X-Linked Spondyloepiphyseal Dysplasia Tarda
Synonym: TRAPPC2-Related X-Linked Spondyloepiphyseal Dysplasia Tarda
George E Tiller, MD, PhD.
Author Information and AffiliationsInitial Posting: November 1, 2001; Last Revision: April 6, 2023.
Estimated reading time: 15 minutes
Summary
Clinical description.
In adults, X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is characterized by disproportionately short stature with short trunk and arm span significantly greater than height. At birth, affected males are normal in length and have normal body proportions. Affected males exhibit linear growth deficiency beginning around age six to eight years. Final adult height is typically 137-163 cm. Progressive joint and back pain with osteoarthritis ensues; hip, knee, and shoulder joints are commonly involved but to a variable degree. Hip replacement is often required as early as age 40 years. Interphalangeal joints are typically spared. Motor and cognitive milestones are normal.
Diagnosis/testing.
The clinical diagnosis of X-linked SEDT can be established in a male proband with characteristic radiographic findings (which typically appear prior to puberty) including: multiple epiphyseal abnormalities, platyspondyly with characteristic superior and inferior "humping" seen on lateral view, scoliosis, hypoplastic odontoid process, short femoral necks, and coxa vara; evidence of premature osteoarthritis appears in young adulthood. The molecular diagnosis of X-linked SEDT can be established in a male proband with suggestive findings and a hemizygous pathogenic variant in TRAPPC2 identified by molecular genetic testing. The molecular diagnosis of X-linked SEDT can be established in a female proband with osteoarthritis and a heterozygous pathogenic variant in TRAPPC2 identified by molecular genetic testing.
Management.
Treatment of manifestations: Treatment for scoliosis and kyphoscoliosis per orthopedic surgeon; surgical intervention may include spine surgery (correction of scoliosis or kyphosis). Pain management as needed for osteoarthritis; joint replacement (hip, knee, shoulder) as needed.
Surveillance: Cervical spine films prior to school age and before any surgical procedure involving general anesthesia to assess for clinically significant odontoid hypoplasia. Annual follow up for assessment scoliosis and joint pain.
Agents/circumstances to avoid: Extreme neck flexion and extension in individuals with odontoid hypoplasia. Activities and occupations that place undue stress on the spine and weight-bearing joints.
Evaluation of relatives at risk: Presymptomatic testing in males at risk may obviate unnecessary diagnostic testing for other causes of short stature and/or osteoarthritis.
Genetic counseling.
By definition, X-linked SEDT is inherited in an X-linked manner. When performed, molecular genetic testing of all mothers of affected sons determined that regardless of family history all were carriers of a pathogenic variant in TRAPPC2. Carrier females are at a 50% risk of transmitting the TRAPPC2 pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will not be affected. None of the sons of an affected male will be affected; all daughters will be carriers of the TRAPPC2 pathogenic variant. Carrier testing of at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the pathogenic variant in the family has been identified.
Diagnosis
No consensus clinical diagnostic criteria for X-linked spondyloepiphyseal dysplasia tarda have been published.
Suggestive Findings
X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) should be suspected in males with the following findings:
Disproportionate short stature in adolescence or adulthood and a relatively short trunk and barrel-shaped chest. Upper- to lower-body segment ratio is usually about 0.8. Arm span typically exceeds height by 10-20 cm. Short neck, dorsal kyphosis, and lumbar hyperlordosis may be evident by puberty.
Early-onset osteoarthritis, especially in the hip joints
A family history consistent with X-linked recessive inheritance. A positive family history is contributory but not necessary.
Absence of cleft palate and retinal detachment (frequently present in SED congenita; see
Differential Diagnosis)
Establishing the Diagnosis
The clinical diagnosis of X-linked SEDT can be established in a male proband with characteristic radiographic findings, or the molecular diagnosis can be established in a male proband with suggestive findings and a hemizygous pathogenic (or likely pathogenic) variant in TRAPPC2 identified by molecular genetic testing (see Table 1) if radiographic findings are inconclusive.
Note: (1) Per ACMG/AMP variant interpretation guidelines, the terms "pathogenic variants" and "likely pathogenic variants" are synonymous in a clinical setting, meaning that both are considered diagnostic and both can be used for clinical decision making [Richards et al 2015]. Reference to "pathogenic variants" in this section is understood to include any likely pathogenic variants. (2) Identification of a hemizygous TRAPPC2 variant of uncertain significance does not establish or rule out the diagnosis.
Radiographic Findings
The following radiographic findings may not be manifest in an affected male in early childhood and typically appear prior to puberty ():
Radiographs of a male age 31 years with SEDT A. Platyspondyly with superior and inferior humping of vertebral bodies
Multiple epiphyseal abnormalities
Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
Scoliosis / kyphoscoliosis
Hypoplastic odontoid process
Short femoral necks
Coxa vara
Evidence of premature osteoarthritis beginning in young adulthood
Radiographs of symptomatic males should be reviewed by a radiologist experienced with bone dysplasias.
Molecular Genetic Testing
Testing approaches can include single-gene testing and a multigene panel:
Single-gene testing. Sequence analysis of TRAPPC2 is performed first to detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If no variant is detected by the sequencing method used, the next step is to perform gene-targeted deletion/duplication analysis to detect exon and whole-gene deletions or duplications.
A multigene panel that includes
TRAPPC2 and other genes of interest (see
Differential Diagnosis) may also be considered. This method may be especially useful if expert radiographic interpretation is not available. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
GeneReview; thus, clinicians need to determine which multigene panel is most likely to identify the genetic cause of the condition while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests.
For an introduction to multigene panels click
here. More detailed information for clinicians ordering genetic tests can be found
here.
Table 1.
Molecular Genetic Testing Used in X-linked Spondyloepiphyseal Dysplasia Tarda
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| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|
|
TRAPPC2
| Sequence analysis 3 | 84% 4 |
| Gene-targeted deletion/duplication analysis 5 | 16% 6 |
| Unknown 7 | NA | Rare |
- 1.
- 2.
- 3.
Sequence analysis detects variants that are benign, likely benign, of uncertain significance, likely pathogenic, or pathogenic. Variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.
- 4.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2020]
- 5.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 6.
Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis
- 7.
It is unknown whether negative molecular analysis reflects locus heterogeneity or clinical misdiagnosis.
Clinical Characteristics
Clinical Description
Males. At birth, affected males are normal in length and have normal body proportions. Affected males exhibit linear growth deficiency beginning around grade school (age 6-8 years). Adults with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) have disproportionately short stature with short trunk and arm span significantly greater than height. Final adult height is typically 137-163 cm [Whyte et al 1999, Jones et al 2013, Rimoin et al 2013].
Scoliosis/kyphoscoliosis and odontoid hypoplasia are known radiographic features. Data on the incidence, onset, and severity of these features have not been published.
Osteoarthritis. Progressive joint and back pain with osteoarthritis ensues; hip, knee, and shoulder joints are commonly involved to variable degrees. Hip replacement is often required as early as age 40 years. Interphalangeal joints are typically spared.
Affected males achieve normal motor and cognitive milestones. Life span and intelligence appear normal.
Heterozygous females. Carrier females typically show no phenotypic changes, but mild symptoms of osteoarthritis have been reported [Whyte et al 1999].
Genotype-Phenotype Correlations
Data are inadequate to reliably correlate clinical severity to a specific TRAPPC2 pathogenic variant. All pathogenic variants identified thus far, irrespective of their molecular basis, result in an almost identical phenotype, including the true null variants.
Nomenclature
Spondyloepiphyseal dysplasia is a general term that describes the radiographic abnormalities seen in several skeletal dysplasias, including pseudoachondroplasia. The "congenita" form is evident at birth, whereas the "tarda" form is usually evident by school age.
SED tarda commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive "tarda" forms have been described.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023], X-linked spondyloepiphyseal dysplasia tarda is referred to as TRAPPC2-related X-linked spondyloepiphyseal dysplasia tarda and included in the spondyloepi(meta)physeal dysplasias group.
Differential Diagnosis
X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is distinguished from other forms of spondyloepiphyseal dysplasia (SED) by its later onset and X-linked inheritance (see Table 2).
Other
SED tarda,
autosomal forms (rare). A dominant form (OMIM
184100) may be caused by pathogenic variants in
COL2A1; a recessive form has been described clinically but not molecularly defined.
Scheuermann disease (OMIM
181440) is a term applied to premature osteoarthritis of the spine regardless of etiology.
Management
Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT), the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Table 3.
Recommended Evaluations Following Initial Diagnosis in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
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| System/Concern | Evaluation | Comment |
|---|
|
Skeleton
| Complete radiographic survey to incl scoliosis series if clinically indicated | To assess extent of skeletal manifestations |
|
Cervical spine
| Flexion-extension radiographs of cervical spine Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
| To assess for clinically significant odontoid hypoplasia |
Genetic
counseling
| By genetics professionals 1 | To inform affected persons & their families re nature, MOI, & implications of SEDT to facilitate medical & personal decision making |
MOI = mode of inheritance
- 1.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations
Table 4.
Treatment of Manifestations in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
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Manifestation/
Concern | Treatment | Considerations/
Other |
|---|
Odontoid
hypoplasia
| Precautions during intubation/surgery to avoid hyperextension | Obtain cervical spinal films prior to any surgical procedure involving general anesthesia to assess for clinically significant odontoid hypoplasia. |
Scoliosis/
Kyphoscoliosis
|
|
|
Osteoarthritis
|
|
Surveillance
Table 5.
Recommended Surveillance for Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
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| System/Concern | Evaluation | Frequency |
|---|
|
Odontoid hypoplasia
| Flexion-extension radiographs of cervical spine | Obtain prior to school age to assess for clinically significant odontoid hypoplasia. |
Scoliosis/
Kyphoscoliosis
| Clinical eval w/spine radiographs if clinically indicated | Annually |
|
Osteoarthritis
| Clinical eval for osteoarthritis | Annually |
Agents/Circumstances to Avoid
The following should be avoided:
In individuals with odontoid hypoplasia, extreme neck flexion and extension
Activities and occupations that place undue stress on the spine and weight-bearing joints
Evaluation of Relatives at Risk
If the TRAPPC2 pathogenic variant in the family is known, presymptomatic genetic testing of at-risk males allows early diagnosis and may obviate unnecessary diagnostic testing for other causes of short stature and/or osteoarthritis.
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 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, mode(s) of 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; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional. —ED.
Mode of Inheritance
By definition, X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is inherited in an X-linked manner.
Risk to Family Members
Parents of a proband
The father of a male proband with X-linked SEDT will not have the disorder nor will he be hemizygous for the causative pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her DNA, she most likely has germline mosaicism. Although no instances of maternal germline mosaicism have been reported, it remains a possibility.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a de novo pathogenic variant, in which case the mother is not a carrier.
In reported individuals for whom molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a
TRAPPC2 pathogenic variant regardless of family history [
Gedeon et al 2001]. Mothers of affected sons who are not carriers have not been reported to date.
Sibs of a proband. The risk to sibs of a male proband with X-linked SEDT depends on the genetic status of the mother:
If the mother of the proband has a TRAPPC2 pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%.
If the proband represents a simplex case and if the TRAPPC2 pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is presumed to be low but greater than that of the general population because of the theoretic possibility of maternal germline mosaicism.
Offspring of a male proband. Affected males transmit the TRAPPC2 pathogenic variant to all of their daughters and none of their sons.
Other family members. The maternal aunts and maternal female cousins of a male proband may be at risk of being carriers and the aunts' offspring, depending on their sex, may be at risk of being carriers or of being affected.
Carrier Detection
Identification of female heterozygotes requires either prior identification of the TRAPPC2 pathogenic variant in the family or, if an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no pathogenic variant is identified, by gene-targeted deletion/duplication analysis.
Note: Females who are heterozygotes (carriers) for X-linked SEDT may develop minimal clinical findings related to the disorder [Whyte et al 1999].
Prenatal Testing and Preimplantation Genetic Testing
Once the X-linked SEDT-causing pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
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.
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.
X-Linked Spondyloepiphyseal Dysplasia Tarda: Genes and Databases
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Data are compiled from the following standard references: gene from
HGNC;
chromosome locus from
OMIM;
protein from UniProt.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
here.
Molecular Pathogenesis
TRAPPC2 (previously SEDL) encodes the 140-amino acid protein "sedlin," which appears to be ubiquitously expressed [Gedeon et al 1999, Gécz et al 2000]. Sedlin is an essential component of the TRAPP (trafficking protein particle) complex that is required for the export of procollagen trimers (e.g., type II collagen) from the endoplasmic reticulum to the Golgi, which ultimately permits incorporation of these proteins into the extracellular matrix [Venditti et al 2012].
Mechanism of disease causation. Loss of function
TRAPPC2-specific laboratory technical considerations.
TRAPPC2 contains six exons with the translation start site in exon 3. The exon and multiexon deletions (see also HGMD in Table A) would not be detected in heterozygous females by sequence analysis (see Table 1). Sequence analysis should include flanking intronic sequences, which is customary to evaluate splice junctions. This is particularly important with TRAPPC2, as there is an expressed pseudogene which is devoid of introns [Gécz et al 2000].
Notable TRAPPC2
variants. X-linked SEDT-causing pathogenic variants in TRAPPC2 include splice site, nonsense, and missense variants and deletions.
Table 6.
Notable Recurrent TRAPPC2 Pathogenic Variants
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Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.
GeneReviews follows the standard naming conventions of the Human Genome Variation Society (varnomen.hgvs.org). See Quick Reference for an explanation of nomenclature.
Chapter Notes
Author History
George E Tiller, MD, PhD (2001-present)
Vickie L Hannig, MS; Vanderbilt University Medical Center (2001-2020)
Revision History
6 April 2023 (sw) Revision: "
TRAPPC2-Related X-Linked Spondyloepiphyseal Dysplasia Tarda" added as a synonym; Nosology of Genetic Skeletal Disorders: 2023 Revision [
Unger et al 2023] added to
Nomenclature5 November 2020 (sw) Comprehensive update posted live
11 June 2015 (me) Comprehensive update posted live
15 February 2011 (me) Comprehensive update posted live
5 April 2006 (me) Comprehensive update posted live
10 February 2004 (me) Comprehensive update posted live
30 December 2003 (cd) Revision: change in test availability
1 November 2001 (me) Review posted live
16 May 2001 (gt) Original submission
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