Bannerman et al. (1971) cited early reports of this disorder (e.g., Nilsonne, 1927; Barber, 1960) and reviewed the clinical features in a large American family of English origin originally described by Jacobsen (1939). They described the major features ... Bannerman et al. (1971) cited early reports of this disorder (e.g., Nilsonne, 1927; Barber, 1960) and reviewed the clinical features in a large American family of English origin originally described by Jacobsen (1939). They described the major features of the disorder as short stature first evident in childhood between 5 and 14 years; shortness due to impaired growth of the spine; radiologically, characteristic flattening of vertebrae with central humping; dysplastic changes of femoral heads and neck; and minor changes in other bones. Bony changes lead to secondary osteoarthritis, which becomes troublesome in the forties and may be disabling in the sixties. Bannerman (1981) reviewed this material and concluded that heterozygotes show no abnormality such as short stature. Several females had arthritic complaints; e.g., M.Z., the daughter and mother of affected males, had considerable 'arthritis' from age 33 years and by age 51 had almost no movement in either hip and, by x-ray, bony fusion of the left hip. The radiographic features of this disorder are so distinctive that the diagnosis seems unequivocal in the sexually normal, 29-year-old woman (with normal XX karyotype including banding) reported by Monteiro de Pina Neto et al. (1982). No other persons in the family were affected. The authors suggested that she was heterozygous and that chance lyonization of most X chromosomes with the normal allele had occurred. Heuertz et al. (1993) suggested that this disorder was first described by Maroteaux et al. (1957) in a study of 3 large kindreds with 11 affected persons. The disorder is characterized by short stature which becomes evident between 10 and 14 years of age and leads to an average adult height of 1.45 m. Radiologic diagnosis cannot be established before 4 to 6 years of age. Bone changes of the femoral head lead to secondary osteoarthritis during adulthood and some patients require total arthroplasty of the hip before the age of 40 years. Whyte et al. (1999) described the clinical and radiographic evaluation of a second large American kindred with X-linked recessive SEDT, the first such family being the classic family reported by Jacobsen (1939).
Gedeon et al. (1999) detected 3 dinucleotide deletions in the SEDL gene (300202.0001-300202.0003) in 3 Australian families, resulting in frameshifts premature stop codons.
In an Ashkenazi Jewish family with SEDT, Bar-Yosef et al. (2004) identified a ... Gedeon et al. (1999) detected 3 dinucleotide deletions in the SEDL gene (300202.0001-300202.0003) in 3 Australian families, resulting in frameshifts premature stop codons. In an Ashkenazi Jewish family with SEDT, Bar-Yosef et al. (2004) identified a single nucleotide deletion at position 613 in the SEDL gene (300202.0011). The authors stated that this was the first report of an SEDL mutation in a Jewish family.
X-linked SEDT is suggested in males with the following findings: ...
DiagnosisClinical DiagnosisX-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)TestingRoutine 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):FigureFigure 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 TestingGene. TRAPPC2 (previously known as SEDL) is the only gene in which mutations are known to cause X-linked spondyloepiphyseal dysplasia tarda. Clinical testingSequence 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 SEDTView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityMalesHeterozygous FemalesTRAPPC2Sequence analysisSequence variants 2100% 380% 4ClinicalDeletion/ duplication analysis 5Deletion/duplication of one or more exons or the whole gene 20% 620%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. 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.6. Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysisInterpretation 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.Genetically Related (Allelic) DisordersNo other phenotypes are known to be associated with mutations in TRAPPC2.
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]. ...
Natural HistoryMales. 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].
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....
Genotype-Phenotype CorrelationsData 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.
X-linked spondyloepiphyseal dysplasia tarda is distinguished from other forms of spondyloepiphyseal dysplasia (SED) by its later onset and X-linked inheritance. These other forms of SED include the following: ...
Differential DiagnosisX-linked spondyloepiphyseal dysplasia tarda is distinguished from other forms of spondyloepiphyseal dysplasia (SED) by its later onset and X-linked inheritance. These other forms of SED include the following: SED congenita, inherited in an autosomal dominant manner; usually evident at birth with disproportionately short stature and diagnostic radiographic changes. Affected individuals often have midline cleft palate and are at risk for hearing loss and high myopia with retinal detachment. It is the most common form of SED. SED congenita is caused by mutations in COL2A1, the gene encoding type II collagen. SED tarda, autosomal forms (rare). A dominant form may be caused by mutations in COL2A1; a recessive form has been described clinically but not molecularly defined. Morquio syndrome (mucopolysaccharidosis type IV), inherited in an autosomal recessive manner, is caused by deficiency in one of two enzymes: N-acetyl-galactosamine-6-sulfatase or beta-galactosidase. It is characterized by mild dysostosis multiplex, odontoid hypoplasia, short stature, and cloudy corneas. Multiple epiphyseal dysplasia (MED), inherited in an autosomal dominant manner, presents early in childhood, usually with pain in the hips and/or knees after exercise. Adult height is either in the lower range of normal or mildly shortened. The limbs are relatively short in comparison to the trunk. Pain and joint deformity progress, resulting in early-onset osteoarthritis particularly of the large weight-bearing joints. By definition, the spine is normal, although Schmorl bodies and irregular vertebral end plates may be observed. Mutations in five genes have been shown to cause dominant MED: COMP, COL9A1, COL9A2, COL9A3, and MATN3. Scheuermann disease, a term applied to premature osteoarthritis of the spine, regardless of the etiology Spondyloperipheral dysplasia, inherited in an autosomal dominant manner; also presents with short hands, feet, and ulnae. One family has been reported with a mutation in COL2A1. Stickler syndrome, inherited in an autosomal dominant manner, is variable and can include myopia, cataract, and retinal detachment; hearing loss that is both conductive and sensorineural; midfacial underdevelopment and cleft palate (either alone or as part of the Robin sequence); and mild spondyloepiphyseal dysplasia and/or precocious arthritis. Most affected individuals have a truncation mutation in COL2A1; mutations in COL11A1 and COL11A2 have also been described. Some individuals do not have an identified mutation. Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with X-linked spondyloepiphyseal dysplasia tarda (SEDT), the following is noted:...
ManagementEvaluations 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 ManifestationsSurgical 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. SurveillanceAffected 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 AvoidIn 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. Evaluation of Relatives at RiskIf 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. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch 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.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Spondyloepiphyseal Dysplasia Tarda, X-Linked: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDTRAPPC2Xp22.2Trafficking protein particle complex subunit 2TRAPPC2 homepage - Mendelian genesTRAPPC2Data 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 Spondyloepiphyseal Dysplasia Tarda, X-Linked (View All in OMIM) View in own window 300202TRACKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2; TRAPPC2 313400SPONDYLOEPIPHYSEAL DYSPLASIA TARDA, X-LINKED; SEDTNormal allelic variants. TRAPPC2 (previously known as SEDL) is composed of six exons, with the start site for translation located in exon 3. No normal allelic variants have been reported. Pathologic allelic variants. Mutations in TRAPPC2 (SEDL) causing X-linked SEDT include splice site mutations, nonsense mutations, deletions, and rare missense mutations. Examples include: dinucleotide deletions in exons 3, 4, and 5; tetranucleotide deletion in exon 6; pentanucleotide deletion in exon 5; splice donor site mutations 3' to exons 3 and 4; splice acceptor site mutations 5' to exons 2, 3, 4, 5, and 6; nonsense mutations in exons 3, 4, 5, and 6; missense mutations (detailed in Table 3); and deletions of exons 3, 6, and 4-6. Table 2 summarizes recurrent mutations. Note: The exonic and multiexonic deletions (see also HGMD in Table A) would not be detected in female carriers by sequence analysis (see Table 1).Table 2. Recurrent Pathologic Allelic Variants in TRAPPC2 (SEDL)View in own window% of All Affected IndividualsPathologic Allelic Variant 1~18%c.93+5G>A ~5%c.157_158delAT~4%c.191_192delTG~13% c.271_275delCAAGA ~9%Other recurrent mutations As reviewed by Gedeon et al [2001], Savarirayan et al [2003], Shaw et al [2003], and Fiedler et al [2004]1. See Table 3 for detailed information on each mutation.Table 3. Selected TRAPPC2 (SEDL) Pathologic Variants View in own windowDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference Sequencesc.93+5G>A (IVS3+5G>A)--NM_001011658.3 NP_001011658.1c.139G>Tp.Asp47Tyr c.157_158delATp.Met53Valfs*35c.191_192delTGp.Val64Glyfs*24c.218C>Tp.Ser73Leuc.248T>Cp.Phe83Serc.271_275delCAAGAp.Gln91Argfs*9c.389T>Ap.Val130AspSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. TRAPPC2 encodes a 140-amino acid protein of unknown function, which appears to be ubiquitously expressed [Gedeon et al 1999, Gecz et al 2000]. Functional motifs within the protein sequence have yet to be identified. Based on function of the yeast homolog, sedlin may be involved with intracellular protein trafficking, as part of the TRAPP (transport protein particle) complex [Jang et al 2002]. Other studies have demonstrated localization of TRAPPC2 to the nucleus, where it interacts with various transcription factors [Jeyabalan et al 2010, Liu et al 2010].Abnormal gene product. Almost all mutations identified in TRAPPC2 are predicted to generate a null allele or truncated protein product.