NKX3-2 – spondylo-megaepiphyseal-metaphyseal dysplasia

Spondylo-megaepiphyseal-metaphyseal dysplasia is a rare autosomal recessive skeletal dysplasia characterized by disproportionate short stature, absent ossification of vertebral bodies and pelvic bones, and metaphyseal flaring. A perinatal lethal case presented with disproportionate short stature (HP:0003498), abnormal facial shape (HP:0001999), talipes equinovarus (HP:0001762), and duodenal atresia (HP:0002247); skeletal survey revealed total absence of vertebral, pubic and ischial ossification and broad femora with tented ribs. Molecular analysis identified homozygosity for a novel NKX3-2 frameshift variant, c.507_508del (p.Gly171CysfsTer55), confirming the diagnosis (PMID:29704686). No additional unrelated families or segregation data have been reported to date.

Functional assessment in a rat model of vitamin A deficiency–induced congenital scoliosis demonstrated significant down-regulation of Nkx3-2 expression during somitogenesis, supporting a critical role for NKX3-2 in axial skeletal development (PMID:31044535). Despite concordant expression data, overall evidence remains limited to a single proband and preliminary functional studies. Key Take-home: NKX3-2 sequencing should be considered in neonates with suggestive skeletal features to enable early SMMD diagnosis and management.

References

• European journal of medical genetics • 2019 • A novel NKX3-2 mutation associated with perinatal lethal phenotype of spondylo-megaepiphyseal-metaphyseal dysplasia in a neonate. PMID:29704686
• Journal of cellular and molecular medicine • 2019 • LncRNA-SULT1C2A regulates Foxo4 in congenital scoliosis by targeting rno-miR-466c-5p through PI3K-ATK signalling. PMID:31044535

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