Diaphanospondylodysostosis: Full Case Report with Novel Pathogenic BMPER Mutation

Diaphanospondylodysostosis is an extremely rare, recessively inherited, perinatal lethal skeletal disorder associated with BMPER gene mutations. Clinically it is characterized by defects in costovertebral ossification, absent ribs, hypertelorism, short nose with depressed nasal bridge, low-set ears, and short neck. At the extraosseous level, the most frequent pathologic finding is nephroblastomatosis with multicystic kidneys. We present the case of a child of non-consanguineous parents who died at 2 months of age in our center. Autopsy showed a marked costovertebral ossification defect, perilobar nephrogenic rests and loss of white matter with periventricular leukomalacia. After genetic study, the diagnosis of diaphanospondylodysostosis was confirmed. A previously undescribed germinal mutation in the BMPER gene (c.576 + 2dupT) was found.

Osteoporosis: From Molecular Mechanisms to Therapies 3.0

Osteoporosis is a common skeletal disorder that occurs as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the six articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 3.0”, a continuation of our 2020 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies". These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.

Outcomes of Temporary Hemiepiphyseal Stapling for Correcting Genu Valgum in Children with Multiple Osteochondromas: A Single Institution Study

Background: Multiple osteochondromas is a rare skeletal disorder characterized by the presence of osteocartilaginous protrusions causing bony deformities, especially around the knee. Guided growth by temporary hemiepiphyseal stapling is the treatment of choice to correct the deformity by modulating the residual physeal growth of the lower limbs. Although this procedure is increasingly practiced, inconclusive evidence exists regarding its effectiveness in children with multiple osteochondromas. The study aims to compare the outcomes of temporary hemiepiphyseal stapling for correcting genu valgum in children with multiple osteochondromas vs. idiopathic cases. Methods: In this retrospective cohort study, we included patients admitted at a single institution from 2008 to 2018. A total of 97 children (77 idiopathic, 20 multiple osteochondromas) were enclosed, accounting for 184 limbs treated by temporary hemiepiphyseal stapling. We investigated if children with multiple osteochondromas had a similar successful rate of correction, rate of complications, and correction velocity compared to children with idiopathic genu valgum. Results: Overall, 151 limbs (82%) achieved complete correction or overcorrection, with idiopathic cases having a significantly higher rate of success compared to pathologic cases (88% vs. 55%; p < 0.001). In addition, multiple osteochondromas children sustained a higher rate of major complications (p = 0.021) and showed significantly lower correction velocity (p = 0.029). Conclusion: Temporary hemiepiphyseal stapling is effective in both idiopathic and multiple osteochondromas children, although the latter often achieved incomplete correction, had a higher risk of complications, and required a longer time of stapling. We suggest to anticipate the timing of intervention; otherwise, children with multiple osteochondromas and severe valgus deformity, approaching skeletal maturity, could undergo combined femoral and tibial stapling.

Palatoplasty for the Patient With Campomelic Dysplasia—Report of a Case and Review of the Literature

Campomelic dysplasia (CMPD) is a skeletal disorder resulting from SOX9 gene mutations. Palatoplasty is rare due to a high lethality rate in infants from respiratory distress. Our patient had characteristic symptoms of CMPD, including short bowed limbs, macrocephaly, low-set ears, short palpebral fissures, hypertelorism, a flat nasal bridge, a long philtrum, micrognathia, and a cleft palate. We performed a Furlow palatoplasty when the patient was 2 years 9 months of age, after respiratory conditions had stabilized. We reviewed the literature of CMPD cases that underwent palatoplasty and discussed the optimal timing and surgical methods.

An Extremely Rare, Atypical and Genetically-Undetermined Form of Osteopetrosis

: Osteopetrosis is an uncommon skeletal disorder characterized by generalized sclerosis of bones due to defective osteoclast function. A wide variation in clinical severity of the disease has been observed. Radiographic features and genetic testing are usually used to diagnose the condition. In the present study, we present a case of an extremely rare, atypical and genetically-undetermined form of Osteopetrosis. This patient had some clinical and radiological features of craniometaphyseal dysplasia along with atypical radiological signs of osteopetrosis.

Osteoporosis in Inflammatory Arthritides: New Perspective on Pathogenesis and Treatment

Osteoporosis is a skeletal disorder characterized by impaired bone strength and increased risk of fragility fracture and is among the most relevant comorbidities of rheumatic diseases. The purpose of the present review is to discuss the pathogenesis of local and systemic bone involvement in inflammatory arthritides, especially Rheumatoid Arthritis, Psoriatic Arthritis, and Spondyloarthritides, as well as the effect of anti-rheumatic treatments and anti-osteoporotic medication on bone health and fracture incidence, including recent data on novel therapeutic perspective.

Osteoporosis: From Molecular Mechanisms to Therapies 2.0

Osteoporosis is a common skeletal disorder, occurring as a result of an imbalance between bone resorption and bone formation, with bone breakdown exceeding bone building. Bone resorption inhibitors, e.g., bisphosphonates, have been designed to treat osteoporosis. Teriparatide, an anabolic agent, stimulates bone formation and corrects the characteristic changes in the trabecular microarchitecture. However, these drugs are associated with significant side effects. It is therefore crucial that we continue to research the pathogenesis of osteoporosis and seek novel modes of therapy. This editorial summarizes and discusses the themes of the ten articles published in our Special Issue “Osteoporosis: From Molecular Mechanisms to Therapies 2.0”, a continuation of our 2019 Special Issue "Osteoporosis: From Molecular Mechanisms to Therapies" (https://www.mdpi.com/journal/ijms/special_issues/osteoporosis_ijms). These Special Issues detail important global scientific findings that contribute to our current understanding of osteoporosis.

Gorlin Syndrome: Recent Advances in Genetic Testing and Molecular and Cellular Biological Research

Gorlin syndrome is a skeletal disorder caused by a gain of function mutation in Hedgehog (Hh) signaling. The Hh family comprises of many signaling mediators, which, through complex mechanisms, play several important roles in various stages of development. The Hh information pathway is essential for bone tissue development. It is also the major driver gene in the development of basal cell carcinoma and medulloblastoma. In this review, we first present the recent advances in Gorlin syndrome research, in particular, the signaling mediators of the Hh pathway and their functions at the genetic level. Then, we discuss the phenotypes of mutant mice and Hh signaling-related molecules in humans revealed by studies using induced pluripotent stem cells.

GAS5 protects against osteoporosis by targeting UPF1/SMAD7 axis in osteoblast differentiation

Osteoporosis is a common systemic skeletal disorder resulting in bone fragility and increased fracture risk. It is still necessary to explore its detailed mechanisms and identify novel targets for the treatment of osteoporosis. Previously, we found that a lncRNA named GAS5 in human could negatively regulate the lipoblast/adipocyte differentiation. However, it is still unclear whether GAS5 affects osteoblast differentiation and whether GAS5 is associated with osteoporosis. Our current research found that GAS5 was decreased in the bones and BMSCs, a major origin of osteoblast, of osteoporosis patients. Mechanistically, GAS5 promotes the osteoblast differentiation by interacting with UPF1 to degrade SMAD7 mRNA. Moreover, a decreased bone mass and impaired bone repair ability were observed in Gas5 heterozygous mice, manifesting in osteoporosis. The systemic supplement of Gas5-overexpressing adenoviruses significantly ameliorated bone loss in an osteoporosis mouse model. In conclusion, GAS5 promotes osteoblast differentiation by targeting the UPF1/SMAD7 axis and protects against osteoporosis.

Effects of Enzyme Replacement Therapy for Primary Teeth in a Patient with Infantile Hypophosphatasia

Hypophosphatasia (HPP) is a skeletal disorder characterized by hypomineralization of bone, with early exfoliation of primary teeth. Alkaline phosphatase enzyme replacement therapy (ERT) has been shown to improve bone hypomineralization for patients with HPP, although its dental effects are unknown. A 20-month-old Japanese boy diagnosed with infantile HPP was referred to our clinic because of early exfoliation of primary teeth. The patient had been followed by a pediatrician since the age of 3 months, due to slow weight gain. At the age of 12 months, primary incisors showed sudden exfoliation; at the age of 19 months, a diagnosis of HPP was made based on bone and dental manifestations. ERT was initiated at the age of 21 months. The patient demonstrated stable periodontal conditions of primary molars that erupted after initiation of ERT, due to improved alveolar bone and tooth mineralization. Thus, ERT may improve both dental and systemic conditions.