Pseudoachondroplasia
Pseudoachondroplasia is a type of short-limbed dwarfism, deriving its name from phenotypic similarity to achondropla- sia. It is characterized by normal facies, short-limbed dwarfism, joint laxity, and epiphyseal and metaphyseal abnormalities in the growing child.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Pseudoachondroplasia: autosomal dominant with complete penetrance
b. Pseudoachondroplasia types II: autosomal recessive (small percentage of cases from parental gonadal mosaicism)
2. Cause
a. Mutations in the gene encoding cartilage oligomeric matrix protein (COMP) on the centromeric region of 19p (19p13.1-p12)
i. Deletions: Approximately 40–50% of cases of pseudoachondroplasia have deletion mutations in exon 13 of the COMP gene.
ii. Specific base substitutions iii. Duplications
b. Allelic to multiple epiphyseal dysplasia, which is also caused by COMP mutations
c. All mutations associated with pseudoachondroplasia and multiple epiphyseal dysplasia: found in exons encoding the type III repeat region or C-terminal domain of COMP
d. Mutations in extracellular matrix proteins, COMP, types II and IX collagens, and matrilin-3
i. Producing a spectrum of mild to severe chon- drodysplasias characterized by epiphyseal and vertebral abnormalities
ii. Disruption of protein processing and excessive accumulation of some of these proteins in the rough endoplasmic reticulum that appears to compromise cellular function
CLINICAL FEATURES
1. Normal at birth 2. Normal intelligence
3. Normal craniofacial appearance
4. Waddling gait and diminished linear growth at about 2 years of age
5. Rhizomelic short-limbed dwarfism
a. Body proportion resembling achondroplasia b. Usually detectable at age 2–4 years
6. Spine
a. Accentuated lumbar lordosis b. Scoliosis
c. Kyphosis
d. Chronic compression myelopathy secondary to habitual atlantoaxial dislocation
7. Extremities
a. Bowing of the long bones b. Deformities of the lower limbs
i. Secondary to ligamentous laxity
ii. Ranging from genu varum (bowed legs), genu valgum (knock knees), and genu recurvatum iii. A “wind-swept deformity” (bow-leg on one side
and knock-knee on the other side)
c. Markedly shortened hands (without trident configura- tion) and feet
d. Ulnar deviation of the wrist
e. Flexion contractures of the elbow and knees f. Brachydactyly
g. “Telescoping” fingers 8. Joint
a. Lax ligament
b. Premature osteoarthritis c. Contractures of the hips 9. Prognosis
a. Good survival
b. Early arthrosis, notably in the hip and knee joints c. Possible myelopathy secondary to atlantoaxial dislo-
cations
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Tubular bones
i. Irregularities and fragmentations of the develop- ing epiphyses
ii. Shortened tubular bones iii. Brachydactyly
iv. Delayed epiphyseal ossification (delayed bone age) v. Small phalangeal epiphyses (miniepiphyses) vi. Small, irregular carpal bones
vii. Irregular, widened (frayed), mushroomed meta- physes
viii. Coxa vara b. Pelvis
i. Delayed ossification of the capital femoral epi- physes, which become flattened and small when ossified
ii. Commonly observed sclerosis and irregularity of the acetabular roof
c. Vertebrae
i. Characteristic anterior beaking or tonguing (in lateral view of the lumbar spines)
a) Due to delayed ossification of the annular epiphyses
b) Vertebrae becoming more normal in appear- ance after puberty
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PSEUDOACHONDROPLASIA 827
i. Characteristic platyspondyly in childhood ii. Kyphoscoliosis
iii. Lumbar lordosis iv. Odontoid hypoplasia
v. Atlantoaxial dislocations d. Ribs: spatulate
2. Histology of growth plates
a. Irregular arrangement of chondrocytes without col- umn formation
b. Irregular provisional calcification
c. Intracytoplasmic inclusions in chondrocytes 3. EM of chondrocytes
a. Showing distinctive giant rough endoplasmic reticu- lum cisternae filled with punctuate material
b. The material composed of alternating electron-lucent and electron-dense layers in a unique lamellar appearance 4. Molecular diagnosis
a. Techniques
i. Mutation screening in exons of the COMP gene using SSCP and sequence analysis
ii. COMP mutation screening in RNA isolated from skin fibroblast cell line
b. Particularly useful in adult patients where radiologi- cal diagnosis can be difficult
GENETIC COUNSELING
1. Recurrence risk
a. Autosomal dominant inheritance i. Patient’s sibs
a) 50% if one of the parent is affected b) Not increased if parents are normal ii. Patient’s offspring: 50%
b. Autosomal recessive inheritance i. Patient’s sibs
a) 25% for true autosomal recessive inheritance b) Slightly increased risk in case of parental gonadal mosaicism (depending on the degree of mosaicism)
ii. Patient’s offspring: not increased unless the spouse is also carrying the gene
2. Prenatal diagnosis
a. Prenatal ultrasonography unlikely to detect the skele- tal changes, which will not manifest until about 2 years of age
b. Prenatal diagnosis possible in the family at risk and the disease-causing COMP mutation has been charac- terized in an affected individual
3. Management a. Supportive
b. Surgical correction of the leg deformities c. Hip replacement for severe hip contractures
d. Cervical stabilization procedures for cervical cord com- pression with progressive neurologic symptoms and signs
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Fig. 1. A girl with pseudoachondroplasia at 2 and half years (upper) with normal craniofacial appearance, mild short stature, and waddling gate and at 6 years (lowers) with short limbs, accentuated lumbar lor- dosis, and short stature.
Fig. 2. Radiographs of the spine show characteristic anterior beaking of the lumbar spine and mild scoliosis.
PSEUDOACHONDROPLASIA 829
Fig. 3. Radiographs of the pelvis and lower extremities showing irreg- ular, horizontal acetabular roof, delayed epiphyseal ossification, and wide mushroom-shape metaphyses.
Fig. 4. Radiograph of the upper extremities showing markedly widened and defective metaphyseal and epiphyseal ossifications in the proximal humerus, distal radius and ulna.
Fig. 5. Radiographs of the hands and feet show grossly disturbed metaphyseal and epiphyseal ossification, short and stubby tubular bones, somewhat widened metacarpals and metatarsals, and small and markedly irregular carpal and tarsal bones.
