870
Schmid Metaphyseal Chondrodysplasia
Schmid metaphyseal chondrodysplasia (SMCD) is a mild hereditary chondrodysplasia resulting from growth plate carti- lage abnormalities.
GENETICS/BASIC DEFECTS
1. Inheritance
a. Autosomal dominant b. Variable expression 2. Molecular pathogenesis
a. SMCD: caused by heterozygous mutations in the gene (COL10A1 mapped to chromosome 6q21-q22) for Type X collagen, a short-chain collagen whose expression is largely restricted to the hypertrophic chondrocytes of growth plate cartilage
i. Most mutations reside in the carboxylterminal globular domain (CN1)
ii. Two mutations observed in a putative signal pep- tide cleavage site
b. Growth plate abnormalities of SMCD: resulting from collagen X haploinsufficiency, a reduction by 50% in collagen X
CLINICAL FEATURES
1. Mild to moderate short-limbed dwarfism 2. Bowed legs
3. Waddling gait, often a presenting sign at second year 4. Coxa vara
5. Genu varum
6. Exaggerated lumbar lordosis 7. Flared anterior rib cage 8. Leg pain during childhood 9. Prognosis
a. Radiological changes appearing early with a tendency to heal and change slowly with time, giving rise to mildly dwarfed patients
b. Normal intelligence
DIAGNOSTIC INVESTIGATIONS
1. Radiography a. Hip
i. Abnormal acetabular roofs
ii. Enlarged capital femoral epiphyses iii. Coxa vara
iv. Femoral bowing
v. Abnormal proximal femoral metaphyses b. Knee
i. Abnormal distal femoral metaphyses ii. Abnormal proximal tibial metaphyses iii. Abnormal proximal fibular metaphyses c. Ankle
i. Abnormal distal tibial metaphyses
ii. Abnormal distal fibular metaphyses d. Wrist
i. Abnormal distal radial metaphyses ii. Abnormal distal ulnar metaphyses e. Ribs: anterior cupping, splaying and sclerosis
f. Wide metaphyses with cupping and fraying g. Short and stubby long bones
h. Normal metacarpals and phalanges i. Normal spine
2. Histology: variable bone changes
a. Mild sharp serrations of the metaphyses with increased density of the provisional zone of calcification b. Irregularity with flaring and fragmentation and
widening of the growth plate
3. Molecular genetic analysis of COL10A1 mutation a. Mutation analysis
b. Mutation scanning
GENETIC COUNSELING
1. Recurrence risk
a. Patient’s sib: low recurrence risk unless a parent is affected
b. Patient’s offspring: 50%
2. Prenatal diagnosis by amniocentesis or CVS: can be offered to families at-risk for DMCD with a previously characterized disease-causing COL10A1 mutation 3. Management
a. Supportive
b. Orthopedic management of bowed legs: generally does not require orthopedic surgery
REFERENCES
Bateman JF, Freddi S, Nattrass G, et al.: Tissue-specific RNA surveillance?
Nonsense-mediated mRNA decay causes collagen X haploinsufficiency in Schmid metaphyseal chondrodysplasia cartilage. Hum Mol Genet 12:217–225, 2003.
Beluffi G, Fiori P, Notarangelo CD, et al.: Metaphyseal dysplasia type Schmid.
Early X-ray detection and evolution with time. Ann Radiol (Paris) 26:237–243, 1983.
Beluffi G, Fiori P, Schifino A, et al.: Metaphyseal dysplasia, type Schmid. Prog Clin Biol Res 104:103–110, 1982.
Bonaventure J, Chaminade F, Maroteaux P: Mutations in three subdomains of the carboxy-terminal region of collagen type X account for most of the Schmid metaphyseal dysplasias. Hum Genet 96:58–64, 1995.
Chan D, Jacenko O: Phenotypic and biochemical consequences of collagen X mutations in mice and humans. Matrix Biol 17:169–184, 1998.
Chan D, Ho MS, Cheah KS: Aberrant signal peptide cleavage of collagen X in Schmid metaphyseal chondrodysplasia. Implications for the molecular basis of the disease. J Biol Chem 276:7992–7997, 2001.
Chan D, Weng YM, Graham HK, et al.: A nonsense mutation in the carboxyl- terminal domain of type X collagen causes haploinsufficiency in Schmid metaphyseal chondrodysplasia. J Clin Invest 101:1490–1499, 1998.
Dharmavaram RM, Elberson MA, Peng M, et al.: Identification of a mutation in type X collagen in a family with Schmid metaphyseal chondrodyspla- sia. Hum Mol Genet 3:507–509, 1994.
SCHMID METAPHYSEAL CHONDRODYSPLASIA 871
Dimson SB: Metaphyseal dysostosis type Schmid. Proc R Soc Med 61:1260–1261, 1968.
Lachman RS, Rimoin DL, Spranger J: Metaphyseal chondrodysplasia, Schmid type. Clinical and radiographic delineation with a review of the literature.
Pediatr Radiol 18:93–102, 1988.
Matsui Y, Yasui N, Kawabata H, et al.: A novel type X collagen gene mutation (G595R) associated with Schmid-type metaphyseal chondrodysplasia.
J Hum Genet 45:105–108, 2000.
Miller SM, Paul LW: Roentgen observations in familial metaphyseal dysosto- sis. Radiology 83: 665–673, 1964.
Milunsky J, Maher T, Lebo R, et al.: Prenatal diagnosis for Schmid metaphy- seal chondrodysplasia in twins. Fetal Diagn Ther 13:167–168, 1998.
Sawai H, Ida A, Nakata Y, et al.: Novel missense mutation resulting in the sub- stitution of tyrosine by cysteine at codon 597 of the type X collagen gene
associated with Schmid metaphyseal chondrodysplasia. J Hum Genet 43:259–261, 1998.
Schmid F: Beitrag zur dysostosis enchondralis metaphysaria. Monatsschr Kinderheilk 97:393–397, 1949.
Schmid TM, Linsenmayer TF: Immunohistochemical localization of short chain cartilage collagen (type X) in avian tissues. J Cell Biol 100:598–605, 1985.
Wallis GA, Rash B, Sweetman WA, et al.: Amino acid substitutions of con- served residues in the carboxyl-terminal domain of the alpha 1(X) chain of type X collagen occur in two unrelated families with metaphyseal chondrodysplasia type Schmid. Am J Hum Genet 54:169–178, 1994.
Wallis GA, Rash B, Sykes B, et al.: Mutations within the gene encoding the alpha 1 (X) chain of type X collagen (COL10A1) cause metaphyseal chondrodyspla- sia type Schmid but not several other forms of metaphyseal chondrodysplasia.
J Med Genet 33:450–457, 1996.
Warman ML, Abbott M, Apte SS, et al.: A type X collagen mutation causes Schmid metaphyseal chondrodysplasia. Nat Genet 5:79–82, 1993.
872 SCHMID METAPHYSEAL CHONDRODYSPLASIA
Fig. 1. Three young children with Schmid metaphyseal chondrodys- plasia showing short stature, lumbar lordosis, and bowing of the legs.
Radiographs showed genu varum and metaphyseal widening with fraying and cupping. Epiphyses are normal.
SCHMID METAPHYSEAL CHONDRODYSPLASIA 873
