Leukoencephalopathy with calcifications, developmental brain abnormalities and skeletal dysplasia due to homozygosity for a hypomorphic CSF1R variant: A report of three siblings.

We report three siblings homozygous for CSF1R variant c.1969 + 115_1969 + 116del to expand the phenotype of "brain abnormalities, neurodegeneration, and dysosteosclerosis" (BANDDOS) and discuss its link with "adult leukoencephalopathy with axonal spheroids and pigmented glia" (ALSP), caused by heterozygous CSF1R variants. We evaluated medical, radiological, and laboratory findings and reviewed the literature. Patients presented with developmental delay, therapy-resistant epilepsy, dysmorphic features, and skeletal abnormalities. Secondary neurological decline occurred from 23 years in sibling one and from 20 years in sibling two. Brain imaging revealed multifocal white matter abnormalities and calcifications during initial disease in siblings two and three. Developmental brain anomalies, seen in all three, were most severe in sibling two. During neurological decline in siblings one and two, the leukoencephalopathy was progressive and had the MRI appearance of ALSP. Skeletal survey revealed osteosclerosis, most severe in sibling three. Blood markers, monocytes, dendritic cell subsets, and T-cell proliferation capacity were normal. Literature review revealed variable initial disease and secondary neurological decline. BANDDOS presents with variable dysmorphic features, skeletal dysplasia, developmental delay, and epilepsy with on neuro-imaging developmental brain anomalies, multifocal white matter abnormalities, and calcifications. Secondary neurological decline occurs with a progressive leukoencephalopathy, in line with early onset ALSP. Despite the role of CSF1R signaling in myeloid development, immune deficiency is absent. Phenotype varies within families; skeletal and neurological manifestations may be disparate.

Osteomesopyknosis associated with a novel ALOX5 variant that impacts the RANKL pathway.

BACKGROUND: Bone tissue homeostasis relies on the coordinated activity of the bone-forming osteoblasts and bone-resorbing osteoclasts. Osteomesopyknosis is considered a distinctive rare sclerosing skeletal disorder of unelucidated pathophysiology and presumably autosomal dominant transmission. However, the causal genes are unknown. METHODS: We present a case report encompassing clinical assessments, imaging studies, and whole-exome sequencing analysis, complemented by functional in vitro experiments. RESULTS: This new case of osteomesopyknosis was associated with a missense ALOX5 variant predicted to induce protein misfolding and proteasomal degradation. Transfection experiments demonstrated that the variant was associated with reduced protein levels restored by proteasomal inhibition with bortezomib. Likewise, gene expression analysis showed that the mutated gene was associated with a decreased RANKL/OPG ratio, which is a critical driver of osteoclast precursor differentiation. CONCLUSION: Our data indicate impaired bone resorption as the underlying mechanism of this rare osteosclerosis, implicating ALOX5 pathogenic variants as potential etiological factors.

Osteopathia striata with cranial sclerosis as a cancer predisposition syndrome: The first report of neuroblastoma and review of all cancers in OSCS.

Osteopathia Striata with Cranial Sclerosis (OSCS) is a rare genetic condition primarily characterized by metaphyseal striations of long bones, bone sclerosis, macrocephaly, and other congenital anomalies. It is caused by pathogenic variants in AMER1, a tumor suppressor and a WNT signaling repressor gene with key roles in tissue regeneration, neurodevelopment, tumorigenesis, and other developmental processes. While somatic AMER1 pathogenic variants have frequently been identified in several tumor types (e.g., Wilms tumor and colorectal cancer), whether OSCS (i.e., with AMER1 germline variants) is a tumor predisposition syndrome is not clear, with only nine cases reported with tumors. We here report the first case of neuroblastoma diagnosed in a male child with OSCS, review all previously reported tumors diagnosed in individuals with OSCS, and discuss potential tumorigenic mechanisms of AMER1. Our report adds to the accumulating evidence suggesting OSCS is a tumor predisposition condition, highlighting the importance of maintaining a high index of suspicion for the associated tumors when evaluating patients with OSCS. Importantly, Wilms tumor stands out as the most commonly observed tumor in OSCS patients, underscoring the need for regular surveillance.

Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2.

Introduction: Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease caused by mutations in genes responsible for the formation and development of adipocytes. Bone abnormalities are described. However, there is a scarcity of data. Objective: To describe bone characteristics in a large CGL1 and 2 case series. Methods: Cross-sectional study that assessed bone radiological features of CGL patients of a reference hospital in Fortaleza (CE), Brazil. Patients underwent clinical and bone mineral metabolism evaluation, radiographs of the axial and appendicular skeleton and bone mineral density (BMD) assessment by DEXA (dual energy X-ray absorptiometry). Results: Nineteen patients were included, fourteen were CGL1 and 5, CGL2. Median age was 20 years (8-42) and 58% were women. Median BMI and percentage of body fat were, respectively, 21 Kg/m² (16-24), and 10.5% (7.6-15). The median leptin concentration was 1 ng/mL (0.1-3.3). Diabetes mellitus and dyslipidemia were present in 79% and 63% of patients, respectively. Median calcium and phosphate were normal in almost all patients (95%). Median parathyroid hormone and 25-OH-vitamin D were 23 pg/mL (7-75) and 28 ng/mL (18-43). Osteolytic lesions, osteosclerosis and pseudo-osteopoikylosis, were present in 74%, 42% and 32% of patients, respectively. Lytic lesions were found predominantly in the extremities of long bones, bilaterally and symmetrically, spine was spared. Osteosclerosis was present in axial and appendicular skeleton. Pseudo-osteopoikilosis was found symmetrically in epiphyses of femur and humerus, in addition to the pelvis. BMD Z-score greater than +2.5 SD was observed in 13 patients (68.4%). BMD was higher in CGL1 compared to CGL2 in lumbar spine and total body in adults. No associations were found between high BMD and HOMA-IR (p=0.686), DM (p=0.750), osteosclerosis (p=0.127) or pseudo-osteopoikilosis (p=0.342), and, between pain and bone lesions. Fractures were found in 3 patients. Conclusion: Bone manifestations are prevalent, heterogeneous, and silent in CGL1 and CGL2. Osteolytic lesions are the most common, followed by osteosclerosis and pseudo-osteopoikilosis. Bone mass is high in most cases. There was no pain complaint related to bone lesions. Thus, systematic assessment of bone manifestations in CGL is essential. Studies are needed to better understand its pathogenesis and clinical consequences.

Gingival proteomics reveals the role of TGF beta and YAP/TAZ signaling in Raine syndrome fibrosis.

Raine syndrome (RNS) is a rare autosomal recessive osteosclerotic dysplasia. RNS is caused by loss-of-function disease-causative variants of the FAM20C gene that encodes a kinase that phosphorylates most of the secreted proteins found in the body fluids and extracellular matrix. The most common RNS clinical features are generalized osteosclerosis, facial dysmorphism, intracerebral calcifications and respiratory defects. In non-lethal RNS forms, oral traits include a well-studied hypoplastic amelogenesis imperfecta (AI) and a much less characterized gingival phenotype. We used immunomorphological, biochemical, and siRNA approaches to analyze gingival tissues and primary cultures of gingival fibroblasts of two unrelated, previously reported RNS patients. We showed that fibrosis, pathological gingival calcifications and increased expression of various profibrotic and pro-osteogenic proteins such as POSTN, SPARC and VIM were common findings. Proteomic analysis of differentially expressed proteins demonstrated that proteins involved in extracellular matrix (ECM) regulation and related to the TGFß/SMAD signaling pathway were increased. Functional analyses confirmed the upregulation of TGFß/SMAD signaling and subsequently uncovered the involvement of two closely related transcription cofactors important in fibrogenesis, Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). Knocking down of FAM20C confirmed the TGFß-YAP/TAZ interplay indicating that a profibrotic loop enabled gingival fibrosis in RNS patients. In summary, our in vivo and in vitro data provide a detailed description of the RNS gingival phenotype. They show that gingival fibrosis and calcifications are associated with, and most likely caused by excessed ECM production and disorganization. They furthermore uncover the contribution of increased TGFß-YAP/TAZ signaling in the pathogenesis of the gingival fibrosis.

A Mosaic Variant in CTNNB1/ß-catenin as a Novel Cause for Osteopathia Striata With Cranial Sclerosis.

CONTEXT: Osteopathia striata with cranial sclerosis (OSCS) is a rare bone disorder with X-linked dominant inheritance, characterized by a generalized hyperostosis in the skull and long bones and typical metaphyseal striations in the long bones. So far, loss-of-function variants in AMER1 (also known as WTX or FAM123B), encoding the APC membrane recruitment protein 1 (AMER1), have been described as the only molecular cause for OSCS. AMER1 promotes the degradation of ß-catenin via AXIN stabilization, acting as a negative regulator of the WNT/ß-catenin signaling pathway, a central pathway in bone formation. OBJECTIVE: In this study, we describe a Dutch adult woman with an OSCS-like phenotype, namely, generalized high bone mass and characteristic metaphyseal striations, but no genetic variant affecting AMER1. RESULTS: Whole exome sequencing led to the identification of a mosaic missense variant (c.876A > C; p.Lys292Asn) in CTNNB1, coding for ß-catenin. The variant disrupts an amino acid known to be crucial for interaction with AXIN, a key factor in the ß-catenin destruction complex. Western blotting experiments demonstrate that the p.Lys292Asn variant does not significantly affect the ß-catenin phosphorylation status, and hence stability in the cytoplasm. Additionally, luciferase reporter assays were performed to investigate the effect of p.Lys292Asn ß-catenin on canonical WNT signaling. These studies indicate an average 70-fold increase in canonical WNT signaling activity by p.Lys292Asn ß-catenin. CONCLUSION: In conclusion, this study indicates that somatic variants in the CTNNB1 gene could explain the pathogenesis of unsolved cases of osteopathia striata.

Raine syndrome: Prenatally identified severe craniofacial phenotype with multisuture synostosis and brain abnormalities associated with variants in FAM20C.

Raine syndrome (MIM 259775) is a rare autosomal recessive disorder, first described by Raine et al. in 1989, with an estimated prevalence of <1/1,000,000. This is due to pathogenic variants in FAM20C characterized by osteosclerosis, typical craniofacial features, and brain calcifications. Here, we report a novel variant in FAM20C, describe a uniquely severe craniofacial and CNS phenotype of Raine syndrome, and correlate it with prenatal findings. Fetal phenotyping was based on ultrasound and MRI. Solo exome sequencing was performed from DNA extracted from postmortem skin biopsy. Targeted parental variant testing was subsequently performed. A homozygous missense variant NM_020223.4 (c.1445 G > A (p.Gly482Glu)) was identified in FAM20C associated with Raine syndrome. The infant had the characteristic dysmorphic features seen in Raine syndrome. He had particularly significant CNS manifestations consisting of multisuture craniosynostosis with protrusion of the brain parenchyma through fontanelles and cranial lacunae. Histological sections of the brain showed marked periventricular gliosis with regions of infarction, hemorrhage, and cavitation with global periventricular leukomalacia. Numerous dystrophic calcifications were diffusely present. Here, we demonstrate the identification of a novel variant in FAM20C in an infant with the characteristic features seen in Raine syndrome. The patient expands the characteristic phenotype of Raine syndrome to include a uniquely severe CNS phenotype, first identified on prenatal imaging.

Hdac1 and Hdac2 positively regulate Notch1 gain-of-function pathogenic signaling in committed osteoblasts of male mice.

BACKGROUND: Skeletal development requires precise extrinsic and intrinsic signals to regulate processes that form and maintain bone and cartilage. Notch1 is a highly conserved signaling receptor that regulates cell fate decisions by controlling the duration of transcriptional bursts. Epigenetic molecular events reversibly modify DNA and histone tails by influencing the spatial organization of chromatin and can fine-tune the outcome of a Notch1 transcriptional response. Histone deacetylase 1 and 2 (HDAC1 and HDAC2) are chromatin modifying enzymes that mediate osteoblast differentiation. While an HDAC1-Notch interaction has been studied in vitro and in Drosophila, its role in mammalian skeletal development and disorders is unclear. Osteosclerosis is a bone disorder with an abnormal increase in the number of osteoblasts and excessive bone formation. METHODS: Here, we tested whether Hdac1/2 contribute to the pathogenesis of osteosclerosis in a murine model of the disease owing to conditionally cre-activated expression of the Notch1 intracellular domain in immature osteoblasts. RESULTS: Importantly, selective homozygous deletions of Hdac1/2 in osteoblasts partially alleviate osteosclerotic phenotypes (Col2.3kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/flox ; Hdac2flox/flox ) with a 40% decrease in bone volume and a 22% decrease in trabecular thickness in 4 weeks old when compared to male mice with heterozygous deletions of Hdac1/2 (Col2.3 kb-Cre; TGRosaN1ICD/+ ; Hdac1flox/+ ; Hdac2flox/+ ). Osteoblast-specific deletion of Hdac1/2 in male and female mice results in no overt bone phenotype in the absence of the Notch1 gain-of-function (GOF) allele. CONCLUSIONS: These results provide evidence that Hdac1/2 contribute to Notch1 pathogenic signaling in the mammalian skeleton. Our study on epigenetic regulation of Notch1 GOF-induced osteosclerosis may facilitate further mechanistic studies of skeletal birth defects caused by Notch-related GOF mutations in human patients, such as Adams-Oliver disease, congenital heart disease, and lateral meningocele syndrome.

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.

Mutations of family with sequence similarity 20-member C gene causing lethal and nonlethal Raine syndrome causes hypophosphatemia rickets.

Family with sequence similarity 20-member C (FAM20C) is a kinase specific to most of the secreted phosphoproteome. FAM20C has been identified as the causative gene of Raine syndrome, initially characterized by lethal osteosclerosis bone dysplasia. However, since the identification of the cases of nonlethal Raine syndrome characterized by hypophosphatemia rickets, the previous definition of Raine syndrome has become debatable and raised a question about the role of mutations of FAM20C in controversial skeletal manifestation in the two forms of the disease. In this study, we aimed to investigate the influence of FAM20C mutations on skeletogenesis. We developed transgenic mice expressing Fam20c mutations mimicking those associated with human lethal and nonlethal Raine syndrome. The results revealed that transgenic mice expressing the mutant Fam20c found in the lethal (KO;G374R) and nonlethal (KO;D446N) Raine syndrome exhibited osteomalacia without osteosclerotic features. Additionally, both mutants significantly increased the expression of the Fgf23, indicating that Fam20c deficiency in skeletal compartments causes hypophosphatemia rickets. Furthermore, as FAM20C kinase activity catalyzes the phosphorylation of secreted proteomes other than those in the skeletal system, global FAM20C deficiency may trigger alterations in other systems resulting in osteosclerosis secondary to hypophosphatemia rickets. Together, the findings of this study suggest that FAM20C deficiency primarily causes hypophosphatemia rickets or osteomalacia; however, the heterogeneous skeletal manifestation in Raine syndrome was not determined solely by specific mutations of FAM20C. The findings also implicated that rickets or osteomalacia caused by FAM20C deficiency would deteriorate into osteosclerosis by the defects from other systems or environmental impacts.

AXIN1 bi-allelic variants disrupting the C-terminal DIX domain cause craniometadiaphyseal osteosclerosis with hip dysplasia.

Sclerosing skeletal dysplasias result from an imbalance between bone formation and resorption. We identified three homozygous, C-terminally truncating AXIN1 variants in seven individuals from four families affected by macrocephaly, cranial hyperostosis, and vertebral endplate sclerosis. Other frequent findings included hip dysplasia, heart malformations, variable developmental delay, and hematological anomalies. In line with AXIN1 being a central component of the ß-catenin destruction complex, analyses of primary and genome-edited cells harboring the truncating variants revealed enhanced basal canonical Wnt pathway activity. All three AXIN1-truncating variants resulted in reduced protein levels and impaired AXIN1 polymerization mediated by its C-terminal DIX domain but partially retained Wnt-inhibitory function upon overexpression. Addition of a tankyrase inhibitor attenuated Wnt overactivity in the AXIN1-mutant model systems. Our data suggest that AXIN1 coordinates the action of osteoblasts and osteoclasts and that tankyrase inhibitors can attenuate the effects of AXIN1 hypomorphic variants.

Intracranial calcification in Fam20c-deficient mice recapitulates human Raine syndrome.

FAM20C (family with sequence similarity 20-member C) is a protein kinase that phosphorylates secretory proteins, including the proteins that are essential to the formation and mineralization of calcified tissues. FAM20C loss-of-function mutations cause Raine syndrome in humans, characterized by generalized osteosclerosis, distinctive craniofacial dysmorphism, along with extensive intracranial calcification. Our previous studies revealed that inactivation of Fam20c in mice led to hypophosphatemic rickets. In this study, we examined the expression of Fam20c in the mouse brain and investigated brain calcification in Fam20c-deficient mice. Reverse transcription polymerase chain reaction (RT-PCR), Western-blotting and in situ hybridization analyses demonstrated the broad expression of Fam20c in the mouse brain tissue. X-ray and histological analyses showed that the global deletion of Fam20c (mediated by Sox2-cre) resulted in brain calcification in mice after postnatal 3 months and that the calcifications were bilaterally distributed within the brain. There was mild perifocal microgliosis as well as astrogliosis around calcospherites. The calcifications were first observed in the thalamus, and later in the forebrain and hindbrain. Furthermore, brain-specific deletion (mediated by Nestin-cre) of Fam20c in mice also led to cerebral calcification at an older age (postnatal 6 months), but no obvious skeletal or dental defects. Our results suggest that the local loss of FAM20C function in the brain may directly account for intracranial calcification. We propose that FAM20C plays an essential role in maintaining normal brain homeostasis and preventing ectopic brain calcification.

Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review.

To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (ß-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1-4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and ß-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.

Neurological manifestations in patients and disease carriers in an Italian family with osteosclerosis.

BACKGROUND: Hereditary cranial hyperostosis is a rare disease never described in Italy, so the neurological manifestations in patients and carriers of the disease have been little studied. METHODS: We describe the neurological and neuroimaging features of patients and carriers of the gene from a large Italian family with sclerosteosis. RESULTS: In this family, genetic testing detected the homozygous p.Gln24X (c.70C > T) mutation of the SOST gene in the proband and a heterozygous mutation in 9 siblings. In homozygous adults, severe craniofacial hyperostosis was manifested by cranial neuropathy in childhood, chronic headache secondary to intracranial hypertension, and an obstructive sleep apnea syndrome in adults. In one of the adult patients, there was a compressible subcutaneous swelling in the occipital region caused by transosseous intracranial-extracranial occipital venous drainage, a compensation mechanism of obstructed venous drainage secondary to cranial hyperostosis. Mild cranial hyperostosis causing frequent headache and snoring was evident in the nine heterozygous subjects. CONCLUSIONS: Multiple cranial neuropathies and headache in children, while severe chronic headache and sleep disturbances in adults, are the neurological manifestations of the first Italian family with osteosclerosis. It is reasonable to extend neurological and neuroimaging evaluation to gene carriers as well.

Osteopetrosis: Gene-based nosology and significance Dysosteosclerosis.

Dysosteosclerosis (DSS) refers to skeletal dysplasias that radiographically feature focal appendicular osteosclerosis with variable platyspondyly. Genetic heterogeneity is increasingly reported for the DSS phenotype and now involves mutations of SLC29A3, TNFRSF11A, TCIRG1, LRRK1, and CSF1R. Typical radiological findings are widened radiolucent long bones with thin cortices yet dense irregular metaphyses, flattened vertebral bodies, dense ribs, and multiple fractures. However, the radiographic features of DSS evolve, and the metaphyseal and/or appendicular osteosclerosis variably fades with increasing patient age, likely due to some residual osteoclast function. Fractures are the principal presentation of DSS, and may even occur in infancy with SLC29A3-associated DSS. Cranial base sclerosis can lead to cranial nerve palsies such as optic atrophy, and may be the initial presentation, though not observed with SLC29A3-associated DSS. Gene-specific extra-skeletal features can be the main complication in some forms of DSS such as CSF1R- associated DSS. Further genetic heterogeneity is likely, especially for X-linked recessive DSS and cases currently with an unknown genetic defect. Distinguishing DSS can be challenging due to variable clinical and radiological features and an evolving phenotype. However, defining the DSS phenotype is important for predicting complications, prognosis, and instituting appropriate health surveillance and treatment.

Osteopathia striata with cranial sclerosis causing a compressive optic neuropathy.

BACKGROUND: Osteopathia striata combined with cranial sclerosis (OS-CS) is an inherited skeletal dysplasia that manifests with macrocephaly, orofacial abnormalities, thickened craniofacial bones, and vertically oriented radiodensities of the long bones. CASE REPORT: Here, we present a severe case of OS-CS in a 4-year-old girl causing optic neuropathy as shown by radiographic evidence, ophthalmic findings, and histopathology. Previous genetic testing in this patient revealed a de novo heterozygous mutation in AMER1 (c.1057C>T, p.Arg353Ter). Although the patient had a pre-existing, appropriately functioning, ventriculoperitoneal (VP) shunt, a subsequent MRI of the brain and orbits showed narrowing of the bilateral optic nerve canals secondary to osseous thickening causing bilateral optic nerve atrophy, worse on the left. The patient underwent staged bilateral orbital osteotomies, optic canal decompression, and bilateral frontal craniotomy, and at 11 months postoperatively, her vision remained stable. Conclusions: While up to 50% of the patients with OS-CS may experience hearing loss due to cranial nerve compression, we present a case of severe visual loss secondary to OS-CS-associated optic nerve compression.

Altered sulfation status of FAM20C-dependent chondroitin sulfate is associated with osteosclerotic bone dysplasia.

Raine syndrome, a lethal osteosclerotic bone dysplasia in humans, is caused by loss-of-function mutations in FAM20C; however, Fam20c deficiency in mice does not recapitulate the human disorder, so the underlying pathoetiological mechanisms remain poorly understood. Here we show that FAM20C, in addition to the reported casein kinase activity, also fine-tunes the biosynthesis of chondroitin sulfate (CS) chains to impact bone homeostasis. Specifically, FAM20C with Raine-originated mutations loses the ability to interact with chondroitin 4-O-sulfotransferase-1, and is associated with reduced 4-sulfation/6-sulfation (4S/6S) ratio of CS chains and upregulated biomineralization in human osteosarcoma cells. By contrast, overexpressing chondroitin 6-O-sulfotransferase-1 reduces CS 4S/6S ratio, and induces osteoblast differentiation in vitro and higher bone mineral density in transgenic mice. Meanwhile, a potential xylose kinase activity of FAM20C does not impact CS 4S/6S ratio, and is not associated with Raine syndrome mutations. Our results thus implicate CS 4S/6S ratio imbalances caused by FAM20C mutations as a contributor of Raine syndrome etiology.

Inhibition of interleukin-1ß reduces myelofibrosis and osteosclerosis in mice with JAK2-V617F driven myeloproliferative neoplasm.

Interleukin-1ß (IL-1ß) is a master regulator of inflammation. Increased activity of IL-1ß has been implicated in various pathological conditions including myeloproliferative neoplasms (MPNs). Here we show that IL-1ß serum levels and expression of IL-1 receptors on hematopoietic progenitors and stem cells correlate with JAK2-V617F mutant allele fraction in peripheral blood of patients with MPN. We show that the source of IL-1ß overproduction in a mouse model of MPN are JAK2-V617F expressing hematopoietic cells. Knockout of IL-1ß in hematopoietic cells of JAK2-V617F mice reduces inflammatory cytokines, prevents damage to nestin-positive niche cells and reduces megakaryopoiesis, resulting in decrease of myelofibrosis and osteosclerosis. Inhibition of IL-1ß in JAK2-V617F mutant mice by anti-IL-1ß antibody also reduces myelofibrosis and osteosclerosis and shows additive effects with ruxolitinib. These results suggest that inhibition of IL-1ß with anti-IL-1ß antibody alone or in combination with ruxolitinib could have beneficial effects on the clinical course in patients with myelofibrosis.

Novel WTX nonsense mutation in a family diagnosed with osteopathia striata with cranial sclerosis: Case report.

ABSTRACT: Rationale: Osteopathia striata with cranial sclerosis is characterized by linear striations in the metaphysis of the long bones and pelvis with cranial sclerosis. It is an X-linked dominant sclerosing bone dysplasia and affected males show fetal or neonatal lethality. Mutations in the gene encoding Wilms tumor on the X chromosome (WTX) was identified as the cause of X-linked osteopathia striata with cranial sclerosis. About 30 pathogenic mutations in WTX have been reported recently. We have identified a novel nonsense mutation in the family diagnosed as osteopathia striata with cranial sclerosis. PATIENT CONCERNS: The proband came to our attention at age 9 for the evaluation of toe-out gait and planovalgus deformity. Clinically, the proband showed coarse facial features including frontal bossing, ocular hypertelorism, wide depressed nasal bridge, dental malocclusion, mild macrocephaly and low set ears. Radiologically, sclerotic linear striations were seen in the X-rays of the pelvis and the metaphyseal region of femur and tibia and the cranial sclerosis was observed. The proband's mother presented similar facial features and the X-rays of the pelvis, femur, and tibia revealed same sclerotic linear striations as the proband's. DIAGNOSES: Osteopathia striata with cranial sclerosis. INTERVENTIONS: A genetic analysis was conducted on genomic DNA isolated from peripheral blood leukocytes of the proband and the mother for confirming the clinical suspicion of osteopathia striata with cranial sclerosis. WTX on Xq11.2 gene was analyzed in direct sequencing for coding exons including intron-exon boundaries. OUTCOMES: One novel nonsense mutation (c.1003C>T, p.Gln335∗) and known single nucleotide variant were observed in a heterozygous form. LESSONS: We found a novel nonsense mutation in a family diagnosed as osteopathia striata with cranial sclerosis. The relationship between various clinical features and genetic mutations can be clarified by accumulation of genetic database.