Spondyloepiphyseal Dysplasia

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Spondyloepiphyseal dysplasia

Definition

Spondyloepiphyseal dysplasia is a rare hereditary disorder characterized by growth deficiency, spinal malformations, and, in some cases, ocular abnormalities.

Description

Spondyloepiphyseal dysplasia is one of the most common causes of short stature. There are two forms of spondyloepiphyseal dysplasia. Both forms are inherited and both forms are rare.

Congenital spondyloepiphyseal dysplasia

Congenital spondyloepiphyseal dysplasia is primarily characterized by prenatal growth deficiency and spinal malformations. Growth deficiency results in short stature (dwarfism). Abnormalities of the eyes may be present, including nearsightedness (myopia ) and retina (the nerve-rich membrane lining the eye) detachment in approximately half of individuals with the disorder. Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant genetic trait.

Congenital spondyloepiphyseal dysplasia is also known as SED, congenital type; SED congenita; and SEDC.

Spondyloepiphyseal dysplasia tarda

Spondyloepiphyseal dysplasia tarda primarily affects males. It is characterized by dwarfism and hunched appearance of the spine. The disorder doesn't become evident until five to 10 years of age. Spondyloepiphyseal dysplasia tarda is an X-linked recessive inherited disorder.

Spondyloepiphyseal dysplasia tarda is also known as SEDT; spondyloepiphyseal dysplasia, late; and SED tarda, X-linked.

Genetic profile

Both forms of the disorder are inherited, however they are inherited differently.

Congenital spondyloepiphyseal dysplasia

Congenital spondyloepiphyseal dysplasia is thought to probably always result from abnormalities in the COL2A1 gene , which codes for type II collagen. Collagen is a protein that is a component of bone, cartilage, and connective tissue. A variety of abnormalities (such as deletions and duplications) involving the COL2A1 gene may lead to the development of the disorder.

It is one of a group of skeletal dysplasias (dwarfing conditions) caused by changes in type II collagen. These include hypochondrogenesis ; spondyloepimetaphyseal dysplasia, Strudwick (SEMD); and Kniest dysplasia. Type 2 collagen is the major collagen of a component of the spine called the nucleus pulposa, of cartilage, and of vitreous (a component of the eye). All of these conditions have common clinical and radiographic findings including spinal changes resulting in dwarfism, myopia, and retinal degeneration.

Congenital spondyloepiphyseal dysplasia is inherited as an autosomal dominant genetic trait. In autosomal dominant inheritance , a single abnormal gene on one of the autosomal chromosomes (one of the first 22 "nonsex" chromosomes) from either parent can cause the disease. One of the parents will have the disease (since it is dominant) and is the carrier. Only one parent needs to be a carrier in order for the child to inherit the disease. A child who has one parent with the disease has a 50% chance of also having the disease.

Autosomal recessive inheritance of congenital spondyloepiphyseal dysplasia has been considered in cases when a child with the disorder is born to parents who are not affected by the disorder. It considered more likely that in these cases the disorder resulted from germline mosaicism in the collagen Type II gene of the parent. Germline mosaicism occurs when the causal mutation, instead of involving a single germ cell, is carried only by a certain proportion of the germ cells of a given parent. Thus, the parent carries the mutation in his or her germ cells and therefore runs the risk of generating more than one affected child, but does not actually express the disease.

Spondyloepiphyseal dysplasia tarda

Spondyloepiphyseal dysplasia tarda is caused by mutations in the SEDL gene, which is located on the X chromosome at locus Xp22.2-p22.1.

Spondyloepiphyseal dysplasia tarda is inherited as an X-linked disorder. The following concepts are important to understanding the inheritance of an X-linked disorder. All humans have two chromosomes that determine their gender: females have XX, males have XY. X-linked recessive, also called sex-linked, inheritance affects the genes located on the X chromosome. It occurs when an unaffected mother carries a disease-causing gene on at least one of her X chromosomes. Because females have two X chromosomes, they are usually unaffected carriers. The X chromosome that does not have the disease-causing gene compensates for the X chromosome that does. For a woman to show symptoms of the disorder, both X chromosomes would have the disease-causing gene. That is why women are less likely to show such symptoms than males.

If a mother has a female child, the child has a 50% chance of inheriting the disease gene and being a carrier who can pass the disease gene on to her sons. On the other hand, if a mother has a male child, he has a 50% chance of inheriting the disease-causing gene because he has only one X chromosome. If a male inherits an X-linked recessive disorder, he is affected. All of his daughters will be carriers, but none of his sons.

Demographics

It has been estimated that spondyloepiphyseal dysplasia affects about one in 100,000 individuals.

Congenital spondyloepiphyseal dysplasia affects both males and females. Spondyloepiphyseal dysplasia tarda affects mostly males.

Signs and symptoms

Congenital spondyloepiphyseal dysplasia

Congenital spondyloepiphyseal dysplasia is characterized by these main features:

Prenatal growth deficiency occurs prior to birth, and growth deficiencies continue after birth and throughout childhood, resulting in short stature (dwarfism). Adult height ranges from approximately 36-67 in (91-170 cm).
Spinal malformations include a disproportionately short neck and trunk and a hip deformity wherein the thigh bone is angled toward the center of the body (coxa vara). Abnormal front-to-back and side-to-side curvature of the spine (kyphoscoliosis) may occur, as may an abnormal inward curvature of the spine (lumbar lordosis). Spinal malformations are partially responsible for short stature.
Hypotonia (diminished muscle tone), muscle weakness, and/or stiffness is exhibited in most cases.
Progressive nearsightedness (myopia) may develop and/or retinal detachment. Retinal detachment, which can result in blindness, occurs in approximately 50% of cases.
An abnormally flat face, underdevelopment of the cheek bone (malar hypoplasia), and/or cleft palate may present in some individuals with congenital spondyloepiphyseal dysplasia.
Additional associated abnormalities may include underdevelopment of the abdominal muscles; a rounded, bulging chest (barrel chest) with a prominent sternum (pectus carinatum); diminished joint movements in the lower extremities; the heel of the foot may be turned inward toward body while the rest of the foot is bent downward and inward (clubfoot ); and rarely, hearing impairment due to abnormalities of the inner ear may occur.

The hypotonia, muscle weakness, and spinal malformations may result in a delay in affected children learning to walk. In some cases, affected children may exhibit an unusual "waddling" gait.

Spondyloepiphyseal dysplasia tarda

Symptoms of spondyloepiphyseal dysplasia tarda are not usually apparent until five to 10 years of age. At that point, a number of symptoms begin to appear:

abnormal growth causes mild dwarfism,
spinal growth appears to stop and the trunk is short,
the shoulder may assume a hunched appearance,
the neck appears to become shorter,
the chest broadens (barrel chest),
additional associated abnormalities may include unusual facial features such as a flat appearance to the face. Progressive degenerative arthritis may affect hips and other joints of the body.

Spine and hip changes become evident between 10 and 14 years of age. In adolescence, various skeletal abnormalities may cause pain in the back, hips, shoulders, knees and ankles, a large chest cage, and relatively normal limb length. In adulthood, height usually ranges from 52 to 62 inches; hands, head and feet appear to be normal size.

Diagnosis

X rays may be used to diagnose spondyloepiphyseal dysplasia when it is suspected.

Congenital spondyloepiphyseal dysplasia

Individuals with congenital spondyloepiphyseal dysplasia have characteristic x rays that show delayed ossification of the axial skeleton with ovoid vertebral bodies. With time, the vertebral bodies appear flattened. There is delayed ossification of the femoral heads, pubic bones, and heel. The coxa vara deformity of the hip joint is common.

It should be noted that x rays of individuals with spondyloepimetaphyseal dysplasia type Strudwick are virtually identical to congenital spondyloepiphyseal dysplasia. In early childhood, irregularity in the region beneath the ends of bones (metaphyseal) and thickening of the bones (sclerosis) are noted in spondyloepimetaphyseal dysplasia type Strudwick. Also, there is platyspondyly (flattened vertebral bodies) and odontoid hypoplasia.

Spondyloepiphyseal dysplasia tarda

Radiologic diagnosis cannot be established before 4-6 years of age. Symptoms usually begin to present between five and 10 years of age. Symptomatic changes in the spine and hips usually present between 10 and 14 years of age.

In adults, vertebral changes especially in the lumbar region, may be diagnostic. Ochronosis (pigment deposits in cartilage, ligaments, and tendons) is suggested by apparent intervertebral disc calcification, and the vertebral bodies are malformed and flattened with most of the dense area part of the vertebral plate.

Genetic counseling

Genetic counseling may be of benefit for patients and their families.

In congenital spondyloepiphyseal dysplasia, only one parent needs to be a carrier in order for the child to inherit the disorder. A child has a 50% chance of having the disorder if one parent has the disorder and a 75% chance of having the disease if both parents have congenital spondyloepiphyseal dysplasia.

In spondyloepiphyseal dysplasia tarda, if a mother has a male child, he has a 50% chance of inheriting the disease-causing gene. A male who inherits an X-linked recessive disorder is affected, and all of his daughters will be carriers, but none of his sons.

Prenatal testing

Prenatal testing may be available to couples at risk for bearing a child with spondyloepiphyseal dysplasia. Testing for the genes responsible for congenital spondyloepiphyseal dysplasia and spondyloepiphyseal dysplasia tarda is possible. Congenital spondyloepiphyseal dysplasia testing may be difficult, however, since although the gene has been located, there is variability in the mutations in the gene amongst persons with the disorder.

Either chorionic villus sampling (CVS) or amniocentesis may be performed for prenatal testing. CVS is a procedure to obtain chorionic villi tissue for testing. Examination of fetal tissue can reveal information about the defects that lead to spondyloepiphyseal dysplasia. Chorionic villus sampling can be performed at 10–12 weeks gestation.

Amniocentesis is a procedure that involves inserting a thin needle into the uterus, into the amniotic sac, and withdrawing a small amount of amniotic fluid. DNA can be extracted from the fetal cells contained in the amniotic fluid and tested. Amniocentesis is performed at 16–18 weeks gestation.

Treatment and management

Individuals with spondyloepiphyseal dysplasia should be under routine health supervision by a physician who is familiar with the disorder, its complications, and its treatment.

Congenital spondyloepiphyseal dysplasia

Treatment is mostly symptomatic, and may include:

Orthopedic care throughout life. Early surgical interventional may be needed to correct clubfoot and/or cleft palate. Hip, spinal, and knee complications may occur, and hip replacement is sometimes warranted in adults. Additionally, arthritis may develop due to poorly developed type II collagen. Spinal fusion may be indicated if evaluation of the cervical vertebrae C1 and C2 detects odontoid hypoplasia. If the odontoid is hypoplastic or small, it may predispose to instability and spinal cord compression in congenital spondyloepiphyseal dysplasia).
Ophthalmologic examinations are important for the prevention of retinal detachment and treatment of myopia and early retinal tears if they occur.
Hearing should be checked and ear infections should be closely monitored. Tubes may need to be placed in the ear.
Due to neck instability, persons with SEDC should exercise caution to avoid activities/sports that could result in trauma to the neck or head.

Individuals with congenital spondyloepiphyseal dysplasia should be closely monitored during anesthesia and for complications during a respiratory infection. In particular, during anesthesia, special attention is required to avoid spinal injury resulting from lax ligaments causing instability in the neck. This condition may also result in spinal injury in contact sports and car accidents. Chest constriction may also cause decreased lung capacity.

Spondyloepiphyseal dysplasia tarda

Treatment is mostly symptomatic, and may include:

Physical therapy to relieve joint stiffness and pain.
Orthopedic care may be needed at different times throughout life. Bone changes of the femoral head often lead to secondary osteoarthritis during adulthood and some patients require total replacement of the hip before the age of 40 years.

Some individuals with short stature resulting from spondyloepiphyseal dysplasia may consider limb-lengthening surgery. This is a controversial surgery that lengthens leg and arm bones by cutting the bones, constructing metal frames around them, and inserting pins into them to move the cut ends apart. New bone tissue fills in the gap. While the surgery can be effective in lengthening limbs, various complications may occur.

Prognosis

Prognosis is variable dependent upon severity of the disorder. Generally, congenital spondyloepiphyseal dysplasia is more symptomatic than spondyloepiphyseal dysplasia tarda. Neither form of the disorder generally leads to shortened life span. Cognitive function is generally normal.

Resources

BOOKS

Medical Genetics, edited by Lynn B. Jorde, et al. 2nd ed. St. Louis: Mosby, 1999.

PERIODICALS

Gecz, J., et al. "Gene Structure and Expression Study of the SEDL Gene for Spondyloepiphyseal Dysplasia Tarda." Genomics 69 (2000): 242-51.

Gedeon, A.K., et al. "Identification of the Gene (SEDL) Causing X-linked Spondyloepiphyseal Dysplasia Tarda." Nature Genetics 22 (1999): 400-404.

ORGANIZATIONS

Human Growth Foundation. 997 Glen Cove Ave., Glen Head, NY 11545. (800) 451-6434. Fax: (516) 671-4055. <http://[email protected]>.

Little People of America, Inc. National Headquarters, PO Box 745, Lubbock, TX 79408. (806) 737-8186 or (888) LPA-2001. [email protected]. <http://www.lpaonline.org>.

Little People's Research Fund, Inc. 80 Sister Pierre Dr., Towson, MD 21204-7534. (410) 494-0055 or (800) 232-5773. Fax: (410) 494-0062. <http://pixelscapes.com/lprf>.

MAGIC Foundation for Children's Growth. 1327 N. Harlem Ave., Oak Park, IL 60302. (708) 383-0808 or (800) 362-4423. Fax: (708) 383-0899. [email protected]. <http://www.magicfoundation.org/ghd.html>.

Short Stature Foundation. 4521 Campus Drive, #310, Irvine, CA 92715. (714) 559-7131 or (800) 243-9273.