CCN2 – Kyphomelic Dysplasia

CCN2 encodes connective tissue growth factor, a secreted matricellular protein essential for chondrocyte proliferation and differentiation. Kyphomelic dysplasia is an autosomal recessive skeletal disorder characterized by bowing of the long bones, particularly the femora, combined with craniofacial anomalies and short stature. Evidence from two consanguineous families establishes CCN2 as the causal gene for kyphomelic dysplasia.(PMID:39506047)

In a recent study, exome sequencing of three probands from two unrelated families with six affected offspring revealed two novel homozygous CCN2 variants that segregated fully with disease: a missense variant c.443G>A (p.Cys148Tyr) and a frameshift variant c.779_786del (p.Pro260LeufsTer7).(PMID:39506047) All affected individuals exhibited short stature, cleft palate, micro-retrognathia, and radiographic features of kyphomelia and bowing of long bones.

Segregation analysis demonstrated complete concordance of biallelic CCN2 variants in six affected sibs from two families (affected_relatives = 6), meeting criteria for strong genetic linkage. The variant spectrum includes at least one loss-of-function allele (c.779_786del (p.Pro260LeufsTer7)) and one deleterious missense allele (c.443G>A (p.Cys148Tyr)).

Functional studies in animal models corroborate the human findings: Ccn2-deficient mice exhibit twisted limbs, shortened and kinked sterna, domed cranial vault, micrognathia, and cleft palate, mirroring the human phenotype. CRISPR–Cas9–mediated knockout of ccn2a in zebrafish F0 embryos produced altered body curvature, craniofacial cartilage defects, and bent or absent tails, confirming loss-of-function pathogenicity.(PMID:39506047)

The combined genetic and experimental data support a loss-of-function mechanism for CCN2 in kyphomelic dysplasia, consistent with haploinsufficiency of a key extracellular signaling factor. No conflicting reports have been described.

Key Take-home: Biallelic loss-of-function variants in CCN2 cause autosomal recessive kyphomelic dysplasia, and genetic testing of CCN2 should be incorporated into the diagnostic evaluation of patients with bowing skeletal dysplasia and craniofacial anomalies.

References

• Unknown • Unknown • Title not provided PMID:39506047

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