Osteogenesis imperfecta (OI) is a large group of genetically heterogeneous diseases resulting from decreased bone density and an abnormal microarchitecture, which are clinically manifested by abnormal bone fractures. A distinctive clinical feature of this group of diseases is the presence of spontaneous fractures and skeletal deformities. However, the clinical manifestations of different types of OI are characterized by marked polymorphism with variable severity of skeletal and extra-skeletal features. Previous studies have shown that a mutation (c.-14C>T) in the IFITM5 gene is responsible for autosomal dominant OI type V. However, the mutation has a variable expression pattern and marked clinical heterogeneity. In this study, a clinical and genetic analysis of 12 cases with molecularly confirmed OI type V from 12 unrelated families was performed. Significant clinical heterogeneity of the disease with the same molecular defect was detected. In six subjects (50%), there were no classic signs of OI type V (formation of a hyperplastic bone callus, calcification of the interosseous membrane and dislocation of the radial head). In all cases, the mutation occurred de novo.

Calvarial doughnut lesions (CDL) with bone fragility with or without spondylometaphyseal dysplasia (MIM: #126550) is a rare autosomal dominant skeletal disorder characterized by low bone mineral density, spinal and peripheral fractures, and specific sclerotic lesions of the cranial bones. In the current classification of skeletal disorders, the disease is included in the group of bone fragility disorders along with osteogenesis imperfecta. The disease is caused by pathogenic variants in the SGMS2 gene, the protein product of which is sphingomyelin synthase 2, which primarily contributes to sphingomyelin (SM) synthesis—the main lipid component of the plasma membrane essential for bone mineralization. To date, 15 patients from eight families with CDL with bone fragility have been described in the literature, and a recurrent variant c.148C>T (p.Arg50Ter) in the SGMS2 gene has been identified, which was found in patients from six families. We diagnosed the disease in 11 more patients from three unrelated families, caused by the same heterozygous nonsense variant c.148C>T (p.Arg50Ter) in the SGMS2 gene. Our results show wide interfamilial and intrafamilial phenotypic variability in patients with a detected recurrent variant in the SGMS2 gene, the presence of which must be taken into consideration in the diagnosis of the disease. The primary analysis of this variant will contribute to optimal molecular genetic diagnostics, which can reduce diagnostic costs and time.

Pathogenic variants in the FKBP10 gene lead to a spectrum of rare autosomal recessive phenotypes, including osteogenesis imperfecta (OI) Type XI, Bruck syndrome Type I (BS I), and the congenital arthrogryposis-like phenotype (AG), each with variable clinical manifestations that are crucial for diagnosis. This study analyzed the clinical-genetic characteristics of patients with these conditions, focusing on both known and newly identified FKBP10 variants. We examined data from 15 patients, presenting symptoms of OI and joint contractures. Diagnostic methods included genealogical analysis, clinical assessments, radiography, whole exome sequencing, and direct automated Sanger sequencing. We diagnosed 15 patients with phenotypes due to biallelic FKBP10 variants—4 with OI Type XI, 10 with BS I, and 1 with the AG-like phenotype—demonstrating polymorphism in disease severity. Ten pathogenic FKBP10 variants were identified, including three novel ones, c.1373C>T (p.Pro458Leu), c.21del (p.Pro7fs), and c.831_832insCG (p.Gly278Argfs), and a recurrent variant, c.831dup (p.Gly278Argfs). Variant c.1490G>A (p.Trp497Ter) was found in two unrelated patients, causing OI XI in one and BS I in the other. Additionally, two unrelated patients with BS I and epidermolysis bullosa shared identical homozygous FKBP10 and KRT14 variants. This observation illustrates the diversity of FKBP10-related pathology and the importance of considering the full spectrum of phenotypes in clinical diagnostics.

Osteogenesis imperfecta type VI is a rare autosomal recessive disorder characterized by bone fragility and defective mineralization, caused by pathogenic variants in the SERPINF1 gene. This study aimed to expand the understanding of OI type VI by analyzing clinical, radiological, and molecular findings in four patients from three unrelated families. Genotyping revealed two novel SERPINF1 variants, c.185G>T (p.Gly62Val) and c.992_993insCA (p.Glu331Asnfs), in a compound heterozygous state in one patient, and a known pathogenic variant, c.261_265dup (p.Leu89Argfs26), in a homozygous form in three patients. Clinical manifestations included early-onset fractures, severe skeletal deformities, impaired mobility, and growth failure. Radiological assessments revealed multilevel and multiplanar bone deformities and metaphyseal widening. RNA analysis demonstrated that the c.992_993insCA variant results in a truncated PEDF protein without triggering nonsense-mediated decay. Population screening identified a carrier frequency of 0.0044 for the c.261_265dup variant, suggesting a founder effect in the Tuvinian population. These findings expand the mutational spectrum of the SERPINF1 gene and provide new insights into the phenotypic variability of OI type VI. Our results highlight the importance of genetic screening in isolated populations and emphasize the need for further research to develop more effective therapeutic approaches for patients with limited response to bisphosphonate therapy.

BACKGROUND: Bruck syndrome is a rare disorder that features osteogenesis imperfecta, combined with severe congenital joint contractures often with pterygia, short stature, severe limb deformities, and progressive scoliosis. Its two forms, Bruck syndrome types 1 and 2, have similar clinical manifestations without osomal recessive inheritance and are caused by pathogenic variants of the nucleotide sequences in the FKBP10 and PLOD2 genes, respectively. CLINICAL CASES: The article demonstrates phenotypic and radiographic features as well as laboratory values of siblings with Bruck syndrome type 2 (a 10-year-old boy and a 13-year-old girl) born to healthy parents in a consanguineous marriage. The boy had congenital flexion contractures of the knee and elbow joints, few fractures, and severe kyphoscoliosis. The girl had no congenital joint contractures but had kyphoscoliosis, more severe osteoporosis, and a history of having more fractures than her younger brother. DISCUSSION: The cases demonstrated the significant phenotypic intrafamilial variability of Bruck syndrome type 2, caused by a newly identified homozygous variant c.1885AG (p.Thr629Ala) in PLOD2, which consists of varying degrees of osteoporosis, and the presence and severity of contractures. CONCLUSIONS: The description of the given clinical observation was made to draw attention to a rare pathology and expand doctors’ knowledge about the variability of clinical manifestations of Bruck syndrome. Genetic diagnostics is necessary for the timely diagnosis of Bruck syndrome, determining the prognosis and developing patient management techniques.

BACKGROUND: Osteoporosis–pseudoglioma syndrome (OMIM #259770) is an ultrarare autosomal recessive disease characterized by congenital or infant blindness, severe osteoporosis, and spontaneous bone fractures. The syndrome is caused by pathogenic variants in the LRP5 gene, which encodes a protein involved in the transmission of signals in the Wnt/β-catenin signaling pathway. To date, 77 pathogenic variants associated with osteoporosis–pseudoglioma syndrome have been registered in LRP5, mainly localized in the second and third beta-propeller domains of the protein, which have a high affinity for the Wnt ligand. CLINICAL CASES: Two siblings presented with clinical manifestations of osteoporosis–pseudoglioma syndrome caused by a pathogenic homozygous missense variant c.1481GA (p.Arg494Gln) in LRP5. The phenotype of the patients was characterized by a combination of blindness, low bone-mineral density, short stature, and fractures and deformities of long tubular bones and the spine. DISCUSSION: The rarity of the osteoporosis–pseudoglioma syndrome and the similarity of the clinical manifestations of various skeletal disorders and their genetic heterogeneity lead to a late diagnosis and treatment. CONCLUSIONS: We are the first to present the clinical, radiological, and genetic characteristics of two siblings with clinical manifestations of osteoporosis–pseudoglioma syndrome. Its rarity necessitates detailed description of the clinical and genetic characteristics of this syndrome. Molecular genetic testing is an important part of a comprehensive diagnosis.