What question did this study set out to answer?

To delineate the clinical and molecular spectrum of PLOD2-associated disease in patients with Bruck syndrome type 2.

May 7, 2026Genes0 citationsOpen Access

Clinical Variability Within the PLOD2-Associated Phenotypic Continuum: Three Novel Variants in Four Patients from a Descriptive Case Series

EMElena S. MerkuryevaResearch Centre for Medical Genetics ЕMЕ. А. MelnikPirogov Russian National Research Medical University VKVladimir M. KenisNorth-Western State Medical University named after I.I. Mechnikov

Key Points

To delineate the clinical and molecular spectrum of PLOD2-associated disease in patients with Bruck syndrome type 2.
Descriptive case series involving four patients from three families
Clinical, radiological, and molecular evaluations conducted
Molecular testing through targeted next-generation sequencing and Sanger sequencing for variant confirmation
Four novel PLOD2 variants identified in patients with varying disease severity
Mutations led to bone fragility ranging from 3 months to 4 years for first fracture
Clinical features included absent congenital contractures and additional skeletal deformities

Abstract

Background/Objectives: Bruck syndrome type 2 (BS2) is an ultra-rare autosomal recessive disorder within the osteogenesis imperfecta (OI) spectrum caused by biallelic pathogenic variants in PLOD2, which encodes lysyl hydroxylase 2 (LH2), an enzyme essential for bone-specific collagen cross-linking. Marked clinical heterogeneity complicates diagnosis, particularly in patients with atypical or incomplete presentations. We aimed to further delineate the clinical and molecular spectrum of PLOD2-associated disease. Methods: In this descriptive case series, we performed clinical, radiological, and molecular evaluations of four patients from three unrelated families, including two previously reported siblings. Molecular testing comprised targeted next-generation sequencing or whole-exome sequencing, followed by Sanger sequencing for variant confirmation and familial segregation analysis where feasible. Results: Four PLOD2 variants (NM₁82943. 3) were identified: homozygous c. 1885A > G (p. Thr629Ala) in two siblings; c. 8dup (p. (Cys4MetfsTer35) ) and c. 2222G > A (p. (Gly741Glu) ) in one patient; and homozygous c. 2027A > C (p. (Tyr676Ser) ) in one infant. Three variants were previously unreported. Two missense variants remained classified as variants of uncertain significance, and the phase of the two heterozygous variants detected in one patient could not be established because a paternal sample was unavailable. Clinical severity was variable: age at first fracture ranged from 3 months to 4 years, and cumulative fracture burden ranged from 3 to multiple recurrent fractures. One 10-year-old patient had a severe OI-like phenotype without congenital contractures. Older patients showed additional axial and pelvic involvement, including craniovertebral junction abnormalities and acetabular protrusion. Conclusions: This case series broadens the range of clinical presentations observed in PLOD2-associated disease and indicates that severe bone fragility may occur in the absence of congenital contractures. These findings support inclusion of PLOD2 in the differential diagnosis of patients with unexplained bone fragility and progressive skeletal deformities. Additional well-characterized cases and functional studies are needed to refine genotype–phenotype correlations and clarify the clinical significance of newly identified variants.

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