The progress of medication-related osteonecrosis of the jaw with conservative initial treatment: A 12-year retrospective study of 129 patients.

This retrospective study aimed to examine the course and prognosis of medication-related osteonecrosis of the jaw (MRONJ) initially treated conservatively and the effects of various factors affecting treatment outcomes. We evaluated 129 patients with MRONJ between January 2008 and December 2018 at a university hospital. The factors examined included sex, age, stage of MRONJ (1-3), type of bone modifying agents (bisphosphonate or denosumab), primary disease (osteoporosis or malignant tumor), medical history (diabetes and rheumatoid arthritis), use of corticosteroids, the trigger of MRONJ (teeth extraction or others), and separation of sequestrum, using logistic regression analysis. Patients with MRONJ were treated conservatively as the initial treatment in accordance with the position paper of the American Association of Oral and Maxillofacial Surgeons. Of the 129 patients, 59 (45.7%) were cured, and the condition of 70 (54.3%) remained unchanged or worsened. The overall cure rates at 12, 36, and 60 months were 25.8%, 50.8%, and 72.4% respectively. The cure rate of stage 1 was lower than that of stages 2 and 3 at 80 months. In multivariate analysis, it was found that 37 (64.9%) of 57 patients with osteoporosis as a primary disease were cured (odds ratio [OR], 7.7; 95% confidence interval [CI], 2.4-24.4). In addition, 40 (69.0%) of 58 patients with separation of sequestrum were cured (OR, 8.9; 95% CI, 3.4-23.5). The cure rate was significantly higher in patients with osteoporosis than in those with cancer when the treatment outcomes of primary disease were compared using the Kaplan-Meier method (p < 0.01). It was also significantly higher in patients who had separation of sequestrum than in those who did not (p < 0.05). Our results suggest that primary disease and separation of sequestrum were associated with favorable outcomes in patients with MRONJ initially treated conservatively. MRONJ had a poor prognosis with conventional treatment carried according to the stage of the disease. This was especially prominent when conservative treatment was employed for mild cases.

Mandibular Fracture in a Patient Taking a Direct Oral Anticoagulant.

ABSTRACT: A 74-year-old man presented with hemorrhage from the mandible after an injury caused by a 5 × 3 × 3-cm metal square column flying from a 45-ton press machine that struck the right side of his face. He is a known atrial fibrillation patient and is on rivaroxaban, a direct oral anticoagulant. An approximately 8-cm Y-shaped wound with persistent hemorrhage was observed in the right mandible, and the mandible was displaced between the right mandibular canine and first premolar. Although the patient showed no dyspnea, the sublingual region showed a slight dark purple swelling; fiberoptic nasal intubation was performed. Computed tomography at 3.5 hours after the injury revealed a comminuted fracture of the right mandibular body, edema at the floor of the mouth, nasal cavity, upper pharynx to hypopharynx, and the pharyngeal airway around the endotracheal tube. Open reduction and internal fixation were performed. Rivaroxaban was started again 3 days after surgery.

Genial Tubercle Fracture.

Genial tubercle fracture is a rare mandibular fracture. It is classified into 2 different types based on the mechanism of injury, including type I, associated with an atrophied edentulous mandible or denture, and type II, associated with mandibular fracture. Although type I usually can be treated by only observation, type II may cause obstruction of the pharyngeal airway due to hematoma and edema of the floor of the mouth. In this report, genial tubercle fracture associated with mandibular fracture caused by a traffic accident was reported. Reconstructed 3-dimensional images of the pharyngeal airway indicated that there was almost no airway space around the intratracheal tube at the naso- and oropharynx.

A 7q31.33q32.1 microdeletion including LRRC4 and GRM8 is associated with severe intellectual disability and characteristics of autism.

A 4-year-old boy with severe intellectual disability (ID) and characteristics of autism was found to have a de novo 1.9-Mb microdeletion in 7q31.33q32.1, in which LRRC4, GRM8, and 11 other genes were included. GRM8 is associated with attention deficit hyperactivity disorder. LRRC4 is related to synaptic cell adhesion molecules, some of which are associated with autism. The deletion of LRRC4 may be responsible for the severe ID and characteristics of autism observed in the present patient.

7p22.1 microdeletions involving ACTB associated with developmental delay, short stature, and microcephaly.

There are no published reports of patients harboring microdeletions involving the 7p22.1 region. Although 7p22.1 microdeletions are rare, some reports have shown microduplications encompassing this region. In this study, we report five patients with overlapping deletions of the 7p22.1 region. The patients exhibited clinical similarities including non-specific developmental delay, short stature, microcephaly, and other distinctive features. The shortest region of overlap within the 7p22.1 region includes five genes, FBXL18, ACTB, FSCN1, RNF216, and ZNF815P. Of these genes, only ACTB is known to be associated with an autosomal dominant trait. Dominant negative mutations in ACTB are responsible for Baraitser-Winter syndrome 1. We analyzed ACTB expression in immortalized lymphocytes derived from one of the patients and found that it was reduced to approximately half that observed in controls. This indicates that ACTB expression is linearly correlated with the gene copy number. We suggest that haploinsufficiency of ACTB may be responsible for the clinical features of patients with 7p22.1 microdeletions.

A de novo microdeletion in a patient with inner ear abnormalities suggests that the 10q26.13 region contains the responsible gene.

Microdeletions in the 10q26.1 region are related to intellectual disability, growth delay, microcephaly, distinctive craniofacial features, cardiac defects, genital abnormalities and inner ear abnormalities. The genes responsible for inner ear abnormalities have been narrowed to fibroblast growth factor receptor 2 gene (FGFR2), H6 family homeobox 2 gene (HMX2) and H6 family homeobox 3 gene (HMX3). An additional patient with distinctive craniofacial features, congenital deafness and balance dysfunctions showed a de novo microdeletion of 10q26.11q26.13, indicating the existence of a gene responsible for inner ear abnormalities in this region.

Use of targeted next-generation sequencing for molecular diagnosis of craniosynostosis: Identification of a novel de novo mutation of EFNB1.

Craniofrontonasal syndrome (CFNS; MIM#304110) is characterized by asymmetric facial features with hypertelorism and a broad bifid nose due to synostosis of the coronal suture. CFNS shows a unique X-linked inheritance pattern (most affected patients are female and obligate male carriers exhibit a mild manifestation or no typical features at all) associated with the ephrin-B1 gene (EFNB1) located in the Xq13.1 region. In this study, we performed targeted, massively parallel sequencing using a next-generation sequencer, and identified a novel EFNB1 mutation, c.270_271delCA, in a Japanese female patient with craniosynostosis. Because subsequent Sanger sequencing identified no mutation in either parent, this mutation was determined to be de novo in origin. After obtaining molecular diagnosis, a retrospective clinical evaluation confirmed the clinical diagnosis of CFNS in this patient. Comprehensive molecular diagnosis using a next-generation sequencer would be beneficial for early diagnosis of the patients with undiagnosed craniosynostosis.

Characteristics of patients with benign partial epilepsy in infancy without PRRT2 mutations.

Mutations in the proline-rich transmembrane protein 2 gene (PRRT2) are known to cause clinical symptoms of paroxysmal kinesigenic dyskinesia (PKD), benign partial epilepsy in infancy (BPEI), and infantile convulsions with choreoathetosis (ICCA) syndrome; however, not all patients with BPEI have PRRT2 mutations, and the genetic backgrounds for such patients are still unknown. To characterize BPEI patients without PRRT2 mutations, we analyzed unrelated 63 patients with BPEI. Sanger sequencing identified PRRT2 mutations in 33 probands (52%). The most common insertion, c.649dup, was identified in 28 probands. Two novel truncation mutations, c.232dup and c.503_504del were identified independently. 16p11.2 microdeletion was not detected in patients without PRRT2 mutations. PRRT2 mutation detection rates were 21/31 (68%) and 12/32 (38%) in probands who were positive or negative for family history, respectively, indicating a significant difference between the two groups. In this study, 20 probands with BPEI were negative for family history of BPEI and negative for PRRT2 mutation. BPEI in these probands may be due to complex genetic predispositions. Because the possibility remains that a second gene contributes to BPEI, further studies are necessary in patients with BPEI but no PRRT2 mutation, especially in Asian people.

Leukoencephalopathy associated with 11q24 deletion involving the gene encoding hepatic and glial cell adhesion molecule in two patients.

Leukoencephalopathies are heterogeneous entities with white matter abnormalities. Mutations of the gene encoding hepatic and glial cell adhesion molecule (HEPACAM) located on 11q24 are related to one of the leukoencephalopathies: megalencephalic leukoencephalopathy with subcortical cysts type 2 (MLC2). Genomic copy number aberrations were analyzed by microarray comparative hybridization for two patients. One patient who presented with abnormal intensity of the white matter had been previously been diagnosed with the typical genotype and phenotype of Jacobsen syndrome due to an 11q subtelomere deletion, which was further characterized here. In a second patient who exhibited the characteristic finding of leukoencephalopathy, an interstitial deletion of 11q24 was also identified. HEPACAM was involved in both deletions. We therefore suggest that haploinsufficiency of HEPACAM, a gene previously associated with the features of MLC2 and located on the overlapping deletion region between the two patients, might be related to the observed white matter abnormalities.

Mutations in the genes encoding eukaryotic translation initiation factor 2B in Japanese patients with vanishing white matter disease.

OBJECTIVE: Vanishing white matter disease (VWM) is a chronic, progressive leukoencephalopathy associated with episodes of rapid deterioration following minor stress events such as head traumas or infectious disorders. The white matter of the patients with VWM exhibits characteristic radiological findings. METHOD: The genes encoding all five subunits of eukaryotic translation initiation factor 2B (EIF2B) were analyzed in patients, who were tentatively diagnosed with VWM, by Sanger sequencing. RESULTS: Seven mutations were identified in the genes encoding the subunits 1, 2, 4, and 5 of EIF2B. Among them, one mutation (p.V83E) in the subunit 2 (EIF2B2) was recurrently identified in three alleles, indicating the most common mutation in Japanese patients with VWM. Two patients were homozygous, and the other four patients were compound heterozygous. CONCLUSION: All patients showed white matter abnormalities with various degrees. One patient showed manifestations of end-stage VWM disease. Some patients showed late onset and slow progression associated with brain magnetic resonance imaging displaying T2 high intensity only in the deep white matter. There was clinical heterogeneity among patients with VWM.

An association of 19p13.2 microdeletions with Malan syndrome and Chiari malformation.

Patients with microdeletions in the 19p13.2 chromosomal region show developmental delays, overgrowth, and distinctive features with big head appearances. These manifestations are now recognized as Sotos syndrome-like features (Sotos syndrome 2) or Malan syndrome. We identified three female patients with 19p13.2 deletions involving NFIX, a gene responsible for Malan syndrome. We compared the genotypic and phenotypic data of these patients with those of the patients previously reported. The most of the clinical features were found to overlap; however, Chiari malformation type I was observed in two of the three patients evaluated in this study. Because Chiari malformation type I has never been reported in the patients with NSD1-related Sotos syndrome, this finding indicates the possible role of 19p13.2 deletion in patients with mimicking features of Sotos syndrome but have negative NSD1 testing results.

Single nucleotide variations in CLCN6 identified in patients with benign partial epilepsies in infancy and/or febrile seizures.

Nucleotide alterations in the gene encoding proline-rich transmembrane protein 2 (PRRT2) have been identified in most patients with benign partial epilepsies in infancy (BPEI)/benign familial infantile epilepsy (BFIE). However, not all patients harbor these PRRT2 mutations, indicating the involvement of genes other than PRRT2. In this study, we performed whole exome sequencing analysis for a large family affected with PRRT2-unrelated BPEI. We identified a non-synonymous single nucleotide variation (SNV) in the voltage-sensitive chloride channel 6 gene (CLCN6). A cohort study of 48 BPEI patients without PRRT2 mutations revealed a different CLCN6 SNV in a patient, his sibling and his father who had a history of febrile seizures (FS) but not BPEI. Another study of 48 patients with FS identified an additional SNV in CLCN6. Chloride channels (CLCs) are involved in a multitude of physiologic processes and some members of the CLC family have been linked to inherited diseases. However, a phenotypic correlation has not been confirmed for CLCN6. Although we could not detect significant biological effects linked to the identified CLCN6 SNVs, further studies should investigate potential CLCN6 variants that may underlie the genetic susceptibility to convulsive disorders.

Microarray analysis of 50 patients reveals the critical chromosomal regions responsible for 1p36 deletion syndrome-related complications.

OBJECTIVE: Monosomy 1p36 syndrome is the most commonly observed subtelomeric deletion syndrome. Patients with this syndrome typically have common clinical features, such as intellectual disability, epilepsy, and characteristic craniofacial features. METHOD: In cooperation with academic societies, we analyzed the genomic copy number aberrations using chromosomal microarray testing. Finally, the genotype-phenotype correlation among them was examined. RESULTS: We obtained clinical information of 86 patients who had been diagnosed with chromosomal deletions in the 1p36 region. Among them, blood samples were obtained from 50 patients (15 males and 35 females). The precise deletion regions were successfully genotyped. There were variable deletion patterns: pure terminal deletions in 38 patients (76%), including three cases of mosaicism; unbalanced translocations in seven (14%); and interstitial deletions in five (10%). Craniofacial/skeletal features, neurodevelopmental impairments, and cardiac anomalies were commonly observed in patients, with correlation to deletion sizes. CONCLUSION: The genotype-phenotype correlation analysis narrowed the region responsible for distinctive craniofacial features and intellectual disability into 1.8-2.1 and 1.8-2.2 Mb region, respectively. Patients with deletions larger than 6.2 Mb showed no ambulation, indicating that severe neurodevelopmental prognosis may be modified by haploinsufficiencies of KCNAB2 and CHD5, located at 6.2 Mb away from the telomere. Although the genotype-phenotype correlation for the cardiac abnormalities is unclear, PRDM16, PRKCZ, and RERE may be related to this complication. Our study also revealed that female patients who acquired ambulatory ability were likely to be at risk for obesity.

Growth patterns of patients with 1p36 deletion syndrome.

1p36 deletion syndrome is one of the most common subtelomeric deletion syndromes. Obesity is frequently observed in patients with this syndrome. Thus, it is important to evaluate the growth status of an individual patient. For this purpose, we accumulated recorded growth data from 44 patients with this syndrome and investigated the growth patterns of patients. Most of the patients showed weight parameters within normal limits, whereas a few of these patients showed intrauterine growth delay and microcephaly. The length of the patients after birth was under the 50th centile in most patients. Many patients showed poor weight gain after birth, and only two female patients were overweight. These findings indicate two different phenotypes of the 1p36 deletion syndrome. The overweight patients with 1p36 deletion started excessive weight gain after two years of life. This characteristic of the patients with 1p36 deletion syndrome is similar to Prader-Willi syndrome.

An emerging phenotype of Xq22 microdeletions in females with severe intellectual disability, hypotonia and behavioral abnormalities.

The majority of Xq22 duplications seen in patients with Pelizaeus-Merzbacher disease (PMD) include proteolipid protein 1 (PLP1), the gene responsible for PMD, and neighboring genes. Some cases result from larger duplications up to 7 Mb in size. In comparison, the deletions including PLP1 seen in PMD patients are small. In this study, we present the genetic and clinical information for five female patients with deletions involving the Xq22 region, and review the correlation between the genotype and phenotype. Three of the five patients show similar large deletions (>3 Mb) ranging from Xq22.1 to Xq22.3 and all manifest severe intellectual disability, hypotonia and behavioral abnormalities. The most striking similarity among them are the behavioral problems, including poor eye contact and sleep disturbance. We propose that this represents an emerging distinctive microdeletion syndrome encompassing PLP1 in female patients. The possible candidate region responsible for such distinctive features has been narrowed down to the neighboring region for PLP1, including the interleukin 1 receptor accessory protein-like 2 (IL1RAPL2) gene and the clustered brain expressed X-linked (BEX) genes. The gene(s) responsible for severe neurological features in the patients in this study would be located in the regions proximate to PLP1; thus, males with the deletions involving the gene(s) would be lethal, and finally, the sizes of the deletions in PMD patients would be smaller than those of the duplications.

Overlapping microdeletions involving 15q22.2 narrow the critical region for intellectual disability to NARG2 and RORA.

Microdeletions in the 15q22 region have not been well documented. We collected genotype and phenotype data from five patients with microdeletions involving 15q22.2, which were between 0.7 Mb and 6.5 Mb in size; two were of de novo origin and one was of familial origin. Intellectual disability and epilepsy are frequently observed in patients with 15q22.2 deletions. Genotype-phenotype correlation analysis narrowed the critical region for such neurologic symptoms to a genomic region of 654 Kb including the NMDA receptor-regulated 2 gene (NARG2) and the PAR-related orphan receptor A gene (RORA), either of which may be responsible for neurological symptoms commonly observed in patients with deletions in this region. The neighboring regions, including the forkhead box B1 gene (FOXB1), may also be related to the additional neurological features observed in the patients with larger deletions.

Narrowing of the responsible region for severe developmental delay and autistic behaviors in WAGR syndrome down to 1.6 Mb including PAX6, WT1, and PRRG4.

Interstitial deletions of the 11p13 region are known to cause WAGR (Wilms tumor, aniridia, genitourinary malformation, and "mental retardation") syndrome, a contiguous gene deletion syndrome due to haploinsufficiencies of the genes in this region, including WT1 and PAX6. Developmental delay and autistic features are major complications of this syndrome. Previously, some genes located in this region have been suggested as responsible for autistic features. In this study, we identified two patients who showed the chromosomal deletions involving 11p13. Patient 1, having an 8.6 Mb deletion of chr11p14.1p12:29,676,434-38,237,948, exhibited a phenotype typical of WAGR syndrome and had severe developmental delay and autistic behaviors. On the other hand, Patient 2 had a larger aberration region in 11p14.1-p12 which was split into two regions, that is, a 2.2-Mb region of chr11p14.1: 29,195,161-31,349,732 and a 10.5-Mb region of chr11p13p12: 32,990,627-43,492,580. As a consequence, 1.6 Mb region of the WAGR syndrome critical region was intact between the two deletions. This patient showed no symptom of WAGR syndrome and no autistic behaviors. Therefore, the region responsible for severe developmental delay and autistic features on WAGR syndrome can be narrowed down to the region remaining intact in Patient 2. Thus, the unique genotype identified in this study suggested that haploinsufficiencies of PAX6 or PRRG4 included in this region are candidate genes for severe developmental delay and autistic features characteristic of WAGR syndrome.

Microdeletions of 5.5 Mb (4q13.2-q13.3) and 4.1 Mb (7p15.3-p21.1) associated with a saethre-chotzen-like phenotype, severe intellectual disability, and autism.

We observed a patient with a Saethre-Chotzen-like phenotype with severe neurological features. Saethre-Chotzen syndrome (acrocephalosyndactyly type III; SCS; OMIM #101400) is an autosomal dominant craniosynostosis syndrome characterized by craniofacial and mild limb abnormalities. The phenotypic features of chromosomal microdeletions involving the 7p21.1, where the twist homolog 1 gene (TWIST1) responsible for SCS is located, are recognized as a contiguous gene deletion syndrome with SCS and other phenotypic manifestations. In this study, we identified microdeletions in 4q13.2 and 7p21.1 in a patient with SCS and severe neurological features including developmental delay and autistic behavior. In comparison to other SCS patients with intragenic mutations or small deletions in 7p21.1, neurological features seen in this patient were extremely severe, likely modified by a concurrent deletion of 4q13.2. Both microdeletions were de novo and paternal in origin. Further information on such concurrent chromosomal deletions should be accumulated for better understanding of the mechanism.

A novel homozygous mutation of GJC2 derived from maternal uniparental disomy in a female patient with Pelizaeus-Merzbacher-like disease.

Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, motor developmental delay, ataxia, and progressive spasticity. The gap junction protein gamma-2 gene (GJC2), encoding the gap junction protein connexin 47, is one of the genes responsible for this condition. In this study, a novel homozygous mutation in GJC2 (c.746C>G; p.P249R) was identified in a 21-year-old female patient with PMLD. Although her mother was a carrier of this mutation, the Mendelian inheritance pattern could not be determined because the paternal sample was unavailable. Alternatively, chromosomal microarray testing together with single nucleotide polymorphism typing (CGH+SNP) was performed to determine the gene copy number and analyze the haplotype in the 1q42.13 region in which GJC2 is located. The result showed no deletion, but the GJC2 region was involved in the loss-of-heterozygosity region. Furthermore, haplotype of chromosome 1, in which GJC2 is located, revealed that both copies of chromosome 1 were derived from the patient's mother, indicating maternal uniparental disomy of chromosome 1. This study showed the advantage of the SNP genotyping microarray for detecting the origin of the mutation.

De novo triplication of 11q12.3 in a patient with developmental delay and distinctive facial features.

BACKGROUND: Triplication is a rare chromosomal anomaly. We identified a de novo triplication of 11q12.3 in a patient with developmental delay, distinctive facial features, and others. In the present study, we discuss the mechanism of triplications that are not embedded within duplications and potential genes which may contribute to the phenotype. RESULTS: The identified triplication of 11q12.3 was 557 kb long and not embedded within the duplicated regions. The aberrant region was overlapped with the segment reported to be duplicated in 2 other patients. The common phenotypic features in the present patient and the previously reported patient were brain developmental delay, finger abnormalities (including arachnodactuly, camptodactyly, brachydactyly, clinodactyly, and broad thumbs), and preauricular pits. CONCLUSIONS: Triplications that are not embedded within duplicated regions are rare and sometimes observed as the consequence of non-allelic homologous recombination. The de novo triplication identified in the present study is novel and not embedded within the duplicated region. In the 11q12.3 region, many copy number variations were observed in the database. This may be the trigger of this rare triplication. Because the shortest region of overlap contained 2 candidate genes, STX5 and CHRM1, which show some relevance to neuronal functions, we believe that the genomic copy number gains of these genes may be responsible for the neurological features seen in these patients.