Novel LOX Start‐Loss Variant Mimicking Arterial Tortuosity Syndrome in Neonatal Cutis Laxa: A Diagnostic Challenge

ABSTRACT

Cutis laxa comprises a group of rare connective tissue disorders characterized by loose, inelastic skin due to defects in elastic fiber formation, with autosomal recessive forms presenting early with multisystem involvement. Recently, biallelic variants in the LOX gene have been proposed to cause a severe form of autosomal recessive cutis laxa (ARCL), although evidence remains limited. We report a neonate with generalized cutis laxa, dysmorphic features, and extensive vascular abnormalities. Imaging revealed marked tortuosity of the aortic arch, descending thoracic aorta, cervical arteries, and pulmonary arteries, along with involvement of the systemic venous system. Whole exome sequencing identified a homozygous start‐loss variant in the LOX gene, predicted to result in loss‐of‐function. The patient remained under cardiology follow‐up but succumbed at 2 years of age. Lysyl oxidase plays a critical role in collagen and elastin cross‐linking within the extracellular matrix, and its disruption provides a plausible mechanism for the observed phenotype. While previously reported cases have described predominantly arterial involvement, the additional presence of venous tortuosity in our patient expands the phenotypic spectrum of this emerging entity. This report adds to the limited evidence supporting LOX as a candidate gene for ARCL and highlights the importance of molecular diagnostics in delineating rare connective tissue disorders.