Phenotypic and genetic characteristics of a Dutch cohort of patients with X-linked osteoporosis due to PLS3 genetic variants

X-linked osteoporosis, caused by plastin 3 (PLS3) genetic variants, is a rare disease, characterized by low BMD and early-onset fractures, primarily affecting men. Our aim was to further elucidate the phenotypic characteristics, including sex-differences and genotype–phenotype analysis, in individuals with PLS3 variants. Our cohort comprises of 28 patients from 11 families, 18 men and 10 women, with a different PLS3 variant in each family. Demographic, clinical, and genetic features, imaging and laboratory tests, and treatment details were retrospectively reviewed. Men, (median age 47.0 y), demonstrated low Z-scores of the lumbar spine (−2.8 ± 1.7) and femoral neck (−1.7, IQR: −2.9-0.8). Most women (median age 49.5 y) had normal BMD, two had osteoporosis and one osteopenia. Moreover, men experienced a higher total number of fractures than women (men: 12.0, IQR: 6.7, 18.5, women: 2.0, IQR: 0.7, 5.2). Within one large family (n = 10) there was considerable heterogeneity regarding BMD and fractures, which might be explained by differences in factors like physical exercise (PE) or in (poly) genetic background. Extra-skeletal characteristics such as (mild) blue discoloration of the sclerae (men: 33.3%, women: 30.0%), joint hypermobility (44.4%, 70.0%) and skin hyperlaxity (50.0%, 20.0%) were observed. No relation was found between types and locations of variants and various clinical endpoints in men, using data from our cohort and the literature. Regarding treatment, all men and 40% of women received bone-active therapy, mostly oral bisphosphonates. Adult men demonstrated a 16.6% mean increase in the BMD of the lumbar spine (p = .03), after a median treatment duration of 6 y. In summary, this is so far the largest study of patients with X-linked osteoporosis, including an extensive genotype–phenotype analysis. A potential protective role of increasing weight-bearing PE in osteoporosis severity, as well as effects of penetrance, genetic background, or other environmental or lifestyle factors, need further study.