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.

Comparison of effect between dartos fascia and tunica vaginalis fascia in TIP urethroplasty: a meta-analysis of comparative studies.

BACKGROUND: Tubularized incised plate (TIP) urethroplasty is the most commonly performed procedure for hypospadias. Several flap procedures have been recommended to decrease the postoperative complication rate in TIP repair, but no single flap procedure is ideal. This study aimed to compare the outcomes of dartos fascia (DF) and tunica vaginalis fascia (TVF) as intermediate layers in TIP urethroplasty. METHODS: We searched PubMed, EMBASE, the Cochrane Library, Web of Science, clinicaltrials.gov, and other sources for comparative studies up to April 16, 2020. Studies were selected by the predesigned inclusion criteria. The primary outcomes were postoperative complications. The secondary outcomes were functional and cosmetic outcomes. RESULTS: The pooled RR with 95% CI were calculated. We extracted the relevant information from the included studies. Only 6 comparative studies were included. No secondary outcomes were reported. The RR of the total complications rate for DF was 2.41 (95% CI 1.42-4.07, P = 0.0001) compared with TVF in TIP repair. For each postoperative complication, the RRs were 6.48 (2.20-19.12, P = 0.0007), 5.95 (1.13-31.30, P = 0.04), 0.62 (0.25-1.52, P = 0.29), and 0.75 (0.23-2.46, P = 0.64) for urethrocutaneous fistula, prepuce-related complications, meatal/urethral stenosis, and wound-related complications, respectively. CONCLUSIONS: This meta-analysis reveals that compared to DF, TVF is a better option in TIP repair in terms of decreasing the incidence of the total postoperative complications, urethrocutaneous fistula, and prepuce-related complications. However there is limited evidence for functional and cosmetic outcomes. Overall, larger prospective studies and long-term follow-up data are required to further demonstrate the superiority of TVF over DF. TRIAL REGISTRATION: PROSPERO CRD42019148554.

Diagnostic performance of convolutional neural network-based Tanner-Whitehouse 3 bone age assessment system.

BACKGROUND: Bone age can reflect the true growth and development status of a child; thus, it plays a critical role in evaluating growth and endocrine disorders. This study established and validated an optimized Tanner-Whitehouse 3 artificial intelligence (TW3-AI) bone age assessment (BAA) system based on a convolutional neural network (CNN). METHODS: A data set of 9,059 clinical radiographs of the left hand was obtained from the picture archives and communication systems (PACS) between January 2012 and December 2016. Among these, 8,005/9,059 (88%) samples were treated as the training set for model implementation, 804/9,059 (9%) samples as the validation set for parameters optimization, and the remaining 250/9,059 (3%) samples were used to verify the accuracy and reliability of the model compared to that of 4 experienced endocrinologists and 2 experienced radiologists. The overall variation of TW3-metacarpophalangeal, radius, ulna and short bones (RUS) and TW3-Carpal bone score, as well as each bone (13 RUS + 7 Carpal) between reviewers and the AI, were compared by Bland-Altman (BA) chart and Kappa test, respectively. Furthermore, the time consumption between the model and reviewers was also compared. RESULTS: The performance of TW3-AI model was highly consistent with the reviewers' overall estimation, and the root mean square (RMS) was 0.50 years. The accuracy of the BAA of the TW3-AI model was better than the estimate of the reviewers. Further analysis revealed that human interpretations of the male capitate, hamate, the first distal and fifth middle phalanx and female capitate, the trapezoid, and the third and fifth middle phalanx, were most inconsistent. The average image processing time was 1.5±0.2 s in the TW3-AI model, which was significantly shorter than manual interpretation. CONCLUSIONS: The diagnostic performance of CNN-based TW3 BAA was accurate and timesaving, and possesses better stability compared to diagnostics made by experienced experts.

Paediatric type 2 diabetes in China-Pandemic, progression, and potential solutions.

China is gradually taking its place as one of the world's economic giants and concurrently learning to cope with the burden of diseases that are more common in the developed world, such as paediatric type 2 diabetes mellitus. The prevalence of type 2 diabetes has been recently observed among children and adolescents in China; hence, there is a lack of information about the incidence, prevalence, pathogenesis, and pathophysiology of the disease. Diagnosis, treatment, and management have been standardized to a large degree, but there is still a need for data regarding optimal management protocols and how to achieve the best control over current state of the disease. The objective of this review is to consolidate the available information about paediatric diabetes, with a focus on the increasing prevalence of type 2 diabetes in Chinese youth. Here we emphasize the prevention strategies and have included literature with respect to pathogenesis, diagnosis, and treatment published in English and Chinese within the past 10 years.

[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.

[Effects of obesity on peak level of luteinizing hormone in gonadotropin-releasing hormone agonist test and obesity-related hormones in girls with central precocious puberty].

OBJECTIVE: To explore the effects of obesity on the peak level of luteinizing hormone (LH) in the gonadotropin-releasing hormone (GnRH) agonist test and obesity-related hormones in girls with central precocious puberty (CPP). METHODS: Three hundred and thirty-three girls with CPP who underwent the GnRH agonist test between 2012 and 2014 were classified into three groups: normal weight (n=123), overweight (n=108), and obesity (n=102), according to body mass index (BMI). The sexual development indices were compared between the three groups. Twenty girls were randomly selected from each group for evaluation of the serum levels of leptin, sex hormone binding globulin (SHBG), neurokinin B, and kisspeptin. The correlation of BMI with the levels of various hormones was assessed using Pearson correlation analysis. RESULTS: There was no significant difference in mean age at diagnosis between the three groups; however, the bone age was significantly higher in the overweight and obesity groups than in the normal weight group (P<0.05). The peak level of LH in the GnRH agonist test and SHBG level in the normal weight group were significantly higher than those in the overweight and the obesity groups, while the serum levels of leptin and neurokinin B were significantly lower in the normal weight group than in the overweight and the obesity groups (P<0.05). BMI was negatively correlated with the peak level of LH in the GnRH agonist test and SHBG level (P<0.05), and positively correlated with the levels of leptin and neurokinin B (P<0.05). CONCLUSIONS: The effects of BMI on the result of the GnRH agonist test and levels of obesity-related hormones should be taken into account in girls with precocious puberty.

Impact of BMI on gonadorelin-stimulated LH peak in premenarcheal girls with idiopathic central precocious puberty.

OBJECTIVE: To clarify the impact of body mass index (BMI) on luteinizing hormone (LH) secretion in response to gonadorelin (GnRH) stimulation testing in girls diagnosed with idiopathic central precocious puberty (ICPP). METHODS: Retrospective single-center cohort study was carried out in 865 confirmed ICPP girls who underwent GnRH stimulation tests. Pubertal development according to Tanner, sex hormone parameters, and LH secretion in response to GnRH-stimulation was compared. RESULTS: Around 609 girls were of normal weight (70.4%), while 168 children (19.4%) were overweight, and 88 (10.2%) were obese. Peak LH levels after GnRH were much higher in the normal-weight group, with a median of 9.1 mIU ml(-1) (interquartile 5.2-13.1), compared with the median peak LH in the overweight and obese groups (8.5 mIU ml(-1), interquartile 5.3-11.6, and 6.2 mIU ml(-1), interquartile 5.3-11.0, respectively P < 0.001 for all comparisons). Peak LH/FSH ratio was also lower in the obese group (median 0.6, interquartile 0.68-0.90) compared with the normal-weight (median 0.8, interquartile 0.61-1.11) and overweight (median 0.8, interquartile 0.64-0.92) groups. CONCLUSIONS: Higher BMI is associated with lower LH response to GnRH-stimulation testing in girls with ICPP. It is recommended that BMI should be considered when interpreting GnRH-stimulation tests.

Aberrant hepatic microRNA expression in nonalcoholic fatty liver disease.

BACKGROUND/AIM: Emerging evidence suggests that microRNA (miRNA) mediated gene regulation influences the maintenance of metabolic homeostasis, particularly the states of obesity and insulin resistance, thereby providing a potential link between miRNAs and nonalcoholic fatty liver disease (NAFLD). METHODS: Sprague-Dawley rats fed a high-fat diet (HFD) were used to establish a rat model of NAFLD. The miRNA expression profile of liver tissues was evaluated using Illumina HiSeq deep sequencing. Selected miRNAs were then validated by real-time PCR at both 4- and 12-week time points. Furthermore, the expression levels of these miRNAs were assessed in HepG2 cells and human hepatocytes treated with free fatty acids (FFAs) and proinflammatory factors (tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). RESULTS: Our results showed that consumption of a HFD for 4 weeks caused simple steatosis, which progressed to steatohepatitis at 12 weeks. miRNA deep sequencing analysis identified 44 known up-regulated miRNAs (fold change >1.5) and 12 down-regulated miRNAs (fold change <0.5). Among the abnormally expressed miRNAs, miR-200a, miR-200b, miR-200c, miR-146a, miR-146b and miR-152 were up-regulated both in vitro and vivo. Interestingly, the expression levels of these six miRNAs were increased in HepG2 cells and human hepatocytes after treatment with FFAs and proinflammatory factors. CONCLUSION: These findings suggest a critical role for miRNAs in the pathogenesis of NAFLD.

X-linked recessive combined pituitary hormone deficiency is mapped to Xp22.3-Xp11 in a Chinese family.

Genetic mutations have been identified in a modest proportion of patients with combined pituitary hormone deficiency (CPHD). We reported a 3-generation family consisting of 18 members, including 5 affected males (the proband, his 2 brothers, his cousin, and his maternal uncle; III1-III4, II8) suffered with CPHD. MRI of the pituitary gland showed hypoplasia of the pituitary gland in affected members. By 19 STR markers and linkage analysis, we found that the disease gene localized between the DXS987 and DXS1226 markers (LOD score=2.408, θ=0). All affected male patients inherited the same haplotype from the female carrier (I4). The proband's mother (II4) and her sister (II3, II6) were obligate female carriers. However, the unaffected males (II(7), II(9)) in the family did not have this haplotype. These observations confirm a new X-linked recessive inherited disease in a Chinese family with CPHD and the pathogenic gene is mapped to Xp22.1-Xp11.

WT1 mutation as a cause of 46 XY DSD and Wilm's tumour: a case report and literature review.

AIM: The Wilms' Tumour gene is thought to have tumour suppressor activity and to play an important role in nephrogenesis, genitourinary development, haematopoiesis and sex determination. WT1 mutations will impair gonadal and urinary tract development and have been demonstrated to cause syndromes of WAGR, Denys-Drash and Fraiser. METHODS: To elucidate the role of constitutional mutations of WT1, in the expression of the different clinical feature, we describe a 14-year-9-month nonmosaic XY sex-reversed woman with pure gonadal dysgenesis (46, XY karyotype, completely female external genitalia, normal Mullerian ducts, absence of Wolffian ducts, streak gonads) who had right kidney removed at 7 months of age because of Wilms' tumour and was diagnosed as secondary thrombocytopenia (Plt 60-80 × 10(9) /L) since she was 4 years old. We sequenced the genomic DNA of all the 10 exons of the WT1 in which mutations may occur in proposita. RESULTS: A new de novo insertion mutation in the first exon was found. A 'GCCGCCTCACTCC' is inserted between codon 138 and 139, resulting in the creation of a stop codon and a truncated protein. CONCLUSION: The present data provide further evidence to support the role of WT1 in diverse cellular functions.

[Clinical analysis of 13 cases with growth hormone deficiency combined with pituitary stalk interruption].

OBJECTIVE: To analyze the clinical characteristics of the patients with pituitary stalk interruption syndrome (PSIS), and to achieve better comprehension of this disease. METHOD: Data of 13 patients with PSIS were retrospectively analyzed for the clinical, laboratory and imaging features. RESULT: All the 13 patients (9 male, 4 female) had the chief complaint of growth retardation, 81.5 - 135.0 cm in body height, which were minus two standard deviations below the average of the normal children of same age and same sex. GH stimulated peak levels were all below 5 microg/L; Among them, one was accompanied by delayed sexual development, one by central diabetes insipidus, one was complicated with central hypothyroidism and one was accompanied by central adrenocortical hypofunction. CONCLUSION: The most remarkable clinical manifestations of patients with PSIS were growth retardation, partial or complete adenohypophyseal dysfunction. MRI revealed absence of pituitary stalk or anterior pituitary hypoplasia with ectopic posterior pituitary gland.

A rabbit model of pediatric nonalcoholic steatohepatitis: the role of adiponectin.

AIM: To create a rabbit model of pediatric nonalcoholic steatohepatitis (NASH) and to evaluate the role of adiponectin in the process. METHODS: Thirty-two specific pathogen-free male New Zealand rabbits were divided randomly into three groups: (1) the normal control group (n = 10) was fed with standard diet for 12 wk; (2) the model group A (n = 11); and (3) model group B (n = 11) were fed with a high-fat diet (standard diet + 10% lard + 2% cholesterol) for 8 and 12 wk, respectively. Hepatic histological changes were observed and biochemical parameters as well as serum levels of adiponectin, interleukin (IL)-6, IL-10 and tumor necrosis factor (TNF)-alpha were measured. RESULTS: Typical histological hepatic lesions of NASH were observed in both model groups described as liver steatosis, liver inflammatory infiltration, cytologic ballooning, perisinusoidal fibrosis and overall fibrosis. Compared with the normal control group, there were significant increases in model groups A and B in weight gain (1097.2 +/- 72.3, 1360.5 +/- 107.6 vs 928.0 +/- 58.1, P < 0.05, P < 0.01), liver weight (93.81 +/- 6.64, 104.6 +/- 4.42 vs 54.4 +/- 1.71, P < 0.01), Lg (ALT) (1.9 +/- 0.29, 1.84 +/- 0.28 vs 1.60 +/- 0.17, P < 0.01), and Lg (TG) (1.03 +/- 0.24, 1.16 +/- 0.33 vs 0.00 +/- 0.16, P < 0.01). Weight gain was much more in model group B than in model group A (1360.5 +/- 107.6 vs 1097.2 +/- 72.3, P < 0.05). But, there was no significant difference between the two groups concerning the other indexes. Pro-inflammatory cytokines (IL-6 and TNF-alpha) increased in model group B compared with that of control and model group A (IL-6: 1.86 +/- 0.21 vs 1.41 +/- 0.33, 1.38 +/- 0.42, P < 0.01; TNF-alpha: 1.18 +/- 0.07 vs 0.66 +/- 0.08, 0.86 +/- 0.43, P < 0.01, P < 0.05), whereas serum adiponectin and IL-10 decreased in model groups compared with that in the control (adiponectin: A: 21.87 +/- 4.84 and B: 21.48 +/- 4.60 vs 27.36 +/- 7.29, P < 0.05. IL-10: A: 1.72 +/- 0.38 and B: 1.83 +/- 0.39 vs 2.26 +/- 0.24, P < 0.01). Lg (TC) and the degree of liver fatty infiltration was an independent determinant of serum adiponectin level analyzed by stepwise multiple regressions, resulting in 29.4% of variances. CONCLUSION: This rabbit model produces the key features of pediatric NASH and may provide a realistic model for future studies. Adiponectin level partially reflects the severity of liver steatosis, but not the degree of liver inflammation.

Early activation of the inhibin B/FSH axis in obese Tanner stage G1PH1 boys.

OBJECTIVE: To determine whether early activation of the inhibin B/FSH axis is detectable in prepubertal obese boys. METHODS: Thirty-five simple obese Tanner stage G1PH1 boys with body mass index over 25 aged 8-11 years old and 25 age-matched nonobese healthy prepubertal boys (G1PH1) were clinically examined and testicular size measured by ultrasound. Serum inhibin B, testosterone, LH, FSH, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS) and bone age were measured. GnRH-stimulating tests were performed in the obese children and the relationships between inhibin B and bone age, testicular volume, DHEA, DHEAS, and stimulated peak LH, FSH and testosterone were analysed. RESULTS: The majority of basal LH and testosterone levels were undetectable in both groups of G1PH1 children and no difference was apparent between the groups. However, testicular volume (left 1.21 ml vs 0.83 ml, right 1.15 ml vs 0.81 ml), bone age, DHEA and DHEAS levels were significantly higher in obese children. Inhibin B was detectable in all children. Basal levels were significantly higher in obese children (103.3 ng/l vs 60.95 ng/l, P < 0.001) and correlated with testicular volume (left: rs = 0.655, right: rs = 0.638, P < 0.001) and bone age (rs = 0.554, P < 0.05). Basal FSH levels did not correlate with inhibin B. However, after GnRH stimulation, a clear negative correlation between peak FSH and basal inhibin B was apparent (rs = -0.583, P < 0.001) consistent with early activation of the inhibin B/FSH axis. CONCLUSIONS: Activation of the inhibin B/FSH axis is apparent in obese Tanner stage G1PH1 boys and appears to represent an early hormonal change of puberty in these individuals.

[Nonalcoholic steatohepatitis in obese children: the prevalence and possible mechanism].

OBJECTIVE: To investigate the prevalence of nonalcoholic steatohepatitis (NASH) in obese children and its possible mechanism. METHODS: Three subgroups were classified according to their body mass index (BMI) in 123 obese children with BMI over 23 aged 7 to 16:34 cases with BMI> or =31 group; 57 cases with 25< or =BMI<30 group; 32 cases with 23< or =BMI<25 group. Ultrasonographic and biochemical parameters including serum alanine aminotransferase (ALT), serum aspartate aminotransferase (AST), serum cholesterol, serum triglyceride, serum uric acid and free glucose to free insulin ratio (FGIR) were assayed. Twenty four children suspected as benign acanthosis nigricans underwent skin biopsy and its association with nonalcoholic steatohepatitis was also discussed. RESULTS: Ninety-nine children (80.49 %) showed abnormal hepatic sonograms and 54 were diagnosed as NASH with the prevalence of 43.90%. Compared with the other two groups, BMI> or =31 group was significantly higher in prevalence of abnormal hepatic sonograms, NASH, decreased FGIR and risk of benign acanthosis nigricans (P<0.01). Fifty-four children diagnosed as NASH showed significantly higher incidence of hyperlipidemia, insulin resistance and higher body mass index as compared with 24 subjects without fatty liver changes. In 54 NASH children, 20(37.04%) had benign acanthosis nigricans. By bivariate analysis, ALT and AST were correlated well with BMI, cholesterol, triglyceride and FGIR (r(s)=0.413, 0.290, 0.379, -0.477, P<0.01; r(s)=0.359, 0.349, 0.348, -0.369, P<0.01). CONCLUSION: There is a high prevalence of nonalcoholic steatohepatitis in simple obese children and high incidence of benign acanthosis nigricans in NASH subjects. BMI> or=30 is a high risk factor of being NASH. Severe disturbance of lipid metabolism and insulin resistance may be involved in the mechanism of NASH.

[Simplified gonadorelin stimulation test in diagnosis of precocious puberty].

OBJECTIVE: To assess the diagnostic value of the simplified gonadorelin stimulation test for precocious puberty. METHODS: Two hundred and ninety-two girls with signs of advanced breast development received the gonadorelin stimulation test. According to the result of gonadorelin stimulation test, the girls were divided into 3 groups: 151 with central precocious puberty (CPP),119 with premature thelarche (PT) and 22 with peripheral precocious puberty (PPP). RESULTS: LH or FSH levels at 15 min, 30 min, 60 min in PPP group were not significantly different (P>0.05). Those were significantly different in PT group (P<0.01). The highest levels of LH were at 30 min and the highest levels of FSH were at 60 min. LH or FSH levels at 15 min, 30 min, 60 min in CPP group were significantly different (P<0.01) with the highest levels at 30 min. The ratio of basal LH and FSH >0.2 had a diagnostic sensitivity of 48.3 % and specificity of 69.7%. Taking the LH/FSH ratio >0.9 at 15 min, 30 min, 60 min as cut-off value, the diagnostic sensitivity was 80.1%, 68.9% and 38.4%, and the specificity was 90.8%, 96.6% and 69.7%, respectively. CONCLUSION: The LH/FSH ratio>0.9 at 15 min after gonadorelin stimulation test can be used as a cut-off value to differentiate CPP from PT and blood sample at 60 min were not necessary.