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Spondyloepiphyseal Dysplasia Tarda

NORD is very grateful to George E. Tiller, MD, PhD, Department of Genetics, Southern California Permanente Medical Group, Los Angeles, CA, for assistance in the preparation of this report.

Synonyms of Spondyloepiphyseal Dysplasia Tarda

  • SED tarda
  • X-linked spondyloepiphyseal dysplasia

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Spondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder that only affects males. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk, and premature osteoarthritis.

Symptoms

Symptoms of SEDT are usually not apparent until six to eight years of age, hence the distinction "tarda" or "late". This is the most obvious distinction from the congenital form (SED congenita, or SEDC), which is usually obvious at birth. Unlike SEDC, cleft palate and retinal detachment are not associated with SEDT.

At about 6 to 8 or 10 years, spinal growth appears to decline and then stops. Limb growth continues, resulting in a disproportionately short trunk. Arm span may exceed height by 4 to 8 inches. The shoulders may assume a hunched appearance, the neck appears short and the chest broadens (barrel chest). During adolescence, various skeletal abnormalities may cause pain in the back, hips, shoulders, knees and ankles. Some individuals with SEDT may have a flat appearance to the face, but the shape of the head is usually normal. As adults, people with SEDT have mild dwarfism, with a short trunk, large chest cage and relatively normal limb length. Hands, head and feet appear to be normal size, and final adult height usually ranges from 4'10" to 5'6".

Causes

SEDT is inherited as an X-linked recessive genetic trait. The locus has been mapped to the short arm of the X chromosome at Xp22.2-p22.1. The gene, known as SEDL or TRAPPC2, is widely expressed in tissues throughout the body, but when mutated or deleted appears to only affect cartilage. The protein product, sedlin, is thought to function in intracellular protein trafficking [Venditti et al, 2012] or gene regulation [Jeyabalan et al, 2010]. There are no other disorders linked to TRAPPC2.

Chromosomes, which are present in the nucleus of all cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome Xp22.2-p22.1" refers to a region between bands 22.1 and 22.2 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes, but one of the X chromosomes is normally "turned off" early in fetal development, and most of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder, but rarely display any of its manifestations.

Males have one X chromosome and, if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males cannot pass an X-linked gene to their sons because fathers pass their Y chromosome to their male offspring. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.

Affected Populations

SEDT does not exhibit any ethnic predisposition. Affected individuals have been described in European, American, Asian, and Australian populations (but not in African-Americans to date). One estimate suggests that the incidence is 2 persons per million.

Related Disorders

Morquio syndrome or mucopolysaccharidosis IV is an autosomal recessively inherited metabolic disorder that is usually detectable by 18 months of age. Its features include marked disproportionate short stature, clouding of the cornea, hearing loss, enlarged liver, and excretion of excessive mucopolysaccharides in the urine. This disorder affects males and females equally. (For more information, choose "Morquio" as your search term in the Rare Disease Database.)

Spondyloepiphyseal dysplasia congenita (SED, or SEDC) is a disorder with autosomal dominant inheritance and considerable variability in the severity of symptoms. It is characterized by flat facial profile, marked nearsightedness, , short-trunk dwarfism, waddling gait, normally sized hands and feet, and increased incidence of retinal detachment, cleft palate, and clubfoot. This disorder, which is often detectable at birth, affects males and females equally. (For more information, choose "SED" as your search term in the Rare Disease Database.)

Multiple epiphyseal dysplasia (MED), like SEDC, is usually dominantly inherited and affects males and females equally. The disorder is detectable between two and five years of age with the appearance of a waddling gait and variable short stature. Patients may experience pain as a result of osteoarthritic changes in the joints. Mutations in one of at least six possible genes are responsible for MED.

Standard Therapies

Diagnosis
The diagnosis of SEDT is usually made on the basis of characteristic radiological (X-ray) findings. These appear in late childhood but usually before puberty.[[no paragraph]] Some of these signs are: flattened vertebral bodies (platyspondyly), typical distortions of the upper and lower vertebral surfaces ("humping"), short necks of the thigh bones (femurs), an angular deformity of the neck of the femur (coxa vara), and signs of early arthritis, especially in the hip joints.

Molecular testing for mutations in the SEDL (TRAPPC2) gene is commercially available.

Treatment
Treatment is supportive and symptomatic. Hip replacement may be necessary by the fourth to fifth decade of life.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

Contact for additional information about spondyloepiphyseal dysplasia tarda:

George E Tiller, MD, PhD
Regional Chief, Department of Genetics
Kaiser Permanente
4900 Sunset Blvd
Los Angeles, CA 90027 USA
Tel 323-783-1916 (voicemail)
Tel 323-783-5612 (secretary)
FAX 323-783-5208

Organizations related to Spondyloepiphyseal Dysplasia Tarda

References

TEXTBOOKS
Jones KL, ed. Smith's Recognizable Patterns of Human Malformation. 7th ed. WB Saunders, Philadelphia, 2013.

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, pp 3709-3753.

Hicks J. Spondyloepiphyseal Dysplasia Tarda. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:729-30.

JOURNAL ARTICLES
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;337:1668-1672.

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.

Gedeon AK, Tiller GE, Le Merrer M, et al. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet. 2001;68:1386-97.

Tiller GE, Hannig VL, Dozier D, et al. A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda. Am J Hum Genet.2001;68:1398-407.

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 1999;78:9-25.

INTERNET
Tiller GE, Hannig VL. X-Linked Spondyloepiphyseal Dysplasia Tarda. 2001 Nov 1 [Updated 2011 Feb 15]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews[Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1145/ Accessed Feb 24, 2014.

X-linked spondyloepiphyseal dysplasia tarda. Genetics Home Reference (GHR). June 2008 Available at: http://ghr.nlm.nih.gov/condition=xlinkedspondyloepiphysealdysplasiatarda Accessed Feb 24, 2014.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spondyloepiphyseal Dysplasia Tarda, X-Linked. Entry No: 313400. Last edited 10/25/2012. Available at: http://omim.org/entry/313400 Accessed Feb 24, 2014.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Tracking Protein Particle Complex, Subunit 2. Entry No: 300202. Last edited 10/25/2012. Available at: http://omim.org/entry/300202 Accessed Feb 24, 2014.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2014/03/05 00:00:00 GMT+0

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