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X-Linked Spondyloepiphyseal Dysplasia Tarda

, MD, PhD.

Author Information

Initial Posting: ; Last Update: November 5, 2020.

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 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.

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 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 1MethodProportion of Probands with a Pathogenic Variant 2 Detectable by Method
TRAPPC2 Sequence analysis 3, 484% 5
Gene-targeted deletion/duplication analysis 616% 7
Unknown 8NARare
1.
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)DisorderMOIClinical Features of Differential Diagnosis DisorderDistinguishing Features/
Comment
CCN6
(WISP3)
Progressive pseudorheumatoid dysplasia (PED)ARPredominant 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 1Usually 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.)ADMild-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)ADPresents 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.)ARDysostosis 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/ConcernEvaluationComment
Skeleton Complete radiographic survey to incl scoliosis series if clinically indicatedTo 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 patients w/delayed ossification in upper cervical spine)
To assess for clinically significant odontoid hypoplasia
Genetic
counseling
By genetics professionals 1To inform patients & their families re nature, MOI, & implications of SEDT in order to facilitate medical & personal decision making
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
TreatmentConsiderations/
Other
Odontoid
hypoplasia
Precautions during intubation/surgery to avoid hyperextensionObtain cervical spinal films prior to any surgical procedure involving general anesthesia to assess for clinically significant odontoid hypoplasia.
Scoliosis/
Kyphoscoliosis
  • Treatment per orthopedic surgeon
  • Spine surgery (correction of scoliosis or kyphosis) may be indicated.
Osteoarthritis
  • Chronic pain management
  • Surgical intervention may incl joint replacement (hip, knee, shoulder).

Surveillance

Table 5.

Recommended Surveillance for Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda

System/ConcernEvaluationFrequency
Odontoid hypoplasia Flexion-extension radiographs of cervical spineObtain prior to school age to assess for clinically significant odontoid hypoplasia.
Scoliosis/
Kyphoscoliosis
Clinical eval w/spine radiographs if clinically indicatedAnnually
Osteoarthritis Clinical eval for osteoarthritisAnnually

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:

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].

Related Genetic Counseling Issues

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

Family planning

  • The optimal time for determination of genetic risk, clarification of genetic status, 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.

DNA banking. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been established (i.e., the causative genetic alteration/s are unknown).

Prenatal Testing and Preimplantation Genetic Testing

Once the X-linked SEDT-causing pathogenic variant has been identified in an affected family member, prenatal testing for a pregnancy at increased risk 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.

  • Human Growth Foundation (HGF)
    997 Glen Cove Avenue
    Suite 5
    Glen Head NY 11545
    Phone: 800-451-6434 (toll-free)
    Fax: 516-671-4055
    Email: hgf1@hgfound.org
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • MAGIC Foundation
    4200 Cantera Drive #106
    Warrenville IL 60555
    Phone: 800-362-4423 (Toll-free Parent Help Line); 630-836-8200
    Fax: 630-836-8181
    Email: contactus@magicfoundation.org
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Fax: 310-206-5266
    Email: Salon@mednet.ucla.edu

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

GeneChromosome LocusProteinLocus-Specific DatabasesHGMDClinVar
TRAPPC2 Xp22​.2 Trafficking protein particle complex subunit 2 TRAPPC2 database TRAPPC2 TRAPPC2

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.

Table B.

OMIM Entries for X-Linked Spondyloepiphyseal Dysplasia Tarda (View All in OMIM)

300202TRACKING PROTEIN PARTICLE COMPLEX, SUBUNIT 2; TRAPPC2
313400SPONDYLOEPIPHYSEAL DYSPLASIA TARDA, X-LINKED; SEDT

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

Reference SequencesDNA Nucleotide
Change
Predicted
Protein Change
% of All Affected
Individuals w/Variant
Comment [Reference]
NM_001011658​.3
NP_001011658​.1
c.93+5G>A--~18%Reviewed by Gedeon et al [2001], Tiller et al [2001], Shaw et al [2003], & Fiedler et al [2004]
c.157_158delATp.Met53ValfsTer35~5%
c.191_192delTGp.Val64GlyfsTer24~4%
c.271_275delCAAGAp.Gln91ArgfsTer9~13%

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

  • 5 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

References

Literature Cited

  • 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]
  • Gécz 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]
  • 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]
  • 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]
  • Jones KL, Jones MC, del Campo M. Smith's Recognizable Patterns of Human Malformation. 7 ed. Philadelphia, PA: WB Saunders; 2013.
  • 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;99:328–30. [PubMed: 11252002]
  • Rimoin DL, Lachman RS, Unger S. Chondrodysplasias. In: Rimoin DL, Pyeritz RE, Korf BR, eds. Emery & Rimoin’s Principles and Practice of Medical Genetics. 6 ed. New York, NY: Academic Press; 2013.
  • 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]
  • Shu SG, Tsai CR, Chi CS. Spondyloepiphyseal dysplasia tarda: report of one case. Acta Paediatr Taiwan. 2002;43:106–8. [PubMed: 12041616]
  • Stenson PD, Mort M, Ball EV, Evans K, Hayden M, Heywood S, Hussain M, Phillips AD, Cooper DN. The Human Gene Mutation Database: towards a comprehensive repository of inherited mutation data for medical research, genetic diagnosis and next-generation sequencing studies. Hum Genet. 2017;136:665–77. [PMC free article: PMC5429360] [PubMed: 28349240]
  • 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;68:1398–407. [PMC free article: PMC1226126] [PubMed: 11326333]
  • Venditti R, Scanu T, Santoro M, Di Tullio G, Spaar A, Gaibisso R, Beznoussenko GV, Mironov AA, Mironov A Jr, Zelante L, Piemontese MR, Notarangelo A, Malhotra V, Vertel BM, Wilson C, De Matteis MA. Sedlin controls the ER export of procollagen by regulating the Sar1 cycle. Science. 2012;337:1668–72. [PMC free article: PMC3471527] [PubMed: 23019651]
  • 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;78:9–25. [PubMed: 9990351]
  • 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]
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