Spondyloepiphyseal dysplasia tarda X-linked

Other Names: SED; X linked spondyloepiphyseal dysplasia tarda; X-linked spondyloepiphyseal dysplasia

X-linked spondyloepiphyseal dysplasia tarda is a condition that impairs bone growth and occurs almost exclusively in males. The name of the condition indicates that it affects the bones of the spine (spondylo-) and the ends of long bones (epiphyses) in the arms and legs. "Tarda" indicates that signs and symptoms of this condition are not present at birth, but appear later in childhood, typically between ages 6 and 10.

Epidemiology

The prevalence of X-linked spondyloepiphyseal dysplasia tarda is estimated to be 1 in 150,000 to 200,000 people worldwide.

Cause

Mutations in the TRAPPC2 gene cause X-linked spondyloepiphyseal dysplasia tarda. The TRAPPC2 gene provides instructions for producing the protein sedlin. Sedlin is part of a large group of proteins called the trafficking protein particle (TRAPP) complex, which plays a role in the transport of proteins between various cell compartments (organelles). Research shows that sedlin is required for transporting large proteins out of the endoplasmic reticulum, which is an organelle that is involved in protein processing and transport. For example, sedlin is needed to move large molecules called procollagens out of the endoplasmic reticulum so they can be processed by enzymes to create smaller mature collagen proteins, which strengthen and support connective tissues, such as skin, bone, cartilage, tendons, and ligaments.

Almost all TRAPPC2 gene mutations that cause X-linked spondyloepiphyseal dysplasia tarda result in a nonfunctional sedlin protein. As a result, large proteins, including procollagen, cannot be transported out of the endoplasmic reticulum. A lack of procollagen transport results in a decrease in mature collagen in cells and impairs the development of bones, cartilage, and other connective tissues. It is likely that this disruption in bone development leads to many of the signs and symptoms of X-linked spondyloepiphyseal dysplasia tarda, although it is unclear why the skeletal problems do not appear until later in childhood.

In about 10 percent of affected males, an identified mutation in the TRAPPC2 gene is not found. The cause of the condition in these individuals is unknown.

Inheritance

X-linked recessive inheritance

X-linked spondyloepiphyseal dysplasia tarda is inherited in an X-linked recessive pattern. The TRAPPC2 gene is located on the X chromosome, which is one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. In females (who have two X chromosomes), a mutation must be present in both copies of the gene to cause the disorder. Males are affected by X-linked recessive disorders much more frequently than females. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons. In X-linked recessive inheritance, a female with one mutated copy of the gene in each cell is called a carrier. She can pass on the altered gene, but usually does not experience signs and symptoms of the disorder. In rare cases, however, females who carry a TRAPPC2 gene mutation may develop osteoarthritis in early adulthood.

Signs and symptoms

Males with X-linked spondyloepiphyseal dysplasia tarda have skeletal abnormalities and short stature. Affected boys grow steadily until late childhood, when their growth slows. Their adult height ranges from 4 feet 6 inches (137 cm) to 5 feet 4 inches (163 cm). Impaired growth of the spinal bones (vertebrae) primarily causes the short stature.

Spinal abnormalities include flattened vertebrae (platyspondyly) with hump-shaped bulges, progressive thinning of the discs between vertebrae, and an abnormal curvature of the spine (scoliosis or kyphosis). These spinal problems also cause back pain in people with this condition. Individuals with X-linked spondyloepiphyseal dysplasia tarda have a short torso and neck, and their arms are disproportionately long compared to their height.

Other skeletal features of X-linked spondyloepiphyseal dysplasia tarda include an abnormality of the hip joint that causes the upper leg bones to turn inward (coxa vara); multiple abnormalities of the epiphyses, including a short upper end of the thigh bone (femoral neck); and a broad, barrel-shaped chest. A painful joint condition called osteoarthritis that typically occurs in older adults often develops in early adulthood in people with X-linked spondyloepiphyseal dysplasia tarda and worsens over time, most often affecting the hips, knees, and shoulders.

Diagnosis

The diagnosis of X-linked SEDT, which relies on a combination of clinical and radiographic features, is usually possible in childhood. Adolescent and adult males have disproportionately short stature with 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. Characteristic radiographic findings, which typically appear prior to puberty, include: 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; and evidence of premature osteoarthritis beginning in young adulthood. TRAPPC2 (SEDL) is the only gene in which pathogenic variants are known to cause X-linked SEDT. Molecular genetic testing reveals a pathogenic variant in TRAPPC2 in more than 80% of males with a clinical diagnosis of X-linked SEDT.

Treatment

Many affected individuals require joint replacement surgery (hip, knee, shoulder) or spine surgery (correction of scoliosis or kyphosis). Hip replacement is often required as early as 30 years of age. Chronic pain management is standard and often required before or after surgery. Affected individuals should be regularly followed by a professional familiar with this condition for the development of joint pain and scoliosis.

Prognosis

Affected males usually show signs and symptoms of this condition between 5 and 10 years of age. Progressive joint and back pain usually increases with age. The hips, knees, and shoulder joints are commonly involved to variable degrees. The joints in the hands and feet are usually not affected. Given the skeletal and joint abnormalities seen in this condition, affected individuals are often advised to avoid activities that place undue stress on the spine and weight-bearing joints. Affected males appear to have a normal lifespan and intelligence. Normal motor and cognitive milestones are usually achieved.

NIH genetic and rare disease info

• NIH info on Spondyloepiphyseal dysplasia tarda X-linked

Spondyloepiphyseal dysplasia tarda X-linked is a rare disease.

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