Collagen XII-related disorders (COLXII-RD) are a heterogenous group of disorders with overlapping symptoms involving both connective tissue and muscle, clinically manifesting with hyperlaxity, contractures, and weakness of variable clinical severity. Biallelic loss-of-function (LOF), as well as dominantly acting variants in COL12A1, have been recognized to cause COLXII-RD, with the disease severity being notably more severe in patients with recessive LOF COLXII-RD. While additional dominant cases have now been reported, fewer cases of the presumed more severe recessive COLXII-RD have been documented.
Here, we present detailed clinical, immunohistochemical and imaging data on seven additional patients from six families, with biallelic pathogenic variants in COL12A1. In line with the initial report, four patients present with a consistent severe congenital phenotype, with significant myopathic muscle involvement on imaging and severe weakness with minimal attainment of motor skills, respiratory insufficiency, scoliosis, dysphagia and poor weight gain requiring G-tube feeds. In contrast, the remaining three patients manifest a milder phenotype, presenting with congenital hypotonia and hyperlaxity with subsequent steady improvement, acquisition of motor skills such as independent ambulation and muscle imaging consistent with diffuse mild muscle involvement. Gum hypertrophy was a notable finding at birth across the disease severity spectrum. This cohort of patients thus expands the clinical spectrum associated with biallelic variants in COL12A1 to now also include a milder overlap phenotype of muscle and connective tissue disease. This series reviews the clinical presentation, immunostaining, muscle imaging, and explores the genotype-phenotype correlations for recessive COLXII-RD and thus highlights a still novel recognizable overlap syndrome.