Spondyloepiphyseal Dysplasia Tarda

Disease Overview

Summary

Spondyloepiphyseal dysplasia tarda (SEDT; SEDL) is a rare, hereditary skeletal disorder. Physical characteristics include moderate short stature (dwarfism), moderate-to-severe spinal deformities, barrel-shaped chest, disproportionately short trunk and premature osteoarthritis. It is inherited as an X-linked recessive disorder and typically only males will develop SEDT.

Introduction
SEDT commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive “tarda” forms have been described. In the 2023 revision of the Nosology of Genetic Skeletal Disorders, X-linked SEDT is referred to as TRAPPC2-related X-linked spondyloepiphyseal dysplasia tarda and included in the group of conditions called spondyloepi(meta)physeal dysplasias.

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Synonyms

• SED tarda
• X-linked spondyloepiphyseal dysplasia
• SEDL
• SEDT
• TRAPPC2-related X-linked spondyloepiphyseal dysplasia tarda

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Signs & Symptoms

Young boys with SEDT do not typically show signs of the condition and have otherwise normal height and body proportions until the age of 6 to 8 years old. Around this time, symptoms of the disorder begin to develop, hence the word “tarda” in SEDT which refers to the later onset of this condition.

At ages 6 to 8 years, the following symptoms may be seen: spine growth slows and eventually stops while the arms and legs continue to grow. This results in a disproportionately short trunk (the part of the body containing the chest, stomach and back) as well as height below normal for age (short stature). Arm growth can result in an arm span that exceeds the child’s height by 4 to 8 inches. The chest can become rounded and protrude outwards in a bulging manner (barrel-shaped chest).

Around puberty other symptoms may develop, but some of these may develop before puberty. These symptoms include a short neck and skeletal abnormalities of the spine that can cause rounding of the upper back (dorsal kyphosis) or an excessive inward curvature of the lower spine (lumbar hyperlordosis). These skeletal abnormalities can also cause a wearing down of the cartilage at the ends of the bones (osteoarthritis), often seen earliest in the hips but also in the joints of the back, knees, ankles and shoulders. Osteoarthritis can cause discomfort and pain. Where and when osteoarthritis develops varies between boys affected with SEDT.

Regarding the face, some boys may have a flatter appearance to their face (midface retrusion), but the head shape is usually normal.

By adulthood, men with SEDT tend to have normal sized head, hands and feet and normal limb lengths. However, a barrel-shaped chest, short stature and short trunk are more readily apparent. The final height of adults with SEDT typically ranges from 4’10” to 5’6”.

Males with SEDT reach normal motor and cognitive milestones and are expected to have a normal lifespan. While SEDT mostly affects males, rare cases of females with SEDT have been seen though they typically have mild symptoms.

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Causes

SEDT is caused by changes (mutations) in a gene on 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 mutations in this gene appear to only affect cartilage. Mutations have been found to be distributed throughout the gene [Gedeon et al., 2001]. The TRAPPC2 gene encodes the instructions for a protein product called sedlin, which is thought to help transport proteins within the cell. 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.

SEDT is inherited in an X-linked recessive pattern. X-linked genetic disorders are conditions caused by a non-working gene on the X chromosome and manifest mostly in males. Females that have a non-working gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and only one carries the non-working gene. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a non-working gene, he will develop the disease.

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.

If a male with an X-linked disorder can reproduce, he will pass the non-working gene to all of his daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

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Affected populations

SEDT affects individuals of many different ancestral groups. Individuals with SEDT have been reported in European, American, Asian and Australian populations (but not in populations of African ancestry to date). SEDT is estimated to occur in 2 persons per million.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of spondyloepiphyseal dysplasia tarda. Comparisons may be useful for a differential diagnosis.

Morquio syndrome (mucopolysaccharidosis IV) is an autosomal recessive metabolic disorder that is usually diagnosed by 18 months of age. Patients have marked disproportionate short stature, clouding of the cornea, hearing loss, enlarged liver and spleen, and excretion of excessive mucopolysaccharides in the urine. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “mucopolysaccharidosis IV” as your search term in the Rare Disease Database.)

Autosomal dominant multiple epiphyseal dysplasia (MED) is a disorder with autosomal dominant inheritance and variable severity of symptoms. Unlike SEDT, it affects males and females equally. Symptoms of MED appear between two and five years of age and include a waddling gait and short stature. Individuals with MED may experience pain because of osteoarthritis in the joints. Dysfunction of one of at least five possible genes are responsible for MED. (For more information, choose “dominant multiple epiphyseal dysplasia” as your search term in the Rare Disease Database.)

Progressive pseudorheumatoid dysplasia (PPD or PPAC) is a disorder with autosomal recessive inheritance that is usually diagnosed between three and six years of age. Patients have stiff joints, short stature, abnormal walking pattern and widening of the ends of fingers, toes and other bones. Unlike SEDT, this disorder affects males and females equally.

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 stature, waddling gait, normally sized hands and feet and increased incidence of retinal detachment, cleft palate and clubfoot. Unlike SEDT, this disorder is often diagnosed at birth and affects males and females equally. (For more information, choose “SEDC” as your search term in the Rare Disease Database.)

Stickler syndrome refers to a group of connective tissue disorders. Mutations in one of at least six possible genes are responsible for Stickler syndrome. Some types of Stickler syndrome have autosomal dominant inheritance and others have autosomal recessive inheritance, depending on what gene is involved. The symptoms of this disorder vary greatly from one individual to another. Most often the eyes, ears, skeleton and joints are affected. Individuals with Stickler syndrome can have nearsightedness, retinal holes and detachments, hearing loss, facial flatness, musculoskeletal problems or other issues. Unlike SEDT, this disorder affects males and females equally. (For more information, choose “Stickler” as your search term in the Rare Disease Database.)

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Diagnosis

A diagnosis of SEDT is usually made through radiological findings (X-ray), but a diagnosis can also be made through molecular genetic testing.

In radiological diagnosis of SEDT, X-ray is used to look for characteristic skeletal abnormalities that are usually seen in late childhood but before puberty. These features include abnormal growth at the ends of bones (multiple epiphyseal dysplasia), flattened bones in the spine (platyspondyly), excessive curvature (“humping”) of the upper or lower spine, a sideways curvature of the spine (scoliosis), shortened bones of the thighs and structural deformities in the round ball of the hip bone (coxa vara).

By adulthood, some other radiological findings that can lead to a diagnosis of SEDT include an abnormal narrowing of the space between the spinal discs and evidence of early osteoarthritis in the skeletal system, especially in the hip joints.

For a molecular diagnosis of SEDT, a genetic test can be used to look for specific mutations in the TRAPPC2 gene that are known or expected to be disease-causing (pathogenic).

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Standard Therapies

Treatment

Treatment is supportive and directed towards the specific symptoms that are apparent in each person. Individuals with abnormal sideways curving of the spine (scoliosis) or a rounded, hunched back (kyphoscoliosis) may need to meet with a specialist who can help assess and treat problems of the skeleton and associated muscles and joints (an orthopedic surgeon). In some patients, spine surgery might be recommended to help correct the spine. Some individuals may also need to have hip, knee or shoulder replacement surgeries later in life.

Genetic counseling is recommended for affected individuals and their families.

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Clinical Trials and Studies

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

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

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/

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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

Kim JJ, Lipatova Z & Segev N.Trapp complexes in secretion and autophagy. Frontiers in cell and developmental biology. Front Cell Dev Biol. 2016; 4:20.
Published online 2016 Mar 30. doi: 10.3389/fcell.2016.00020

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. X-Linked Spondyloepiphyseal Dysplasia Tarda. 2001 Nov 1 [Updated 2020 Nov 5]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1145/ Accessed March 30, 2022.

X-linked spondyloepiphyseal dysplasia tarda. Genetics Home Reference. Updated 8/18/20. Available at: https://ghr.nlm.nih.gov/condition=xlinkedspondyloepiphysealdysplasiatarda Accessed March 30, 2022.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Spondyloepiphyseal Dysplasia Tarda, X-Linked. Entry No: 313400. Last edited 02/01/2017. Available at: https://omim.org/entry/313400 Accessed March 30, 2022.

Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Tracking Protein Particle Complex, Subunit 2. Entry No: 300202. Last edited04/25/2014. Available at: https://omim.org/entry/300202 Accessed March 30, 2022.

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