X-Linked Spondyloepiphyseal Dysplasia Tarda
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 variant in TRAPPC2 identified by molecular genetic testing (see Table 1) if radiographic findings are inconclusive.
Radiographic Findings
The following radiographic findings may not be manifest in an affected male in early childhood and typically appear prior to puberty (Figure 1):
Figure 1.
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.Note: Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 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 at the most reasonable cost 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
| Gene 1 | Method | Proportion of Probands with a Pathogenic Variant 2 Detectable by Method |
|---|---|---|
| TRAPPC2 | Sequence analysis 3, 4 | 84% 5 |
| Gene-targeted deletion/duplication analysis 6 | 16% 7 | |
| Unknown 8 | NA | Rare |
- 1.
See Table A. Genes and Databases for chromosome locus and protein.
- 2.
See Molecular Genetics for information on allelic variants detected in this gene.
- 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.
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation requires additional testing by gene-targeted deletion/duplication analysis.
- 5.
Data derived from the subscription-based professional view of Human Gene Mutation Database [Stenson et al 2017]
- 6.
Gene-targeted deletion/duplication analysis detects intragenic deletions or duplications. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a gene-targeted microarray designed to detect single-exon deletions or duplications.
- 7.
Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis
- 8.
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.
Prevalence
The prevalence is 1:150,000-1:200,000 [Wynne-Davies & Gormley 1985].
Pathogenic variants in TRAPPC2 have been found in several populations including European [Gedeon et al 2001], Japanese [Matsui et al 2001], and Chinese [Shu et al 2002], an observation suggesting that no specific population is at increased risk.
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).
Table 2.
Forms of Spondyloepiphyseal Dysplasia of Interest in the Differential Diagnosis of X-Linked Spondyloepiphyseal Dysplasia Tarda
| Gene(s) | Disorder | MOI | Clinical Features of Differential Diagnosis Disorder | Distinguishing Features/ Comment |
|---|---|---|---|---|
| CCN6 (WISP3) | Progressive pseudorheumatoid dysplasia (PED) | AR | Predominant involvement of articular cartilage w/progressive joint stiffness & enlargement & w/o inflammation. Onset (age ~3-6 yrs) begins w/involvement of interphalangeal joints; later involvement of large joints & spine causes significant joint contractures, gait disturbance, & scoliosis &/or kyphosis, → abnormal posture & significant morbidity. Short stature (<3rd centile) becomes evident in adolescence. | Unlike X-linked SEDT, joint swelling & hand involvement are common features of PED. |
| COL2A1 | SED congenita (SEDC) (See Type II Collagen Disorders Overview.) | AD 1 | Usually evident at birth w/disproportionate short stature, short extremities, broad chest, characteristic facies, myopia, & ↑ incidence of cleft palate & hearing loss. Delayed/poor ossification of vertebrae & pubic bones; long bones are short w/hypoplastic epiphyses. ↑ risk for tracheolaryngomalacia & related respiratory complications & retinal detachment. ↑ risk for cervical instability. | SED congenita is most common form of SED. |
| Spondyloperipheral dysplasia (See Type II Collagen Disorders Overview.) | AD | Mild-to-moderate disproportionate short stature & short extremities, brachydactyly type E, short ulnae, variable clubfeet, cleft palate, myopia, & hearing loss; ovoid vertebra, delayed ossification of pubic bones, & flattened & irregular epiphyses in long bones. Premature hip arthrosis causes joint pain. | ||
| COL2A1 COL9A1 COL9A2 COL9A3 COL11A1 COL11A2 | Stickler syndrome | AD AR 2 | Connective tissue disorder; can incl high myopia, hearing loss (both conductive & sensorineural); midfacial underdevelopment & cleft palate (either alone or as part of Robin sequence); & mild SED &/or precocious arthritis. | |
| COL9A1 COL9A2 COL9A3 COMP MATN3 | Multiple epiphyseal dysplasia, autosomal dominant (MED) | AD | Presents early in childhood, usually w/pain in hips &/or knees after exercise; affected children complain of fatigue w/long-distance walking; waddling gait may be present. Adult height in lower range of normal or mildly shortened; limbs relatively short compared to trunk; progressive pain & joint deformity → early-onset osteoarthritis esp of large weight-bearing joints. | By definition, spine in MED is normal, although Schmorl bodies & irregular vertebral end plates may be observed. |
| GALNS GLB1 | Morquio syndrome (MPS IVA & MPS IVB) (See GLB1 Disorders.) | AR | Dysostosis multiplex, odontoid hypoplasia, short stature, hepatomegaly & cloudy corneas |
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; SED = spondyloepiphyseal dysplasia; SEDT = spondyloepiphyseal dysplasia tarda
- 1.
Rare instances of autosomal recessive inheritance in SEDC have been reported (see Type II Collagen Disorders Overview).
- 2.
Stickler syndrome caused by pathogenic variants in COL2A1, COL11A1, or COL11A2 is inherited in an autosomal dominant manner; Stickler syndrome caused by pathogenic variants in COL9A1, COL9A2, or COL9A3 is inherited in an autosomal recessive manner.
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
| System/Concern | Evaluation | Comment |
|---|---|---|
| Skeleton | Complete radiographic survey to incl scoliosis series if clinically indicated | To assess extent of skeletal manifestations |
| Cervical spine |
| To assess for clinically significant odontoid hypoplasia |
| Genetic counseling | By genetics professionals 1 | To inform patients & their families re nature, MOI, & implications of SEDT in order 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
| 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
| 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.