Chondrodysplasia with Congenital Joint Dislocations, CHST3-Related

Clinical characteristics.

Chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3) is characterized by short stature of prenatal onset, joint dislocations (knees, hips, radial heads), clubfeet, 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 and vision are normal.

Diagnosis/testing.

The diagnosis of CDCJD-CHST3 is established in a proband with characteristic clinical and radiographic features and biallelic pathogenic variants in CHST3 identified by molecular genetic testing.

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. Treatment of cardiac manifestations as needed per cardiologist; treatment of dental anomalies as needed per dentist.

Surveillance: Clinical joint and spine evaluation with orthopedist with experience in skeletal dysplasia; radiographs as recommended per orthopedist; if normal at the time of diagnosis, echocardiogram should be repeated per cardiologist or every five years; follow up with dentist annually or as needed.

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

Genetic counseling.

CDCJD-CHST3 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a CHST3 pathogenic variant, each sib of an affected individual has a 25% chance at conception of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Once the CHST3 pathogenic variants have been identified in an affected family member, carrier testing for at-risk family members and prenatal/preimplantation genetic testing for a pregnancy at increased risk are possible.

Suggestive Findings

Chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3) should be suspected in individuals with the following clinical radiographic features and family history.

Clinical features

• Joint dislocations at birth (knees, hips, radial heads) with short stature (See Figure 1.)
• Clubfeet
• 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

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 (See Figure 2.)
  • Notching of the vertebral bodies, similar in appearance to coronal clefts (See Figure 3.)
• Normal thumbs (not spatulate)
• Normal or (more rarely) slightly advanced bone age (especially carpal)

Family history is consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity). Absence of a known family history does not preclude the diagnosis.

Establishing the Diagnosis

The diagnosis of CDCJD-CHST3 is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in CHST3 identified by molecular genetic testing (see Table 1).

Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variant" and "likely pathogenic variant" are synonymous in a clinical setting, meaning that both are considered diagnostic and can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this GeneReview is understood to include likely pathogenic variants. (2) Identification of biallelic CHST3 variants of uncertain significance (or of one known CHST3 pathogenic variant and one CHST3 variant of uncertain significance) does not establish or rule out the diagnosis.

Molecular genetic testing approaches can include a combination of gene-targeted testing (single gene testing, multigene panel) and comprehensive genomic testing (exome sequencing, genome sequencing). Gene-targeted testing requires that the clinician determine which gene(s) are likely involved (see Option 1), whereas comprehensive genomic testing does not (see Option 2).

Clinical Description

Most children with chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3) 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]. The prenatal presentation may be that of arthrogryposis [Muys et al 2017].

At birth, affected infants are noted to have short stature (birth length: 39-44 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. Clubfeet are also frequently seen. Despite the congenital joint dislocations, 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, Searle et al 2014].

In a large family reported from Oman, the adult heights ranged from 110 cm to 130 cm [Rajab et al 2004], while in a large Pakistani family the mean adult height was 84 cm [Waryah et al 2016]. A review article included information on three adults with heights of 117 cm, 121 cm, and 134.5 cm [Unger et al 2010]. Adult height appears to be severely affected in all individuals with CDCJD-CHST3, but with some intrafamilial variability and large interfamilial variability.

Many adults develop arthritic-type changes. They also develop spinal kyphosis, frequently in the cervical spine, and (rarely) scoliosis.

Cardiac manifestations. Minor heart valve dysplasia with valvular insufficiency has been described in multiple reports, including one in the kindred from Oman [Hall 1997, Rajab et al 2004, Tuysuz et al 2009, Otaify et al 2023, Singh et al 2024]. There are occasional reports of structural cardiac malformations such as atrial septal defect, but it is not yet clear if CHST3 pathogenic variants are causally linked [Otaify et al 2023].

Tooth anomalies (microdontia, delayed eruption) have been reported in the large Omani kindred as well as several individuals from Egypt [Rajab et al 2004, Otaify et al 2023].

Intellect, vision, and hearing is usually normal [Unger et al 2010, Singh et al 2024]. However, in a large Pakistani kindred, at least six affected individuals also had mixed hearing loss; thus, this may be an associated feature [Waryah et al 2016]. One additional individual of Pakistani origin was reported to have mild bilateral hearing loss on audiometry but no clinical signs of hearing impairment [Kausar et al 2022].

Other. Sagittal craniosynostosis has been reported in a single individual [Searle et al 2014], while "sclerosis of sutures" was reported in three unrelated individuals [Srivastava et al 2017].

Genotype-Phenotype Correlations

No genotype-phenotype correlations have been observed. The phenotype reported thus far has been strikingly homogeneous regardless of type of CHST3 pathogenic variant [Unger et al 2010]. Persons with homozygous pathogenic missense variants are no less severely affected than those with nonsense variants.

Nomenclature

In 1950, Dr LJ Larsen described autosomal dominant Larsen syndrome, now known to be caused by pathogenic variants in FLNB. 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 affected individuals and through recruitment of individuals with autosomal recessive Larsen syndrome, several investigators showed that, in fact, all the various reports of autosomal recessive Larsen syndrome, humerospinal 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.

• Humerospinal 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 humerospinal 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 "chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3)" has been proposed as an unbiased and inclusive designation for this disorder and is the current designation used in the Nosology of Genetic Skeletal Disorders [Unger et al 2023]. However, 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. The term "recessive Larsen syndrome" is more appropriate for CDCJD-CHST3 than for the B4GALT7-associated linkeropathy, as bilateral knee dislocation at birth is much more common in CHST3 deficiency than in B4GALT7 deficiency.

Prevalence

No firm data regarding the prevalence of CDCJD-CHST3 are available. More than 100 probands (including familial recurrences) have been reported, with many of these individuals from consanguineous families.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with CDCJD-CHST3, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see Table 4).

Surveillance

To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in Table 5 are recommended.

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 ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Mode of Inheritance

Chondrodysplasia with congenital joint dislocations, CHST3-related (CDCJD-CHST3) is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

• The parents of an affected child are presumed to be heterozygous for a CHST3 pathogenic variant.
• Molecular genetic testing is recommended for the parents of the proband to confirm that both parents are heterozygous for a CHST3 pathogenic variant and to allow reliable recurrence risk assessment.
• If a pathogenic variant is detected in only one parent and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the pathogenic variants identified in the proband occurred as a de novo event in the proband or as a postzygotic de novo event in a mosaic parent [Jónsson et al 2017]. If the proband appears to have homozygous pathogenic variants (i.e., the same two pathogenic variants), additional possibilities to consider include:
  • A single- or multiexon deletion in the proband that was not detected by sequence analysis and that resulted in the artifactual appearance of homozygosity;
  • Uniparental isodisomy for the parental chromosome with the pathogenic variant that resulted in homozygosity for the pathogenic variant in the proband.
• Heterozygotes (carriers) are asymptomatic. There is no evidence that they are at increased risk for degenerative joint disease.

Sibs of a proband

• If both parents are known to be heterozygous for a CHST3 pathogenic variant, each sib of an affected individual has at conception 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.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing CDCJD-CHST3.

Offspring of a proband. Unless an affected individual's reproductive partner also has CDCJD-CHST3 or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in CHST3.

Other family members. Each sib of the proband's parents is at 50% risk of being a carrier of a CHST3 pathogenic variant.

Carrier Detection

Carrier testing for at-risk relatives requires prior identification of the CHST3 pathogenic variants in the family.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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.
• Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with CDCJD-CHST3, particularly if consanguinity is likely and/or both partners are of the same ancestry. A founder variant has been identified in the Amish community (see Table 6).

Prenatal Testing and Preimplantation Genetic Testing

Once the CHST3 pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing for CDCJD-CHST3 is possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

CHST3 encodes carbohydrate sulfotransferase 3, 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.

Sulfation studies as well as the nature of the known pathogenic variants and the mode of inheritance suggest that the pathogenesis of the disorder results from decreased/absent catalytic activity of the enzyme. No hot spots have been identified, but the majority of known pathogenic variants are clustered in the sulfotransferase domain.

Mechanism of disease causation. Loss of function

Revision History

• 1 August 2024 (sw) Comprehensive update posted live
• 31 January 2019 (sw) Comprehensive update posted live
• 1 September 2011 (me) Review posted live
• 28 March 2011 (asf) Original submission

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