Practice Essentials
Spondyloepiphyseal dysplasia (SED) is a descriptive term for a group of disorders with primary involvement of the vertebrae and epiphyseal centers resulting in a short-trunk disproportionate dwarfism. Spondylo- refers to the spine, epiphyseal refers to the growing ends of bones, and dysplasia refers to abnormal growth.
Two major types of SED are recognized: SED congenita and SED tarda. Spranger and Wiedemann first described SED congenita in 1966, [1] and Spranger and Langer provided a further review of 29 patients in 1970. [2] In 1969, Fraser noted the particular association of SED with myopia, retinal detachment, and deafness. [3] In 1939, Jacobsen recognized SED tarda in a report of 20 patients. [4]
The American Academy of Pediatrics (AAP) and the Committee on Genetics have made recommendations to assist the pediatrician in caring for children with SED and their families. A clinical geneticist may be of help to provide counseling to the family. A geneticist may also be a valuable resource for the pediatrician seeking additional information or consultation.
Orthopedic and other surgical procedures are indicated in patients with SED (see Treatment). Although these can be performed safely in most patients, specific structural and physiologic abnormalities should be carefully considered, especially by the anesthesia team.
The Skeletal Dysplasia Management Consortium has developed best practice guidelines for diagnosis and management of type II collagen skeletal dysplasias (including SED). [5]
Pathophysiology
Dwarfing conditions are frequently referred to as short-limb or short-trunk types, according to whether the limbs or the trunk is more extensively involved. SED, metatropic dysplasia, and Kniest syndrome are considered short-trunk dwarfing conditions.
SED is a generalized dysplasia with primary involvement of the vertebrae and proximal epiphyseal centers. Other generalized dysplasias with significant vertebral involvement, such as spondylometaphyseal dysplasia or spondyloepimetaphyseal dysplasia, affect the metaphyseal region of the long bone or the metaphyseal and epiphyseal regions of the long bone, respectively. [6]
The clinical and radiographic differences among the various spondylodysplasias are frequently age-related. SED congenita is a nonlethal form of congenital dwarfism characterized by typical skeletal dysplasias, vertebral changes, and ocular manifestations. It can be diagnosed at birth. In contrast, SED tarda is milder than SED congenita and later in onset, and appearance may be normal at birth.
With the increasing molecular definition of several types of collagen and recognition of the concentration of certain types in cartilage tissue, many skeletal dysplasias came to be defined as collagen abnormalities. Studies have indicated abnormal synthesis of type II collagen in SED congenita.
Type II collagen is a primary matrix protein of physeal and epiphyseal cartilage. Because an abnormality in type II collagen should affect the molecules throughout the body, it remains unclear how the currently defined abnormality can translate into major structural abnormalities of the vertebrae and capital femoral epiphysis while leaving the distal femur, proximal tibia, and other regions structurally unaffected.
Other rare forms of SED have been described. SED Maroteaux type is a form with manifestations limited to the musculoskeletal system. [7] SED tarda Toledo type is a form of SED tarda with peripheral corneal opacities and a qualitative abnormality of urinary mucopolysaccharides, mainly chondroitin-6-sulfate. Wynne-Davies recognized a form of SED tarda associated with progressive arthropathy similar to juvenile rheumatoid arthritis. [8] Kohn recognized an autosomal recessive variant of SED tarda associated with intellectual disability. [9]
Similarly, other forms of SED, such as SED with brachydactyly and SED tarda Namaqualand type (NSED), have been recognized and classified under the International Nomenclature and Classification of the Osteochondrodysplasias. Bailey suggested two groups in addition to SED congenita and SED tarda: pseudo-Morquio disease and pseudoachondroplasia SED. [10]
In this article, only the most common types of SED (ie, SED congenita and SED tarda) are discussed in detail. [11]
Etiology
Spondyloepiphyseal dysplasia congenita
Genetic
SED congenita is transmitted as an autosomal dominant trait. The gene for SED congenita has been mapped to the long arm of chromosome 12 (12q14.3). Gonadal mosaicism has been reported. Advanced paternal age is recognized as a risk factor.
Most cases result from random new mutations. Average-sized siblings have no increased risk of producing a child with SED congenita. When both parents are affected, 50% of offspring are heterozygous and affected; 25% are homozygous, which is ordinarily fatal in the first few months of life; and 25% are unaffected. When one parent is affected, the chance of transmitting this gene to each child is 50%. [12, 13, 14, 15, 16, 17]
A few cases of SED related to pathogenic variants in the gene for membrane-bound transcription factor peptidase, site 1 (MBTPS1), have been reported. [18]
Molecular
SED congenita is caused by mutations in COL2A1 (type II collagen alpha 1 chain) on chromosome 12. [19, 20, 21] These result in abnormal type II collagen. Type II collagen is the major collagen of nucleus pulposus (spine), cartilage, and vitreous (eye).
Other skeletal dysplasias affected by collagen II include achondrogenesis type II, hypochondrogenesis, Kniest dysplasia, Stickler dysplasia, autosomal forms of SED tarda, and spondylometaepiphyseal (Strudwick) dysplasia.
Spondyloepiphyseal dysplasia tarda
Genetic
SED tarda is genetically distinct from SED congenita. Although it may be transmitted as an X-linked recessive, autosomal recessive, or autosomal dominant trait, the X-linked recessive type is most common. [22]
The X-linked form has been mapped to the Xp22 region. Only males are affected, and mothers are carriers. Carrier females have a 25% risk of having an affected son, a 25% risk of having an unaffected son, a 25% risk of having a carrier daughter, and a 25% risk of having a noncarrier daughter. None of the sons of an affected male are affected; all daughters of an affected male are carriers. A case has been reported in which a girl with Turner syndrome had a diagnosis of SED tarda. [23]
Molecular
The X-linked form of SED tarda is caused by mutation in SEDL (the SED late gene). SEDL has been identified on band Xp22. It encodes a protein of 140 amino acids with a role in vesicular transport. [24]
More than 20 novel mutations affecting SEDL have been recognized; the most common type of SEDL-gene disruption was deletion, representing 40% of the types of identified mutations.
Epidemiology
International statistics
SED congenita is a rare genetic disorder. The prevalence is approximately 3.4 per million population. [8] The incidence is approximately 1 per 100,000 live births.
Age-related demographics
SED congenita can be diagnosed at birth.
In SED tarda, appearance may be normal at birth, but the condition becomes apparent later in life. Typically, the condition is clinically manifested around puberty. However, radiographic abnormalities may appear earlier.
Sex-related demographics
SED congenita is autosomal dominant; hence, males and females are affected in equal numbers. Occasional cases of autosomal recessive forms have been identified.
SED tarda is X-linked recessive; hence, only males are affected. However, certain autosomal forms have been recognized, so females are occasionally affected.
Race-related demographics
Most of the studies on SED involve patients from North America, Europe, and South Africa. Isolated cases have been reported from Asia and other Arab countries. Though patterns of inheritance have been identified, most cases result from sporadic mutation. No racial predilection has been shown to exist.
Prognosis
SED is nonlethal, and life expectancy is not reduced. However, morbidity is increased, and regular monitoring and follow-up care should be encouraged. Morbidity associated with SED may include the following conditions:
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Neck instability
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Spinal deformities such as scoliosis, kyphosis, or lordosis
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Ocular abnormalities such as myopia or retinal detachment [25]
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Hearing deficits
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Equinovarus foot
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Degenerative joint disease of the hips, knees, or shoulders
A small study by Matsushita et al found that adult patients with SED experience deterioration of health-related quality of life. [26] Nevertheless, it must be remembered that patients with SED live as long as people without SED. They can have families and are able to contribute to society, and they should be encouraged to live a productive and active life.
Patient Education
A clinical geneticist may be of help to provide counseling to the family. The proper establishment of the mode of inheritance aids in genetic counseling.
Patients with neck instability should be advised regarding activity restrictions (see Activity).
Dwarfism resource sites include LPA Online and Dwarfism.org. These comprehensive sites provide information on various organizations, specialized equipment, and tips on activities of daily living.
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Spondyloepiphyseal dysplasia. Radiograph of the pelvis depicting delayed ossification of capital femoral epiphyses, metaphyseal flaring, horizontal acetabular roofs, triangular fragment on the inferior aspect of the broad femoral neck, and coxa vara.
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Spondyloepiphyseal dysplasia. Radiograph of the spine depicting increased anteroposterior diameter, platyspondyly, posterior wedging of the vertebrae, and increased lumbar lordosis.
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Spondyloepiphyseal dysplasia. Radiograph of the upper cervical vertebrae depicting ununited odontoid process.
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Spondyloepiphyseal dysplasia. Radiograph of the chest, depicting bell-shaped chest and decreased height of the trunk due to platyspondyly.
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Spondyloepiphyseal dysplasia. Radiograph of shoulder, depicting severe epiphyseal involvement of proximal humerus, leading to premature osteoarthritis.
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Clinical picture of a child with spondyloepiphyseal dysplasia. The child had a limp when she walked. The radiographs reveal Perthes-like changes. Both the hips appear to be in a similar stage of progression.
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Clinical picture of a girl with spondyloepiphyseal dysplasia. The sitting height is significantly affected. The trunk is disproportionately shorter than the extremities. The radiographs reveal platyspondyly.
Tables
Characteristic |
SED Congenita |
Morquio Disease |
Inheritance |
Autosomal dominant |
Autosomal recessive |
Molecule affected |
Collagen type II |
Mucopolysaccharides |
Clinical manifestation |
Birth |
End of first year |
Flared ilia |
Absent |
Present |
Os pubis ossification |
Absent |
Present |
Acetabular angle |
Small |
Wide |
Femoral neck |
Varus |
Valgus |
Hands and feet affected |
Minimal |
Severe |
Eye changes |
Myopia, retinal tears |
Corneal clouding |
Keratosulfaturia |
Absent |
Present |
