Spondyloepiphyseal dysplasia (SED) refers to a group of dis- orders with primary involvement of the vertebrae and epiphyseal centers resulting in a short-trunk disproportionate dwarfism. Two major types (congenita and tarda) will be discussed here.
GENETICS/BASIC DEFECTS
1. Genetic basis of SED a. SED congenita
i. Autosomal dominant inheritance
ii. Spondyloepiphyseal dysplasia congenita gene mapped to chromosome 12q13
iii. Gonadal mosaicism reported
iv. Advanced paternal age recognized as a risk factor b. SED tarda
i. X-linked recessive inheritance a) Most common
b) The gene mapped to Xp22.12-p22.31 ii. Autosomal recessive inheritance
iii. Autosomal dominant inheritance 2. Molecular basis of SED
a. SED congenita
i. Caused by mutations in COL2A1 gene, which encodes the α1(II) chain of type II collagen. The gene was mapped on chromosome 12.
ii. The mutations result in abnormal type II collagen, which is the major collagen of nucleus pulposus of the spine, hyaline cartilages, fibrocartilages, and vitreous humor of the eyes
iii. Other skeletal dysplasias affected by collagen II abnormalities
a) Autosomal forms of SED tarda b) Achondrogenesis type II c) Hypochondrogenesis d) Kniest dysplasia e) Stickler dysplasia
f) Spondylometaepiphyseal (Strudwick) dys- plasia
b. SED tarda, X-linked form
i. Caused by mutations in SEDL (SED late) gene (designated “sedlin”), mapped on Xp22.2-p22.1 ii. SEDL gene encodes a protein of 140 amino acids
with a role in vesicular transport.
iii. Over thirty novel mutations affecting the SEDL gene recognized: the most common type of SEDL-gene disruption being deletion, represent- ing 50% of identified mutations
CLINICAL FEATURES
1. SED congenita
a. Clinical features present at birth
b. Short newborn with disproportionately shortened trunk c. Delayed motor development
d. Short neck
e. Cervical myelopathy resulting from atlantoaxial instability, odontoid hypoplasia, and spinal cord com- pression, often presenting at age 5–10 years
i. Delayed motor development ii. Decreased endurance iii. Progressive motor weakness
iv. Hypotonia v. Sleep apnea
vi. Alterations in respiration
vii. Pyramidal tract signs (spasticity, hyperreflexia, Babinski sign, and clonus)
f. Respiratory insufficiency may develop secondary to thoracic dysplasia
g. Barrel-shaped chest with pectus carinatum deformity h. Protuberant abdomen
i. Spine abnormalities i. Lumbar lordosis
ii. Thoracic kyphoscoliosis evident in adolescence j. Hip abnormalities
i. Hip flexion contractures ii. Coxa vara
a) An almost universal finding b) Varying severity
c) Progressive
d) Associated progressive hip dislocation if lig- amentous laxity present
iii. The delayed ossification of the capital femoral epiphysis predisposing the hip to deformation with flattening, lateral extrusion, hinge abduc- tion, and premature osteoarthritis
k. Knee abnormalities
i. Valgus alignment of the knees often associated with overgrowth of the medial femoral condyle ii. Rare genu varum
l. Other clinical features
i. Gait problems often attributed to hip and knee deformities
ii. Clubfeet (talipes equinovarus) present in some patients
iii. Ocular anomalies
a) Myopia and retinal detachment (>50%):
important clinical findings in many patients b) Cataracts
c) Buphthalmos secondary glaucoma, and stra- bismus
d) Clear corneas iv. Deafness
v. Cleft palate
vi. Abdominal or inguinal hernias 2. SED tarda
a. X-linked recessive form i. Normal appearance at birth 927
ii. Variable age of onset
a) Hip and trunk features appearing around 4 years of age
b) Diagnosis not recognized until the adoles- cent years in some patients
iii. Only males are affected
iv. Mild disproportionate trunk shortening v. Barrel-shaped chest
vi. Atlantoaxial instability secondary to odontoid hypoplasia
vii. Progressive joint and back pain with osteoarthri- tis commonly involving hip, knee, elbows, and shoulder joints
viii. Hip involvement
a) Hip pain or stiffness presenting around the first or second decade of life
b) Changes mimic bilateral Legg-Calve-Perthes disease
c) Varying degrees of coxa magna, flattening, extrusion, and subluxation
d) Osteoarthritis of the hip, a common sequelae ix. Kyphoscoliosis
x. Lumbar lordosis xi. Epiphyseal involvement
a) Primarily in the shoulders, hips, and knees b) Symmetrical and bilateral
xii. Rare association with nephrotic syndrome xiii. Craniofacial appearance, vision, and hearing not
affected in X-linked SED tarda xiv. Normal intelligence
xv. Normal life span b. Autosomal recessive form
i. Onset between the age of 4 and 10 years ii. Hip pain becomes worse with increasing age iii. Waddling gait
iv. Short stature
v. Disproportionately short trunk vi. Accentuated spinal curvatures vii. Restricted mobility of the hip joints c. Autosomal dominant form
i. Clinical features identical to those in the reces- sive form of SED tarda
ii. Hip pain and waddling gait noted after the 4th year of life
iii. Mild shortness of the trunk
iv. Progressive hip changes causing considerable discomfort
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. SED congenita
i. A generalized delay in the development of ossi- fication centers
a) Absent epiphyseal centers of the distal femur and proximal tibia, os pubis, calcaneus, and talus, which are usually present at birth b) Femoral heads usually not visible on radi-
ographs until patients are aged 5 years c) Femoral capital epiphyses: flattened and irreg-
ular in shape when they appear on radiographs
ii. Vertebral abnormalities
a) Varying degrees of platyspondyly
b) Oval, trapezoid, or pear-shaped vertebrae resulting from posterior wedging of verte- bral bodies
c) Incompletely fused ossification centers of the vertebral bodies
d) End plate irregularities and intervertebral disk spaces narrowing become obvious with an increased anteroposterior diameter of the vertebral bodies in adolescents and young adults
e) Exaggerated lumbar lordosis
f) Progressive kyphoscoliosis developing in late childhood
g) Odontoid hypoplasia or os odontoideum leading to atlantoaxial instability: common iii. Pelvic abnormalities
a) Short and small iliac crests with horizontal acetabular roofs and delayed ossification of the pubis
b) Small iliac bones with lack of normal flaring of the iliac wings
c) Deep acetabular fossae appearing empty due to the severely retarded ossification of femoral heads
d) Varying severity of coxa vara
e) Delayed ossification of the femoral head predisposing hip to deformation with flat- tening, lateral extrusion, hinge abduction, and premature osteoarthritis
iv. Tubular bone abnormalities
a) Delayed ossification centers of the distal femur and proximal tibia leading to flatten- ing and irregularity
b) Genu valgum usually present with over- growth of the medial femoral condyle c) Relatively short and broad long tubular
bones
d) Presence of some metaphyseal flaring espe- cially in the region of the distal femur and proximal and distal humerus
e) Delayed or disorganized ossification of carpal and tarsal centers with occasional extra epiphyses
b. SED tarda, X-linked recessive form
i. Radiographic changes usually apparent in children older than 4–6 years (not evident at birth)
ii. Changes suggestive of atlantoaxial instability, platyspondyly, kyphoscoliosis, and epiphyseal involvement similar to those seen in patients with SED congenita
iii. Predominantly affecting the spinal vertebral bodies and epiphyses during skeletal growth iv. A mound of bone (“donkey hump”) typically
present in the central and posterior portions of the superior and inferior end plates on lateral radiographs in patients with X-linked recessive type of SED tarda (not features of the autosomal dominant or recessive types of SED tarda).
However, absence of ossification at the upper and lower anterior margins of the vertebral bodies is considered to be the distinctive radiographic feature
v. Symmetric epiphyseal involvement primarily in the shoulders, hips, and knees
vi. Delayed ossification predisposing the weight bearing joints of the lower extremities to defor- mation and premature osteoarthritis
vii. Changes in the hip (dysplastic changes of femoral heads and neck), mimic bilateral Legg- Calve-Perthes disease
viii. Presence of varying degrees of coxa magna, flat- tening, extrusion, and subluxation
ix. Minor skeletal changes in carrier women with X-linked recessive SED tarda in a 6-generation kindred from Arkansas
a) Subtle abnormal shape of the pelvis and knees
b) Premature occurrence of degenerative changes in the spine leading to frequent complaint of arthralgia in the middle age c. SED tarda, autosomal recessive form
i. Irregular upper and lower plates of the vertebral bodies
ii. Anteriosuperior ossification defects of some vertebras
iii. Less frequent findings
a) Additional ossification defects of the anteri- oinferior edges of the vertebral bodies b) Anterior protrusion f central portions of the
vertebral bodies iv. Femoral heads
a) Well developed capital femoral epiphyses in the younger child
b) Progressive flattening and destruction of the femoral heads with advancing age
c) Milder abnormalities in the knee joints d) Small and irregular carpal bones
e) Slightly short and irregular metacarpals and phalanges in some patients
d. SED tarda, autosomal dominant form
i. Accentuated dorsal flattening of the vertebral bodies in the younger patient
ii. Platyspondyly with a rectangular shape of the vertebral bodies in the older patient
iii. Mild and slowly progressive deformities of cap- ital femoral epiphyses and knee epiphyses iv. Slightly short phalanges and metacarpals with
narrowing of the joint spaces 2. MRI
a. To delineate cord compression due to C1–C2 instability b. To evaluate severe spinal deformities prior to surgical
intervention
c. To evaluate the condition of the epiphyseal centers prior to reconstructive procedures
3. CT scan
a. To assess the configuration of bones and joints prior to surgical intervention
b. To reconstruct three-dimensional images for help in surgical planning of severe cases
4. Hip arthrography
a. To document congruity of the femoral head or hinged abduction
b. To evaluate severe varus deformity of the femoral neck 5. Laboratory features of SED congenita
a. Fine metachromatic inclusions in the peripheral lym- phocytes
b. Normal urinary excretion of acid mucopolysaccha- rides including keratosulfate
c. Histopathology
i. Mildly disorganized physis (epiphyseal growth plate)
ii. Chondrocytes containing PAS-positive cytoplas- mic inclusions
iii. Ultrastructurally the inclusions correspond to the accumulations of finely granular material in dilated cisterns of rough endoplasmic reticulum.
6. Molecular genetic analysis
a. Mutations in COL2A1 gene in SED congenita b. Mutation in SEDL gene in X-linked recessive SED tarda
i. Mutation types a) Deletions b) Splice mutations c) Missense mutations d) Nonsense mutations
ii. Detected in >80% of affected males with X- linked spondyloepiphyseal dysplasia tarda iii. Molecular genetic testing in new patients relied
largely on mutation screening by sequencing the entire coding region
iv. Carrier testing of at-risk female relatives avail- able once the mutation has been identified in the proband
GENETIC COUNSELING
1. Recurrence risk a. Patient’s sib
i. Spondyloepiphyseal dysplasia congenita (autoso- mal dominant): recurrence risk low unless pres- ence of parental gonadal mosaicism
ii. Spondyloepiphyseal dysplasia tarda, X-linked a) The risk to sibs depends on the carrier status
of the mother
b) When the mother is a carrier: a 25% risk of having an affected brother; a 25% risk of hav- ing an unaffected brother; a 25% risk of having a carrier sister; a 25% risk of having a noncarrier sister
c) When the mother is not a carrier: the risk to sibs is low (the risk of gonadal mosaicism in mothers not yet known)
iii. Spondyloepiphyseal dysplasia tarda, autosomal recessive: 25%
iv. Spondyloepiphyseal dysplasia tarda, autosomal dominant: low unless a parent is affected b. Patient’s offspring
i. Spondyloepiphyseal dysplasia congenita, auto- somal dominant
a) When the spouse is not affected: 50% of off- spring will be affected
b) When the spouse is also affected with spondyloepiphyseal dysplasia congenita:
50% of offspring are heterozygous and affect- ed; 25% are homozygous, which is ordinarily fatal in the first few months of life; and 25%
are unaffected.
ii. Spondyloepiphyseal dysplasia tarda
a) Autosomal recessive form: recurrence risk to offspring low unless the spouse is a carrier b) Autosomal dominant form: 50%
iii. Spondyloepiphyseal dysplasia tarda, X-linked recessive
a) None of the sons of an affected male will be affected.
b) All daughters of an affected male are carriers.
2. Prenatal diagnosis
a. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS available in families at risk for SED congenita, provided the disease-causing muta- tion (COL2A1) is identified in the proband
b. Molecular genetic diagnosis on fetal DNA from amniocytes or CVS possible in families at risk for X- linked SED tarda, provided the disease-causing muta- tion (SEDL) is identified in the proband
3. Management a. SED congenita
i. Supportive care including psychosocial support ii. Tracheostomy for severe respiratory difficulties
to maintain adequate ventilation
iii. Posterior atlantoaxial fusion for patients with signs and symptoms of atlantoaxial instability measuring 8 mm or more or myelopathy iv. Brace for scoliosis initially
v. Posterior spinal fusion for severe scoliosis or for patients resistant to bracing
vi. Surgical correction for hip and knee abnormalities vii. Surgical correction of equinovarus deformities unmanageable by physical therapy or serial casting
b. SED tarda, X-linked type i. Supportive care
a) Avoid activities and occupations that place undue stress on the spine and weight bearing joints to prevent premature arthritis
b) Chronic pain management
c) Psychosocial support for the patient and family
ii. Bracing for scoliosis
iii. Posterior spinal fusion for severe scoliosis iv. Posterior stabilization for atlantoaxial instability
v. Valgus or valgus-extension intertrochanteric osteotomy to improve hip congruity
vi. Total joint arthroplasty for osteoarthritis in adult- hood
vii. Management of hip dysplasia
a) Acetabular augmentation if the acetabulum is insufficient to contain the enlarged femoral head (coxa magna)
b) May require hip replacement
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Fig. 1. A neonate with SED congenita showing moderately shortened limbs, short trunk and large head. Radiograph shows small oval verte- bral bodies, reniform ilia and moderately shortened limb bones.
Fig. 2. Photomicrograph of a neonate with SED congenita shows fre- quent presence of cytoplasmic inclusions in the chondrocytes of rest- ing cartilage and the zone of proliferation. The cytoplasmic inclusion is a dilated rough endoplasmic reticulum containing finely granular material.
Fig. 4. An adult with SED showing short-trunk dwarfism. Radiographs showed flat vertebral bodies, severe scoliosis, and retarded ossification of femoral head and neck.
Fig. 3. A boy with SED congenita showing short trunk, short, broad chest with pectus excavatum, globoid abdomen, and hyperlordosis.
Radiographs showed lack of ossification of the femoral epiphysis, short femoral neck, generalized platyspondyly, and thoracolumbar scoliosis.
