Expanding the phenotypic spectrum of TNFRSF11A-associated dysosteosclerosis: a case with intracranial extramedullary hematopoiesis.

Dysosteosclerosis (DOS) is a rare sclerosing bone dysplasia characterized by osteosclerosis and platyspondyly. DOS is genetically heterogeneous and causally associated with mutations in three genes, SLC29A3, CSF1R, and TNFRSF11A. TNFRSF11A has been known as the causal gene for osteopetrosis, autosomal recessive 7, and is recently reported to cause DOS in three cases, which show a complex genotype-phenotype relationship. The phenotypic spectrum of TNFRSF11A-associated sclerosing bone dysplasia remains unclear and needs to be characterized further in more cases with molecular genetic diagnosis. Here, we report another TNFRSF11A-associated DOS case with a homozygous missense mutation (p.R129C). The mutation effect is different from the previous three cases, in which truncated or elongated RANK proteins were generated in isoform specific manner, thus enriching our understanding of the genotype-phenotype association in TNFRSF11A-associated sclerosing bone dysplasia. Besides DOS, our case presented with intracranial extramedullary hematopoiesis, which is an extremely rare condition and has not been identified in any other sclerosing bone dysplasias with molecular genetic diagnosis. Our findings provide the fourth case of TNFRSF11A-associated DOS and further expand its phenotypic spectrum.

The phenotypic spectrum of AMER1-related osteopathia striata with cranial sclerosis: The first Canadian cohort.

Osteopathia striata with cranial sclerosis (OSCS; OMIM# 300373) is a rare X-linked disorder caused by mutations of the AMER1 gene. OSCS is traditionally considered a skeletal dysplasia, characterized by cranial sclerosis and longitudinal striations in the long bone metaphyses. However, OSCS affects many body systems and varies significantly in phenotypic severity between individuals. This case series focuses on the phenotypic presentation and development of individuals with OSCS. We provide an account of 12 patients with OSCS, ranging from 5 months to 38 years of age. These patients were diagnosed with OSCS after genetic testing confirmed pathogenic mutations in AMER1. Patient consent was obtained for photos and participation. Data were collected regarding perinatal history, dysmorphic features, and review of systems. This case series documents common facial dysmorphology, as well as rare extraskeletal features of OSCS, including two patients with intestinal malrotation and two patients with pyloric stenosis. We share four apparently nonmosaic males with OSCS (one de novo and three maternal variants). We also provide a clinical update on a patient who was previously published by Chénier et al. (2012). American Journal of Medical Genetics Part A, 158, 2946-2952. More research is needed to investigate the links between genotype and phenotype and assess the long-term comorbidities and overall quality of life of individuals with OSCS.

Automated Osteosclerosis Grading of Clinical Biopsies Using Infrared Spectroscopic Imaging.

Osteosclerosis and myefibrosis are complications of myeloproliferative neoplasms. These disorders result in excess growth of trabecular bone and collagen fibers that replace hematopoietic cells, resulting in abnormal bone marrow function. Treatments using imatinib and JAK2 pathway inhibitors can be effective on osteosclerosis and fibrosis; therefore, accurate grading is critical for tracking treatment effectiveness. Current grading standards use a four-class system based on analysis of biopsies stained with three histological stains: hematoxylin and eosin (H&E), Masson's trichrome, and reticulin. However, conventional grading can be subjective and imprecise, impacting the effectiveness of treatment. In this Article, we demonstrate that mid-infrared spectroscopic imaging may serve as a quantitative diagnostic tool for quantitatively tracking disease progression and response to treatment. The proposed approach is label-free and provides automated quantitative analysis of osteosclerosis and collagen fibrosis.

Fetal ultrasonographic findings including cerebral hyperechogenicity in a patient with non-lethal form of Raine syndrome.

Raine syndrome is a rare osteosclerotic bone dysplasia characterized by craniofacial anomalies and intracranial calcification. Most patients with Raine syndrome are of Arab ancestry and die during the neonatal period. We herein report a Japanese patient with non-lethal Raine syndrome who presented with characteristic cerebral hyperechogenicity and a hypoplastic nose by fetal ultrasonography. She was admitted to the NICU due to pyriform aperture stenosis. Craniofacial abnormalities, intracranial calcification, osteosclerosis, chondrodysplasia punctata, and a mutation of FAM20C was identified. She was subsequently discharged without surgical intervention and is now 2 years old with mild neurodevelopmental delays. Images of cerebral hyperechogenicity by fetal ultrasonography in a non-lethal case were described herein for the first time. This patient represents a rare occurrence of a child with Raine syndrome born to Japanese parents and confirms that this syndrome is not always lethal. Even if Raine syndrome is suspected in a fetus due to cerebral hyperechogenicity and a hypoplastic nose, cerebral hyperechogenicity without pulmonary hypoplasia does not always predict lethality or severe neurodevelopmental delays. The information provided herein will be useful for prenatal counseling.

Identification of a novel LRRK1 mutation in a family with osteosclerotic metaphyseal dysplasia.

Osteosclerotic metaphyseal dysplasia (OSMD) is a rare skeletal dysplasia characterized by osteosclerotic metaphyses with osteopenic diaphyses of the long tubular bones. Our previous study identified a homozygous elongation mutation in leucine-rich repeat kinase 1 gene (LRRK1) in a patient with OSMD and showed that Lrrk1 knockout mice exhibited phenotypic similarity with OSMD. Here we report a second LRRK1 mutation in Indian sibs with OSMD. They had homozygous mutation (c.5971_5972insG) that produces an elongated mutant protein (p.A1991Gfs*31) similar to the first case. The sibs had normal stature, normal intelligence and recurrent fractures. The common radiographic feature was asymmetric and variable sclerosis of vertebral end plates, pelvic margin and metaphyses of tubular bones. One of the sibs had facial dysmorphisms, dentine abnormalities and acro-osteolysis. A comparison between the three OSMD cases with LRRK1 mutations with different ages suggested that the sclerotic lesions resolved with age. Our findings further support that LRRK1 would cause a subset of OSMD cases.

Prognostic significance of a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in primary myelofibrosis patients.

AIMS: To evaluate whether a comprehensive histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis in bone marrow trephine biopsies (BMBs) of primary myelofibrosis (PMF) patients may have prognostic implications. METHODS AND RESULTS: Reticulin fibrosis, collagen deposition and osteosclerosis were graded from 0 to 3 in a series of 122 baseline BMBs. Then, we assigned to each case a comprehensive score [reticulin, collagen, osteosclerosis (RCO) score, ranging from 0 to 9] that allowed us to distinguish two groups of patients, with low-grade (RCO score 0-4) and high-grade (RCO score 5-9) stromal changes. Of 122 patients, 88 displayed a low-grade and 34 a high-grade RCO score. The latter was associated more frequently with anaemia, thrombocytopenia, peripheral blood blasts and increased lactate dehydrogenase levels. The RCO score was correlated strictly with overall mortality (P = 0.013) and International Prognostic Scoring System (IPSS) risk categories, and was able to discriminate the overall survival of both low- and high-grade patients (log-rank test: P < 0.001). Moreover, it proved to be more accurate than the European Consensus on Grading of Bone Marrow Fibrosis (ECGMF grade) in identifying high-risk patients with poor prognosis. Finally, a combined analysis of RCO scores and IPSS risk categories in an integrated clinical-pathological evaluation was able to increase the positive predictive value (PPV) for mortality in high-risk patients. CONCLUSION: The comprehensive RCO score, obtained by histological evaluation of reticulin fibrosis, collagen deposition and osteosclerosis was prognostically significant and more accurate than ECGMF grade in identifying high-risk patients and improved PPV when applied in addition to IPSS.

Osteomesopyknosis--a benign axial hyperostosis that can mimic metastatic disease.

We report two cases of an axial osteosclerosis with histopathologic findings of osteomesopyknosis in siblings. Osteomesopyknosis is a benign hereditary osteosclerosis that can show a radiologic pattern similar to blastic metastatic disease. The aim of this article is to inform radiologists about the existence of this benign condition and its various radiologic manifestations. Therefore, we discuss the principal differential diagnosis and point out the key imaging findings of osteomesopyknosis in order to avoid overdiagnosis in future cases.

Asymptomatic, nonexpansile radiopacity of the jaw associated with external root resorption: a diagnostic dilemma.

Incidental radiopacities of the jaws are commonly identified on routine intraoral and extraoral radiographs. Dentists should be able to develop a differential diagnosis of these lesions. This article presents 2 cases in which mandibular radiopacities associated with external root resorption were identified incidentally and discusses the differential diagnosis of these lesions. Both patients were referred by their general practitioners to dental specialists for further evaluation of homogenous osteosclerotic foci surrounding and resorbing the roots of the permanent mandibular right first molar. The lesions were asymptomatic, caused no cortical expansion, and were static over time. The clinical and radiographic features were consistent with a diagnosis of idiopathic osteosclerosis (IO). External root resorption is present in 10%-12% of cases of IO and often involves the permanent mandibular first molars.

A comparative analysis of magnetic resonance imaging and high-resolution peripheral quantitative computed tomography of the hand for the detection of erosion repair in rheumatoid arthritis.

OBJECTIVES: To investigate whether MRI allows the detection of osteosclerosis as a sign of repair of bone erosions compared with high-resolution peripheral quantitative computed tomography (HR-pQCT) as a reference and whether the presence of osteosclerosis on HR-pQCT is linked to synovitis and osteitis on MRI. METHODS: A total of 103 RA patients underwent HR-pQCT and MRI of the dominant hand. The presence and size of erosions and the presence and extent (grades 0-2) of osteosclerosis were assessed by both imaging modalities, focusing on MCP 2 and 3 and wrist joints. By MRI, the presence and grading of osteitis and synovitis were assessed according to the Rheumatoid Arthritis MRI Score (RAMRIS). RESULTS: Parallel evaluation was feasible by both modalities on 126 bone erosions. Signs of osteosclerosis were found on 87 erosions by HR-pQCT and on 22 by MRI. False-positive results (MRI(+)CT(-)) accounted for 3%, while false-negative results (MRI(-)CT(+)) accounted for 76%. MRI sensitivity for the detection of osteosclerosis was 24% and specificity was 97%. The semi-quantitative scoring of osteosclerosis was reliable between MRI and HR-pQCT [intraclass correlation coefficient 0.917 (95% CI 0.884, 0.941), P < 0.001]. The presence of osteosclerosis on HR-pQCT showed a trend towards an inverse relationship to the occurrence and extent of osteitis on MRI [χ(2)(1) = 3.285; ϕ coefficient = -0.124; P = 0.070] but not to synovitis [χ(2)(1) = 0.039; ϕ coefficient = -0.14; P = 0.844]. CONCLUSION: MRI can only rarely detect osteosclerosis associated with bone erosions in RA. Indeed, the sensitivity compared with HR-pQCT is limited, while the specificity is high. The presence of osteitis makes osteosclerosis more unlikely, whereas the presence of synovitis is not related to osteosclerosis.

Chronic osteomyelitis of the mandible: diagnosis and management--an institution's experience over 7 years.

PURPOSE: The objective of this study was to retrospectively evaluate and report the associated factors with the diagnosis and management of 24 patients with chronic osteomyelitis of the mandible seen at the authors' institution during the past several years. PATIENTS AND METHODS: Only cases of chronic osteomyelitis of the mandible not associated with antiresorptive medications or radiotherapy to the maxillofacial region were included in the study. After confirmation of the diagnosis, initial clinical and radiologic findings, treatment approach, and outcome were evaluated for each patient. Fourteen male and 10 female patients (average age, 53.75 yr; range, 22 to 83 yr) were included. RESULTS: The peak incidence of the disease was recorded in the fifth and sixth decades of life. An uneventful healing was observed in 20 patients (83.3%). One of 18 patients (5.5%) who underwent segmental resections developed a secondary infection and was managed with intravenously administered antibiotics. Three of 6 patients (50%) who were treated with marginal resections remained symptomatic after surgery. CONCLUSION: Independent of the cause and presentation of the disease, complete resolution of the infection should be the main focus of management in patients with chronic osteomyelitis of the mandible, and findings of this retrospective study indicate that a conservative surgical approach is more likely to result in a less than ideal outcome.

[INVESTIGATION OF THE LEVEL OF MINERAL DENSITY OF SKELETAL OSSEOUS TISSUE IN PATIENTS WITH PERIODONTAL TISSUE DISEASES].

Results of investigation of mineral density condition of skeletal osseous tissue in patients with inflammatory and dystrophic-inflammatory diseases of periodontal tissues with ultrasound densitometry method have been presented. Various changes of osseous tissue of skeletal bones have been detected: osteopenia, osteoporosis and osteosclerosis, which correlated with the severity of pathological process in periodontium. Analysis of the obtained results has been carried out depending on patients' sex as well as form and severity degree of the course of periodontal diseases. It has been established that the peak of detected impairments of mineral density in the skeleton is due to osteopenia, the degree of severity of which deteriorates with the severity of pathological process in periodontal tissues, especially in women.

Imaging findings in 22 cases of Schnitzler syndrome: characteristic para-articular osteosclerosis, and the "hot knees" sign differential diagnosis.

BACKGROUND AND PURPOSE: Schnitzler syndrome is characterized by chronic urticaria, monoclonal gammopathy, and a risk of developing lymphoproliferative disorders. Patients frequently present with bone pain, fever, arthralgia, and lymphadenopathy. The purpose of this study is to retrospectively review and evaluate potentially attributable imaging abnormalities in a series of patients with clinically diagnosed Schnitzler syndrome. MATERIALS AND METHODS: Clinical and pathological chart review identified 22 patients meeting Strasbourg criteria for Schnitzler syndrome. Imaging of these patients was retrospectively reviewed by a musculoskeletal radiologist and a radiology fellow to determine and characterize significant "positive" findings that could potentially be attributed to their primary disease process. RESULTS: Evidence of abnormal bone remodeling was present in 64% (14/22) of patients with 40 bone abnormalities. Lesions were predominantly or entirely sclerotic and most commonly involved the distal femora (n = 11), proximal tibiae (nine), and innominate bones (six). Patterns of involvement were variable, but typically eccentrically intramedullary, cortical, and juxta-articular. Skeletal surveys and targeted radiographs identified only 37% (10/27) of abnormal bones subsequently "positive" by additional modalities. PET and bone scans were all positive in patients with bone sclerosis (13/13 and 17/17 bone sites, respectively). CONCLUSIONS: Schnitzler syndrome often presents with characteristic osteosclerosis, most commonly around the knees and in the pelvis. In patients with a suggestive clinical history, the radiologist could direct an appropriate imaging strategy or might to be the first to suggest the diagnosis. Bone scan may be the most appropriate initial screening tool in suspected cases.

Maxillomandibular osteomyelitis associated with osteopetrosis.

Osteopetrosis is a heterogeneous disorder characterized by abnormal bone remodeling and increased bone density primarily due to defective osteoclast resorption. The diagnosis is based on a history of numerous fractures and radiological findings indicative of osteosclerosis, usually sufficient for a definitive diagnosis. We present a quite rare case of osteopetrosis complicated by recurrent episodes of maxillomandibular osteomyelitis associated with cutaneous fistulization and purulent nasal discharge. We used intravenous antibiotic therapy and necrotic bone debridement that prevented the appearance of acute infections over a 3-year follow-up, but the complete healing of the case was not achieved.

Computed tomography and magnetic resonance imaging of maxillofacial lesions in renal osteodystrophy.

PURPOSE: This study aims to describe the computed tomography (CT) and magnetic resonance (MR) imaging appearance of maxillofacial lesions in renal osteodystrophy. PATIENTS AND METHODS: We retrospectively reviewed the CT and MR imaging of maxillofacial region in 9 patients (6 females and 3 males with mean age of 31 yr) with renal osteodystrophy. They presented with facial swelling (n = 6), facial disfigurement (n = 2), and oral cavity mass (n = 1). They underwent CT and MR imaging of the maxillofacial region. RESULTS: Brown tumors (n = 6) were seen in the mandible (n = 4) and maxilla (n = 2). They appeared as mixed lytic and sclerotic (n = 4) and sclerotic (n = 2) lesions at CT. The lesions appeared as hypointense at T1-weighted images and of mixed signal intensity at T2-weighted images with intense contrast enhancement (n = 6). Uremic leontiasis ossea (n = 2) appeared at CT as diffuse hyperostosis with protruded maxilla and obliterated sinus. At MR imaging, there was expansion of the maxilla with obliteration of the maxillary sinuses and protrusion of the mandible. The lesion exhibited low signal intensity at T1-weighed images. At T2-weighted images, the lesion showed low signal intensity with small hyperintense lesions. Dystrophic calcification (n = 2) was seen in the parotid and the check. CONCLUSION: We concluded that CT and MR imaging are helpful for diagnosis and treatment planning of maxillofacial lesions of patients with renal osteodystrophy.

Moyamoya disease/cerebral vasculopathy in osteopathia striata with cranial sclerosis: a rare but important complication.

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant sclerosing osteodysplasia, due to AMER1 pathogenic variants. Characteristic features include craniofacial sclerosis and long-bone metaphyseal striations. Moyamoya disease (a type of progressive cerebral vasculopathy) and other types of cerebral vascular disease are not currently clearly associated with OSCS (except for two separate case reports), and can often first present with stroke. Through informal networks with UK-based bone experts and the UK skeletal dysplasia group, three cases from the UK and Ireland were identified. Medical literature was also reviewed to identify the known cases of OSCS with the described complications. We report four females, in whom OSCS and cerebral vasculopathy co-exist, with varying clinical outcomes. There appears to be an emerging association between OSCS and cerebral vasculopathy, which pre-disposes patients to stroke. Given this, screening OSCS patients for cerebral vasculopathy may be of value, especially pre-surgery. Further research regarding optimal screening and management is needed. The mechanism of cerebral vasculopathy and its progression remain unclear.

Hand-Schüller-Christian disease and Erdheim-Chester disease: coexistence and discrepancy.

Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) share similar clinical features and mechanisms. In very rare circumstances, the two diseases coexist in the same patient. Here we report such a patient, who was first diagnosed with Hand-Schüller-Christian disease (HSC), a type of LCH. Several years later, the patient presented with severe exophthalmos and osteosclerosis on radiograph. New biopsy revealed ECD. We also analyze 54 cases of LCH and 6 cases of ECD diagnosed in our hospital, as well as their progression during a follow-up period of 8 years. In five cases of HSC (9.3% of LCH), a triad of central diabetes insipidus, hyperprolactinemia, and pituitary stalk thickening on magnetic resonance imaging (MRI) preceded the typical bone lesions by 4-9 years. In addition, LCH was featured as elevated plasma alkaline phosphatase (ALP), which was normal in ECD. Combined with a literature review, several features are summarized to differentiate ECD from HSC. In patients with diabetes insipidus, concomitant hyperprolactinemia and pituitary stalk thickening on MRI indicate a possible HSC. Additionally, if osteosclerosis is observed in a patient with LCH, the coexistence of ECD should be considered.

An extremely rare case: osteosclerotic metaphyseal dysplasia.

OMD (osteosclerotic metaphyseal dysplasia) is a very rare sclerosing bone disorder, first described by G. Nishimura in two Japanese siblings in 1993 (6). We report the case of a 12-month-old male with hypotonia, developmental delay and sclerosis of the metaphyses and epiphyses of specific bones. This 36-week gestation boy was born to a 26 year old gravida 5 para 1 Turkish mother and a 27 year old nonconsanguineous father. Radiographic findings obtained during the hospital stay included bilateral symmetrical osteosclerosis of the metaphyseal portions of the long bones in the upper and lower extremities with osteopenic shafts. Narrow bands of metaphyseal osteosclerosis were detected in the short tubular bones of the hands and feet. Growing parts of bilateral scapula, iliac, pubic and ischial bones show sclerotic bands. In addition superior and inferior plates of vertebras, transverse processes of sacral vertebras, all visible epiphyses, carpal and tarsal bones also show sclerotic changes. The scalp was unaffected. Based on the clinical, radiographic, and laboratory findings, a diagnosis of OMD was made. We do not know any of the osteosclerotic bone disorder with changes including hypotonia, mental and motor developmental delay and metaphyseal sclerosis of the bones with a unique distribution except OMD. The syndrome is characterized by developmental delay of a progressive nature, hypotonia, elevated alkaline phosphatase, and late-onset spastic paraplegia 18 years ago. Our patient is the 4th case of OMD described in the literature share some clinical and radiological similarities with other three reported cases of osteosclerotic metaphyseal dysplasias.

Case Report: Osteosclerotic metaphyseal dysplasia with optic nerve involvement and progressive osteonecrosis of the jaw due to a novel LRRK1 mutation.

Background: Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel LRRK1 variant. Cases: The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous LRRK1 c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript. Conclusion: Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of LRRK1 variants in this phenotype raise the question of whether LRRK1 should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.

Osteopathia striata with cranial sclerosis and developmental delay in a male with a mosaic deletion in chromosome region Xq11.2.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked disease caused by mutations involving WTX (FAM123B), a tumor suppressor protein with dual functions. OSCS typically affects females whereas males generally have fetal or neonatal lethality. Surviving affected males have characteristic facial dysmorphisms, skeletal features such as macrocephaly and short stature, neurodevelopmental disabilities and a high prevalence of neuromuscular anomalies. On imaging, hemizygous males display marked cranial and peripheral skeletal sclerosis without the metaphyseal striations that are seen in women with OSCS. Observations of striation in males may be indicative of a somatic mosaic mutation in WTX. To date only two cases of surviving males haves been confirmed with mosaic point mutations in WTX. We report on the first case of a male with a mosaic deletion of the entire WTX gene. We show that a mosaic deletion in a hemizygous male patient can cause a mild phenotype of OSCS, including facial and skull base bone striations, nasal stenosis, conductive hearing loss, global developmental delay, and mild facial dysmorphology without short stature or macrocephaly.