Schmid metaphyseal dysplasia

MCDS (metaphyseal chondrodysplasia, Schmid type) is the most common and least severe of the metaphyseal chondrodysplasias, presenting with disproportionate short stature, genu varum, a waddling gait, and shortened limbs. Clinical and radiological features are typically absent during infancy and emerge in early childhood as weight-bearing and longitudinal growth advance. Short stature is the most frequent presenting feature and persists throughout the disease course; however, shortened limbs, waddling gait, short femoral necks, bowed femora or tibiae, and metaphyseal irregularities of the long bones may also dominate the early clinical picture. Lumbar lordosis, coxa vara, and joint pain are variably present. Facial features, head size, cognition, and extraskeletal development are typically normal. Inter- and intrafamilial variability in severity is pronounced.

MCDS is a rare skeletal dysplasia with an estimated prevalence of approximately 1 in 170,000–330,000 individuals.

MCDS is caused by heterozygous pathogenic variants in COL10A1 (6q22.1), which encodes the α1 chain of type X collagen, a protein expressed by hypertrophic chondrocytes in the growth plate. Essentially all reported cases are associated with heterozygous COL10A1 variants, although rare biallelic cases with a more severe phenotype have been described. Mutant collagen X is retained intracellularly, triggering endoplasmic reticulum stress and activation of the unfolded protein response. This disrupts hypertrophic chondrocyte differentiation and growth-plate organisation,
resulting in the characteristic metaphyseal abnormalities of MCDS.

MCDS is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% risk of inheriting the pathogenic COL10A1 variant. Although most affected individuals have an affected parent, de novo pathogenic variants occur and were identified in approximately 18% of cases in one cohort. In individuals with a de novo pathogenic variant, the recurrence risk for future siblings is low but not zero because of the possibility of parental germline mosaicism.

The diagnosis of MCDS is established in an individual with characteristic clinical and radiographic findings and can be confirmed by identification of a heterozygous pathogenic variant in COL10A1. Radiographs typically show metaphyseal flaring, fraying, and splaying of the femora, tibiae, and fibulae, short femoral necks with coxa vara, and bowing of the long bones; wrist involvement at the distal radius and ulna has also been reported. Normal serum calcium, phosphate, 25-hydroxyvitamin D, β-CTX, and P1NP concentrations help distinguish MCDS from rickets, which can show overlapping metaphyseal abnormalities on imaging.

• Identification of the underlying COL10A1 pathogenic variant confirms the clinical diagnosis and provides the basis for accurate genetic counselling and predictive testing.
• A confirmed molecular diagnosis can inform condition-specific surveillance and clinical management, including monitoring of skeletal manifestations and planning of orthopaedic interventions.

• Meng L, Hu J, Sun L, Zhang Q, Wang O, Jiang Y, et al. Clinical, molecular characteristics, and genotype-phenotype relationships of metaphyseal chondrodysplasia type Schmid. Calcif Tissue Int. 2025;117(1):5. PMID: .
• Shepherd RF, Kerns JG, Ranganath LR, Gallagher JA, Taylor AM. Lessons from rare forms of osteoarthritis. Calcif Tissue Int. 2021;109(3):291-302. PMID: .
• Wu H, Wang S, Li G, Yao Y, Wang N, Sun X, et al. Characterization of a novel COL10A1 variant associated with Schmid-type metaphyseal chondrodysplasia and a literature review. Mol Genet Genomic Med. 2021;9(5). PMID: .
• Tan WH, Rücklin M, Larionova D, Ngoc TB, Joan van Heuven B, Marone F, et al. A Collagen10a1 mutation disrupts cell polarity in a medaka model for metaphyseal chondrodysplasia type Schmid. iScience. 2024;27(4):109405. PMID: .