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Last updated:
May 06, 2015
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NORD gratefully acknowledges Shital N. Parikh, MD, FACS, Associate Professor of Orthopaedic Surgery, Cincinnati Children’s Hospital Medical Center, University of Cincinnati School of Medicine, for assistance in the preparation of this report.
Summary
Spondyloepiphyseal dysplasia congenita (SEDC) is a rare genetic disorder characterized by deformities that begin before birth (prenatally), including skeletal and joint malformations involving the spine, hips and knees, and abnormalities affecting the eyes. Such growth deformities lead to children being shorter than normally would be expected based upon their age and gender (short stature or dwarfism). Some individuals may develop hearing and vision problems. Additional findings can occur in some cases. Intelligence is unaffected. SEDC is caused by mutations in the type II collagen (COL2A1) gene. The disorder is inherited in an autosomal dominant manner, but most cases occur due to a new (de novo) mutation with no previous family history.
Introduction
Spondyloepiphyseal dysplasia is a form of skeletal dysplasia (osteochondrodysplasia), a broad term for a group of disorders characterized by abnormal growth or development of cartilage or bone. SEDC is characterized by distinctive skeletal malformations affecting the long bones of the arms and legs as well as the bones of the spine (vertebrae). Characteristic involvement includes underdevelopment and fragmentation of the bone and cartilage of the epiphyses, which are the rounded ends or “heads” of the long bones, and underdevelopment or malformation of the vertebrae. There are two main forms of spondyloepiphyseal dysplasia, SEDC and spondyloepiphyseal dysplasia tarda (SEDT).
The specific symptoms and severity of spondyloepiphyseal dysplasia congenita can vary greatly from one person to another. Affected individuals may not have all of the symptoms discussed below. In most cases, certain symptoms are noticeable at birth (congenital).
Growth deficiency that occurs before birth is a characteristic finding. Growth deficiency continues through childhood and results in disproportionate short stature. Short stature is when a child is below the average height for a person of the same age and gender. Disproportionate means that the arms appear long in relation to the torso. Affected individuals may also have a disproportionately short neck. The head, hands and feet are average-sized. Final adult height usually ranges between 2.8 and 4.2 feet (84-128cm).
In most cases, affected individuals have spinal malformations including abnormal forward curvature of the spine (lumbar lordosis) and/or abnormal roundback (kyphosis). Kyphosis may be accompanied by sideways curvature of the spine (scoliosis). Abnormal spinal curvature may worsen with age. Some individuals may have instability of the spine in the neck (cervical vertebrae), which can increase the risk of spinal injury in that area (cervical myelopathy). An individual with a stable cervical spine may develop instability later during life.
Stiffness and diminished joint mobility at the knees, elbows, and hips may develop over time. Joint abnormalities may lead to the development of hip deformity in which the thigh bone is angled toward the center of the body (coxa vara) and/or knee deformities, including bow legs (genu varum) and ‘knock knees’ (genu valgum). Individuals with SEDC are more likely to develop pain, inflammation and damage in affected joints at an early age (early-onset osteoarthritis). Dislocation of affect joints (e.g. dislocation of the hips) can also occur.
Affected individuals are prone to dislocation of neck bones, back pain, and compression of the sciatic nerve (sciatica), which runs from the lower back, behind the hips and buttocks and down each leg. Sciatica can cause pain, tingling and numbness along the sciatic nerve. A broad, barrel-shaped chest is common. Protrusion of the breastbone (sternum) and ribs may also occur (pectus carinatum). Children are more likely to have clubfeet at birth. Some affected individuals may experience difficulty straightening the arms and legs (limited extension).
Affected children may also exhibit diminished muscle tone (hypotonia) and muscle weakness, which, along with the spinal malformations, can result in delays in affected children learning to walk. In some cases, affected children may exhibit an unusual “waddling” manner of walking (abnormal gait).
In some cases, affected individuals also have an abnormally flat face, underdevelopment of the cheek bone (malar hypoplasia), and/or incomplete closure of the roof of the mouth (cleft palate). Eye abnormalities can also occur including widely spaced eyes (hypertelorism), progressive nearsightedness (myopia) and, degeneration of the thick transparent substance that fills the center of the eyes (vitreous humor) and of the nerve-rich membrane lining the eye (retina), a condition known as vitreoretinal degeneration. Less often, affected individuals may develop detachment of the retina from the underlying tissue of the eye. Flashing lights or eye “floaters” may be the initial symptoms of retinal detachment. Individuals with severe nearsightedness (“high” myopia) are at a greater risk for retinal detachment than those without high myopia.
Children may develop progressive sensorineural hearing loss, in which sound vibrations are not properly transmitted to the brain due to a defect of the inner ear or the auditory nerve. Although intelligence is usually unaffected, there may be delay in children attaining certain developmental milestones.
Some infants with SEDC may experience breathing difficulties shortly after birth, particularly if they have an underdeveloped or extremely small rib cage. Breathing difficulties usually decrease as an infant grows older. In certain cases, abnormal curvature of the spine and an abnormally developed chest can lead to breathing difficulties by preventing the lungs to fully fill with air (restrictive lung disease). This can lead to chronic breathing issues, sleep apnea, chronic respiratory infections, and potentially heart failure in middle age. Prompt and appropriate treatment can reduce this risk.
Spondyloepiphyseal dysplasia congenital is caused by a mutation in the COL2A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.
SEDC can occur as a new (sporadic or de novo) mutation, which means that the gene mutation has occurred at the time of the formation of the egg or sperm for that child only, and no other family member will be affected. The disorder is usually not inherited from or “carried” by a healthy parent. The mutation is then inherited as an autosomal dominant trait (i.e. is transmitted from either an affected mother or father to their child).
Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent (autosomal), or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child.
Investigators have determined that the COL2A1 gene is located on the long arm (q) of chromosome 12 (12q13.11). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body 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.
The COL2A1 contains instructions for creating (encoding) type II collagen. Collagen is one of the most abundant proteins in the body and a major building block of connective tissue, which is the material between cells of the body that gives the tissue form and strength. There are many different types of collagen, which are indicated by Roman numerals. Type II collagen is most prevalent in cartilage and the jelly-like fluid that fills the center of the eyes (vitreous humor). Collagen is also found in bone. Mutations to the COL2A1 gene result in diminished levels of functional type II collagen. Changes in the composition of this collagen ultimately lead to abnormal skeletal growth in SEDC and related disorders.
Males and females are affected in equal numbers. The exact incidence or prevalence is unknown, but spondyloepiphyseal dysplasia congenita is estimated to occur in approximately 1 in 100,000 live births. Collectively, the skeletal dysplasias are estimated to occur in approximately 1 in 5,000 individuals in the general population.
A diagnosis of spondyloepiphyseal dysplasia congenita is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A diagnosis may be suspected at birth because of characteristic findings.
Clinical Testing and Workup
Basic x-rays (radiography) can be used to provide a thorough, careful examination of the entire bone system (complete skeletal survey) in order to detect changes in the skeleton that are characteristic of SEDC.
More advanced imaging techniques such as magnetic resonance imaging (MRI) and computed tomography (CT) scans can be used to assess skeletal health, particularly prior to surgery to correct skeletal malformations. An MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures.
Molecular genetic testing can confirm a diagnosis. Molecular genetic testing can detect mutations in the gene known to cause of SEDC, but is available only as a diagnostic service at specialized laboratories.
Treatment
Treatment is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, specialists in diagnosing and treating musculoskeletal disorders (orthopedic surgeons), specialists in diagnosing and treating eye disorders (ophthalmologists), rheumatologists, physical therapists and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment. Genetic counseling may be of benefit for affected individuals and their families. Psychosocial support for the entire family is essential as well.
Specific therapies are symptomatic and supportive. Physicians may carefully monitor affected infants to ensure prompt detection and appropriate prevention or corrective treatment of breathing (respiratory) difficulties. Regular eye (ophthalmologic) exams are required to detect and assess nearsightedness and to prevent retinal detachment. Retinal detachment can be repaired surgically. Standard physical therapy, which can improve joint motion and avoid muscle degeneration (atrophy), can be beneficial.
In some cases, surgery may be necessary to achieve better positioning and to increase the range of motion in certain joints. Surgery may be necessary to treat malformation of the hips and, in some cases, total hip replacement surgery (total hip arthroplasty) may be necessary. Surgery or bracing may be able to treat abnormal curvature of the spine. Surgical procedures may be recommended to correct other abnormalities of the spine and knee as well as to close a cleft palate. Clubfoot may also be treated with splinting or surgery.
In children with cervical instability, spinal fusion surgery or the implanting of a rod to stabilize the spine may be necessary. This rod known as a ‘growing rod’ treats spinal deformity in a child, but allows for the continued and controlled growth of the spine.
Specific physical findings associated with SEDC, specifically a short neck, cervical spine instability, reduced lung capacity, and small airways, can complicate the use of anesthesia. Affected individuals need to be evaluated before undergoing procedures that require anesthesia.
Affected individuals should avoid activities that can cause trauma to the head or neck such as contact sports. SEDC while causing physical issues does not usually reduce life expectancy. Intelligence is usually unaffected and most individuals raise families and lead productive, active and full lives.
A registry for skeletal dysplasias has been set up at the University of California Los Angeles. A registry is a special database that contains information about individuals with a specific disorder or group of conditions. The collection of data about rare disorders may enable researchers to increase the understanding of such disorders, expand the search for treatments, and accelerate clinical trials into specific treatment options. For more information, physicians can contact:
International Skeletal Dysplasia Registry
UCLA
615 Charles E. Young Drive, South RM 410
Los Angeles CA 90095-7358
Phone: 310-825-8998
Website: https://isdr.csmc.edu/
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:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
For information about clinical trials sponsored by private sources, in the main, contact:
For more information about clinical trials conducted in Europe, contact: https://www.clinicaltrialsregister.eu/
Please note that some of these organizations may provide information concerning certain conditions potentially associated with this disorder.
TEXTBOOKS
Toriello HV, Smith SD, Eds. Hereditary Hearing Loss and Its Syndromes. 3rd ed. Oxford University Press, New York, NY; 2013;350-351.
Gorlin RJ, Cohen MMJr, Hennekam RCM. Eds. Syndromes of the Head and Neck. 4th ed. Oxford University Press, New York, NY; 2001:226-271.
JOURNAL ARTICLES
Xu L Qiu X, Zhu A, Yi L, Qiu Y. A novel mutation in COL2A1 leading to spondyloepiphyseal dysplasia congenita in a three-generation family. Eur Spine J. 2014;23:271-277.
https://www.ncbi.nlm.nih.gov/pubmed/24736929
Veeragagu A, Lad SP, Camara-Quintana JQ, Jiang B, Shuer L. Neurosurgical interventions for spondyloepiphyseal dysplasia congenita: clinical presentation and assessment of the literature. World Neurosurg. 2013;80:3-4. https://www.ncbi.nlm.nih.gov/pubmed/22381876
Warman ML, Cormier-Daire V, Hall C, et al. Nosology and classification of genetic skeletal disorders: 2010 revision. Am J Med Genet A. 2011;155:943-968. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3166781/
Krakow D, Rimoin DL. The skeletal dysplasias. Genet Med. 2010;12:327-341. https://www.ncbi.nlm.nih.gov/pubmed/20556869
Nishimura G, Haga N, Kitoh H, et al. The phenotypic spectrum of COL2A1 mutations. Hum Mutat. 2005;26:36-43. https://www.ncbi.nlm.nih.gov/pubmed/15895462
Donahue LR, Chang B, Mohan S, et al. A missense mutation in the mouse Col2a1 gene causes spondyloepiphyseal dysplasia congenita, hearing loss, and retinoschisis. J Bone Miner Res. 2003;18:1612-1621. https://www.ncbi.nlm.nih.gov/pubmed/12968670
Gembun Y, Nakayama Y, Shirai Y, et al. A case report of spondyloepiphyseal dysplasia congenita. J Nippon Med Sch. 2001;68:186-89. https://www.ncbi.nlm.nih.gov/pubmed/11301365
Tiller GE, Rimoin DL, Murray LW, Cohn DH. Tandem duplication within a type II collagen gene (COL2A1) exon in an individual with spondyloepiphyseal dysplasia. Proc Natl Acad Sci USA. 1990;87:3889-93. https://www.ncbi.nlm.nih.gov/pubmed/2339128
Anderson IJ, Goldberg RB, Marion RW, Upholt WB, Tsipouras P. Spondyloepiphyseal dysplasia congenital: genetic linkage to type II collagen (COL2AI). Am J Hum Genet. 1990;46:896-901. https://www.ncbi.nlm.nih.gov/pubmed/1971141
INTERNET
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:183900; Last Update:09/24/2012. Available at: https://www.omim.org/entry/183900 Accessed March 2, 2015
Parikh S, Crawford AH, Batra P. Spondyloepiphyseal Dysplasia. Emedicine Journal, November 25 2013. Available at: https://emedicine.medscape.com/article/1260836-overview Accessed March 2, 2015.
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