MMP13 – Metaphyseal chondrodysplasia, Spahr type

Metaphyseal chondrodysplasia, Spahr type (MDST) is a rare autosomal recessive skeletal dysplasia characterized by moderate short stature, metaphyseal irregularities, and knee pain without biochemical abnormalities of rickets. Affected individuals often present in childhood with genu varum, bowing of the legs, and increased fracture susceptibility.

Biallelic MMP13 variants underlie MDST. In the original pedigree, five homozygous individuals segregated a recurrent missense c.619T>G (p.Trp207Gly) variant (PMID:24648384) in an autosomal recessive manner. Two consanguineous Iraqi siblings and three Filipino siblings displayed the same clinical features and homozygosity for c.619T>G (PMID:27576021, PMID:36873332). A singleton 7-year-old boy harbored novel splice-site and multiple loss-of-function MMP13 alleles, expanding the variant spectrum (PMID:31413057).

Collectively, 11 affected individuals from four unrelated families have been described with homozygous missense (n=2) and various loss-of-function (n≥9) MMP13 alleles (e.g., c.619T>G (p.Trp207Gly)) segregating with MDST, supporting a strong gene–disease association (PMID:24648384, PMID:27576021, PMID:31413057, PMID:36873332).

Functional modeling of the p.Trp207Gly substitution predicts disruption of a key hydrogen bond within the calcium-binding catalytic domain of MMP13, consistent with loss of collagenolytic activity and impaired growth plate remodeling. Although no in vivo models specific to MDST have been reported, structural data concord with the autosomal recessive loss-of-function mechanism.

No conflicting evidence has been reported. Molecular confirmation of MMP13-related MDST enables precise differentiation from dominant metaphyseal anadysplasia and informs recurrence risk and genetic counseling.

Key take-home: Genetic testing for MMP13 is clinically useful for diagnosis of MDST, guiding prognosis and family planning.

References

• American journal of medical genetics. Part A • 2014 • MMP13 mutations are the cause of recessive metaphyseal dysplasia, Spahr type. PMID:24648384
• Clinical dysmorphology • 2017 • Metaphyseal dysplasia, Spahr type; missense MMP13 mutations in two Iraqi siblings. PMID:27576021
• BMJ case reports • 2019 • Metaphyseal dysplasia, Spahr type: a mimicker of rickets. PMID:31413057
• Journal of orthopaedic case reports • 2022 • Metaphyseal Dysplasia, Spahr Type; A Case Report of Variable Expressivity in Non-Consanguineous Filipino Siblings. PMID:36873332

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