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Spondyloepiphyseal Dysplasia

Spondyloepiphyseal Dysplasia and Spondyloepimetaphyseal Dysplasia

Spondyloepiphyseal dysplasia (SED) is an inherited form of skeletal dysplasia that results from the malformation and underdevelopment of the spinal vertebrae and other bones such as the hips and knees. There are two main types of SED known as congenita and tarda. Each is inherited differently and diagnosed at different periods of the child's life.


Presentation

The clinical presentation varies between the 2 forms of SED.

SED congenita

This type may be diagnosed at birth as the neonate features a short stature accompanied by a disproportionate trunk. Furthermore, the stretched fingers of the young infants will reach their knees as opposed to the thigh. Moreover, they exhibit significantly low measurements of the head-to-pubis as well as the pubis-to-heel segments [3]. Also, the proximal and middle parts of the limbs are profoundly short while the hands and feet are normal. These patients have varied degrees of coxa vara. Note that the height of adults with significant coxa vara falls in the range of 90 to 120cm. Furthermore, patients experience hip pain and trouble with walking as they are predisposed to early osteoarthritis. Additionally, valgus abnormalities and clubfeet may be present as well.

Further skeletal deformities include abnormal spinal curvature such as scoliosis, kyphosis, and kyphoscoliosis, which from early and progress swiftly. Other complications include spinal cord compression, spastic paraparesis, and cervical myelopathy. The latter may lead to respiratory difficulty, delayed motor development, hypotonia, weakness, and sleep apnea. Abnormal gait, ocular anomalies including cataracts and myopia with retinal detachment, deafness, and abdominal or inguinal hernias may occur. Frequently observed features include a cleft palate, flat face, wide-set eyes with a normal head circumference. Furthermore, they may present with a barrel-shaped chest. Intelligence is not affected in SED individuals.

SED tarda

This mild form manifests after the age of 4 years old. The trunk is only mildly disproportionately shortened and dwarfism may not even be present. Moreover, most adults reach a height of greater than 153cm. If not recognized in childhood, SED tarda may not be diagnosed until adolescence during which the patient experiences hip pain or scoliosis. Skeletal abnormalities such as those affecting the spinal vertebra give rise to atlantoaxial instability. Additionally, scoliosis, kyphosis, or lumbar lordosis can develop and progressively worsen. The clinical picture includes back pain, stiffness [6], osteoarthritis of the hips and knees, leg angular deformities, and/or neurologic deficits.

Note that adolescent and adult males that exhibit disproportionate trunks and barrel-shaped chests should raise suspicion for this disorder.

Turkish
  • Here we describe the identification of a mutation (857T C predicting the substitution L286P) in CHST3 in a Turkish family and extend the clinical phenotype of SED-Omani type to include congenital joint dislocation, club feet, ventricular septal defect[ncbi.nlm.nih.gov]
Severe Pain
  • A search for mutations in the gene for type II procollagen (COL2A1) was carried out in a family with late-onset spondyloepiphyseal dysplasia resulting in short sature, restricted mobility and severe pain in joints, deforming arthritis in the hips, and[ncbi.nlm.nih.gov]
Regurgitation
  • In addition to the previously noted skeletal features, affected members of this family also had cardiac involvement including mitral, tricuspid and/or aortic regurgitations and type E brachydactyly.[ncbi.nlm.nih.gov]
  • Our proband had heart problem with mitral regurgitation, and has had a son, who died of congenital heart disease at the age of 7 months. It is likely that involvement of cardiac valvular connective tissue is an important feature of SEDCJD.[aoj.amegroups.com]
Genu Valgum
  • valgum, cubitus valgus, mild brachydactyly, camptodactyly, microdontia, and normal intelligence.[ncbi.nlm.nih.gov]
  • valgum is usually present; - Cervical Spine: - atlantoaxial instability : - may occur due to odontoid hypoplasia or os odontoideum ; - may result in cervical myelopathy; - Spine: - involvement of vertebrae and epiphyseal centers results in a short trunk[wheelessonline.com]
  • […] vision due to myopia or retinal detachment hip pain due to coxa varus decreased walking distance due to poor muscular endurance and skeletal deformities Physical exam inspection short stature flatened facies kyphoscoliosis lumbar lordosis coxa vara genu[orthobullets.com]
  • Schlüsselwörter Skelettdysplasien Coxa vara congenita Genu varum Genu valgum Achskorrektur This is a preview of subscription content, log in to check access.[link.springer.com]
  • The clinical findings in DEEC are: Disproportionate dwarfisms (with short spine, kyphoscoliosis, pectus carinatus), genu valgum, etc. The epiphyses are poorly ossified and deformed.[roderic.uv.es]
Spine Pain
  • This complication often requires surgical fusion of the upper spine. Pain, a common and universal complaint, starts in early childhood and is exacerbated by exercise. Activities that stress the joints should be avoided.[rarediseases.org]
Severe Brachydactyly

Workup

For individuals with features of dwarfism, skeletal deformities, and other concerns, SED should be one of the main differentials. The clinical evaluation should include a full patient and family history, a physical examination, and the relevant studies. Note that the features of SED will likely be apparent to the parents and/or pediatrician leading to an early assessment and recognition.

Laboratory tests

Histological studies may demonstrate metachromatic inclusions in peripheral lymphocytes. Additionally, the resting zone of the growth plate in chondrocytes can contain vacuoles and periodic acid-Schiff (PAS)–stained cytoplasmic inclusions .

Imaging studies

Radiography should be performed in the initial workup for SED congenita [7]. Specifically, X-rays with multiple views of the thoracolumbar vertebrae, lumbar and sacral regions, the skull, wrist, elbows, hips, and knees [8] are all essential in the workup. The views include:

  • Skull: anteroposterior, lateral
  • Cervical skull: anteroposterior, later, and open mouth views while in flexion, extension, and neutral positions
  • Thoracolumbar and sacral vertebrae: anteroposterior and lateral
  • Wrist: posteroanterior
  • Elbows: anteroposterior and lateral
  • Hips: anteroposterior and lateral
  • Knees: anteroposterior and lateral

Since the SED tarda manifests above the age of 4 years old, radiographic evidence may not be evident in children younger than that. Furthermore, while the thoracic vertebrae are affected to a greater degree in tarda versus the congenita, both types have similar radiographic changes indicative of atlantoaxial instability, kyphoscoliosis, and epiphyseal abnormalities.

Another imaging technique, magnetic resonance imaging (MRI) displays cord compression and reveals changes in epiphyseal centers. Hence, MRI is useful for surgical planning for those who require reconstructive surgeries. Computed tomography (CT) scan provides an assessment of the bones and joints for surgical planning as well. Finally, hip arthrography reveals varus deformity of the femoral neck when present and is, therefore, a helpful tool.

Prenatal test

Prenatal genetic testing can be provided.

Treatment

The therapeutic approach for SED is multidisciplinary that should be implemented in conjunction with a neurologist, orthopedic surgeon, ophthalmologist, pulmonologist, geneticist, physical therapist, and supportive health professionals. Furthermore, the American Academy of Pediatrics and Committee on Genetics have proposed guidelines regarding the management of SED in order to ensure full support is provided for the patients and their families.

With regards to the specific consultations, neurology is necessary for the evaluation of the patient's motor skills, neurologic deficits, and other signs while ophthalmology is essential in congenita patients since numerous eye pathologies including retinal conditions are associated with this form. Additionally, pulmonology is required for the assessment of the lung function since SED is associated complications such as pneumonia and apnea.

Surgery

Surgical intervention is often indicated in SED patients due to the structural and physiologic defects resulting from this disorder. In the congenita variant, the orthopedic sequelae are attributed to the atlantoaxial instability and skeletal disorders [9]. Specifically, those with atlantoaxial instability or neurologic abnormalities warrant posterior atlantoaxial fusion. Tarda patients with scoliosis may require posterior spinal fusion if the condition is not improving with bracing. Finally, total joint arthroplasty may beneficial in adults with osteoarthritis [10].

Genetic counseling

This should be offered to educate and guide the parents regarding what the disorder entails, its modes of inheritance, and further information. Additionally, a geneticist can assist the medical team by providing details to clarify the type of dwarfism exhibited by the patient. Finally, a geneticist can provide the family with further resources for support.

Other

Physical therapy, mental health therapy, and other resources are very beneficial and helpful for SED patients. Additionally, support for parents and families is important as well.

Prognosis

While individuals with SED have a normal life expectancy, there are morbidities associated with this genetic disorder. The sequelae include spinal and hip deformities, coxa vara, degenerative joint disease (shoulders, hips, or knees), atlantoaxial instability, and deafness. Also, ocular abnormalities like retinal detachment may occur [5]. Overall, good quality of life is attainable with good health care and early intervention.

Etiology

There are 2 main forms of SED, which are SED congenita and SED tarda.

SED congenita

This type occurs due to mutations in the COL2A gene on chromosome 12 [1], which is inherited through an autosomal dominant pattern as well as de novo mutations. COL2A1 codes for type II collagen alpha 1 chain, which is the predominant collagen present in the cartilage, spine, and eye. One risk factor is advanced paternal age.

SED tarda

This type is transmitted most frequently through the X-linked recessive trait although this may also occur through autosomal recessive [2], or autosomal dominant patterns. The mutation is found on the SEDL gene, which codes for a protein that is involved in vesicular transport. There are 21 identified mutations that affect this gene as deletion accounts for 40% of mutations.

Epidemiology

This rare disease has an incidence of approximately 1 per 100,000 population. Furthermore, its prevalence is about 3.4 per 1 million [3]. With regards to patient demographics, the congenita type form affects both genders equally while the tarda class occurs in males only although the autosomal traits also affect females. In terms of age, SED congenita is present at birth while the tarda develops typically at puberty. Finally, there is no preference for race although the majority of studies have been conducted on patients from North America, Europe, and South Africa.

Sex distribution
Age distribution

Pathophysiology

A class of congenital dwarfism, SED is a dysplasia characterized by a short trunk as it affects the vertebrae and the epiphyseal center of the long bones. SED congenita is typically recognized at birth and features vertebral defects, skeletal dysplasias, and ocular involvement whereas the tarda variant occurs at a late onset and is milder overall.

The pathogenesis of SED congenita is attributed to the abnormal synthesis of type II collagen, one of the main matrix proteins of cartilage. Note that it is not understood why some bones are affected but not all. For example, the vertebrae and capital femoral epiphysis are involved but the distal femur and other bones are normal. With regards to SED tarda, the pathogenesis is explained by the bone malformation especially seen in the vertebrae [4].

Prevention

Since this is a hereditary disorder, it cannot be prevented. However, affected individuals and their family members are encouraged to seek genetic counseling to gain understanding and guidance about the disorder.

Summary

Spondyloepiphyseal dysplasia (SED) is a rare genetic disorder that is characterized by the abnormal growth and development of the vertebrae and proximal epiphyseal centers ultimately yielding a disproportionate short-trunk dwarfism. SED can be classified as either the cogenita or tarda type. The former is an autosomal dominant disorder in which the mutation involves a gene that codes for type II collagen alpha 1 chain while SED tarda is transmitted through different modes with X-linked recessive being the most common.

The clinical picture of SED congenita typically presents at birth. The tarda form develops after the age of 4 years in terms of clinical manifestations of the trunk or hips. Generally, SED patients exhibit spinal and hip deformities, shortened trunk, atlantoaxial instability, neurologic deficits, ocular pathologies, and deafness among other complications.

The workup includes a thorough patient and family history, a complete physical examination, and various diagnostic tests - histologic studies, imaging tools, and genetic testing. Imaging is useful in demonstrating the bone abnormalities, especially in surgical planning.

Treating and managing SED requires a multidisciplinary approach with a medical team consisting of neurology, orthopedic surgery, ophthalmology, clinical genetics, physical therapy, and other health professional services as needed. Moreover, surgical intervention is paramount in many patients with skeletal abnormalities.

Patient Information

What is spondyloepiphyseal dysplasia?

Spondyloepiphyseal dysplasia (SED) is a form of dwarfism, in which the individual inherits a bone growth disorder, skeletal abnormalities, eye problems, and deafness. The term spondylo means spine, while epiphysis refers to the end segments of the bone that grow, and lastly, dysplasia means abnormal growth. This disorder has 2 main types, which are known as SED congenita and SED tarda. In the first form, the patient inherits a genetic mutation through an autosomal dominant pattern. This means that the affected child receives one bad copy from the affected parent and one good copy from the normal parent. In other words, an affected parent has a 50% chance of passing this type of SED to offspring. SED tarda can be inherited in different ways particularly the x-linked recessive mode. This means that only males are affected while the mothers are carriers.

What are the signs and symptoms?

SED congenita is usually diagnosed at birth or early infancy whereas SED tarda is diagnosed after the age of 4 years old.

How is it diagnosed?

The clinician will ask questions about the patient's history as well as that of the family. Additionally, a full physical exam is performed followed by various tests that may include x-rays, MRI, and CT scans of the spine, hips, and other bones.

How is it treated?

The treatment includes a thorough and comprehensive management plan formed by a team of neurology, orthopedic surgery, ophthalmology, clinical genetics, physical therapists, and other health professionals as needed. Many patients will require surgery to repair and/or stabilize the spine, hips, knees, or other joints.

Eye care is very important since patients can develop retinal disease and even visual troubles. Neurologic evaluation is needed to assess symptoms associated with nerve compression. Note that there are various resources available to help the patients and their families cope and succeed with SED.

What is the prognosis?

Patients with SED are expected to have a full life expectancy. With good and complete care, the patient can improve the symptoms of the disorder.

Can it be prevented?

This is a hereditary disorder so it cannot be prevented. However, prenatal genetic counseling is available for affected patients and their families in order to learn about SED, what it means, how it is passed from parent to child, etc. There are also genetic tests that can be offered.

References

Article

  1. Li S, Zhou H, Qin H, Guo H, Bai Y. A novel mutation in the COL2A1 gene in a Chinese family with Spondyloepiphyseal dysplasia congenita. Joint Bone Spine. 2014; Jan; 81(1):86-9.
  2. Kohn G, Elrayyes ER, Makadmah I, et al. Spondyloepiphyseal dysplasia tarda: a new autosomal recessive variant with mental retardation. Journal of Medical Genetics. 1987; 24(6):366-9.
  3. Wynne-Davies R, Hall C, Ansell BM. Spondylo-epiphysial dysplasia tarda with progressive arthropathy. A "new" disorder of autosomal recessive inheritance. Journal of Bone and Joint Surgery. 1982; 64(4):442-5.
  4. 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 (Baltimore). 1999; 78(1):9-25.
  5. Ikegawa S, Iwaya T, Taniguchi K, Kimizuka M. Retinal detachment in spondyloepiphyseal dysplasia congenita. Journal of Pediatric Orthopedics. 1993; 13(6):791-2.
  6. Nakamura K, Miyoshi K, Haga N, Kurokawa T. Risk factors of myelopathy at the atlantoaxial level in spondyloepiphyseal dysplasia congenita. Archives of Orthopaedic and Trauma Surgery. 1998. 117(8):468-70.
  7. Spranger JW, Langer LO Jr. Spondyloepiphyseal dysplasia congenita. Radiology. 1970; 94(2):313-22.
  8. Shapiro F. Pediatric Orthopedic Deformities: Basic Science, Diagnosis and Treatment. Academic Press. 2001: chapter 9.
  9. Veeravagu A, Lad SP, Camara-Quintana JQ, Jiang B, Shuer L. Neurosurgical interventions for spondyloepiphyseal dysplasia congenita: clinical presentation and assessment of the literature. World Neurosurgery. 2013; 80(3-4):437.e1-8.
  10. Roy DR. Spectrum of intra-articular findings of the acute and subacute painful hip with multiple epiphyseal dysplasia/spondyloepiphyseal dysplasia. Journal of Pediatric Orthopedics B. 2011; 20(5):284-6.

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Last updated: 2019-07-11 20:20