Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome.

Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000-8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter.

Arteriovenous Fistula Closure Using a Simple Ligation Technique After Kidney Transplantation.

BACKGROUNDS: There are advantages and disadvantages with closure of an arteriovenous fistula (AVF) after kidney transplantation, but some cases require closure. The general procedure for closure is angioplasty with exposure of the anastomotic site, but this is often time-consuming and complicated. We have developed a simpler, less invasive, and shorter procedure for AVF closure, in which the anastomotic site itself is not peeled off and the outflow vein close to this site is ligated using 1-0 silk. In this study, we examined the utility of this procedure. METHODS: A retrospective case series study was conducted by review of electronic medical records of patients and surgeries. All patients (n = 52) who underwent AVF closure after kidney transplantation at our hospital between January 2008 and April 2021 were reviewed. Perioperative and long-term postoperative results were examined. This study was carried out following the ethical standards of the Declaration of Helsinki and Istanbul. Donors were not from prisoners, or from those individuals who are coerced of paid. RESULTS: Simple ligation was performed for 46 patients (88.5%). The median time after renal transplantation was 40 (24.5-66.5) months. Median operative time and blood loss were 20 (12.2-30) minutes and 10 (5-15) mL, respectively. Two patients (4.3%) developed the aneurysm after the AVF closure using the simple ligation. CONCLUSION: The simple ligation technique had a relatively shorter operative time and only 2 cases had aneurysm formation. These results suggest that this technique is an option for closure of an AVF after kidney transplantation.

Trends in occurrence of twin births in Japan.

The rise in the rate of multiple births since the 1980s is due to the effect of advanced maternal age and increased use of assisted reproductive technology (ART). To determine the trends of prevalence in twin births, we studied the data of a population-based birth defects monitoring system during 26 years in Kanagawa Prefecture, Japan. A total of 15,380 twins from 7,690 deliveries were ascertained from 990,978 births in the Kanagawa Birth Defects Monitoring Program (KAMP) during 1981-2008. From the start of KAMP in 1981, the incidence of twin births had been consistently increasing from 57.0 to 98.6 per 10,000 deliveries until 2003, but after this time, the incidence declined to 78.5 in 2007. While the rate of monozygotic twins has been stable (∼40 per 10,000 deliveries) after 1990, that of dizygotic twins increased from 25.3 to 57.3 per 10,000 deliveries until 2002, and recovered to 40.1 in 2007. These results showed the most recent tendency of twin births and indicated that the single embryo transfer method can provide protection and reduction of perinatal risk caused by multiple births.

Division of dorsal vascular complex using soft coagulation without suture ligation during robot-assisted laparoscopic radical prostatectomy: a propensity score-matched study in a single-center experience.

Introduction: Apical dissection and control of the dorsal vascular complex (DVC) affects blood loss, positive surgical margins, and urinary control during robot-assisted laparoscopic radical prostatectomy. Soft coagulation is widely used for hemostasis. However, using soft coagulation to the DVC may affect the continence outcomes. In this study, we described technique and outcomes for division of the DVC after soft coagulation (DVC-SC) compared with delayed ligation of the DVC (D-DVC). Material and methods: Medical records of 170 patients who underwent robot-assisted laparoscopic radical prostatectomy from June 2016 to March 2020 were retrospectively reviewed. To reduce the selection bias, the two groups were matched in a 1:1 ratio on the basis of propensity scores. Perioperative data and results were compared in both groups. Results: Patients undergoing DVC-SC experienced less estimated blood loss compared to patients undergoing D-DVC (median: 105.5 vs 225 ml, p = 0.017). Postoperative continence rates at 1 week, 1, 3, 6 months in DVC-SC group and D-DVC group were 32.5% versus 15%, 62.5% versus 32.5%, 85% versus 67.5%, 95% versus 90%, respectively. Continence was significantly better at 1 month with DVC-SC versus D-DVC (p = 0.013). Conclusions: Division of the DVC after soft coagulation technique did not affect continence after robot-assisted laparoscopic radical prostatectomy despite the thermal division and gave the surgeon good hemostasis with simple procedure.

Novel Technique for Hand-Assisted Laparoscopic Nephrectomy for Advanced Renal Cell Carcinoma with Renal Vein and Inferior Vena Cava Thrombi: Three Case Reports.

Introduction: The treatment of thrombi in the renal vein (RV) and inferior vena cava (IVC) requires advanced laparoscopic experience. We present three cases of hand-assisted laparoscopic nephrectomy (HALN) using a novel technique for treating advanced renal cell carcinoma (RCC) with thrombi in the RV and IVC. Case Presentation. Three patients with RCC with RV or IVC thrombus below level I underwent HALN. Two patients had right RCC with RV and IVC thrombi. One patient had left RCC with an RV thrombus. We hooked a vessel loop to the end of the thrombus and pulled it up manually to make space for vascular processing. The RV was narrowed and dissected using Hem-o-lok clips or an Endo GIA stapler. Conclusion: In carefully selected cases, renal vascular processing could be easily and safely performed using a vessel loop in HALN with thrombectomy.

HRAS mutants identified in Costello syndrome patients can induce cellular senescence: possible implications for the pathogenesis of Costello syndrome.

Costello syndrome (CS) is a congenital disease that is characterized by a distinctive facial appearance, failure to thrive, mental retardation and cardiomyopathy. In 2005, we discovered that heterozygous germline mutations in HRAS caused CS. Several studies have shown that CS-associated HRAS mutations are clustered in codons 12 and 13, and mutations in other codons have also been identified. However, a comprehensive comparison of the substitutions identified in patients with CS has not been conducted. In the current study, we identified four mutations (p.G12S, p.G12A, p.G12C and p.G12D) in 21 patients and analyzed the associated clinical manifestations of CS in these individuals. To examine functional differences among the identified mutations, we characterized a total of nine HRAS mutants, including seven distinct substitutions in codons 12 and 13, p.K117R and p.A146T. The p.A146T mutant demonstrated the weakest Raf-binding activity, and the p.K117R and p.A146T mutants had weaker effects on downstream c-Jun N-terminal kinase signaling than did codon 12 or 13 mutants. We demonstrated that these mutant HRAS proteins induced senescence when overexpressed in human fibroblasts. Oncogene-induced senescence is a cellular reaction that controls cell proliferation in response to oncogenic mutation and it has been considered one of the tumor suppression mechanisms in vivo. Our findings suggest that the HRAS mutations identified in CS are sufficient to cause oncogene-induced senescence and that cellular senescence might therefore contribute to the pathogenesis of CS.

Association between chronic kidney disease and small residual urine volumes in patients with benign prostatic hyperplasia.

AIM: It has been well described that large residual urine volumes (≥300 mL) affect renal function in advanced benign prostatic hyperplasia (BPH). However, it is not clear whether small residual urine volumes (<100 mL) are related to renal function. The present study was performed to examine the association between chronic kidney disease (CKD) and the post-void residual urine volume (PVR) in BPH patients. METHODS: A cross-sectional study was performed in 160 consecutive BPH patients with PVR of less than 100 mL. We first determined the stage of CKD and compared the PVR in subjects with/without CKD. Next, we divided the subjects into three groups according to the extent of PVR (PVR < 12 mL, 12 mL ≤ PVR < 50 mL, 50 mL ≤ PVR < 100 mL) and compared the estimated glomerular filtration rate (eGFR) among these groups. Moreover, risk factors associated with CKD, including the presence of post-void residual urine, were explored by multiple logistic regression analysis. RESULTS: The PVR of the patients with CKD was significantly greater than that of the patients without CKD. The group with the normal PVR (group PVR < 12 mL) had a significantly higher eGFR compared with the other two groups. Multivariate analysis demonstrated that the presence of post-void residual urine (PVR ≥ 12 mL) was a significant and independent risk factor associated with the presence of CKD. CONCLUSION: In BPH patients, the PVR of the patients with CKD was significantly greater than that of the patients without CKD and the presence of post-void residual urine (PVR ≥ 12 mL) was independently associated with CKD, indicating a close association between CKD and small residual urine volumes.

A case of primary retroperitoneal amyloidoma resected laparoscopically.

Amyloidosis is known as a group of diseases that causes various disorders because of deposition of amyloid protein in various organs. Amyloidosis occurring in the retroperitoneum is a rare disease. We report a 75-year-old male patient presented to our hospital because he was identified with a retroperitoneal mass incidentally by CT. Laparoscopic surgery was performed to resect the tumor. In the histopathological specimen, amyloid was found in the fibrous soft tissue by Congo red staining. This is the first report to document a primary solitary amyloidosis of the retroperitoneum without systemic amyloidosis, which was resected using the laparoscopic approach.

A study of innate immunity in patients with end-stage renal disease: special reference to toll-like receptor-2 and -4 expression in peripheral blood monocytes of hemodialysis patients.

It was recently shown that toll-like receptors (TLR) play a critical role in innate immunity. However, no study has been conducted on TLR expression in hemodialysis (HD) patients. The present study was undertaken to examine innate immunity and the roles played by endotoxins (ET) contained in dialysate in HD patients, by analysis of TLR expression and reactivity. TLR-2 and TLR-4 expression on monocytes was investigated by flow cytometry in the following groups of subjects: healthy controls, patients on HD, patients with end-stage renal disease (ESRD) and patients on peritoneal dialysis (PD). The expression of TLRs on monocytes under stimulation with lipopolysaccharide was also investigated. Expression of TLR-4 was lower in the HD group than in the healthy controls (p<0.05), while expression of TLR-2 was lower in the PD group than in the healthy controls (p<0.05). As the duration of dialysis became longer, TLR-4 expression decreased (p<0.01). TLR-2 was not correlated with duration of dialysis, and the magnitude of decrease in TLR-4 expression following stimulation with ET became smaller (p=0.0006). Suppression of expression of TLR-4 was noted in HD patients, and TLR-4 expression was reduced as the duration of dialysis became longer. Reduced TLR-4 expression may be associated with the compromised immune function in HD patients. It seems possible that chronic stimulation with ET suppresses the expression of TLR-4.

Brain MRI findings of older patients with Pallister-Killian syndrome.

Pallister-Killian syndrome (PKS) is a disorder caused by a mosaic tetrasomy of chromosome 12p, which manifests with dysmorphism, intellectual disabilities, auditory disturbance, and epilepsy. Here, we describe the findings of brain magnetic resonance (MR) imaging in two patients with PKS. One patient, a 43-year-old man, showed multiple lesions with high signal intensity on T2-weighted image (WI) in the basal ganglia, and widespread T2 elongation in the periventricular white matter. The same signal change was also present in the pontine base. The other patient, a 37-year-old woman, showed T2-high lesions in the bilateral putamina and the parietal periventricular white matter. There was prominent atrophy of the cerebellum and brainstem in this latter case. Both cases showed cortical atrophy with frontal predominance, with accompanying dilatation of the lateral ventricles. Hypoplastic corpus callosum was also present in both cases. Cerebral atrophy with ventricular dilatation has been often described in PKS cases, but many of the MR findings in the present patients have never been reported. Such findings may appear with advancing age in PKS. Since 12p mosaicism is rarely detected in peripheral blood lymphocytes, examination of buccal mucosal cells with fluorescent in situ hybridization method is preferable for the diagnosis of PKS. Recognition of the characteristic features on cranial MR imaging, in addition to the characteristic facial appearance in adulthood, should prompt the correct diagnosis of adult PKS patients.

Epilepsy and neurological findings in 11 individuals with 1p36 deletion syndrome.

The 1p36 deletion syndrome is a newly delineated multiple congenital anomalies/mental retardation syndrome characterized by mental retardation, growth delay, epilepsy, congenital heart defects, characteristic facial appearance, and precocious puberty. We analyzed 11 patients by fluorescence in situ hybridization (FISH) using commercially available bacterial artificial chromosome and P1-derived artificial chromosome genomic clones to define the chromosomal deletion responsible for the 1p36 deletion syndrome. Cytogenetic investigation revealed two cases with a terminal deletion of 1p36. Nine patients had an apparently normal karyotype with standard G-bands by trypsin using Giemsa (GTG), but FISH screening with the highly polymorphic genetic marker D1Z2, which is mapped to 1p36.3 and contains an unusual reiterated 40-bp variable number tandem repeat, revealed a submicroscopic deletion. All patients had severe to profound mental retardation. Based on the University of California Santa Cruz Genome Browser, we constructed a deletion map and analyzed the relationship between neurological findings and chromosomal deletions for the 11 cases. Six cases had intractable epilepsy and three had no seizures. The common deletion interval was about 1 million base pairs (Mbp) located between RP11-82D16 and RP4-785P20 (Rho guanine exchange factor (GEF) 16). The severity of clinical symptoms correlates with the size of the deletion. This is demonstrated by the 3 patients with at least 8Mbp deletions that display profound mental retardation and congenital heart defects. Although haploinsufficiency of the potassium channel beta-subunit (KCNAB2) is thought to be responsible for intractable seizures in the 1p36 deletion syndrome, this was not the case for 3 of the 11 patients in this study. Further investigation of the 1p36 region is necessary to allow identification of genes responsible for the 1p36 deletion syndrome.

Sotos syndrome associated with a de novo balanced reciprocal translocation t(5;8)(q35;q24.1).

We describe a de novo balanced reciprocal translocation between the long arms of chromosomes 5 and 8 [46,XX,t(5;8)(q35;q24.1)] in a 15-month-old girl with a typical Sotos syndrome phenotype. Involvement of the 5q35 region was previously reported (Maroun et al. [1994: Am J Med Genet 50:291-293]) as one of translocation breakpoints in the present patient. We suggest that the gene responsible for Sotos syndrome is located to a distal long-arm region of chromosome 5.

Paternal UPD14 is responsible for a distinctive malformation complex.

We present a boy and two girls with paternal uniparental disomy of chromosome 14q (patUPD14). One girl had a Robertsonian translocation, whereas two a normal karyotype. Based on the manifestations of these patients and four previously reported patients who all had translocated chromosome 14, The patUPD14 was thought to constitute a distinctive syndrome. The hallmarks included abdominal muscular defects, skeletal anomalies, and characteristic facies. The phenotype of patUPD14 was consistent with that of a previously reported mouse model, i.e., mouse embryos with paternal uniparental disomy of chromosome 12 that has a region orthologous to that of human chromosome 14. Dose effects of newly recognized imprinted genes on human chromosome 14q32, DLK1 and GTL2, could play an important role in the pathogenic mechanism of the distinctive malformation complex.

Favorable seizure outcome in Kabuki make-up syndrome associated with epilepsy.

Kabuki make-up syndrome is a mental retardation-malformation syndrome affecting multiple organ systems, with a broad spectrum of neuromuscular dysfunction and mental ability. The incidence of seizures associated with this syndrome ranges from 10 to 40%. However, details of the seizures in this syndrome have not been adequately reported or thoroughly evaluated. In this study, we analyzed seizure characteristics and clinical outcomes in nine patients with Kabuki make-up syndrome. Four patients had generalized seizures and two patients had complex partial seizures, extended to secondary generalized seizures. West's syndrome, complex partial seizure, and atonic seizure were seen in one case each, respectively. Electroencephalograms showed focal spikes in seven cases, diffuse spike and wave burst in one case, and hypsarrhythmia in one case. Seizures were well controlled in eight cases and incompletely controlled in only one case. Together with mental retardation, epilepsy can be a primary feature of Kabuki make-up syndrome. Epilepsy associated with Kabuki make-up syndrome is mainly localization-related epilepsy with a favorable seizure outcome.

No sex differences in 18 trisomy births in the Kanagawa Birth Defects Monitoring Program.

Trisomy 18 is a common chromosome anomaly. The predominance of female infants is widely accepted in the literature. This study clarified no sex differences in 18 trisomy births.

Nephrogenic adenoma of the bladder: two case reports and literature review.

In the two cases we report here, tumors were diagnosed as nephrogenic adenoma by pathohistological examination. Case 1 was a 72-year-old female presenting with a bladder tumor 8 months after receiving ureteral tumor surgery. Transurethral resection of bladder tumor (TUR-Bt) was performed. Case 2 was a 57-year-old female who had received intravesical bacillus Calmette-Guérin (BCG) treatment 6 times after her fifth TUR-Bt. Two tumors were found by cystoscopy, and TUR-Bt was performed. There have been 39 cases of nephrogenic adenoma of the bladder reported in Japan; 21 were male and 18 female with a mean age of 56.5 years. The main complaint was hematuria, which was seen in 16 cases followed by pollakisuria in 6 cases. Nephrogenic adenoma occurred after surgery of the urinary tract in 16 cases, followed by urinary tract infection in 9 cases and intravesical BCG treatment in 6 cases. The ratio of cases occurring after intravesical BCG treatment has increased since BCG approval for bladder carcinoma treatment in December 1996 in Japan, and an increase in the number of cases is expected in the future.

Ehlers-Danlos syndrome, vascular type: a novel missense mutation in the COL3A1 gene.

We report a 34-year-old Japanese female with the vascular type of Ehlers-Danlos syndrome. She had thin translucent skin, extensive bruising, toe joint hypermobility, left lower extremity varicose veins, and chronic wrist, knee and ankle joint pain. She also had dizziness caused by autonomic dysfunction. Magnetic resonance angiography showed tortuous vertebral and basilar arteries, mild left carotid canal bulging, and right anterior tibial artery hypoplasia. Electron microscopic examinations of a skin biopsy revealed extremely dilated rough endoplasmic reticulum in dermal fibroblasts and wide variability of individual collagen fibril diameters. A molecular analysis using a conventional total RNA method and a high-resolution melting curve analysis using genomic DNA revealed a novel missense mutation within exon 48 of the COL3A1 gene, c.3428G>A, leading to p.Gly1143Glu.

The prevalence of metabolic syndrome in Japanese renal transplant recipients.

BACKGROUND: The prevalence of metabolic syndrome (MS) after renal transplantation has yet to be elucidated. In the present study, we investigated the prevalence of MS in Japanese renal transplant recipients. METHODS: A cross-sectional study was conducted to determine the prevalence of MS in 101 renal transplant recipients at Osaka City University Hospital. The prevalence of MS was determined using the National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATPIII) criteria (modified and original) and the International Diabetes Federation (IDF) criteria. RESULTS: Using the modified (Japanese) NCEP criteria, a total of 24 out of 101 patients (23.8%) had MS including 21 out of 64 male patients (32.8%) and three out of 37 female patients (8.1%). Using the modified (Asian) NCEP criteria, MS was diagnosed in 23 patients (22.8%); 19 male (29.7%) and four female (10.8%). Using the original NCEP criteria, MS was diagnosed in 15 patients (14.9%); 12 male (18.8%) and three female (8.1%). Using the IDF criteria, MS was diagnosed in 16 patients (15.8%); 15 male (23.4%) and one female (2.7%). CONCLUSION: The prevalence of MS differed according to the NCEP criteria used, which had different cut-off points for waist circumference (14.9-23.8%). By the IDF criteria, which cites central obesity as an essential component, the prevalence of MS was slightly lower. Furthermore, in our study, MS was more prevalent in male renal transplant recipients.