Pseudoachondroplasia Pseudoachondroplasia is a type of short-limbed dwarfism, d. Chronic compression myelopathy secondary to habitual deriving its name from phenotypic similarity to achondropla- atlantoaxial dislocation sia. It is characterized by normal facies, short-limbed dwarfism, 7. Extremities joint laxity, and epiphyseal and metaphyseal abnormalities in a. Bowing of the long bones the growing child. b. Deformities of the lower limbs i. Secondary to ligamentous laxity GENETICS/BASIC DEFECTS ii. Ranging from genu varum (bowed legs), genu valgum (knock knees), and genu recurvatum 1. Inheritance iii. A “wind-swept deformity” (bow-leg on one side a. Pseudoachondroplasia: autosomal dominant with and knock-knee on the other side) complete penetrance c. Markedly shortened hands (without trident configura- b. Pseudoachondroplasia types II: autosomal recessive tion) and feet (small percentage of cases from parental gonadal d. Ulnar deviation of the wrist mosaicism) e. Flexion contractures of the elbow and knees 2. Cause f. Brachydactyly a. Mutations in the gene encoding cartilage oligomeric g. “Telescoping” fingers matrix protein (COMP) on the centromeric region of 8. Joint 19p (19p13.1-p12) a. Lax ligament i. Deletions: Approximately 40–50% of cases of b. Premature osteoarthritis pseudoachondroplasia have deletion mutations c. Contractures of the hips in exon 13 of the COMP gene. 9. Prognosis ii. Specific base substitutions a. Good survival iii. Duplications b. Early arthrosis, notably in the hip and knee joints b. Allelic to multiple epiphyseal dysplasia, which is also c. Possible myelopathy secondary to atlantoaxial dislo- caused by COMP mutations cations c. All mutations associated with pseudoachondroplasia and multiple epiphyseal dysplasia: found in exons DIAGNOSTIC INVESTIGATIONS encoding the type III repeat region or C-terminal domain of COMP 1. Radiography d. Mutations in extracellular matrix proteins, COMP, a. Tubular bones types II and IX collagens, and matrilin-3 i. Irregularities and fragmentations of the develop- i. Producing a spectrum of mild to severe chon- ing epiphyses drodysplasias characterized by epiphyseal and ii. Shortened tubular bones vertebral abnormalities iii. Brachydactyly ii. Disruption of protein processing and excessive iv. Delayed epiphyseal ossification (delayed bone age) accumulation of some of these proteins in the v. Small phalangeal epiphyses (miniepiphyses) rough endoplasmic reticulum that appears to vi. Small, irregular carpal bones compromise cellular function vii. Irregular, widened (frayed), mushroomed meta- physes viii. Coxa vara CLINICAL FEATURES b. Pelvis 1. Normal at birth i. Delayed ossification of the capital femoral epi- 2. Normal intelligence physes, which become flattened and small when 3. Normal craniofacial appearance ossified 4. Waddling gait and diminished linear growth at about 2 ii. Commonly observed sclerosis and irregularity of years of age the acetabular roof 5. Rhizomelic short-limbed dwarfism c. Vertebrae a. Body proportion resembling achondroplasia i. Characteristic anterior beaking or tonguing (in b. Usually detectable at age 2–4 years lateral view of the lumbar spines) 6. Spine a) Due to delayed ossification of the annular a. Accentuated lumbar lordosis epiphyses b. Scoliosis b) Vertebrae becoming more normal in appear- c. Kyphosis ance after puberty 826 PSEUDOACHONDROPLASIA 827 i. Characteristic platyspondyly in childhood Briggs MD, Rasmussen IM, Weber JL, et al.: Genetic linkage of mild pseudoa- ii. Kyphoscoliosis chondroplasia (PSACH) to markers in the pericentromeric region of chro- mosome 19. Genomics 18:656–660, 1993. iii. Lumbar lordosis Briggs MD, Mortier GR, Cole WG, et al.: Diverse mutations in the gene for iv. Odontoid hypoplasia cartilage oligomeric matrix protein in the pseudoachondroplasia-multiple v. Atlantoaxial dislocations epiphyseal dysplasia disease spectrum. Am J Hum Genet 62:311–319, d. Ribs: spatulate 1998. 2. Histology of growth plates Briggs MD, Chapman KL: Pseudoachondroplasia and multiple epiphyseal dys- plasia: mutation review, molecular interactions, and genotype to pheno- a. Irregular arrangement of chondrocytes without col- type correlations. Hum Mutat 19:465–478, 2002. umn formation Byers PH: Molecular heterogeneity in chondrodysplasias. (Editorial) Am J b. Irregular provisional calcification Hum Genet 45:1–4, 1989. c. Intracytoplasmic inclusions in chondrocytes Cohn DH, Briggs MD, King LM, et al.: Mutations in the cartilage 3. EM of chondrocytes oligomeric matrix protein (COMP) gene in pseudoachondroplasia and multiple epiphyseal dysplasia. Ann N Y Acad Sci 785:188–194, a. Showing distinctive giant rough endoplasmic reticu- 1996. lum cisternae filled with punctuate material Cooper RR, Ponseti IV, Maynard JA: Pseudoachondroplastic dwarfism. A b. The material composed of alternating electron-lucent and rough-surfaced endoplasmic reticulum storage disorder. J Bone Joint electron-dense layers in a unique lamellar appearance Surg 55A:475–484, 1973. 4. Molecular diagnosis Cranley RE, Williams BR, Kopits SE, et al.: Pseudoachondroplastic dyspla- sia: five cases representing clinical, roentgenographic and histologic a. Techniques heterogeneity. Birth Defects Original Article Series 11(6):205–215, i. Mutation screening in exons of the COMP gene 1975. using SSCP and sequence analysis Deere M, Sanford T, Ferguson HL, et al.: Identification of twelve muta- ii. COMP mutation screening in RNA isolated from tions in cartilage oligomeric matrix protein (COMP) in patients with pseudoachondroplasia. Am J Med Genet 80:510–513, skin fibroblast cell line 1998. b. Particularly useful in adult patients where radiologi- Dennis NR, Renton P: The severe recessive form of pseudoachondroplasia. cal diagnosis can be difficult Pediatr Radiol 3:169–175, 1975. Ferguson Hl, Deere M, Evans R, et al.: Mosaicism in pseudoachondroplasia. GENETIC COUNSELING Am J Med Genet 70:287–201, 1997. Hall JG: Pseudoachondroplasia. Birth Defects Orig Artic Ser 11:187–202, 1. Recurrence risk 1975. a. Autosomal dominant inheritance Hall JG, Dorst JP: Pseudoachondroplastic SED, recessive Maroteaux-Lamy i. Patient’s sibs type. Birth Defects Orig Art Ser V(4):254–259, 1969. a) 50% if one of the parent is affected Hall JG, Dorst JP, Rotta J, McKusick VA: Gonadal mosaicism in pseudoachon- droplasia. Am J Med Genet 28:143–151, 1987. b) Not increased if parents are normal Hecht JT, Nelson LD, Crowder E et al.: Mutations in exon 17B of cartilage ii. Patient’s offspring: 50% oligomeric matrix protein (COMP) cause pseudoachondroplasia. Nature b. Autosomal recessive inheritance Genet 10:325–329, 1995. i. Patient’s sibs Heselson NG, Cremin BJ, Beighton P: Pseudoachondroplasia: a report of 13 cases. Brit J Radiol 59:473–482, 1977. a) 25% for true autosomal recessive inheritance Ikegawa S, Ohashi H, Nishimura G, et al.: Novel and recurrent COMP (car- b) Slightly increased risk in case of parental tilage oligomeric matrix protein) mutations in pseudoachondroplasia gonadal mosaicism (depending on the degree and multiple metaphyseal dysplasia. Hum Genet 103:633–638, of mosaicism) 1998. ii. Patient’s offspring: not increased unless the Kopits SE, Lindstrom JA, McKusick VA: Pseudoachondroplastic dysplasia: pathodynamics and management. In: Bergsma D (ed.): Skeletal spouse is also carrying the gene Dysplasias. Amsterdam: Excerpta Medica (pub.) 1974, pp 341–| 2. Prenatal diagnosis 352. a. Prenatal ultrasonography unlikely to detect the skele- Langer LO Jr, Schaefer GB, Wadsworth DT: Patient with double heterozygos- tal changes, which will not manifest until about 2 ity for achondroplasia and pseudoachondroplasia, with comments on years of age these conditions and the relationship between pseudoachondroplasia and multiple epiphyseal dysplasia, Fairbank type. Am J Med Genet 47: b. Prenatal diagnosis possible in the family at risk and 772–781, 1993. the disease-causing COMP mutation has been charac- Maroteaux P, Stanescu R, Stanescu V, et al.: The mild form of pseudoachon- terized in an affected individual droplasia. Eur J Pediatr 133:227–231, 1980. 3. Management McKeand J, Rotta J, Hecht JT: Natural history study of pseudoachondroplasia. Am J Med Genet 63:406–410, 1996. a. Supportive Newman B, Donnah D, Briggs MD: Molecular diagnosis is important to b. Surgical correction of the leg deformities confirm suspected pseudoachondroplasia. J Med Genet 37:64–65, c. Hip replacement for severe hip contractures 2000. d. Cervical stabilization procedures for cervical cord com- Song HR, Lee KS, Li QW, et al.: Identification of cartilage oligomeric pression with progressive neurologic symptoms and signs matrix protein (COMP) gene mutations in patients with pseudoachon- droplasia and multiple epiphyseal dysplasia. J Hum Genet 48:222–225, 2003. REFERENCES Wynne-Davis R, Hall CM, Young ID: Pseudoachondroplasia: clinical diagnosis Beck M, Lingnau K, Spranger J: Newly synthesized proteoglycans in pseudoa- at different ages and comparison of autosomal dominant and recessive chondroplasia. Bone 9:367–370, 1988. types: a review of 32 patients (26 kindreds). J Med Genet 23:425–434, Briggs MD, Hoffman SMG, King LM, et al.: Pseudoachondroplasia and mul- 1986. tiple epiphyseal dysplasia due to mutations in the cartilage oligomeric Young ID, Moore JR: Severe pseudoachondroplasia with parental consanguinity. matrix protein gene. Nature Genet 10:330–336, 1995. J Med Genet 22:150, 1985. 828 PSEUDOACHONDROPLASIA Fig. 1. A girl with pseudoachondroplasia at 2 and half years (upper) with normal craniofacial appearance, mild short