RESOLUTION OF CALVARIAL HYPEROSTOSIS IN AFRICAN LION CUBS (PANTHERA LEO LEO) AFTER VITAMIN A SUPPLEMENTATION.

Two female (FL 1, FL 2) and one male (ML) 11-wk-old, intact, captive African lion cubs (Panthera leo leo) were presented with a history of mild vestibular signs. Initial serum vitamin A concentrations were low (140 nmol/L) for ML. Calvarial hyperostosis was confirmed using computed tomography (CT) of the head and cervical vertebrae in each cub. CT measurements were adapted in relation to the skull width. ML showed the most pronounced thickening of the tentorium cerebelli and occipital bone, represented by a tentorium cerebelli to skull width ratio (TCR) of 0.08 (FL 1: 0.06, FL 2: 0.05) and a basisphenoid to skull width ratio (BBR) of 0.07 (FL 1: 0.06, FL 2: 0.04). Magnetic resonance imaging (MRI) revealed cerebellar herniation and cervical intramedullary T2-weighted hyperintensity from C1, extending caudally for at least two cervical vertebrae in all cubs. Treatment was initiated with subcutaneous vitamin A supplementation and feeding of whole carcasses. Improvement in ataxia was noticed 3 wk later. Follow-up CT and MRI examinations were performed in ML after 3 and 8 mon. The affected bones appeared slightly less thickened and TCR and BBR had decreased to 0.05 after 3 mon. The cerebellum remained mildly herniated, accompanied by amelioration of cervical T2w hyperintensities. After 8 mon, evaluation and diagnostic imaging revealed further improvement regarding the neurologic status and measurements (TCR 0.05, BBR 0.04) despite persistence of a subtle cerebellar herniation. In conclusion, bone remodeling and improvement in clinical signs may be achievable in young lion cubs presented with calvarial hyperostosis and may be attributable to high-dose vitamin A supplementation.

Dramatic response of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome to tofacitinib monotherapy: a case report.

INTRODUCTION: The synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome is a rare condition. Its treatment remains a challenge for clinicians, and often yields mixed results. CASE: We report the case of a 51-year-old Caucasian woman who presented with SAPHO syndrome with mainly axial involvement. She had been treated with sulfasalazine and anti-inflammatory drugs for many years without any success. A few weeks after starting treatment with tofacitinib, both clinical and biological parameters dramatically improved. Imaging also showed considerable regression of the vertebral and pelvic lesions. However, tofacitinib had to be discontinued due to the occurrence of pulmonary embolism. Consequently, recurrence of bone pain and biologic inflammation was rapidly observed. CONCLUSIONS: Anti-JAKs are an interesting treatment option in the management of SAPHO syndrome that need further clinical trials and assessment for validating response.

[Convexity hyperostotic meningioma en plaque: a systematic review]. / Ploskostnye giperostoticheskie meningiomy svoda cherepa. Sistematicheskii obzor literatury.

BACKGROUND: Planar hyperostotic meningiomas account for 2-9% of intracranial meningiomas. They are characterized by planar node following the contours of the inner surface of the skull. Hyperostosis is present in most cases. Timely diagnosis of skull base tumors is usually simple due to early involvement of the cranial nerves. However, convexity meningiomas en plaque usually reach large dimensions that complicates surgery and radiotherapy. OBJECTIVE: To analyze the current state of diagnosis, molecular biology and surgical treatment of hyperostotic meningiomas en plaque. MATERIAL AND METHODS: A systematic review was performed in accordance with the PRISMA guidelines. Searching for literature data included the following keywords: «planar meningioma¼, «hyperostotic meningioma¼, «meningioma en plaque¼, «infiltrative meningioma¼. We reviewed the PubMed and Google Scholar databases until May 2023 and enrolled only full-text Russian-, English- or French-language reports. RESULTS AND DISCUSSION: Among primary 332 reports, 35 references met the inclusion criteria. We found less severity or absence of focal neurological symptoms, comparable incidence of intracranial hypertension and no histological differences between planar and nodular meningiomas. Analysis of molecular biological features of planar meningiomas, including cell cultures, is feasible. There is no consensus regarding surgical treatment and radiotherapy. Most publications are case reports. CONCLUSION: The results of treatment of planar hyperostotic meningiomas, especially large and giant ones, are unsatisfactory. There is no a generally accepted algorithm for treating patients in the literature. This problem requires further research.

Hidradenitis Suppurativa-Related Autoinflammatory Syndromes: An Updated Review on the Clinics, Genetics, and Treatment of Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PASH), Pyogenic Arthritis, Pyoderma gangrenosum, Acne and Suppurative Hidradenitis (PAPASH), Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis (SAPHO), and Rarer Forms.

Hidradenitis suppurativa (HS) is an autoinflammatory skin disorder of the terminal hair follicle, which can present in sporadic, familial, or syndromic form. A classification has been proposed for the latter, distinguishing cases associated with a known genetic condition, with follicular keratinization disorders or with autoinflammatory diseases. This review focuses on the clinical and genetic features of those entities (ie, pyoderma gangrenosum [PG], acne and HS; PG, acne, pyogenic arthritis and HS; psoriatic arthritis, PG, acne and HS; synovitis, acne, pustulosis, hyperostosis, osteitis; and so forth) for which the collective term HS-related autoinflammatory syndromes is proposed.

Patterns of hyperostosis during the ontogenic development of Atlantic spadefish (Broussonet, 1782) in Brazilian coast.

Marine teleost species of commercial interest are often reported with hyperostosis, an osteological condition that results in bone thickening. Various specimens of Atlantic Spadefish Chaetodipterus faber (n = 86) obtained from artisanal fishermen in Rio de Janeiro, Brazil, were radiographed and assessed to detect the occurrence of hyperostosis across four different size classes. Of the examined individuals, 58.62% displayed signs of hyperostosis, which manifested in eight skeletal regions, notably in the supraoccipital crest, cleithrum and supraneural areas. In the vertebral column, hyperostosis was more frequently observed in haemal spines than in neural spines, predominantly between the sixth and eighth caudal vertebrae. The smallest size class (<200 mm total length) showed a low frequency of hyperostosis at 7.89%. This frequency escalated for larger classes, reaching 94.12% in individuals measuring 200-300 mm in total length and was observed in all individuals exceeding 300 mm. Hyperostosis exhibited an ontogenetic development pattern, where both the occurrence frequencies and the sizes of the affected bones expanded in proportion to the fish size. This is the first description of the hyperostosis pattern of development for the species, an important commercial resource.

An Additional Lrp4 High Bone Mass Mutation Mitigates the Sost-Knockout Phenotype in Mice by Increasing Bone Remodeling.

Pathogenic variants disrupting the binding between sclerostin (encoded by SOST) and its receptor LRP4 have previously been described to cause sclerosteosis, a rare high bone mass disorder. The sclerostin-LRP4 complex inhibits canonical WNT signaling, a key pathway regulating osteoblastic bone formation and a promising therapeutic target for common bone disorders, such as osteoporosis. In the current study, we crossed mice deficient for Sost (Sost-/-) with our p.Arg1170Gln Lrp4 knock-in (Lrp4KI/KI) mouse model to create double mutant Sost-/-;Lrp4KI/KI mice. We compared the phenotype of Sost-/- mice with that of Sost-/-;Lrp4KI/KI mice, to investigate a possible synergistic effect of the disease-causing p.Arg1170Trp variant in Lrp4 on Sost deficiency. Interestingly, presence of Lrp4KI alleles partially mitigated the Sost-/- phenotype. Cellular and dynamic histomorphometry did not reveal mechanistic insights into the observed phenotypic differences. We therefore determined the molecular effect of the Lrp4KI allele by performing bulk RNA sequencing on Lrp4KI/KI primary osteoblasts. Unexpectedly, mostly genes related to bone resorption or remodeling (Acp5, Rankl, Mmp9) were upregulated in Lrp4KI/KI primary osteoblasts. Verification of these markers in Lrp4KI/KI, Sost-/- and Sost-/-;Lrp4KI/KI mice revealed that sclerostin deficiency counteracts this Lrp4KI/KI effect in Sost-/-;Lrp4KI/KI mice. We therefore hypothesize that models with two inactivating Lrp4KI alleles rather activate bone remodeling, with a net gain in bone mass, whereas sclerostin deficiency has more robust anabolic effects on bone formation. Moreover, these effects of sclerostin and Lrp4 are stronger in female mice, contributing to a more severe phenotype than in males and more detectable phenotypic differences among different genotypes.

Long-term follow-up of severe autosomal recessive SP7-related bone disorder.

The SP7 gene encodes a zinc finger transcription factor (Osterix), which is a member of the Sp subfamily of sequence-specific DNA-binding proteins, playing an important role in osteoblast differentiation and maturation. SP7 pathogenic variants have been described in association with different allelic disorders. Monoallelic or biallelic SP7 variants cause Osteogenesis imperfecta type XII (OI12), a very rare condition characterized by recurrent fractures, skeletal deformities, undertubulation of long bones, hearing loss, no dentinogenesis imperfecta, and white sclerae. Monoallelic or biallelic SP7 variants may also cause sclerotic skeletal dysplasias (SSD), partially overlapping with Juvenile Paget's disease and craniodiaphyseal dysplasia, characterized by skull hyperostosis, long bones sclerosis, large ribs and clavicles, and possible recurrent fractures. Here, we report the long-term follow-up of an 85-year-old woman presenting with a complex bone disorder including features of either OI12 (bone fragility with multiple fractures, severe deformities and short stature) or SSD (striking skull hyperostosis with optic atrophy, very large ribs and clavicles and long bones sclerosis). Exome sequencing showed previously undescribed biallelic loss of function variants in the SP7 gene: NM_001173467.2(SP7): c.359_362del, p.(Asp120Valfs*11); NM_001173467.2(SP7): c.1163_1174delinsT, p.(Pro388Leufs*33). RT-qPCR confirmed a severely reduced SP7 transcription compared to controls. Our report provides new insights into the clinical and molecular features and long-term outcome of SP7-related bone disorders (SP7-BD), suggesting a continuum phenotypic spectrum characterized by bone fragility, undertubulation of long bones, scoliosis, and very heterogeneous bone mineral density ranging from osteoporosis to osteosclerosis.

The Accuracy of Classification Systems in Nonsyndromic Sagittal Craniosynostosis.

Numerous classification systems of nonsyndromic sagittal craniosynostosis (NSC) are applied but none has gained a wide acceptance, since each classification is focused on distinct aspects. The aim of the study was to assess the accuracy of 4 classifications of NSC discussed in the literature by defining the associations among the classifications, individual features (sex, age, cranial index), and objective morphologic criteria (frontal bossing, retrocoronal constriction, sagittal ridge, and occipital bulleting). The study was conducted on anonymized thin-cut CT scans of 133 children with NSC 1 to 12 months old (mean age 5.42 mo). The type of cranial dysmorphology was assessed using 4 classification systems, focusing on skull shape, pattern of sagittal suture closure (Heuzé classification), deformation of skull vault (Sakamoto classification), and a single-dominant feature (David classification). Each patient was also independently investigated for the presence of morphologic criteria. A multivariate analysis was performed to explore the relations among the classifications and assess their accuracy. In the analyzed cohort sphenocephaly (38.3%), CFF type by Heuzé (30.8%), type I by Sakamoto (72.9%), and a central type by David (42.9%) were dominant findings. Regarding the morphologic criteria, frontal bossing was observed the most frequently (91.7%). The age of patients and cranial index differed significantly among the shapes of skull and David classifications ( P <0.001). The shape-based system showed the strongest correlation with other classifications and with measurable variables. Other classifications have much in common and some overlap, but none of them constitutes a standalone system to define all aspects of cranial dysmorphology in NSC.

Porotic hyperostosis and cribra orbitalia in samples from the Late Hillfort Period sites at Detkovice - Za zahradama (district Prostejov) and Vídenská street (district Brno), Czech Republic.

Porotic hyperostosis and cribra orbitalia are pathological changes occurring on the human skull. These changes were observed and evaluated on skeletal remains from Detkovice - Za zahradama and Vídenská Street in Brno; both sites are dated back to the 10th to 12th centuries AD. A total of 605 subjects were assessed for age, sex, and the above-stated pathologies using standard methods. The influence of age and sex on the occurrence of these pathologies was examined statistically. Results indicated that at the site of Detkovice - Za zahradama, porotic hyperostosis, and cribra orbitalia do not depend on sex or age. However, at Vídenská Street in Brno, these pathologies do not depend on sex, but they depend on age so a higher incidence of pathologies in juveniles is observed. Differences between both sites could be caused by different numbers of evaluated individuals or different state of preservation of skeletal remains. The aetiology of the origin of these pathologies could not be determined by the methodology used here, but with the prevailing lower age of pathological subjects, a lack of nutrition with consequent absence of iron and developing anaemia might be the cause. Based on our statistical data, we can observe that the pathologies we studied occur more frequently in children older than newborns and younger infants. This may indicate that these studied pathologies arise only during the lifetime of the individual and do not have a prenatal occurrence.

LRP4 site-specific variants in the third ß-propeller domain causes congenital myasthenic syndrome type 17.

LRP4 is expressed in many organs. It mediates SOST-dependent inhibition of bone formation and acts as an inhibitor of WNT signaling. It is also a postsynaptic end plate cell surface receptor at the neuromuscular junction and is central to its development, maintenance, and function. Pathogenic variants of LRP4 that specifically affect the canonical WNT signaling pathway are known to be associated with Cenani-Lenz syndactyly syndrome or the overlapping condition sclerosteosis. However, site-specific pathogenic variants of LRP4 have been associated with the congenital myasthenic syndrome (CMS) type 17 with no abnormal bone phenotype. Only two studies reported biallelic variants of LRP4 associated with CMS17 that presented during childhood. All three reported variants (NM_002334.4: p.Glu1233Ala, p.Glu1233Lys, or p.Arg1277His) are located within the 3'-edge of the third ß-propeller domain of LRP4. We report on a patient with a biallelic variant of the LRP4 gene presenting with a severe and neonatal lethal phenotype; we also provide a literature review of the previously reported patients. A female neonate, born to healthy consanguineous parents, presented with severe hypotonia, congenital diaphragmatic hernia, pulmonary hypertension, and progressive hypoxemia. Two of her siblings presented with a similar condition in the past, and all three died shortly after birth. Clinical exome sequencing revealed homozygosity for the pathogenic variant NM_002334.4:c.3698A > C (p.[Glu1233Ala]).

[Domestic software, medical devices and materials in surgery for hyperostotic craniofacial meningiomas]. / Primenenie otechestvennogo programmnogo obespecheniya, meditsinskikh izdelii i materialov v khirurgii giperostoticheskikh kraniofatsial'nykh meningiom. (Klinicheskii sluchai i obzor literatury).

OBJECTIVE: The modern concept of resection of hyperostotic craniofacial meningiomas involves the desire for one-stage surgery with excision of tumor and simultaneous extensive skull defect closure. MATERIAL AND METHODS: The authors present skull defect closure with an individual implant after resection of cranioorbital meningioma in a 61-year-old man. The neoplasm was accompanied by exophthalmos and eyelid edema. The patient underwent simultaneous microsurgical resection and skull reconstruction with an individual implant. At discharge (7 days after surgery), exophthalmos regressed to 3 mm. After 3 months, ophthalmologist revealed complete regression of exophthalmos. RESULTS: Domestic software and 3D printers were used for implant modeling and preparing the necessary physical models and molds. We intraoperatively used domestic polymer and titanium fixation systems for manufacturing and fixation of implant. CONCLUSION: This clinical case confirms that resection of hyperostotic craniofacial meningioma with simultaneous bone defect closure using domestic analogues of software, technical equipment, materials and methods is possible at all stages of this procedure.

Treatment and monitoring of SAPHO syndrome: a systematic review.

BACKGROUND AND OBJECTIVES: Synovitis acne pustulosis hyperostosis osteitis (SAPHO) is a rare heterogeneous disease of unknown aetiopathology. Externally validated and internationally agreed diagnostic criteria or outcomes and, as a result, prospective randomised controlled trials in SAPHO are absent. Consequently, there is no agreed treatment standard. This study aimed to systematically collate and discuss treatment options in SAPHO. METHODS: Following 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' guidance, a systematic literature search was conducted using PubMed, Scopus and Web of Science databases. Prospective clinical studies and retrospective case collections discussing management and outcomes in SAPHO involving five or more participants were included. Articles not published in English, studies not reporting defined outcomes, and studies solely relying on patient-reported outcomes were excluded. RESULTS: A total of 28 studies (20 observational, 8 open-label clinical studies) reporting 796 patients of predominantly European ethnicity were included. Reported therapies varied greatly, with many centres using multiple treatments in parallel. Most patients (37.1%) received non-steroidal anti-inflammatory drugs alone or in combination. Bisphosphonates (22.1%), conventional (21.7%) and biological (11.3%) disease-modifying antirheumatic drugs were the next most frequently reported treatments. Reported outcomes varied and delivered mixed results, which complicates comparisons. Bisphosphonates demonstrated the most consistent improvement of osteoarticular symptoms and were associated with transient influenza-like symptoms. Paradoxical skin reactions were reported in patients treated with TNF inhibitors, but no serious adverse events were recorded. Most treatments had limited or mixed effects on cutaneous involvement. A recent study investigating the Janus kinase inhibitor tofacitinib delivered promising results in relation to skin and nail involvement. CONCLUSIONS: No single currently available treatment option sufficiently addresses all SAPHO-associated symptoms. Variable, sometimes descriptive outcomes and the use of treatment combinations complicate conclusions and treatment recommendations. Randomised clinical trials are necessary to generate reliable evidence.

Imaging Features of Primary Intraosseous Meningiomas.

OBJECTIVE: To describe the imaging features of primary intraosseous meningiomas (PIMs) to aid an accurate diagnosis. METHODS: Clinical materials and radiological data for 9 patients with pathologically confirmed PIMs were reviewed comprehensively. RESULTS: Most lesions involved inner and outer plates of the calvaria and all were relatively well circumscribed. Upon computed tomography, portions of the solid neoplasm were hyperattenuated or isoattenuated. Hyperostosis was found in many lesions, but calcification was seen rarely. On magnetic resonance imaging, most neoplasms were hypointense on T1-weighted images, hyperintense on T2-weighted images, and heterogeneous on fluid-attenuated inversion recovery images. In most cases, the soft tissue of neoplasms showed hyperintense on diffusion-weighted imaging and hypointense on apparent diffusion coefficient. All lesions were obviously enhanced after gadolinium administration. Each patient accepted surgical treatment and recurrence was not observed during follow-up. CONCLUSIONS: Primary intraosseous meningiomas are very rare tumors that occur usually in later life. They are well-defined and tend to involve the inner and outer plates of the calvaria, with a classic appearance of hyperostosis on computed tomography. Primary intraosseous meningiomas display hypointense on T1-weighted images, hyperintense on T2-weighted images, and hyperattenuated or isoattenuated on computed tomography. Hyperintense on diffusion-weighted imaging, hypointense on apparent diffusion coefficient can also be found. Obvious enhancement supplied additional information for an accurate diagnosis. A neoplasm with these features should raise the suspicion of a PIM.

Observer agreement on the morphology of porous cranial lesions: Results from a workshop at the 2019 meeting of the Paleopathology Association.

OBJECTIVE: This paper presents the results of a 2019 Paleopathology Association workshop that tested observer agreement on porous cranial lesion morphology and presence using multiple sets of existing guidelines for data collection. MATERIALS: Sixteen conference attendees of varying osteological experience served as observers. Three crania were assigned to each of four published guidelines for identifying and categorizing lesion morphology, for a total of twelve well-preserved human crania from the National Museum of Natural History Biological Anthropology Collections. METHODS: Observers assessed each cranium macroscopically according to its assigned set of guidelines. RESULTS: Observer concordance was higher using scoring guidelines with higher-quality photographs, such as the 2019 guidelines from Rinaldo and colleagues. CONCLUSIONS: Data collection guidelines with high-quality color photos may support greater reliability of researcher-generated data on macroscopic skeletal features. SIGNIFICANCE: The conclusions of any research study are only as reliable as the data on which they are based. This work highlights the need for ongoing practices of quality control in a field in which much data results from individual judgement calls. LIMITATIONS: Observer concordance is not a measure of observer accuracy. Sample size is insufficient to draw broadly generalizable conclusions on the reliability of data collected using the guidelines tested, and conference environments are not a facsimile of research settings. SUGGESTIONS FOR FURTHER RESEARCH: Iterative testing of methodological consistency using larger sample sizes and more non-pathological crania is advised to identify the factors that influence observer discordance and to improve guidelines for qualitative assessments.

Patterns description of hyperostosis observed in Atlantic moonfish Selene setapinnis and lookdown Selene vomer.

Hyperostosis manifests itself and develops differently in taxonomically related species. Radiographic images of individuals belonging to different size classes of Atlantic Moonfish Selene setapinnis and Lookdown Selene vomer were obtained from two different estuarine areas of Rio de Janeiro/Brazil. In S. setapinnis, hyperostosis occurred in 65.22% of the specimens analyzed in three different skeletal regions. All specimens of S. vomer had hyperostosis in four regions. Patterns of occurrence were detected in both species, and the affected regions did not coincide in the same bone region, except for the cleithrum. Hyperostosis in S. setapinnis were observed in high frequencies of seventh dorsal pterygiophore, whereas in specimens of S. vomer this condition was detected to a greater extent in the neural spines of the second abdominal vertebra and first to third caudal vertebrae. The data demonstrated a relationship between the sexual maturity and the occurrence and development of hyperostotic bones in ageing process of individuals. It is the first description of S. vomer with a hyperostosis phenomenon for the species on the Brazilian coast.

Sclerostin: clinical insights in muscle-bone crosstalk.

Sclerostin, a protein encoded by the sclerostin (SOST) gene, is mostly expressed in osteocytes. First described in the pathogenesis of three disorders, sclerosteosis, van Buchem's disease, and craniodiaphyseal dysplasia, sclerostin has been identified as an important regulator of bone homeostasis, controlling bone formation by osteoblasts through inhibition of the canonical Wnt signaling pathway. Recent studies have highlighted a hypothetical role of sclerostin in myogenesis, thus modulating the interaction between bone and muscle. This narrative review provides an overview of the clinical implications of sclerostin modulation on skeletal muscle mass and function, and bone metabolism. Improving knowledge about muscle-bone crosstalk may represent a turning point in the development of therapeutic strategies for musculoskeletal disorders, particularly osteosarcopenia.

Inhibiting WNT secretion reduces high bone mass caused by Sost loss-of-function or gain-of-function mutations in Lrp5.

Proper regulation of Wnt signaling is critical for normal bone development and homeostasis. Mutations in several Wnt signaling components, which increase the activity of the pathway in the skeleton, cause high bone mass in human subjects and mouse models. Increased bone mass is often accompanied by severe headaches from increased intracranial pressure, which can lead to fatality and loss of vision or hearing due to the entrapment of cranial nerves. In addition, progressive forehead bossing and mandibular overgrowth occur in almost all subjects. Treatments that would provide symptomatic relief in these subjects are limited. Porcupine-mediated palmitoylation is necessary for Wnt secretion and binding to the frizzled receptor. Chemical inhibition of porcupine is a highly selective method of Wnt signaling inhibition. We treated three different mouse models of high bone mass caused by aberrant Wnt signaling, including homozygosity for loss-of-function in Sost, which models sclerosteosis, and two strains of mice carrying different point mutations in Lrp5 (equivalent to human G171V and A214V), at 3 months of age with porcupine inhibitors for 5-6 weeks. Treatment significantly reduced both trabecular and cortical bone mass in all three models. This demonstrates that porcupine inhibition is potentially therapeutic for symptomatic relief in subjects who suffer from these disorders and further establishes that the continued production of Wnts is necessary for sustaining high bone mass in these models.