Expanding the Genetic and Clinical Spectrum of GZF1 ‐Related Phenotype: A Specific Ocular and Skeletal Disorder Distinguishable From Larsen Syndrome

GZF1-related phenotype (GZF1RP) has been referred to by different names, including autosomal recessive Larsen syndrome (LRS) and "joint laxity, short stature, and myopia". Only ten patients from five families have been reported, all of whom carry biallelic variants of GZF1. They share short stature and joint dislocation with LRS; however, they present with severe ocular manifestations, suggesting that GZF1RP may be specific. In this study, we described three new patients with severe ophthalmologic phenotypes, including congenital glaucoma and abnormal iris morphology. We identified the GZF1: c.1440del (p.His481IlefsTer26) variant in homozygosity in two affected sisters and compound heterozygosity in the third patient: the same c.1440del plus c.1451_1452del (p.Cys484fs). In addition to expanding the molecular spectrum, we identified new radiological findings, such as cervical segmentation defects, carpal shortening, and lower lumbar sacralization, as well as some clinical findings uncommon in previous cases, such as umbilical hernia and congenital heart disease. We also searched for LRS case series with pathogenic variants in FLNB to identify differences between the two entities. The comparison allows us to define a recognizable GZF1RP that includes severe ocular defects, short stature, facial dysmorphism, joint hypermobility/dislocations, scoliosis, thoracic deformity, progressive hearing loss, umbilical hernia, and hypodontia.