CHONDRODYSPLASIA WITH MULTIPLE DISLOCATIONS
SPONDYLOEPIPHYSEAL DYSPLASIA, OMANI TYPE
HUMEROSPINAL DYSOSTOSIS
HSD
CDMD
Spondyloepiphyseal dysplasia with congenital joint dyslocations, CHST3 type
Autosomal recessive Larsen syndrome
Chondrodysplasia with congenital joint dislocations, CHST3 type
SDCD, CHST3 type
Congenital disorder of glycosylation-related bone disorder
-Rare developmental defect during embryogenesis
-Rare genetic disease
Disorder of O-xylosylglycan synthesis
-Rare genetic disease
Primary bone dysplasia with multiple joint dislocations
-Rare bone disease
-Rare developmental defect during embryogenesis
-Rare genetic disease
Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, ... Although patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (see 245600) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia (SED) become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (summary by Unger et al., 2010).
Kozlowski et al. (1974) described 2 half sibs with an unusual skeletal dysplasia of which short humerus with distal bifurcation was one of the more striking features. Other features included coronal cleft vertebrae, subluxation in the elbow joints, ... Kozlowski et al. (1974) described 2 half sibs with an unusual skeletal dysplasia of which short humerus with distal bifurcation was one of the more striking features. Other features included coronal cleft vertebrae, subluxation in the elbow joints, shortening and hypotubulation of the long bones of the legs, widened iliac bones, and talipes equinovarus. Both children, brother and sister, had congenital heart disease from which 1 died at the age of 7.5 months. Kozlowski et al. (1974) suggested that the disorder was inherited as a 'dominant trait with variable penetrance.' They stressed, however, that it was not certain that the children had different fathers or that the father or fathers were normal. Cortina et al. (1979) reported a 2-year-old boy with humeral bifurcation, elbow subluxation, and coronal cleft vertebrae. The patient had a cardiac murmur, but cardiac status was not fully investigated. Hall (1997) reported a 6-month-old boy with short limbs, limited movement at elbow joints, dislocated right knee, and bilateral talipes equinovarus, who also had small thick ears and hypertelorism. Radiography showed short, mildly bowed long bones, slight widening of metaphyses, dislocated right knee, mild platyspondyly with partially fused coronal clefts in the thoracolumbar vertebrae, bifid distal humeri, generalized brachydactyly, and mildly thin ribs. Evaluation of a heart murmur by electrocardiography demonstrated a thickened mitral valve. Rajab et al. (2004) described what appeared to be a distinct type of spondyloepiphyseal dysplasia (SED) in a large inbred kindred in Oman. They evaluated 8 individuals from 2 consanguineous sibships, 1 male and 7 females between ages 2 and 22 years. The families were thought to be related through distant consanguineous loops. The clinical features included near to normal length at birth, short stature with final adult height of 110 to 139 cm, shortening of the upper segment due to severe progressive kyphoscoliosis, severe arthritic changes with joint dislocations, rhizomelic limbs, genu valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia, and normal intelligence. Radiologic studies showed minor metaphyseal changes but major manifestations in the spine and the epiphyses. During the first year of life, the vertebral bodies were of normal height, but the endplates were irregular and the intervertebral space was narrow. With age, the vertebral endplates became increasingly irregular, the intervertebral space diminished further, and individual vertebrae started to fuse, resulting in a severe short-trunk dwarfism with kyphoscoliosis. The epiphyses were small, and precocious osteoarthropathy involving small and large joints was observed; the elbow, wrist, and hip joints were affected starting in infancy and showed restricted movement. Osteoarthropathy and spinal involvement resulted in physical handicap by early adulthood. Rajab et al. (2004) designated this disorder 'spondyloepiphyseal dysplasia, Omani type.' Megarbane and Ghanem (2004) reported a 5-year-old Lebanese boy with severe pre- and postnatal short stature, disproportionately short limbs, and multiple joint dislocations including left hip, knees, and radial heads. Other features included a frontal cowlick, high-arched palate, flat nape, and pectus excavatum. Radiologically he had anisospondyly with coronal clefts of the thoracolumbar vertebrae, subluxation of the radial heads, bilateral hip dislocation, hypoplastic left capital femoral epiphysis, short femoral necks, diffuse osseous demineralization, and delayed bone age. Perez-Aytes et al. (2005) reported a case of humerospinal dysostosis in a boy who was born with rhizomelic shortening of limbs and talipes equinovarus. X-ray findings showed short long bones, vertebral coronal clefts, and distal humeral bifurcation. At 2 years of age, he had short stature, a short thorax, limitation of elbow extension, and genua valga. Psychomotor development was within normal limits. Perez-Aytes et al. (2005) also provided follow-up information on the patient reported by Cortina et al. (1979). At 27 years of age, he had undergone multiple orthopedic surgical interventions primarily for leg deformities. He had severe spine deformities, a short thorax, and limited movement of the elbow joints. His intellectual development was normal, and he worked as a computer expert. There was no cardiac involvement in either patient. Megarbane (2007) reported a 5-year-old Lebanese girl, born of first-cousin parents, who had severe pre- and postnatal short stature, bilateral dislocation of hips, knees, and elbows, and right clubfoot. Skeletal investigation disclosed an anisospondyly, absence of ossification of the odontoid apophysis, incomplete fusion of the neural arches of the cervical vertebrae, abnormal L3 and L4 vertebrae, partial agenesis of the coccyx, abnormal and subluxated radial heads, bilateral dislocation of the hips, dysplastic acetabulae, pseudoacetabulae, hypoplasia of the femoral heads, short femoral necks, short long bones with thin diaphyses, widening of the medullary canal and thinning of the cortical canal, slightly enlarged metaphysis, and diffuse osseous demineralization. Bone age was delayed. Megarbane (2007) noted similarities to the features of an unrelated 5-year-old Lebanese boy originally reported by Megarbane and Ghanem (2004) and provided follow-up on the boy at 9 years of age. On x-ray, in addition to previously described findings, he had narrow disc spaces at C3-C4 and C4-C5, subluxation of C4-C5, marked lumbar lordosis and dorsal kyphosis, herniation of the discs of the dorsolumbar spine, irregular vertebral endplates of the vertebrae of the thoracolumbar spine, lumbar spina bifida occulta, abnormal carpal bones with extra-carpal bones on the left hand, abnormal tarsal bones, accessory medial cuneiforms, slightly flared metaphyses, and abnormal epiphyses. Van Roij et al. (2008) studied 2 Turkish sibs, born of second-cousin parents, with progressive spondyloepiphyseal dysplasia from early childhood. The authors stated that several elements of their clinical presentation differed significantly from the original description of the disorder and suggested that the clinical phenotype should be extended to include congenital joint dislocation, clubfoot, ventricular septal defect, deafness, markedly variable metacarpal shortening, and accessory carpal ossification centers. Tuysuz et al. (2009) reported a 13-year-old girl and her 11.5-year-old brother, born of consanguineous Turkish parents, who had parogressive skeletal dysplasia with severe spinal involvement, short stature, and premature arthrosis and joint contractures, features consistent with the 'Omani type' of spondyloepiphyseal dysplasia. The sibs also displayed mild facial dysmorphism not previously described in Omani SED, including a broad forehead, mild hypertelorism, sparse and high-arched eyebrows, long philtrum, and small cystic ears. Both patients had systolic murmurs; echocardiography revealed mild mitral regurgitation in the sister, and moderate mitral, tricuspid, and aortic regurgitation in her brother. Their 33-year-old paternal uncle, born of consanguineous parents, was also affected and had a similar facial appearance associated with severe short-trunk dwarfism, pectus carinatus, severe kyphoscoliosis, prominence of large joints, and short fourth metacarpals bilaterally. Limited extension of the elbow, hip, and knee joints, precocious osteoarthropathy of the hip joints, genu valgum, hallux valgus, and pes planus were also noted. Evaluation of a systolic murmur by echocardiography revealed moderate mitral, tricuspid, and aortic regurgitation and aortic stenosis. Radiographically the patients had irregularity of vertebral endplates, scoliosis, and narrowing of the intervertebral spaces, which in the uncle had progressed to absence of intervertebral spaces with subsequent fused vertebrae and severe kyphoscoliosis. In addition, the patients had small, irregular epiphyses in the limbs, subluxation of elbow joints, big femoral epiphyses, and irregular, small tibial epiphyses. The hands showed irregular, small, and accessory carpal ossification centers, brachydactyly, and bilateral metacarpal shortening of the third and fourth fingers in the sister and of the fourth finger in the uncle.
In affected members of the consanguineous Omani kindred with spondyloepiphyseal dysplasia (SED) originally described by Rajab et al. (2004), Thiele et al. (2004) identified homozygosity for a missense mutation in the CHST3 gene (R304Q; 608637.0001). They concluded that ... In affected members of the consanguineous Omani kindred with spondyloepiphyseal dysplasia (SED) originally described by Rajab et al. (2004), Thiele et al. (2004) identified homozygosity for a missense mutation in the CHST3 gene (R304Q; 608637.0001). They concluded that this form of SED is caused by deficiency in a specific sulfation of chondroitin sulfate side chains. Hermanns et al. (2008) identified homozygosity or compound heterozygosity for 9 different mutations in the CHST3 gene (see, e.g., 603799.0002-603799.0006) in 6 unrelated patients born with joint dislocations, including 3 patients who carried a diagnosis of recessive Larsen syndrome (245600) and 3 who had been diagnosed with humerospinal dysostosis (HSD); 1 of the latter patients (see 603799.0005) was the boy originally reported by Cortina et al. (1979). None of the patients had the typical flattened facies of Larsen syndrome. Hermanns et al. (2008) stated that the single feature most useful in recognizing CHST3 deficiency seemed to be dysostotic changes in the thoracolumbar spine, namely, widening of the interpedicular distance at L1 on anteroposterior projection and the short and cleft vertebral bodies on lateral projection, which was seen in their patients and was mentioned by both Kozlowski et al. (1974) and Cortina et al. (1979) in their descriptions of HSD; Hermanns et al. (2008) noted that this radiologic feature was also recognizable in Figure 1 of the report on Omani-type SED by Rajab et al. (2004). Given the relatively narrow phenotypic spectrum of these conditions, Hermanns et al. (2008) suggested that the disorders previously designated as Omani-type spondyloepiphyseal dysplasia and humerospinal dysostosis, as well as some patients given a diagnosis of recessive Larsen syndrome, might represent different age-related descriptions of the same condition. In 2 Turkish sibs with spondyloepiphyseal dysplasia and joint dislocations, born of consanguineous parents, van Roij et al. (2008) identified homozygosity for a missense mutation in the CHST3 gene (L286P; 603799.0007). In contrast to the consistent widening of the interpedicular distance at L1 seen in the patients studied by Hermanns et al. (2008), both sibs had narrowing of the interpedicular distance in the lumbar region. In 2 sibs with spondyloepiphyseal dysplasia and their affected uncle from a consanguineous Turkish pedigree, Tuysuz et al. (2009) identified homozygosity for a missense mutation in the CHST3 gene (T141M; 603799.0009). In contrast to the multiple congenital joint dislocations reported in other patients with CHST3 mutations, these patients had only elbow joint dysplasia with radial subluxation and limitation of extension. Tuysuz et al. (2009) noted that their patients also had accessory carpal ossification centers and variable metacarpal shortening similar to the Turkish sibs described by van Roij et al. (2008). Unger et al. (2010) identified homozygous or compound heterozygous mutations in CHST3 in patients with spondyloepiphyseal dysplasia and congenital joint dislocations from 17 families. The patients had presented with various diagnoses, including 15 who had been diagnosed with Larsen syndrome (see, e.g., 603799.0011 and 603799.0012), 2 with chondrodysplasia with multiple dislocations (previously reported by Megarbane and Ghanem, 2004 and Megarbane, 2007; see, e.g., 603799.0002), 1 with humerospinal dysostosis (originally reported by Hall, 1997; see 603799.0010), 1 with Desbuquois syndrome (see 251450), and 1 with spondyloepiphyseal dysplasia. Unger et al. (2010) reviewed the features of these patients and the 6 patients previously found to have mutations in CHST3 by Hermanns et al. (2008), and stated that the clinical and radiographic pattern of joint dislocations, vertebral changes, normal carpal age, lack of facial flattening, and recessive inheritance is characteristic and distinguishes CHST3 deficiency from other disorders with congenital dislocations.
The diagnosis of CHST3-related skeletal dysplasia is based on the combination of characteristic clinical and radiographic signs and confirmation by molecular genetic testing. ...
DiagnosisThe diagnosis of CHST3-related skeletal dysplasia is based on the combination of characteristic clinical and radiographic signs and confirmation by molecular genetic testing. Clinical Diagnosis In persons with CHST3-related skeletal dysplasia reported thus far, clinical findings have been quite consistent. Clinical features Short stature of prenatal onsetJoint dislocations: knees, hips, radial heads (Figure 1)Club feetLimitation of range of motion that can involve all large jointsDevelopment of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhoodFigureFigure 1. A newborn with molecularly confirmed CHST3-related skeletal dysplasia. Note the bilateral dislocation of the knees and radial heads. Radiographic featuresProgressive spondyloepiphyseal dysplasia with joint anomaliesGeneralized mild epiphyseal dysplasia (small epiphyses)Delayed ossification of the capital femoral epiphyses and femoral necksCoxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)Spinal abnormalitiesConspicuous increase in interpediculate distance from T12 to L1 or L2 (Figure 2)Notching of the vertebral bodies, similar in appearance to coronal clefts (Figure 3)Normal thumbs (not spatulate) and normal bone ageFigureFigure 2. Note the conspicuous increase in interpediculate distance from T12 to L1. Also appreciable is the bilateral hip subluxation. FigureFigure 3. Mild platyspondyly is observed. Note also the coronal clefts throughout the lumbar region. TestingBiochemical testing. Cultured fibroblasts can be used to determine proteoglycan sulfation (i.e., sulfotransferase activity). The cells are incubated with [35S] and chondroitin. In all CHST3-deficient patients studied thus far, the incorporation of sulfate at the C6 position was dramatically decreased while incorporation at the C4 position was within normal levels [Hermanns et al 2008, van Roij et al 2008]. This test requires a skin biopsy and thus is more invasive and less widely available than molecular genetic testing. Molecular Genetic Testing Gene. CHST3 is the only gene in which mutations are known to cause CHST3-dysplasia.Clinical testingSequence analysis has identified CHST3 mutations in all individuals with clinical and radiographic findings consistent with CHST3 deficiency [Unger et al 2010]. No instances of large deletions/duplications are known [Unger et al 2010].Table 1. Summary of Molecular Genetic Testing Used in CHST3-Related Skeletal Dysplasia View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityCHST3Sequence analysisSequence variants 2>90% 3Clinical1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. The high detection rate applies only to those individuals with clear clinical and radiographic changes consistent with CHST3 deficiency and not to an unselected population of children with joint dislocations.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing Strategy To confirm/establish the diagnosis in a probandClinical and radiologic features can strongly suggest the diagnosis of CHST3-related skeletal dysplasia [Hermanns et al 2008, Unger et al 2010].Molecular genetic testing by sequencing of the entire coding region is the confirmatory method of choice and allows for precise diagnosis and genetic counseling in the large majority of cases. Biochemical testing of radioactive sulfate incorporation in patient fibroblasts can be useful in those cases in which mutations are not identified or sequence changes of unclear significance have been detected. The diminished sulfation at carbon 6 of proteoglycans offers unambiguous evidence of CHST3 deficiency [Hermanns et al 2008, van Roij et al 2008].Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) Disorders No other phenotypes are known to be associated with mutations in CHST3.
Most children with CHST3-related skeletal dysplasia are identified at birth as having a generalized skeletal disorder. The features of this disorder are generally limited to the skeleton and joints and are progressive in nature. ...
Natural History Most children with CHST3-related skeletal dysplasia are identified at birth as having a generalized skeletal disorder. The features of this disorder are generally limited to the skeleton and joints and are progressive in nature. Occasionally, short stature and knee dislocations are seen on prenatal ultrasound examination [Unger et al 2010].At birth, affected infants are noted to have short stature (birth length: 39 to 44 cm) and joint dislocations: the large majority have bilateral knee luxation or subluxation. The radial heads and hips are the next most commonly affected joints. Club feet are also frequently seen. Despite the joint luxations, the overall phenotype is one of restricted movement and many children undergo multiple corrective procedures with only limited success [Rajab et al 2004, Unger et al 2010].The short stature is of moderate severity. In the large family reported from Oman, the adult heights ranged from 110 cm to 130 cm [Rajab et al 2004]. A recent review article included information on three adults with heights of 117 cm, 121 cm, and 134.5 cm [Unger et al 2010]. Many adults develop arthritic-type changes. They also develop spinal kyphosis, frequently in the cervical spine, and (rarely) scoliosis.Other findings include: Minor heart valve dysplasia in several persons, including one in the kindred from Oman [Hall 1997, Rajab et al 2004, Tuysuz et al 2009]; Non-skeletal complications: inguinal hernia and gastric volvulus; Tooth anomalies (microdontia, delayed eruption), reported in the large Omani kindred though not observed in others [Rajab et al 2004]; Normal Intellect, vision, and hearing [Unger et al 2010].
No genotype-phenotype correlations have been observed. The phenotype reported thus far has been strikingly homogeneous regardless of type of CHST3 mutation [Unger et al 2010]. Persons with homozygous missense mutations are no less severely affected than those with nonsense mutations. ...
Genotype-Phenotype Correlations No genotype-phenotype correlations have been observed. The phenotype reported thus far has been strikingly homogeneous regardless of type of CHST3 mutation [Unger et al 2010]. Persons with homozygous missense mutations are no less severely affected than those with nonsense mutations.
Larsen syndrome (autosomal dominant). Multiple dislocations are often the first sign appreciated by the physician and thus CHST3-related skeletal dysplasia may be mistaken for Larsen syndrome early in the evaluation of an affected individual. See FLNB-Related Disorders....
Differential DiagnosisLarsen syndrome (autosomal dominant). Multiple dislocations are often the first sign appreciated by the physician and thus CHST3-related skeletal dysplasia may be mistaken for Larsen syndrome early in the evaluation of an affected individual. See FLNB-Related Disorders.Despite the finding of congenital dislocations, persons with Larsen syndrome tend to have generalized joint stiffness much like that seen in CHST3-related skeletal dysplasia. Both syndromes should be considered whenever a newborn or fetus is described as having arthrogryposis multiplex congenita (AMC).Birth length is normal in autosomal dominant Larsen syndrome and decreased in CHST3-related skeletal dysplasia [Bicknell et al 2007]. Facial features are distinctive in autosomal dominant Larsen syndrome and normal in CHST3-related skeletal dysplasia. An increased incidence of cleft palate is observed in Larsen syndrome, but not in CHST3-related skeletal dysplasia. Some radiographic features can also help to differentiate the two conditions:In Larsen syndrome the bone age is usually advanced while in CHST3-related skeletal dysplasia it is usually either normal or retarded, with the exception of accelerated carpal ossification, which has been seen in CHST3-related skeletal dysplasia [van Roij et al 2008]. Cervical spine dysplasia is occasionally observed in Larsen syndrome.Analysis of the pedigree, which may suggest the probable mode of inheritance, can help in distinguishing these disorders.Diastrophic dysplasia. Although both CHST3-related skeletal dysplasia and diastrophic dysplasia are characterized by short limbs and club feet, radiographs can usually distinguish them: CHST3-related skeletal dysplasia has specific findings in the spine and lacks the hitchhiker thumb characteristic of diastrophic dysplasia [Rossi & Superti-Furga 2001]. Desbuquois dysplasia. CHST3-related skeletal dysplasia overlaps with Desbuquois dysplasia in that both are associated with prenatal-onset short stature and joint dislocations; however, the facial features in Desbuquois dysplasia are distinctive (marked midface hypoplasia and prominent eyes). Whereas lateral spine x-rays show multiple coronal clefts in both disorders, in Desbuquois dysplasia the bone age is advanced [Huber et al 2009].Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with CHST3-related skeletal dysplasia, the following evaluations are recommended:...
ManagementEvaluations Following Initial Diagnosis To establish the extent of disease in an individual diagnosed with CHST3-related skeletal dysplasia, the following evaluations are recommended:Orthopedic referralReferral to a specialized skeletal dysplasia clinic if availableEchocardiogramTreatment of ManifestationsThe main focus of treatment has thus far been surgical correction of the abnormal joints. Presumably because of the basic defect present in CHST3-related skeletal dysplasia, surgical correction is often only partially successful and most patients have had multiple procedures by adulthood [Unger et al 2010].Of note, physical therapy has not been demonstrated to be effective in this disorder.SurveillanceThus far, heart valve dysplasia has not required correction; thus, no firm guidelines for appropriate surveillance have been developed. Echocardiogram is suggested at time of diagnosis and, if normal, should probably be repeated at intervals of five years.Agents/Circumstances to AvoidActivities with a high impact on joints (e.g., jogging) should be avoided. Obesity, which places an excessive load on the large weight-bearing joints, should be avoided.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch Clinical Trials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. CHST3-Related Skeletal Dysplasia: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDCHST310q22.1Carbohydrate sulfotransferase 3CHST3 @ LOVDCHST3Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for CHST3-Related Skeletal Dysplasia (View All in OMIM) View in own window 143095SPONDYLOEPIPHYSEAL DYSPLASIA WITH CONGENITAL JOINT DISLOCATIONS 603799CARBOHYDRATE SULFOTRANSFERASE 3; CHST3Normal allelic variants. CHST3 is a relatively small gene, comprising three exons. Pathologic allelic variants. Several recurrent mutations have been identified in families of similar ethnic background and, thus, may represent founder mutations [Unger et al 2010]. No hot spots have been identified but the majority of known mutations are clustered in the sulfotransferase domain. Normal gene product. Carbohydrate sulfotransferase 3 is the enzyme responsible for the transfer of sulfate from PAPS to position 6 of N-acetyl galactosamine. Proper sulfation of the chondroitin sulfate proteoglycans is essential for normal cartilage structure.Abnormal gene product. Sulfation studies as well as the nature of the known mutations and the mode of inheritance suggest that the pathogenesis of the disorder results from decreased/absent catalytic activity of the enzyme.