Two novel heterozygous variants in RecA2 domain of the DHX37 cause 46,XY gonadal dysgenesis and testicular regression syndrome.

INTRODUCTION: The pathogenic variants in DEAH-box RNA helicase DHX37 are one of the major causes of 46,XY gonadal dysgenesis and TRS. To date, only 13 different missense variants have been reported. We report two additional cases with different clinical presentation carrying two novel variants in the DHX37 gene. CASE PRESENTATION AND RESULTS: Case 1 (4.4-year-old boy), presented with significant micropenis and cryptorchidism and was diagnosed as TRS. Case 2 (13.5-year-old girl), had a 46,XY karyotype with female external genitalia and was diagnosed as GD. Two novel DHX37 variants affecting the RecA2 domain, p.G478R and p.L627F, were identified in these cases. Both variants identified in the probands were also present in their unaffected mother. DISCUSSION/CONCLUSION: Our findings broaden the variant spectrum of DHX37 in 46,XY DSD individuals.

[Characteristics of genetic variants in 134 patients with Acute myeloid leukemia].

OBJECTIVE: To analyze the characteristics of genetic variants in 134 patients diagnosed with Acute myeloid leukemia (AML). METHODS: Clinical data of the 134 patients with AML (non-acute promyelocytic leukemia) initially diagnosed at the 940th Hospital of the Joint Logistics Support Force of the Chinese People's Liberation Army from June 2017 to June 2022 were retrospectively analyzed. Potential variants of AML-related genes were detected by next-generation sequencing, and the frequency of variants was analyzed by using SPSS v26.0 software, and likelihood ratio χ2 test and Fisher exact test were used for data analysis. RESULTS: The patients had included 72 males and 62 females, with a gender ratio of 1.7 : 1 and a median age of 51 years (9 ~ 86 years old). One hundred twenty patients (76.1%) had harbored at least one genetic variant, including 26 (19.4%) having a single variant, 27 (20.1%) having two variants, and 49 (36.6%) having >= 3 variants. 32 (23.9%) had no detectable variants. Genetic variants detected in over 10% of the 134 patients had included NPM1 (n = 24, 17.91%), FLT3-ITD (n = 21, 15.67%), DNMT3A (n = 20, 14.93%), CEBPA (single variant; n = 14, 10.45%), TET2 (n = 14, 10.45%), and NRAS (n = 14, 10.45%). The patients were also divided into low risk, intermediate risk and high risk groups based on their chromosomal karyotypes. The mutational rates for genes in different groups have varied, with 19 patients from the low risk group harboring variants of NRAS (n = 4, 21.05%), KRAS (n = 4, 21.05%), and KIT (n = 2, 10.53%); and 96 patients from the intermediate risk group harboring variants of NPM1 (n = 24, 25.00%), FLT3-ITD (n = 20, 20.83%), DNMT3A (n = 18, 18.75%), CEBPA (n = 12, 12.50%), and TET2 genes (n = 12, 12.50%). The mutational frequencies for the 19 patients from the high risk group were ASXL1 (n = 7, 21.05%), NRAS (n = 3, 15.97%), TP53 (n = 3, 15.79%), and EZH2 (n = 2, 10.53%). A significant difference was found in the frequencies of KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 gene variants among the low-risk, medium-risk, and high-risk groups. CONCLUSION: AML patients have a high frequency for genetic variants, with 76.1% harboring at least one variant. The frequency of genetic variants have varied among patients with different chromosomal karyotypes, and there are apparent dominant variants. KIT, NPM1, FLT3-ITD, DNMT3A, and ASXL1 may be used as prognostic factors for evaluating their prognosis.

A novel corporoplasty technique with a urethral plate flap in hypospadias repair.

OBJECTIVES: To report a novel corporoplasty technique with a urethral plate flap in hypospadias repair and evaluate its safety and efficacy for ventral lengthening. METHODS: Data were retrospectively collected from consecutive patients with hypospadias who underwent urethral plate flap corporoplasty between July 2021 and March 2022. All patients underwent hypospadias repair using the Duckett technique. The corporoplasty procedure involved the following key steps: the half-spongiosum of the urethral plate was harvested as a flap (with a pedicle attached to the corpus cavernosum); a transverse incision of the tunica albuginea was made adjacent to the pedicle; and the flap was patched onto the corporal defect. RESULTS: The study included 10 patients, with a median age of 20 months. The initial meatal location was penile in two patients, penoscrotal in four patients, and scrotal in four patients. The median ventral curvature was 45° after degloving and urethral plate transection. The median ventral lengthening distance proportional to penis length was 0.21. During the median follow-up of 13.8 months, complications occurred in three cases, including two cases of fistula and one case of urethral stricture with secondary diverticulum. No cases of recurrent ventral curvature, meatal stenosis, or urethral dehiscence were noted. Postoperative ultrasonography showed a good continuation of the tunica albuginea and integrity of the stratum spongiosum at the corporoplasty site. CONCLUSIONS: Urethral plate flap corporoplasty is a simple and effective ventral lengthening procedure. The novel corporoplasty technique allows for anatomical and architectural repair of corporal disproportion.

Case Report: De novo variant in myelin regulatory factor in a Chinese child with 46,XY disorder/difference of sex development, cardiac and urogenital anomalies, and short stature.

The myelin regulatory factor (MYRF; MIM# 608329) gene was first identified as a critical transcription factor involved in oligodendrocyte differentiation and central nervous system myelination. With the recent development of exome sequencing, pathogenic variants of MYRF had been considered as the cause of cardiac-urogenital syndrome (CUGS), 46,XY and 46,XX disorders/differences of sex development (DSDs), and nanophthalmos. Herein, we described a 4-year-7-month-old "girl" with ventricular septal defect, atrial septal defect, patent ductus arteriosus, severe pulmonary hypertension, moderate-to-severe tricuspid regurgitation, enlarged coronary sinus, left superior vena cava, and right lung hypoplasia at birth. Later, the patient developed short stature and amblyopia. Further examination revealed a karyotype 46,XY and visible uterus, whereas the presence of gonads were not explored. Laparoscopy revealed dysplasia of testicular gonad. Whole-exome sequencing (WES) was performed and a de novo heterozygous mutation in MYRF was identified, known as c.2817G > A/p. W939* (NM_001127392.3). Therefore, this case report presented multiple clinical manifestations with syndromic symptoms of CUGS, 46,XY DSD, and ocular symptoms. These new data expanded the phenotype of the MYRF variant and may benefit to characterize the phenotypes caused by the variants of this gene.

Mental health status of children with disorders of sexual development and their correlates.

Disorders of sexual development (DSD) refer to the congenital abnormalities of chromosomes, gonads, or gender anatomy. Children with DSD usually experience more stress. The present study aims to evaluate the mental health status of children with DSD, and to explore the potential relevant factors. We included 30 children with DSD and 30 age- and gender-matched children without DSD as the control group. All the children and their parents completed the scales of the Hamilton Anxiety Scale (HAMA). Children over 8 years old (n = 22) completed the Screen Scale for Child Anxiety Related Emotional Disorders (SCARED), the Depression Self-rating Scale for Children (DSRSC), and the Egna Minnen av Barndoms Uppfostran-own memories of parental rearing practices in childhood. DSD children had significantly higher somatic anxiety, mental anxiety, and total anxiety scores than the control group (p < 0.001). The scores of the SCARED, anxiety, and depression subscales of DSD children were higher than those of control children (p < 0.05 and p < 0.001, respectively). The correlation analysis showed that the score of generalized anxiety was positively related to age and entertainment. The regression analysis showed that age was a major factor that affected generalized anxiety in DSD children, and neuroticism was a major factor of anxiety disorder and separation anxiety in DSD children. Children with DSD have obvious anxiety problems, which are associated with family environmental factors (entertainment, success, and conflicts) and age. It is important to focus emphasis on emotional stability in children with DSD for detecting anxiety-related emotional disorders early.

Immune thrombocytopenic purpura induced by the COVID-19 vaccine after the second dose in a 78-year-old patient: A case report.

Coronavirus disease 2019 (COVID-19) has become a global pandemic, but treatment options remain limited. Up to now, vaccination has been the main strategy to prevent transmission and reduce disease severity. However, with follow-up observations after massive vaccination, immune thrombocytopenic purpura (ITP) induced by COVID-19 vaccines has attracted the attention of investigators. The present study reported the case of a 78-year-old elderly female who presented with 'oral bleeding for 2 days and scattered bleeding spots on the extremities for 1 day' after vaccination with the COVID-19 vaccine (Vero Cells), and blood routine analysis indicated a white blood cell count of 6.27x109/l, hemoglobin levels of 144 g/l and a low platelet (PLT) count of 1x109/l. Bone marrow cytomorphology showed thrombocytopenia, while no platelet-producing megakaryocytes were observed. The patient was diagnosed with ITP and given symptomatic and supportive treatment, such as prednisone acetate 1 mg/kg, recombinant human thrombopoietin, intravenous injection of human immunoglobulin 0.4 g/kg and prevention of bleeding. At 1 week after the treatment started, the patient's PLT count began to increase, and 9 days later, it returned to normal levels. The aim of the present study was to raise the awareness of medical staff regarding this disease and to increase the vigilance of the general public. At the same time, the present study also provided an effective method to manage this type of adverse reaction to the COVID-19 vaccine.

Novel androgen receptor gene variant containing a frameshift mutation in a patient with complete androgen insensitivity syndrome.

A variety of mutations in the androgen receptor (AR) gene are linked to androgen insensitivity syndrome (AIS). AIS is the most common specific cause of 46, XY disorder in sex development. Here, we reported a patient which presented as a female with 46, XY karyotype and normal female external genitalia. The patient was diagnosed with complete AIS caused by a novel mutation (NM_000044, c.2678-2726del, p. Pro893Leufs*35) in the AR gene. Targeted exome sequencing was used to detect the patient's androgen receptor gene mutations. Sanger sequencing was used to validate the mutation. This study showed that a novel mutation of the AR gene can cause complete AIS; the study also broadened the AR mutation spectrum and indicated that targeted exome sequencing could help facilitate the diagnosis of complicated disorders in sexual development.

Surgical management and molecular diagnosis of persistent Müllerian duct syndrome in Chinese patients.

Persistent Müllerian duct syndrome (PMDS) is a rare clinically and genetically overlapping disorder caused by mutations in the anti-Müllerian hormone (AMH) gene or the anti-Müllerian hormone receptor type 2 (AMHR2) gene. Affected individuals present uterus and tubes in normally virilized males and are discovered unexpectedly during other surgeries. Since it is rare and complex, a definitive clinical diagnosis can be missed, and there are no guidelines regarding how to deal with the uterus. In the present study, exome sequencing and Sanger verification were performed for causal variants in 12 PMDS patients. Preoperative diagnoses were made by positive exome sequencing in 8 patients. Of them, 7 patients evoked on the basis of ultrasound indicating bilateral testes on the same side of the body. Twelve different AMH variants (2 frameshift/nonsense, 1 deletion, 8 missense, and 1 in-frame) in 9 patients and 6 different AMHR2 variants (5 missense and 1 splicing) in 3 patients were identified. Seven variants were classified as "pathogenic" or "likely pathogenic", and 4 of them were novel. All but two patients with AMH defects showed low serum AMH concentrations, but all patients with AMHR2 defects showed elevated AMH levels. During surgery, an abnormal vas deferens was observed in half of the patients. Eight patients underwent orchidopexy with uterine preservation. Of them, 2 patients presented complications including irreducible cryptorchidism, and 3 patients developed Müllerian remnant cysts. Three patients underwent subtotal hysterectomy. Of them, one patient had complication of injury to the vas deferens, and one had hemorrhage after operation. This is the first report of PMDS involving a large Chinese population. The present study not only expands the variation spectrum but also provides clinical experience about the management of the uterus.

[Research Status of New Targets MRD Detection in Acute Myeloid Leukemia Recurrence--Review].

Although most acute myeloid leukemia (AML) patients can achieve complete remission (CR) induced by standardized chemotherapy, but the relapse rate after remission remains high. The key reason is its high heterogeneity in cytogenetics and molecular biology. There are evidences show that minimal residual disease (MRD) is closely associated with disease recurrence, so that, finding specific genetic and molecular biological changes as new targets for MRD detection has become a research hotspot in recent years. In this review the intrinsic relationship between relapse of AML and MRD detection of specific molecular events, the application of these new targets in MRD detection and their targeted therapies according to the latest guidelines, so as to achieve the optimal treatment in CR phase.

MiR-155-5p promotes renal interstitial fibrosis in obstructive nephropathy via inhibiting SIRT1 signaling pathway.

Protection against renal fibrosis is important for the management of obstructive nephropathy. We researched the roles and possible mechanism of miR-155-5p in renal interstitial fibrosis, which may provide a potential endogenous target for renal interstitial fibrosis in obstructive nephropathy. Herein, NRK-49F cells were transfected with miR-155-5p mimic, miR-155-5p inhibitor, SIRT1 plasmid and/or SIRT1 siRNA. The unilateral ureteral obstruction (UUO) model was built with male C57 black mice and administrated with SRT1720 by tail vein injection. Levels of miR-155-5p, SIRT1 and relative proteins (TGF-ß1, α-SMA, Collage I and fibronectin) in NRK-49F cells or mice kidney tissues were measured with quantitative reverse transcription polymerase chain reaction or Western blot. The target gene of miR-155-5p was analyzed through TargetScan and dual-luciferase reporter assay. Mice kidney tissue was stained with Masson trichrome. It was found that miR-155-5p overexpression promoted the expressions of fibroblast related proteins expression and inhibited the SIRT1 expression in NRK-49F cells, while miR-155-5p silencing had an opposite effect. SIRT1 can bind with miR-155-5p. MiR-155-5p inhibited the level of SIRT1. Fibroblast related proteins were up-regulated by miR-155-5p and down-regulated by SIRT1 in NRK-49F cells, while the up-regulatory effect of miR-155-5p was reversed by SIRT1. MiR-155-5p expression was up-regulated and SIRT1 expression was down-regulated in the kidney tissue of UUO mice. SRT1720 attenuated the fiber deposition, up-regulated SIRT1 level and down-regulated the levels of fibroblast related proteins in UUO model mice. To conclude, miR-155-5p promotes renal interstitial fibrosis in obstructive nephropathy via inhibiting SIRT1 signaling pathway.

Identification of risk factors associated with numerous reoperations following primary hypospadias repair.

INTRODUCTION: Complications remain the top evaluation priority subsequent to hypospadias repair. Complications vary in further management, and usually require one or more reoperations. Patients and/or their parents concern not only with the success rate of reoperation, but also with the risk of numerous reoperations. OBJECTIVE: To identify the risk factors associated with numerous reoperations following primary hypospadias repair. STUDY DESIGN: Data were collected retrospectively from patients who underwent reoperations for complications following primary hypospadias repair at a single institution from August 2008 to October 2017. RESULTS: A total of 507 patients required reoperations following 2754 primary hypospadias repairs. Eventually, 486 patients were eligibly included with a median age of 2.2 years. The median follow-up period was 6.5 years. Preserved urethral plate urethroplasty for primary repair (including Snodgrass, Onlay and Mathieu techniques) was performed in 307 (63.2%) patients, Duckett technique was performed in 121 (24.9%) patients, and staged urethroplasty (including staged Duckett, Byars and Bracka techniques) was performed in 58 (11.9%) patients. The complications included 302 fistulas, 108 dehiscence, 50 urethral strictures, 18 meatal stenosis, 38 diverticula, 24 mild recurrent ventral curvature and 23 severe recurrent ventral curvature. A total of 363 (74.7%) patients needed 1 reoperation, 87 (17.9%) needed 2 reoperations, 19 (3.9%) needed 3 reoperations, and 17 (3.5%) needed >3 reoperations. Ordinal logistic regression demonstrated that severe recurrent ventral curvature, urethral stricture, dehiscence and primary staged hypospadias repair increased the risk of numerous reoperations, with odds ratios of 75.991-fold, 36.967-fold, 11.765-fold and 3.074-fold, respectively. In contrast, diverticulum decreased the risk, with an odds ratio of 0.443-fold. DISCUSSION: Our data demonstrated significant heterogeneity in the risk of numerous reoperations for each complication. Severe recurrent ventral curvature conferred the highest risk of numerous reoperations, followed by urethral stricture, dehiscence. In additional, our data showed an increased risk of numerous reoperations following primary staged repairs. Identification the risk factors confers advantages in the assessment of postoperative outcomes and anticipation of future reoperations. CONCLUSION: Severe recurrent ventral curvature, urethral stricture, dehiscence and primary staged hypospadias repair were associated with numerous reoperations following primary hypospadias repair.

Leukaemia cutis as a specific skin involvement in chronic myelomonocytic leukaemia and review of the literature: Acknowledgments.

The skin involvement of myeloid leukaemia is conventionally divided into specific malignant lesions and non-specific benign lesions, and these categories are also applicable in chronic myelomonocytic leukaemia (CMML). According to the 2016 World Health Organization (WHO) classification of tumours of haematopoietic and lymphoid tissues, CMML is defined as a myeloid neoplasm with characteristics of myelodysplastic syndrome (MDS) and myeloproliferative neoplasms (MPNs). As a specific cutaneous sign of extramedullary infiltration, leukaemia cutis (LC) is a rare occurrence in patients with CMML, and only approximately 89 cases have been reported in the literature thus far. The clinical features of LC are varied, and LC in CMML exhibits heterogeneous histopathologic features, with manifestations as cutaneous nodules or papules that are composed of blast cells showing either granulocytic or monocytic differentiation. Skin biopsy and further immunohistochemical examination are essential at the time of diagnosis to evaluate pathological type and determine the clinical course. Generally, once diagnosed as LC in CMML, this unusual skin lesion might be an indicator of transformation to acute myeloid leukaemia (AML) and is associated with a poor prognosis. The main treatment is allogeneic stem cell transplantation (ASCT). Therefore, early diagnosis and accurate identification have important therapeutic and prognostic significance in CMML patients with skin infiltration.

[Fetal anteroposterior renal pelvic diameter for predicting antenatal hydronephrosis requiring postnatal surgery].

OBJECTIVE: To assess the value of fetal anteroposterior renal pelvic diameter (APD) in predicting antenatal hydronephrosis requiring surgical treatment after birth. METHODS: A total of 525 cases of antenatal hydronephrosis detected by prenatal ultrasonography (ultrasound index APD ≥ 4 mm in the second trimester and APD ≥ 7 mm in the third trimester) in Zhejiang Prenatal Diagnosis Center from June 2007 to June 2018 were retrospectively analyzed. ROC curve was used to analyze the relationship between these ultrasound indicators and the requirement for surgical treatment after birth. RESULTS: There were 162 cases (30.9%) diagnosed in the second trimester and 363 cases (69.1%) diagnosed in the third trimester; 131 cases were diagnosed pathologically after birth, of which 121 finally underwent surgical treatment. The area under ROC curve (AUC) of APD in middle pregnancy for prediction of requiring surgery 1-12 years after birth was 0.910; the cut-off value of APD was 8.45 mm with a sensitivity of 97.1%, specificity of 70.9%, positive predictive value (PPV) of 47.9%, and negative predictive value (NPV) of 98.9%. The AUC of APD in late pregnancy for prediction of requiring surgery 1-12 years after birth was 0.800; the cut-off value of APD was 12.25 mm with a sensitivity of 66.7%, specificity of 81.2%, PPV of 51.7%, and NPV of 89.1%. CONCLUSIONS: APD in pregnancy can be used to predict whether the fetus with hydronephrosis needs surgical treatment after birth, and the prediction value of APD in the middle pregnancy is better.

Overexpression of OsHSP18.0-CI Enhances Resistance to Bacterial Leaf Streak in Rice.

BACKGROUND: The small heat shock proteins represent a large family of proteins that respond to a wide range of abiotic and biotic stresses. OsHsp18.0-CI confers tolerance to salt and cadmium and interacts with viral RNA-dependent RNA polymerase (RdRp). However, the direct function of OsHsp18.0-CI in resistance against biotic stresses remains unclear in rice. RESULTS: Here, we report that the expression of OsHsp18.0-CI was up-regulated upon inoculation with RS105, a strain of Xanthomonas oryzae pv. oryzicola (Xoc) that causes bacterial leaf streak in rice. In comparison with wild-type, OsHsp18.0-CI overexpression (OE) lines exhibited enhanced resistance to RS105, whereas repression lines exhibited compromised resistance to RS105. In addition, the transcriptional profiles of wild type and OE lines were compared with and without inoculation with RS105. After inoculation with RS105, most of the genes with up-regulated expression were commonly stimulated in the wild type and OE lines, with stronger induction in the OE lines than in wild type. CONCLUSION: Our study reveals that OsHsp18.0-CI positively regulates resistance to Xoc by mediating an enhanced version of the basal defense response in rice.

[Advances in the diagnosis and hormone replacement treatment of 46, XY disorders of sex development].

Disorders of sex development (DSD) is defined as a congenital condition or atypical development of the chromosomal, gonadal, or anatomic sex. The diagnosis, gender assignment, and treatment of DSD require the guidance from experienced multidisciplinary teams. So far there has been no consensus about it in China. Due to dysgenetic gonads, defects in sex steroid biosynthesis or action, or gonadectomy during the prepubertal years, those with DSD suffer from hypogonadism. The hormone replacement therapy of DSD aims at general physiological health and long-term prognosis as well as the avoidance of unnecessary genital and gonadal surgery. This review focuses on the advances in the studies of the diagnosis and hormone replacement therapy of 46,XY DSD.