Juvenile Paget disease (JPD) is a rare autosomal recessive bone disease characterized by escalated bone metabolism leading to skeletal deformities, susceptibility to fractures, and some extraskeletal findings. This genetic disease is associated with changes in the TNFRSF11B gene encoding osteoprotegerin, an important regulator of osteoresorption. Most published JPD cases have been found to carry homozygous TNFRSF11B variants, while compound heterozygous variants in this gene have been reported only twice. We report the first case of JPD diagnosed in the Czech Republic, who presented with a mild phenotype of this disease. The first bone fractures, appeared at 3 years of age. Other clinical manifestations included typical skeletal deformities, macrocephaly, arched chest, lower extremity valgosity, lateral bowing of the thighs, and anterior bowing of the shins. Minor mixed hearing impairment, angioid stripes of the choroidea, and temporary immunodeficiency were present among extra-skeletal findings. Sanger sequencing was performed on both the patient and the parents to test for the presence of TNFRSF11B sequence variants. Molecular genetic analysis showed unique compound heterozygous sequence variants in TNFRSF11B: a paternally inherited variant c.30 + 5G > A, p.(?) and a maternally inherited variant c.329G > T, p.(Gly110Val). Both of the variants were analyzed by several in silico predictive tools indicating, for their strongly supported pathogenicity according to American College of Medical Genetics and Genomics standards. Furthermore, we present diagnostic findings, their treatment, and follow-up care. The newly described variants of TNFRSF11B extend knowledge of this very rare disease. Early diagnosis and antiresorption treatment prevent further fractures and deformity progression, and improve the patient's quality of life. This example of osteoprotegerin deficiency may help us better understand its role in skeletal and non-skeletal systems.

Juvenile Paget disease (JPD) is a very rare disease, mainly caused by biallelic inactivating mutations in the TNFRSF11B gene that encodes osteoprotegerin. Owing to its rarity, the treatment of JPD is largely empirical. Accelerated bone turnover as assessed by biochemical markers, such as alkaline phosphatase (ALP), can be suppressed by bisphosphonate treatment, but it relapses if bisphosphonate treatment is discontinued. In this report, we describe our experience with long-term denosumab treatment in two adults with JPD, homozygous for the "Balkan" mutation (966_969delTGACinsCTT) in TNFRSF11B. Subject 1 started denosumab in age 35 and subject 2 in age 34. Both continue treatment until today, for 13.5 and 12 years, respectively. ALP was steadily normalized in both. Bone pain decreased and mobility improved. Hearing did not further deteriorate and no new fracture occurred. Vision remained unchanged in subject 2, but subject 1 experienced sudden vision loss of the right eye at age 46, which was successfully managed with intravitreal treatment with anti-vascular endothelial growth factor medications. In conclusion, long-term denosumab administration in adults with JPD, who had been previously treated with bisphosphonates, was safe and effective in terms of the skeletal disease, but it may not prevent the emergence of retinopathy.

A TNFRSF11B (TNF Receptor Superfamily Member 11b) gene encodes a soluble decoy receptor, osteoprotegerin (OPG), which has a key role in repressing osteoclast differentiation. In this report, we generated a biallelic knock-out hiPSC line for the TNFRSF11B gene via CRISPR/Cas9. When TNFRSF11B Knock-out hiPSCs were differentiated into mesenchymal progenitor cells (MPCs), the expression level of OPG was significantly decreased compared to normal hiPSC-derived MPCs. This knock-out hiPSCs will provide a chance to study Paget disease of bone 5 (juvenile Paget disease).

Denosumab is a valuable and safe therapy for skeletal disorders in adults and has received regulatory approval to treat osteoporosis and bone metastases. However, denosumab is not licensed for pediatric use due to a lack of high-quality prospective research on children. This study aimed to describe and discuss the benefits and disadvantages of denosumab in treating bone diseases in children and to summarize the current understanding of the role of denosumab therapy in children. A narrative review was conducted using the literature retrieved from the PubMed, Embase, and Cochrane Library databases. In children with type 6 osteogenesis imperfecta (OI), juvenile Paget disease (JPD), and secondary osteoporosis who show poor response to bisphosphonate, the use of denosumab has been reported to improve osteoporosis and increase bone mineral density (BMD). Moreover, for those with relapse, progressive and refractory aneurysmal bone cyst (ABC), fibrous dysplasia (FD), giant cell tumor of bone (GCTB), and central giant cell granuloma (CGCG) lesions, denosumab can improve pain symptoms, control disease progression, and reduce serious adverse events. Although there have been sporadic reports of adverse events such as hypocalcemia during medication and rebound hypercalcemia after discontinuation, early prevention, monitoring, and timely intervention can prevent children from experiencing severe adverse events. The published data indicate that denosumab has efficacy in alleviating disease in multiple refractory bone lesions in children.