage-to-bone transition. Nature 1993, 365:56-61; Jacenko O, Chan D, Franklin A, Ito S, Underhill CB, Bateman JF, Campbell MR: A dominant interference collagen X mutation disrupts hypertrophic chondrocyte pericellular matrix and glycosaminoglycan and proteoglycan distribution in transgenic mice. Am J Pathol 2001, 159:2257-2269; Jacenko O, Roberts DW, Campbell MR, McManus PM, Gress CJ, Tao Z: Linking hematopoiesis to endochondral ossification through analysis of mice transgenic for collagen X. Am J Pathol 2002, 160:2019-2034). Current data indicate that the hematopoietic abnormalities do not result from extraskeletal expression of endogenous collagen X or the transgene. Organs from mice carrying either promoter were screened by immunohistochemistry, in situ hybridization, and Northern blot; transgene and mouse collagen X proteins and messages were detected only in hypertrophic cartilage. Likewise, reverse transcriptase-polymerase chain reaction revealed both transgene and mouse collagen X amplicons only in the endochondral skeleton of mice with the 4.7-kb promoter; however, in mice with the 1.6-kb promoter, multiple organs were transgene-positive. Collagen X and transgene amplicons were also detected in marrow, but likely resulted from contaminating trabecular bone; this was supported by reverse transcriptase-polymerase chain reaction analysis of rat tibial zones free of trabeculae. Our data demonstrate that in mice, the 4.7-kb chicken collagen X promoter restricts transcription temporo-spatially to that of endogenous collagen X, and imply that murine skeleto-hematopoietic defects result from transgene co-expression with collagen X. Moreover, the 4.7-kb hypertrophic cartilage-specific promoter could be used for targeting transgenes to this tissue site in mice.

A glycine to aspartic acid substitution of COL2A1 in a family with the Strudwick variant of spondyloepimetaphyseal dysplasia.

Spondyloepimetaphyseal dysplasia (SEMD) is one of a clinically heterogeneous group of skeletal disorders, characterized by defective growth and modelling of the spine and long bones. Common clinical features include disproportionate short stature, malformed vertebrae and abnormal epiphyses or metaphyses. Some cases have been associated with mutations in the COL2A1 gene. To determine whether the autosomal dominant Strudwick-type SEMD in a three-generation family, showing specific phenotypical features such as chest deformity, limb shortening, myopia and early-onset degenerative osteoarthrosis, might be caused by a novel COL2A1 mutation. Genetic testing and clinical examination of family members. Direct sequencing of PCR-amplified genomic DNA from the COL2A1 gene. A point mutation within exon 20 of the COL2A1 gene was identified that substituted a glycine for an aspartic acid residue at codon 262. All previously reported autosomal dominant mutations causing SEMD have substituted an obligate glycine within the triple helix, in particular at codons 292, 304 and 709 in the three reported Strudwick-type patients. Additionally, a recurrent glycine substitution at codon 154 has been identified in two unrelated Finnish cases with radiological features consistent with the Strudwick subtype. Our sixth helical glycine substitution extends the mutational spectrum and genotype/phenotype correlations of Strudwick-type SEMD.

A novel syndrome of combined immunodeficiency, autoimmunity and spondylometaphyseal dysplasia.

We describe here four patients who appear to have similar clinical and immunological features which constitute a novel syndrome. The patients present with short stature owing to spondylometaphyseal dysplasia and with severe infections as the result of a combined humoral and cellular immune deficiency. Presumably because of dysregulation of the immune system, all patients also developed autoimmune manifestations.

Human 3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase: biochemistry, molecular biology and genetic deficiency.

3'-phosphoadenosine 5'-phosphosulfate (PAPS) synthase (PAPSS) catalyzes the biosynthesis of PAPS which serves as the universal sulfonate donor compound for all sulfotransferase reactions. PAPSS forms PAPS in two sequential steps. First inorganic sulfate combines with ATP to form adenosine 5'-phosphosulfate (APS) and pyrophosphate catalyzed by ATP sulfurylase domain and in the second step, APS combines with another molecule of ATP to form PAPS and ADP catalyzed by APS kinase domain. The bifunctional PAPSS1 is comprised of NH2-terminal APS kinase domain (approximately 1-260 aa), and a COOH-terminal ATP sulfurylase domain (approximately 220-623 aa). In humans there are two major isoforms PAPSS1 and PAPSS2. In brain and skin PAPSS1 is the major expressed isoform, whereas in liver, cartilage and adrenal glands PAPSS2 isoform expression predominates and in various other tissues the proportions of the isoform expressions is purported to vary. The deduced amino acid sequences of the two isoforms reveal 77% identity between PAPSS1 and PAPSS2. In addition there is a splice variant PAPSS2b which contains notably an extra five amino acid sequence GMALP. From human tissues PAPSS1 and a splice variant PAPSS2b has been molecularly cloned, overexpressed, purified and have been biochemically characterized partially. PAPSS2b exhibited an apparent difference towards varying ATP concentration showing a sigmoidal response, with a 0.5 [v/Vmax] at 1.4 mM ATP whereas PAPSS1 exhibited a hyperbolic response with a 0.5 [v/Vmax] at 0.25 mM ATP. Although this being the case, comparison of PAPSS1 and PAPSS2 crude extracts, did not show marked difference in the kinetic properties with either substrates ATP or sulfate leading to speculate that the extra GMALP pentapeptide present in PAPSS2b could be altering the kinetic behavior. The ATP binding sites of the alpha-beta-ATP hydrolysis, active site motif HxxH (425-428 aa) is present in the ATP sulfurylase domain and the beta-gamma-hydrolase motif GxxGxxK (59-65 aa) is present in the APS kinase domain. The motifs are highly conserved between both isoforms. Gene sequence analysis of PAPSS1 (approximately 106 kB) and PAPSS2 (approximately 86.5 kB), revealed a total of 12 exons. Among exons 2-11 the sizes are highly conserved, although intron sizes varied remarkably. Exons 1 and 12 varied in sizes, contained 5'-UTR and 3'-UTR respectively. PAPSS1 and PAPSS2 contained no putative TATA box and CCAAT box. However both PAPSS1 and PAPSS2 possessed many GC boxes. From promoter analysis, it is apparent that both PAPSS1 and PAPSS2 are inducible, perhaps at various time periods, regulated by specific transcription factors. The deficiency of PAPSS2 results in osteochondrodysplasias. Osteochondrodysplasias are genetically heterogeneous group of disorders that affects skeletal development, linear growth, and the maintenance of cartilage and bone. A large inbred family with a distinct form of recessively inherited, spondyloepimetaphyseal dysplasia (SEMD) was mapped to PAPSS2 isoform located in the chromosome region of 10q23-24. PAPSS1 located in the chromosome 4q23 deficiency and consequent effect in lymphocyte recruitment in High Endothelial Venules has been reported. Several single nucleotide polymorphism (SNP) of PAPSS has been identified, some of which are in the coding region (cSNPs), has been shown to have altered enzyme activity.

Use of Distraction Osteogenesis Techniques in Skeletal Dysplasias

The authors report the results of 63 operations performed on patients with skeletal dysplasias using the techniques of distraction osteogenesis. There were a total of 26 patients (16 males, 10 females) with a mean age of 12.5 years. The group had 13 different skeletal dysplasias. In 55 of 63 (87%) of the procedures, the objectives of surgery were achieved. The authors review their results with reference to the type of fixator used and the underlying diagnosis. Circular frames were associated with improved results. Spondylometaphyseal dysplasia and Jeune syndrome were the only dysplasias treated that were associated with significant complications.

Spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form: clinical course and phenotypic variations in four patients.

We describe a 5-year-old boy and a 33-year-old woman with spondyloepimetaphyseal dysplasia with joint laxity leptodactylic form (spondyloepimetaphyseal dysplasia with multiple dislocations) (MIM 6003546), and two 12-year-old girls with the disorder who were previously reported as examples of a variant of sponatrime dysplasia. Their clinical manifestations included midface hypoplasia, micromelic short stature, and generalized joint laxity that caused multiple joint problems, including thoracolumbar scoliosis, hip subluxation, progressive genu valgum with knee and patellar subluxation, elbow subluxation, and malalignment of the wrist. Laryngotracheomalacia was present in two individuals, and myopathy was noted in one. The radiological findings in the four individuals included mild platyspondyly most conspicuous in infancy, narrow interpediculate distances of the lumbar spine evident in infancy, retarded epiphyseal ossification that evolved to epiphyseal dysplasia and later to degenerative joint disease, metaphyseal irregularities and striations present in early childhood, and leptodactylic appearance (slender short tubular bones) of the hand.

Combined spinal epidural anaesthesia for elective caesarean section in a patient with spondylometaphyseal dysplasia.

A patient with spondylometaphyseal dysplasia, an extremely rare form of dwarfism, presented for elective caesarean section. We report the successful management under regional anaesthesia, using a combined spinal epidural technique. There seem to be only two previous reports of spinal anaesthesia and there are no previous reports of the use of combined spinal epidural in a pregnant dwarf. Regional anaesthesia is thought to be complex in these dwarfs due to vertebral malformation and unpredictable anatomy of the spinal canal. They may present difficulties with intubation as well. Spondylometaphyseal dysplasia is reviewed and its anaesthetic implications discussed.

Human 3'-phosphoadenosine 5'-phosphosulfate synthetase 2 (PAPSS2) pharmacogenetics: gene resequencing, genetic polymorphisms and functional characterization of variant allozymes.

3'-Phosphoadenosine 5'-phosphosulfate (PAPS) is the sulfate donor cosubstrate for all sulfotransferase (SULT) enzymes. SULTs catalyze the sulfate conjugation of many endogenous and exogenous compounds, including drugs and other xenobiotics. In humans, PAPS is synthesized from adenosine 5'-triphosphate (ATP) and inorganic sulfate (SO2-4) by two isoforms, PAPSS1 and PAPSS2. Rare mutations that inactivate PAPSS2 are associated with human spondyloepimetaphyseal dysplasia and murine brachymorphism. To determine whether more common genetic polymorphisms that do not completely inactivate the enzyme might be one factor responsible for individual differences in sulfate conjugation, we previously cloned the human PAPSS2 gene. In the present studies, we 'resequenced' all twelve PAPSS2 exons and splice junctions, as well as approximately 500 bp of the 5'-flanking region, using 90 Polymorphism Discovery Resource (PDR) DNA samples from the Coriell Cell Repository. Twenty-two single nucleotide polymorphisms (SNPs) were observed, including four nonsynonymous coding region SNPs (cSNPs) that altered the following amino acids: Glu10Lys, Met281Leu,Val291Met and Arg432Lys. We also observed four insertions/deletions, including one sample that was homozygous for an 81-bp deletion in the 5'-flanking region 286 bp upstream from the site of transcription initiation. Transient expression studies showed that two of the nonsynonymous cSNPS, those that resulted in Glu10Lys and Val291Met alterations in encoded amino acids, showed significant decreases in levels of PAPSS activity. In the case of Glu10Lys, decreased activity was paralleled by a decrease in immunoreactive protein, while the Val291Met allozyme displayed a significant decrease in affinity for both ATP and Na2SO4 when compared to 'wild-type' enzyme, but without a significant alteration in level of immunoreactive protein. It will now be possible to test the hypothesis that these common, functionally significant PAPSS2 genetic polymorphisms might contribute to variations in sulfate conjugation in vivo.

Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis.

Osteoarthritis (OA) is one of the most common musculoskeletal disorders and is characterized by degeneration of articular cartilage. Sulfation of extracellular matrix proteins in articular cartilage is an important step in maintaining normal cartilage metabolism. Two sulfation-related genes have been reported as the causal genes of severe chondrodysplasias: mutations in PAPSS2 (3'-phosphoadenosine 5'-phosphosulfate synthase 2) cause spondylo-epimetaphyseal dysplasia (SEMD), and mutations in SLC26A2 (solute carrier family 26, member 2) cause diastrophic dysplasia. Given their critical roles in cartilage metabolism and the severe phenotypes that result from mutations in these genes, we examined PAPSS2 and SLC26A2 as candidate susceptibility loci for OA. We identified sequence polymorphisms in the coding and core promoter regions of these genes and analyzed their potential association with knee OA within the Japanese population. Ten sequence polymorphisms were detected in PAPSS2 and five in SLC26A2. An association analysis showed suggestive association of one minor polymorphism in the promoter region of SLC26A2. This 4-bp adenine deletion allele, del4A, was over-represented in knee OA (P = 0.043, odds ratio = 3.43) and is thought to confer a minor susceptibility to knee OA within the Japanese population. Haplotype analysis showed no evidence of association with the two genes, however, excluding them as major susceptibility loci for knee OA.

Nuclear localization of PAPS synthetase 1: a sulfate activation pathway in the nucleus of eukaryotic cells.

Sulfation is a major modification of many molecules in eukaryotes that is dependent on the enzymatic synthesis of an activated sulfate donor, 3'-phosphoadenosine 5'-phosphosulfate (PAPS). While sulfate activation has long been assumed to occur in the cytosol, we show in this study that human PAPS synthetase 1 (PAPSS1), a bifunctional ATP sulfurylase/adenosine 5'-phosphosulfate (APS) kinase enzyme sufficient for PAPS synthesis, accumulates in the nucleus of mammalian cells. Nuclear targeting of the enzyme is mediated by its APS kinase domain and requires a catalytically dispensable 21 amino acid sequence at the amino terminus. Human PAPSS1 and Drosophila melanogaster PAPSS localize to the nucleus in yeast and relieve the methionine auxotrophy of ATP sulfurylase- or APS kinase-deficient strains, suggesting that PAPSS1 is fully functional in vivo when targeted to the nucleus. A second PAPS synthetase gene, designated PAPSS2, has recently been described, mutations of which are responsible for abnormal skeletal development in human spondyloepimetaphyseal dysplasia and murine brachymorphism. We found that PAPSS2, which localizes to the cytoplasm when ectopically expressed in mammalian cells, is relocated to the nucleus when coexpressed with PAPSS1. Taken together, these results indicate that a sulfation pathway might exist in the nucleus of eukaryotic cells. -Besset, S., Vincourt, J.-B., Amalric, F., Girard, J.-P. Nuclear localization of PAPS synthetase 1: a sulfate activation pathway in the nucleus of eukaryotic cells.

Developmental coxa vara associated with spondylometaphyseal dysplasia (DCV/SMD): "SMD-Corner Fracture Type" (DCV/SMD-CF) demonstrated in most reported cases

Developmental coxa vara associated with spondylometaphyseal dysplasia (DCV/SMD): "SMD-Corner Fracture Type" (DCV/SMD-CF) demonstrated in most reported cases

Spondyloepimetaphyseal dysplasia with multiple joint dislocations

We report four cases of a Spondyloepimetaphyseal dysplasia (SEMD) characterized by joint laxity and large joint dislocations, especially hips and knees. This condition was first reported as a distinct entity by Hall et al., (J Med Genet 1998; 35:566-572). They described three apparently sporadic patients. We present four unrelated patients (three males and one female) with similar radiogiaphic and clinical findings. Usually, this disorder is manifest in the neonatal period by joint dislocations but normal birth length. The children go on to have significant short stature by the time they are toddlers, as well as scoliosis and progressive joint deformities. They have normal psychomotor development. Three of our four patients also had laryngo/tracheomalacia. The radiographic findings include small irregular epiphyses and metaphyseal abnormalities of the long bones. The changes seen on hand x-rays are unique to this form of SEMD and consist of the characteristic finding of gracile metacarpals and the frequent finding of distal ulnar hypoplasia. As the radiographic findings overlapped somewhat with a severe form of multiple epiphyseal dysplasia (MED), mutation detection was undertaken in one proband. This child had normal sequence of previously established MED loci (COMP, exon 3 of COL9A2, exon 3 of COL9A3) as well as exons 8, 9, and, 10 of COL9A1 and COL2A1. Histology of a cartilage sample on this patient was mildly abnormal but not diagnostic. These four cases aid in confirming that SEMD with multiple joint dislocations is a discrete entity which is most likely inherited as an autosomal dominant trait.

Spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL): Presentation in two unrelated patients in the United States

This is a report of two North American patients with spondyloepimetaphyseal dysplasia with joint laxity, an uncommon autosomal recessive skeletal dysplasia rarely reported outside of South Africa. Patients with SEMDJL have vertebral abnormalities and ligamentous laxity that results in spinal misalignment and progressive severe kyphoscoliosis, thoracic asymmetry, and respiratory compromise resulting in early death. Nonaxial skeletal involvement includes elbow deformities with radial head dislocation, dislocated hips, clubbed feet, and tapered fingers with spatulate distal phalanges. Many affected children have an oval face, flat midface, prominent eyes with blue sclerae, and a long philtrum. Palatal abnormalities and congenital heart disease are also observed. Diagnosis in infancy may be difficult because many of the typical findings are not apparent early and only evolve over time. We review the physical and radiographic findings in two unrelated patients with this disorder in order to increase the awareness of this disorder, particularly for clinicians outside of South Africa.