Clinical Diagnosis

X-linked SEDT is suggested 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 around 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)

Testing

Routine laboratory test results are normal in affected males and carrier females.

Radiographic Findings

Affected males. The diagnosis of X-linked SEDT can be established by the observation of the following radiographic findings, which may not be manifest in early childhood and typically appear prior to puberty (Figure 1):

Figure

Figure 1. Radiographs of a 31-year-old male with SEDT
A. Platyspondyly with superior and inferior humping of vertebral bodies
B. Severe degenerative changes in both hip joints.

• Multiple epiphyseal abnormalities

• Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood

• Scoliosis

• 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.

Carrier females. One report described phenotypically normal females with mild radiologically detectable osteoarthritic changes [Whyte et al 1999].

Molecular Genetic Testing

Gene. TRAPPC2 (previously known as SEDL) is the only gene in which mutations are known to cause X-linked spondyloepiphyseal dysplasia tarda.

Clinical testing

• Sequence analysis. Deletions as well as splice, missense, and nonsense mutations have been identified in roughly 80% of males with clinically diagnosed X-linked SEDT [Gedeon et al 2001, Tiller et al 2001, Savarirayan et al 2003, Shaw et al 2003, Fiedler et al 2004]. Recurrent mutations account for roughly half of all mutations.

• Deletion/duplication analysis can detect exonic and multiexonic deletions (see Molecular Genetics, Pathologic allelic variants) that are not detected in female carriers by sequence analysis and can identify or confirm exonic or multiexonic deletions in males.

Table 1. Summary of Molecular Genetic Testing Used in X-linked SEDT

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Males	Heterozygous Females
TRAPPC2	Sequence analysis	Sequence variants 2	100% 3	80% 4	Clinical
	Deletion/ duplication analysis 5	Deletion/duplication of one or more exons or the whole gene	20% 6	20%

Test Availability refers to availability in the GeneTests Laboratory Directory. GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.

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. Lack of amplification by PCRs prior to sequence analysis can suggest a putative deletion of one or more exons or the entire X-linked gene in a male; confirmation may require additional testing by deletion/duplication analysis. See footnote 6.

4. Sequence analysis of genomic DNA cannot detect deletion of one or more exons or the entire X-linked gene in a heterozygous female.

5. Testing that identifies deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted array GH (gene/segment-specific) may be used. A full array GH analysis that detects deletions/duplications across the genome may also include this gene/segment. See array GH.

6. Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis

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

• In males with characteristic findings on skeletal x-rays and a family history consistent with X-linked inheritance, molecular genetic testing can be used to confirm the diagnosis.

• The majority of mutations detected are point mutations or 2- to 5-bp deletions; therefore, sequence analysis is the first diagnostic test of choice. Affected males in whom specific exon(s) cannot be amplified by PCR are presumed to harbor genomic deletions. Such mutations may possibly be characterized by deletion/duplication analysis.

Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family.

Note: (1) Carriers are heterozygotes for this X-linked recessive disorder and may possibly develop minimal clinical findings attributable to the disorder. (2) Identification of female carriers requires either (a) prior identification of the disease-causing mutation in the family or, (b) if an affected male is not available for testing, molecular genetic testing by sequence analysis. Note: If no mutation is identified, methods to detect gross structural abnormalities may be available in a laboratory offering deletion/duplication analysis.

Predictive testing for at-risk male relatives requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotypes are known to be associated with mutations in TRAPPC2.

Natural History

Males. At birth, affected males are normal in size and have normal body proportions. Affected males exhibit retarded linear growth beginning around grade school (ages six to eight years). Final adult height is typically 137-163 cm [Whyte et al 1999, Jones 2006, Unger et al 2007].

Adults with X-linked SEDT have disproportionately short stature with short trunk and arm span significantly greater than height.

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.

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 gene mutation. All mutations identified thus far, irrespective of their molecular basis, result in an almost identical phenotype, including the true null mutations.

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].

Mutations in TRAPPC2 (SEDL) have been found in several ethnic groups 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with X-linked spondyloepiphyseal dysplasia tarda (SEDT), the following is noted:

• The radiographic survey necessary for an accurate diagnosis also serves to document the extent of disease at the time of presentation.

• Individuals with X-linked SEDT need to be assessed for the possibility of clinically significant odontoid hypoplasia.

Treatment of Manifestations

Surgical intervention may include joint replacement (hip, knee, shoulder) or spine surgery (correction of scoliosis or kyphosis).

Chronic pain management preceding or following orthopedic surgery is standard and often required.

Surveillance

Affected individuals should be followed annually for the development of joint pain and scoliosis.

Cervical spinal films should be obtained prior to:

• School age to assess for clinically significant odontoid hypoplasia;

• Any surgical procedure involving general anesthesia to assess for clinically significant odontoid hypoplasia.

Agents/Circumstances to Avoid

In individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.

Activities and occupations that place undue stress on the spine and weight-bearing joints should be avoided.

Testing of Relatives at Risk

If the disease-causing mutation in the family is known, presymptomatic testing of at-risk males allows early diagnosis and may obviate unnecessary diagnostic testing for other causes of short stature and/or osteoarthritis.

Therapies Under Investigation

Search ClinicalTrials.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.

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

X-linked spondyloepiphyseal dysplasia tarda is inherited in an X-linked recessive manner.

Risk to Family Members

Parents of a proband

• The father of a proband is unaffected and is not a carrier.

• A woman who has an affected son and one other affected male relative is an obligate carrier.

• In reported cases in which molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a mutation in TRAPPC2 (SEDL) 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 depends on the carrier status of the mother.

• If the mother is a carrier, the chance of transmitting the disease-causing mutation in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will usually not be affected.

• If the mother is not a carrier, the risk to sibs is low but greater than that of the general population; although research studies have not identified germline mosaicism in mothers who have one affected son and an otherwise negative family history, the risk of germline mosaicism in mothers is not known.

Offspring of a proband. None of the sons of an affected male will be affected. All daughters will be carriers of the TRAPPC2 mutation.

Other family members of a proband. The proband's maternal aunts and their offspring may be at risk of being carriers or of being affected (depending on their gender, family relationship, and the carrier status of the proband's mother).

Carrier Detection

Carrier testing of at-risk female relatives using molecular genetic techniques is possible if the disease-causing mutation has been identified in an affected family member.

Related Genetic Counseling Issues

See Management, Testing Relatives at Risk for information on testing at-risk relatives for the purpose of early diagnosis and treatment.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

Prenatal testing is possible for pregnancies of women who are carriers. The usual procedure is to determine sex by chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about ten to 12 weeks' gestation or by amniocentesis usually performed at about 15 to 18 weeks' gestation. If the karyotype is 46,XY and if the disease-causing mutation has been identified in a family member, DNA from fetal cells can be analyzed for the known disease-causing mutation.

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

Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include clinical uses of testing available from laboratories listed in the GeneTests Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Literature Cited

1. Fiedler J, Le Merrer M, Mortier G, Heuertz S, Faivre L, Brenner RE. X-linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families. Hum Mutat. 2004;24:103. [PubMed: 15221797]
2. Gecz J, Hillman MA, Gedeon AK, Cox TC, Baker E, Mulley JC. Gene structure and expression study of the SEDL gene for spondyloepiphyseal dysplasia tarda. Genomics. 2000;69:242–51. [PubMed: 11031107]
3. Gedeon AK, Colley A, Jamieson R, Thompson EM, Rogers J, Sillence D, Tiller GE, Mulley JC, Gecz J. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda. Nat Genet. 1999;22:400–4. [PubMed: 10431248]
4. Gedeon AK, Tiller GE, Le Merrer M, Heuertz S, Tranebjaerg L, Chitayat D, Robertson S, Glass IA, Savarirayan R, Cole WG, Rimoin DL, Kousseff BG, Ohashi H, Zabel B, Munnich A, Gecz J, Mulley JC. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet. 2001;68:1386–97. [PMC free article: PMC1226125] [PubMed: 11349230]
5. Jang SB, Kim YG, Cho YS, Suh PG, Kim KH, Oh BH. Crystal structure of SEDL and its implications for a genetic disease spondyloepiphyseal dysplasia tarda. J Biol Chem. 2002;277:49863–9. [PubMed: 12361953]
6. Jeyabalan J, Nesbit MA, Galvanovskis J, Callaghan R, Rorsman P, Thakker RV. SEDLIN forms homodimers: characterisation of SEDLIN mutations and their interactions with transcription factors MBP1, PITX1 and SF1. PLoS One. 2010;5(5):e10646. [PMC free article: PMC2871040] [PubMed: 20498720]
7. Jones KL. Smith's Recognizable Patterns of Human Mutation, 6 ed. Philadelphia: WB Saunders; 2006:426-7.
8. Liu X, Wang Y, Zhu H, Zhang Q, Xing X, Wu B, Song L, Fan L. Interaction of Sedlin with PAM14. J Cell Biochem. 2010;109(6):1129–33. [PubMed: 20108251]
9. Matsui Y, Yasui N, Ozono K, Yamagata M, Kawabata H, Yoshikawa H. Loss of the SEDL gene product (Sedlin) causes X-linked spondyloepiphyseal dysplasia tarda: Identification of a molecular defect in a Japanese family. Am J Med Genet. 2001;99(4):328–30. [PubMed: 11252002]
10. Savarirayan R, Thompson E, Gecz J. Spondyloepiphyseal dysplasia tarda (SEDL, MIM #313400). Eur J Hum Genet. 2003;11:639–42. [PubMed: 12939648]
11. Shaw MA, Brunetti-Pierri N, Kadasi L, Kovacova V, Van Maldergem L, De Brasi D, Salerno M, Gecz J. Identification of three novel SEDL mutations, including mutation in the rare, non-canonical splice site of exon 4. Clin Genet. 2003;64:235–42. [PubMed: 12919139]
12. Shu SG, Tsai CR, Chi CS. Spondyloepiphyseal dysplasia tarda: report of one case. Acta Paediatr Taiwan. 2002;43(2):106–8. [PubMed: 12041616]
13. Tiller GE, Hannig VL, Dozier D, Carrel L, Trevarthen KC, Wilcox WR, Mundlos S, Haines JL, Gedeon AK, Gecz J. A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet. 2001;68:1398–1407. [PMC free article: PMC1226126] [PubMed: 11326333]
14. Unger S, Lachman RS, Rimoin DL: Chondrodysplasias. In: Rimoin DL, Connor JM, Pyeritz RE, Korf BR, eds. Emery & Rimoin’s Principles and Practice of Medical Genetics. 5th ed. New York: Churchill Livingstone; 2007:3709-53.
15. Whyte MP, Gottesman GS, Eddy MC, McAlister WH. X-linked recessive spondyloepiphyseal dysplasia tarda. Clinical and radiographic evolution in a 6-generation kindred and review of the literature. Medicine (Baltimore). 1999;78(1):9–25. [PubMed: 9990351]
16. Wynne-Davies R, Gormley J. The prevalence of skeletal dysplasias. An estimate of their minimum frequency and the number of patients requiring orthopaedic care. J Bone Joint Surg Br. 1985;67:133–7. [PubMed: 3155744]

Revision History

• 15 February 2011 (me) Comprehensive update posted live

• 5 April 2006 (me) Comprehensive update posted to live Web site

• 10 February 2004 (me) Comprehensive update posted to live Web site

• 30 December 2003 (cd) Revision: change in test availability

• 1 November 2001 (me) Review posted to live Web site

• 16 May 2001 (gt) Original submission