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CHST3-Related Skeletal Dysplasia

Synonyms: Chondrodysplasia with Congenital Joint Dislocations, CHST3 Type; CHST3 Deficiency; CHST3-Related Dysplasia. Includes: Humerospinal Dysostosis; Larsen Syndrome, Autosomal Recessive; Spondyloepiphyseal Dysplasia, Omani Type

, MD and , MD.

Author Information
, MD
Department of Pediatrics
University of Lausanne
Lausanne, Switzerland
, MD
Service of Medical Genetics
University of Lausanne
Lausanne, Switzerland

Initial Posting: .

Summary

Disease characteristics. CHST3-related skeletal dysplasia is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), club feet, and limitation of range of motion that can involve all large joints. Kyphosis and occasionally scoliosis with slight shortening of the trunk develop in childhood. Minor heart valve dysplasia has been described in several persons. Intellect, vision, and hearing are normal.

Diagnosis/testing. The diagnosis is based on the radiographic features of progressive spondyloepiphyseal dysplasia with joint anomalies, spinal abnormalities, normal thumbs (not spatulate), and normal bone age. CHST3 is the only gene in which mutations are known to cause CHST3-related skeletal dysplasia.

Management. Treatment of manifestations: Surgical correction of the abnormal joints is the only treatment modality; however, surgical correction is often only partially successful and multiple procedures are needed. Physical therapy has not been effective.

Surveillance: If normal at the time of diagnosis, echocardiogram should probably be repeated every five years.

Agents/circumstances to avoid: Activities with a high impact on joints (e.g., jogging) and obesity.

Genetic counseling. CHST3-related skeletal dysplasia is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal diagnosis for pregnancies at increased risk are possible if the disease-causing mutations in the family have been identified.

Diagnosis

The 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 onset
  • Joint dislocations: knees, hips, radial heads (Figure 1)
  • Club feet
  • Limitation of range of motion that can involve all large joints
  • Development of kyphosis and occasionally scoliosis with slight shortening of the trunk in childhood
Figure 1

Figure

Figure 1. A newborn with molecularly confirmed CHST3-related skeletal dysplasia. Note the bilateral dislocation of the knees and radial heads.

Radiographic features

  • Progressive spondyloepiphyseal dysplasia with joint anomalies
    • Generalized mild epiphyseal dysplasia (small epiphyses)
    • Delayed ossification of the capital femoral epiphyses and femoral necks
    • Coxa valga (increase in the angle formed between the head and neck of the femur and the shaft of the femur)
  • Spinal abnormalities
    • Conspicuous 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 age
Figure 2

Figure

Figure 2. Note the conspicuous increase in interpediculate distance from T12 to L1. Also appreciable is the bilateral hip subluxation.

Figure 3

Figure

Figure 3. Mild platyspondyly is observed. Note also the coronal clefts throughout the lumbar region.

Testing

Biochemical 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 testing

  • Sequence 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

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
CHST3Sequence analysisSequence variants 2>90% 3

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 proband

  • Clinical 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.

Clinical Description

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:

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.

Nomenclature

In 1950, Dr LJ Larsen described autosomal dominant Larsen syndrome, now known to be caused by mutations in FLNB, the gene encoding filamin B [Bicknell et al 2007]. Larsen syndrome is characterized by multiple joint dislocations, dysmorphic facial features, spatulate thumbs, and accelerated carpal ossification (see FLNB-Related Disorders).

Following the delineation of autosomal dominant Larsen syndrome several reports of "autosomal recessive Larsen syndrome" and other similar disorders were published. By careful reevaluation of patients and through recruitment of cases with autosomal recessive Larsen syndrome, several investigators showed that, in fact, all the various reports of autosomal recessive Larsen syndrome, humero-spinal dysostosis, and spondyloepiphyseal dysplasia (SED), Omani type could be attributed to CHST3 deficiency and that the different names had arisen from the part of the phenotype the various authors had emphasized [Hermanns et al 2008, Unger et al 2010]; that is, they were describing the same condition from different viewpoints.

  • Autosomal recessive Larsen syndrome was described in an isolated island population (La Reunion variant) in the 1970s [Laville et al 1994]. Unfortunately, none of these individuals have had CHST3 molecular genetic testing; thus, the hypothesis that the La Reunion variant is actually CHST3 deficiency remains to be tested.
  • Humero-spinal dysostosis was described by Kozlowski et al [1974] in two brothers with joint dislocations and radiographic abnormalities (bifid humeri and coronal clefts). Because the brothers were reported to be half-sibs, autosomal dominant inheritance was suspected and no link was made to autosomal recessive Larsen syndrome.
  • Mégarbané and Ghanem [2004] described “a newly recognized chondrodysplasia with joint dislocations.” Although they made the link to humero-spinal dysostosis, they rejected that diagnosis because the evidence strongly suggested autosomal recessive inheritance.
  • Rajab et al [2004] described a large family originating from Oman with what they termed “a new recessive type of SED with progressive spinal involvement.” The same group went on to demonstrate that the disorder was caused by CHST3 deficiency and renamed the disorder SED, Omani type [Thiele et al 2004].

The name CHST3-related skeletal dysplasia has been proposed as an unbiased and inclusive designation for this disorder. An argument could also be made for retaining the name autosomal recessive Larsen syndrome, as the joint dislocations are the presenting feature and “Larsen syndrome” is usually the first diagnosis considered; thus, the continued use of this designation is open to debate.

Prevalence

No firm data regarding the prevalence of CHST3-related skeletal dysplasia are available. More than 30 cases (including familial recurrences) have been reported.

Differential Diagnosis

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.

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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with CHST3-related skeletal dysplasia, the following evaluations are recommended:

  • Orthopedic referral
  • Referral to a specialized skeletal dysplasia clinic if available
  • Echocardiogram

Treatment of Manifestations

The 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.

Surveillance

Thus 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 Avoid

Activities 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Search 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.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

CHST3-related skeletal dysplasia is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes (i.e., carriers of one mutant allele).
  • Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.
  • To date, neither de novo mutations nor germline mosaicism in parents has been reported.

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
  • Once an at-risk sib is known to be unaffected, the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with CHST3-related skeletal dysplasia are obligate heterozygotes (carriers) for a disease-causing CHST3 mutation.

Other family members. Each sib of the proband’s parents is at 50% risk of being a carrier.

Carrier Detection

Carrier testing for at-risk family members is possible if the disease-causing mutations in the family have been identified.

Related Genetic Counseling Issues

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at approximately 15 to 18 weeks’ gestation or chorionic villus sampling (CVS) at approximately ten to 12 weeks’ gestation. The disease-causing mutations in the family must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • International Skeletal Dysplasia Registry
    Cedars-Sinai Medical Center
    116 North Robertson Boulevard, 4th floor (UPS, FedEx, DHL, etc)
    Pacific Theatres, 4th Floor, 8700 Beverly Boulevard (USPS regular mail only)
    Los Angeles CA 90048
    Phone: 310-423-9915
    Fax: 310-423-1528
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
CHST310q22​.1Carbohydrate sulfotransferase 3CHST3 @ LOVDCHST3

Data 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)

143095SPONDYLOEPIPHYSEAL DYSPLASIA WITH CONGENITAL JOINT DISLOCATIONS
603799CARBOHYDRATE SULFOTRANSFERASE 3; CHST3

Normal 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.

References

Literature Cited

  1. Bicknell LS, Farrington-Rock C, Shafeghati Y, Rump P, Alanay Y, Alembik Y, Al-Madani N, Firth H, Karimi-Nejad MH, Kim CA, Leask K, Maisenbacher M, Moran E, Pappas JG, Prontera P, de Ravel T, Fryns JP, Sweeney E, Fryer A, Unger S, Wilson LC, Lachman RS, Rimoin DL, Cohn DH, Krakow D, Robertson SP. A molecular and clinical study of Larsen syndrome caused by mutations in FLNB. J Med Genet. 2007;44:89–98. [PMC free article: PMC2598053] [PubMed: 16801345]
  2. Hall BD. Humero-spinal dysostosis: report of the fourth case with emphasis on generalized skeletal involvement, abnormal craniofacial features, and mitral valve thickening. J Pediatr Orthop B. 1997;6:11–4. [PubMed: 9039660]
  3. Hermanns P, Unger S, Rossi A, Perez-Aytes A, Cortina H, Bonafé L, Boccone L, Setzu V, Dutoit M, Sangiorgi L, Pecora F, Reicherter K, Nishimura G, Spranger J, Zabel B, Superti-Furga A. Congenital joint dislocations caused by carbohydrate sulfotransferase 3 deficiency in recessive Larsen syndrome and humero-spinal dysostosis. Am J Hum Genet. 2008;82:1368–74. [PMC free article: PMC2427316] [PubMed: 18513679]
  4. Huber C, Oulès B, Bertoli M, Chami M, Fradin M, Alanay Y, Al-Gazali LI, Ausems MG, Bitoun P, Cavalcanti DP, Krebs A, Le Merrer M, Mortier G, Shafeghati Y, Superti-Furga A, Robertson SP, Le Goff C, Muda AO, Paterlini-Bréchot P, Munnich A, Cormier-Daire V. Identification of CANT1 mutations in Desbuquois dysplasia. Am J Hum Genet. 2009;85:706–10. [PMC free article: PMC2775828] [PubMed: 19853239]
  5. Kozlowski KS, Celermajer JM, Tink AR. Humero-spinal dysostosis with congenital heart disease. Am J Dis Child. 1974;127:407–10. [PubMed: 4814886]
  6. Laville JM, Lakermance P, Limouzy F. Larsen's syndrome: review of the literature and analysis of thirty-eight cases. J Pediatr Orthop. 1994;14:63–73. [PubMed: 8113375]
  7. Mégarbané A, Ghanem I. A newly recognized chondrodysplasia with multiple dislocations. Am J Med Genet A. 2004;130A:107–9. [PubMed: 15368507]
  8. Rajab A, Kunze J, Mundlos S. Spondyloepiphyseal dysplasia Omani type: a new recessive type of SED with progressive spinal involvement. Am J Med Genet A. 2004;126A:413–9. [PubMed: 15098240]
  9. Rossi A, Superti-Furga A. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance. Hum Mutat. 2001;17:159–71. [PubMed: 11241838]
  10. Thiele H, Sakano M, Kitagawa H, Sugahara K, Rajab A, Höhne W, Ritter H, Leschik G, Nürnberg P, Mundlos S. Loss of chondroitin 6-O-sulfotransferase-1 function results in severe human chondrodysplasia with progressive spinal involvement. Proc Natl Acad Sci U S A. 2004;101:10155–60. [PMC free article: PMC454181] [PubMed: 15215498]
  11. Tuysuz B, Mizumoto S, Sugahara K, Celebi A, Mundlos S, Turkmen S. Omani-type spondyloepiphyseal dysplasia with cardiac involvement caused by a missense mutation in CHST3. Clin Genet. 2009;75:375–83. [PubMed: 19320654]
  12. Unger S, Lausch E, Rossi A, Mégarbané A, Sillence D, Alcausin M, Aytes A, Mendoza-Londono R, Nampoothiri S, Afroze B, Hall B, Lo IF, Lam ST, Hoefele J, Rost I, Wakeling E, Mangold E, Godbole K, Vatanavicharn N, Franco LM, Chandler K, Hollander S, Velten T, Reicherter K, Spranger J, Robertson S, Bonafé L, Zabel B, Superti-Furga A. Phenotypic features of carbohydrate sulfotransferase 3 (CHST3) deficiency in 24 patients: congenital dislocations and vertebral changes as principal diagnostic features. Am J Med Genet A. 2010;152A:2543–9. [PubMed: 20830804]
  13. van Roij MH, Mizumoto S, Yamada S, Morgan T, Tan-Sindhunata MB, Meijers-Heijboer H, Verbeke JI, Markie D, Sugahara K, Robertson SP. Spondyloepiphyseal dysplasia, Omani type: further definition of the phenotype. Am J Med Genet A. 2008;146A:2376–84. [PubMed: 18698629]

Chapter Notes

Revision History

  • 1 September 2011 (me) Review posted live
  • 28 March 2011 (asf) Original submission
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