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Background. Idiopathic hypogonadotropin hypogonadism (IHH) is caused by hypothalamic-pituitary-gonadal axis dysfunction. This is divided into Kallmann syndrome which has an impaired sense of smell and hypogonadotropin hypogonadism with normal olfactory (nIHH sense. Approximately 60% of patients are associated with Kallmann syndrome, whereas there are approximately 40% with hypogonadotropin hypogonadism (nIHH). This disease is associated with various variants in genes along with different phenotypic characteristics, and even those gene variations could also lead to the cancer formation in patients. So, current study has been designed to investigate and to better understand the characteristics of various IHH-associated genes and the correlation between IHH genes and phenotype. Methods. The cohort included 14 children with IHH (6 patients of KS and 8 patients of IHH), including 13 boys and 1 girl. Exclusion criteria are as follows: diagnosis of secondary hypogonadotropin hypogonadism due to tumor, trauma, drugs, or other systemic diseases. Clinical data and genetic results were analyzed. Results. Almost all male patients showed micropenis (12/13, 92.3%), and few of them had cryptorchidism (5/13, 41.7%). A total of 6 genes, CHD7, PROKR2, ANOS1, FGFR1, SEMA3A, and NDNF, were detected. CHD7 was the most common (11/17, 64.7%), and the main mutation type was missense mutation (14/16, 87.5%). Six reported variants and 10 new variants (5 genes, including entire ANSO1 duplicates) were found. Neonatal variation was detected in 3 patients with IHH. Eight patients inherited the variation from their father, while five patients inherited it from their mother. One patient had both FGFR1 and SEMA3A gene variants, while the other had two different CHD7 gene variants and entire ANSO1 repeats. According to ACMG criteria, 4 variants were pathogenic (P), 2 were possibly pathogenic (LP), and 8 had uncertain significance (US). In patients with P or LP (5/6, 83.3%), we found that extragonadal symptoms were more common. Conclusions. It was concluded that variations in the studied genes could lead to the IHH. Ten new variants have been reported which may lead to different symptoms of IHH. For CHD7 variants, the rare sequencing variants (RSVs) of P or LP showed commonly associated with CHARGE syndrome. Findings of the current study may help for the better diagnosis and treatment of IHH.

Prader-Willi syndrome (PWS) is a rare genetic imprinting disorder resulting from the expression loss of genes on the paternally inherited chromosome 15q11-13. Early-onset life-thriving obesity and hyperphagia represent the clinical hallmarks of PWS. The noncoding RNA gene SNORD116 within the minimal PWS genetic lesion plays a critical role in the pathogenesis of the syndrome. Despite advancements in understanding the genetic basis for PWS, the pathophysiology of obesity development in PWS remains largely uncharacterized. Here, we aimed to investigate the signatures of adipose tissue development and expansion pathways and associated adipose biology in PWS children without obesity-onset at an early stage, mainly from the perspective of the adipogenesis process, and further elucidate the underlying molecular mechanisms.We collected inguinal (subcutaneous) white adipose tissues (ingWATs) from phase 1 PWS and healthy children with normal weight aged from 6 M to 2 Y. Adipose morphology and histological characteristics were assessed. Primary adipose stromal vascular fractions (SVFs) were isolated, cultured in vitro, and used to determine the capacity and function of white and beige adipogenic differentiation. High-throughput RNA-sequencing (RNA-seq) was performed in adipose-derived mesenchymal stem cells (AdMSCs) to analyze transcriptome signatures in PWS subjects. Transient repression of SNORD116 was conducted to evaluate its functional relevance in adipogenesis. The changes in alternative pre-mRNA splicing were investigated in PWS and SNORD116 deficient cells.In phase 1 PWS children, impaired white adipose tissue (WAT) development and unusual fat expansion occurred long before obesity onset, which was characterized by the massive enlargement of adipocytes accompanied by increased apoptosis. White and beige adipogenesis programs were impaired and differentiated adipocyte functions were disturbed in PWS-derived SVFs, despite increased proliferation capacity, which were consistent with the results of RNA-seq analysis of PWS AdMSCs. We also experimentally validated disrupted beige adipogenesis in adipocytes with transient SNORD116 downregulation. The transcript and protein levels of PPARγ, the adipogenesis master regulator, were significantly lower in PWS than in control AdMSCs as well as in SNORD116 deficient AdMSCs/adipocytes than in scramble (Scr) cells, resulting in the inhibited adipogenic program. Additionally, through RNA-seq, we observed aberrant transcriptome-wide alterations in alternative RNA splicing patterns in PWS cells mediated by SNORD116 loss and specifically identified a changed PRDM16 gene splicing profile in vitro.Imbalance in the WAT expansion pathway and developmental disruption are primary defects in PWS displaying aberrant adipocyte hypertrophy and impaired adipogenesis process, in which SNORD116 deficiency plays a part. Our findings suggest that dysregulated adiposity specificity existing at an early phase is a potential pathological mechanism exacerbating hyperphagic obesity onset in PWS. This mechanistic evidence on adipose biology in young PWS patients expands knowledge regarding the pathogenesis of PWS obesity and may aid in developing a new therapeutic strategy targeting disturbed adipogenesis and driving AT plasticity to combat abnormal adiposity and associated metabolic disorders for PWS patients.

Prader-Willi syndrome (PWS) is the most common genetic disease causing childhood morbid obesity. Early diagnosis and treatment are utmost important for improving prognosis and bettering outcome in ...

Background Prader-Willi syndrome (PWS) is a rare and complex genetic disorder caused by lacking expression of imprinted genes on the paternally derived chromosome 15q11-q13 region. This study aimed to characterize the perinatal features of 134 Chinese individuals with PWS. Methods This study included the patients of a PWS registry in China. Anonymous data of 134 patients were abstracted. Perinatal and neonatal presentations were analyzed, and compared between the two PWS genetic subtypes. We also compared the perinatal features of PWS patients with the general population and other previous reported large cohorts from France, UK and USA. Results This study included 134 patients with PWS (115 patients with 15q11-q13 deletion and 19 with maternal uniparental disomy). Higher mean maternal age was found in this cohort (30.5 vs. 26.7), particularly in the maternal uniparental disomy (UPD) group (36.0 vs. 26.7) comparing with the general population. 88.6% of mothers reported a decrease of fetal movements. 42.5 and 18.7% of mothers had polyhydramnios and oligohydramnios during pregnancy, respectively. 82.8% of the patients were born by caesarean section. 32.1% of neonates had birth asphyxia, 98.5% had hypotonia and 97.8% had weak cry or even no cry at neonatal period. Feeding difficulty existed in 99.3% of the infants, 94.8% of whom had failure to thrive. 69.4% of the infants ever used feeding tube during hospitalization, however, 97.8% of them discontinued tube feeding after discharge. Maternal age and pre-pregnancy weight were significantly higher in the UPD group (both P Conclusions Differential diagnosis of PWS should be highlighted if infants having following perinatal factors including polyhydramnios, decreased intrauterine fetal movements, caesarean section, low birth weight, feeding difficulty, hypotonia and failure to thrive. Higher maternal age may be a risk factor of PWS, especially for UPD. Further studies are needed for elucidating the mechanism of PWS.

Angelman syndrome (AS) is a rare neurodevelopmental disease that is caused by the loss of function of the maternal copy of ubiquitin–protein ligase E3A (UBE3A) on the chromosome 15q11–13 region. AS is characterized by global developmental delay, severe intellectual disability, lack of speech, happy disposition, ataxia, epilepsy, and distinct behavioral profile. There are four molecular mechanisms of etiology: maternal deletion of chromosome 15q11–q13, paternal uniparental disomy of chromosome 15q11–q13, imprinting defects, and maternally inherited UBE3A mutations. Different genetic types may show different phenotypes in performance, seizure, behavior, sleep, and other aspects. AS caused by maternal deletion of 15q11–13 appears to have worse development, cognitive skills, albinism, ataxia, and more autistic features than those of other genotypes. Children with a UBE3A mutation have less severe phenotypes and a nearly normal development quotient. In this review, we proposed to review genotype–phenotype correlations based on different genotypes. Understanding the pathophysiology of the different genotypes and the genotype–phenotype correlations will offer an opportunity for individualized treatment and genetic counseling. Genotype–phenotype correlations based on larger data should be carried out for identifying new treatment modalities.

Supplemental Digital Content is available in the text, To investigate the molecular mechanisms of later metabolic health changes in large for gestational age (LGA) newborns by analyzing deoxyribonucleic acid (DNA) methylation patterns in the placenta of LGA and appropriate for gestational age (AGA) newborns. A total of 6 placentas of LGA and 6 placentas of AGA newborns were enrolled as LGA group and AGA group. DNA methylation was analyzed using the Illumina Infinium Human MethylationEPIC BeadChip microarrays and verified via pyrosequencing and reverse transcription-quantitative real-time polymerase chain reaction. Functional enrichment analysis were constructed by gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis based on the differentially methylated regions between LGA and AGA groups. Clinical investigation showed that LGA newborns had significantly lower hemoglobin and blood glucose compared to AGA newborns. Birth weight was negatively correlated to hemoglobin and blood glucose. Genome-wide DNA methylation analysis identified 17 244 methylation variable positions achieving genome-wide significance (adjusted P

Introduction: Prader-Willi syndrome (PWS) is an epigenetic disease. Cerebellar ataxia, mental retardation, and disequilibrium syndrome type 4 (CAMRQ4) is a genetic disorder caused by ATP8A2 gene mutation. AKAP10 gene is related to autosomal dominant cardiac conduction defect and cardiac susceptibility. Here, we report a PWS infant with ATP8A2 and AKAP10 mutations, who presented multiple dysmorphic features and review correlative literature. Case Presentation: A 3-month-old boy presented to our unit because of developmental delay after birth. He had a poor response, feeble cry, hypotonia of extremities, empty scrotum, and characteristic facial features. The whole-exome sequencing showed c.187C>G (p.P63A) in exon 2 originated from his father and c.2138T>C (p.I713T) in exon 23 originated from his mother, which were compound heterozygous variants of the ATP8A2 gene. A c.43delC heterozygous variant in exon 1 of the AKAP10 gene was also detected. Genetic analysis revealed normal copy numbers but abnormal methylation in the 15q11-13 region, which implied nondeletion type PWS. Conclusions: In patients with dysmorphic facial features, hypotonia and developmental delay, PWS should be considered in the differential diagnosis. Moreover, other complicated hereditary diseases should be considered in patients with PWS.

BackgroundPrader-Willi syndrome (PWS) is a rare complex genetic disorder caused by an absence of expression of imprinted genes on the paternally derived chromosome 15q11-q13 region. This study aimed to characterize the perinatal features in a cohort of Chinese individuals with PWS.MethodsWe analyzed anonymous data of 134 patients from the PWS Registry in China. Perinatal and neonatal presentations were analyzed, and compared between the two PWS genetic subtypes. We also compared the perinatal features of PWS patients with the general population and other previous reported large cohorts from France, UK and USA.ResultsThis study included 134 patients with PWS (115 patients with 15q11-q13 deletion and 19 with maternal UPD). High mean maternal age was found in this cohort (30.5 vs. 26.7) comparing with the general population. 88.6% of mothers reported a decrease of fetal movements. 42.5% and 18.7% of mothers had polyhydramnios and oligohydramnios during pregnancy, respectively. 82.8% of the patients were born by caesarean section. 32.1% of neonates had birth asphyxia, 98.5% had hypotonia and 97.8% had weak cry or even no cry at neonatal period. Feeding difficulty existed in 99.3% of the infants, and 94.8% of them had failure to thrive. 69.4% of the infants ever used feeding tube during hospitalization. However, 97.8% of them discontinued tube feeding after discharged home. Maternal age, maternal pre-pregnancy weight and BMI were significantly higher in the UPD group (all PConclusionsPWS should be highlighted for differential diagnosis for infants with following perinatal factors including polyhydramnios, intrauterine decreased fetal movements, cesarean section, low birth weight, feeding difficulty, hypotonia, and failure to thrive. Higher maternal age may be a risk factor for PWS, especially for UPD, and further studies for the mechanism of PWS are required.Author SummaryEarly diagnosis and tailored multidisciplinary treatment are utmost important for better quality of life of the infants with Prader-willi syndrome. Genetic diagnosis for PWS is now easily available; and diagnosis can be made in most patients within the first months of life even prenatally if obstetricians or neonatologists can recognize the perinatal features of PWS well. However, most patients still had a late diagnosis because the early signs of PWS not recognized. Our study highlighted the perinatal features of a large cohort of Chinese patients with PWS, which will benefit for early diagnosis and treatment. We found high incidence of decreased fetal movements, polyhydramnios and delivery by cesarean section, and higher maternal age comparing with the general population. Neonatal features found in our cohort included low birth weight, birth asphyxia, failure to thrive, feeding difficulty, weak cry and hypotonia. We found mothers with UPD had higher maternal age, pre-pregnancy weight and BMI. Most patients required tube feeding during hospitalization, however tube feeding was discontinued by their parents after discharge at home. Nutrition deficiency was a serious problem in infants with PWS. Home tube-feeding instruction should be carried out for parents of PWS patients in China.

Cell-cell fusion of human villous trophoblasts, referred to as a process of syncytialization, acts as a prerequisite for the proper development and functional maintenance of the human placenta. Given the fact that the main components of the Hedgehog signaling pathway are expressed predominantly in the syncytial layer of human placental villi, in this study, we investigated the potential roles and underlying mechanisms of Hedgehog signaling in trophoblastic fusion. Activation of Hedgehog signaling by a variety of approaches robustly induced cell fusion and the expression of syncytial markers, whereas suppression of Hedgehog signaling significantly attenuated cell fusion and the expression of syncytial markers in both human primary cytotrophoblasts and trophoblast-like BeWo cells. Moreover, among glioma-associated oncogene (GLI) family transcriptional factors in Hedgehog signaling, knockdown of GLI2 but not GLI1 and GLI3 significantly attenuated Hedgehog-induced cell fusion, whereas overexpression of the GLI2 activator alone was sufficient to induce cell fusion. Finally, GLI2 not only stabilized glial cell missing-a, a pivotal transcriptional factor for trophoblastic syncytialization, but also formed a transcriptional heterodimer with glial cell missing-a to transactivate syncytin-1, a trophoblastic fusogen, and promote trophoblastic syncytialization. Taken together, this study uncovered a so far uncharacterized role of Hedgehog/GLI2 signaling in trophoblastic fusion, implicating that Hedgehog signaling, through GLI2, could be required for human placental development and pregnancy maintenance.

Rationale Schaaf-Yang syndrome, a rare imprinted hereditary disease caused by MAGEL2 variants, manifests as developmental delay/intellectual disability, neonatal hypotonia, feeding difficulties, contractures, and autism spectrum disorder. Patient concerns Patient 1 and 2 were infant girls presenting facial dysmorphisms, contractures of interphalangeal joints, neonatal hypotonia, feeding difficulties, congenital heart diseases, and respiratory complications. Besides, Patient 2 presented with delayed psychomotor development. Diagnosis Whole-exome sequencing was performed and heterozygous mutations of the MAGEL2 gene were detected in the patients. They were diagnosed as Schaaf-Yang syndrome. Interventions The patients received supportive treatment including mechanical ventilation, parenteral nutrition and gastric tube feeding. Outcomes Whole-exome sequencing revealed de novo heterozygous c.1996dupC pathogenic mutations in the MAGEL2 gene in the 2 patients. They died due to respiratory failure at the age of 20 days and 98 days, respectively. Lessons Our results indicate that MAGEL2 variants can cause congenital heart disease and fatal respiratory complications, broadening the phenotypic spectrum and adding to the fatal cases of Schaaf-Yang syndrome. We highly suggest that the MAGEL2 gene should be added to gene-panels or gene-filters in next-generation sequencing-based diagnostics, which is of great significance for early diagnosis and early intervention of Schaaf-Yang syndrome patients.

Antenatal overexposure to glucocorticoids causes fetal intrauterine growth restriction (IUGR) and adult metabolic disorders. 11β-hydroxysteroid dehydrogenase (11β-HSD) 1 and 2 are key enzymes for glucocorticoid metabolism, however, the detailed effects of antenatal overexposure to glucocorticoids on placental 11β-HSD1 and 2 expression and adult metabolic disorders remain obscure. Here, we report that, in placenta 11β-HSD1 is diffusely localized, whereas 11β-HSD2 is specifically expressed in labyrinthine layer. Exposure of pregnant dams to betamethasone significantly increases the expression of placental 11β-HSD2 but not 11β-HSD1, and decreases the weights of fetuses but not placentas. Antenatal exposure to betamethasone leads to either significant weight loss in the offspring younger than 10-week-old, or weight gain in those older than 14-week-old. Furthermore, antenatal exposure to betamethasone results in coexistence of various metabolic disorders in adult offspring, including hyperglycemia, glucose intolerance, low insulin secretory capacity and hyperlipidemia. The present study demonstrates that exposure of pregnant dams to betamethasone induces the expression of placental 11β-HSD2 but not 11β-HSD1, leads to fetal IUGR and causes adult metabolic disorders, providing evidence for fetal origins of adult diseases and the potential role of placental 11β-HSD2 in them.

The aim of the study was to investigate the molecular mechanisms in childhood adrenocortical tumors (ACTs), which is still unclear. A total of 9 girls and 4 boys with ACTs were enrolled. Relevant clinical features were obtained from records. Immunohistochemistry of vimentin, chromogranin A, S100, synaptophysin, cytokeratin (CK), type 2 3β-hydroxysteroid dehydrogenase (3βHSD), cytochrome P45017α, p53, p21, p27, cyclin D1, Ki-67, insulin growth facter-2 (IGF-2), and β-catenin were undertaken for 13 tumors and 3 adjacent normal tissues. TP53 mutations in exon 2-11 were analyzed for 6 tumors and 3 blood samples. Virilization was the most common presentation (8/13, 61.5%). Immunohistochemically, p53 was positive in 8 of 13 ACTs and none in controls while p21 was positive in 12 of 13 ACTs and none in controls (P = .0036). Ki-67 was positive in 10 of 13 ACTs, but not in normal tissues (P = .0089). Although the expression of p27, cyclin D1, IGF-2 and β-catenin were similar between the ACTs and controls, β-catenin was noted in nuclear of 3 ACTs but not in controls. The difference of type 2 3βHSD and P450c17α was not significant (P > .05, respectively). Four variants of TP53 were identified in the 6 tumors. C215G variant was found in 5 of 6 while A701G and G743A variants were found in 1 case, respectively. A novel C680G variant was also noted in 1 case. It was notable that C215G variant was found in the blood mononuclear cell of 3 patients. In conclusion, p53 variant and p21 overexpression, and abnormal β-catenin distribution may be involved in the etiology and mechanism of childhood ACTs.

Rationale:Sitosterolemia is a rare autosomal recessive disorder of dyslipidemia due to mutations of genes ABCG5 and ABCG8, leading to highly elevated plasma levels of plant sterols and expanded body pools of cholesterol.Patient concerns:We present a 9-year-old and a 7-year-old Chinese boy wi

Background Epithelial to mesenchymal transition (EMT) is critical for human placental development, trophoblastic differentiation, and pregnancy-associated diseases. Here, we investigated the effects of hedgehog (HH) signaling on EMT in human trophoblasts, and further explored the underlying mechanism. Methods Human primary cytotrophoblasts and trophoblast-like JEG-3 cells were used as in vitro models. Quantitative real-time RT-PCR and Western blot analysis were performed to examine mRNA and protein levels, respectively. Lentiviruses expressing short hairpin RNA were used to knock down the target genes. Reporter assays and chromatin immunoprecipitation were performed to determine the transactivity. Cell migration, invasion and colony formation were accessed by wound healing, Matrigel-coated transwell, and colony formation assays, respectively. Results Activation of HH signaling induced the transdifferentiation of cytotrophoblasts and trophoblast-like JEG-3 cells from epithelial to mesenchymal phenotypes, exhibiting the decreases in E-Cadherin expression as well as the increases in vimentin expression, invasion, migration and colony formation. Knockdown of GLI1 and GLI2 but not GLI3 attenuated HH-induced transdifferentiation, whereas GLI1 was responsible for the expression of HH-induced key EMT regulators including Snail1, Slug, and Twist, and both GLI1 and GLI2 acted directly as transcriptional repressor of CDH1 gene encoding E-Cadherin. Conclusion HH through GLI1 and GLI2 acts as critical signals in supporting the physiological function of mature placenta. General significance HH signaling through GLI1 and GLI2 could be required for the maintenance of human pregnancy.

Aim: The purpose of this study was to evaluate the association between the methylenetetrahydrofolate reductase (MTHFR) C/T polymorphism and the prevalence and course of focal segmental glomerulosclerosis (FSGS) in our pediatric population. Methods: Genotypes for MTHFR were determined in 15 primary FSGS patients (male/female, 6/9) and 238 control subjects (male/female, 110/128) by the polymerase chain reaction and restriction fragment length polymorphism method. Results: For the whole group, the genotype frequencies (CC/CT/TT) of MTHFR in FSGS and control subjects were almost comparable. The TT genotype was associated with early onset of the disease as compared with the CC genotype. Furthermore, all the patients with the TT genotype had steroid-resistant FSGS and developed into end-stage renal failure, while those carrying either CC or CT genotype did not. Conclusion: We speculate that the TT genotype may be associated with early development and progression of childhood FSGS. Confirmatory studies using larger and ethnically distinct populations are needed to reveal the role of homocysteine in FSGS with consideration of medical interventions.

The expression of iNOS mRNA and protein levels was studied in hypothyroid rat cerebral cortex during early days after postnatal life.The homogenate of the cerebral cortex was examined using Real-time reverse transcription polymerase chain reaction (real-time RT PCR) and Western blot analysis.ΔCt in hypothyroid group on day 7, 14, 21 was 18.89±0.92, 18.83±0.99, 16.48±0.29, separately. While in control group, ΔCt was 20.32±0.92, 20.07±0.86, 17.96±0.50, separately. Meanwhile, the protein level was detected only in hypothyroid group of 59 ± 5% on day 14. On day 21, iNOS protein expression showed a decrease (p0.05) in hypothyroid group (37 ± 3%), compared with control group (58 ± 4%).Our findings show the successive changes of the iNOS mRNA and protein levels in early postnatal days of hypothyroid rat brain, and confirm the cross-talk between the TH and NO signaling pathway in developing cerebral cortex of rats.

To investigate the role of serum interleukin (IL-18) in children with type 1 diabetes mellitus (T1DM) and diabetic ketoacidosis (DKA).Case-control study.Sixty-one children with T1DM including 28 with DKA and 33 without DKA and 30 age - and sex-matched healthy controls were recruited.Serum IL-18, IL-12, and IFN-gamma levels were measured in all subjects by enzyme linked immunosorbent assay.Serum IL-18 levels were significantly higher in patients with DKA than those in patients without DKA (759.2 +/- 353.8 pg/mL vs. 634.9 +/- 399.7 pg/mL, P = 0.001) and healthy controls (310.0 +/- 265.3 pg/mL). The serum IL-12 and IFN-gamma levels were not different between patients and controls (277.5 +/- 207 pg/mL vs. 351.4 +/- 223.4 pg/mL, P = 0.45 and 7.02 +/- 7.53 pg/mL vs. 5.59 +/- 5.34 pg/mL, P = 0.21, respectively).Serum IL-18 levels are increased in children with type 1 diabetes mellitus and could be a predictor of diabetic ketoacidosis.

This study aimed to investigate the detection rate of chromosome abnormalities in children suspected with congenital disorders in 1 single center, identify any differences according to different classification criteria, and try to enlighten the medical professionals what clinical features should be transferred for cytogenetic analysis. From January 1, 2011 to March 31, 2014, children who were suspected with chromosomal disorders were included. All the cytogenetic analyses were performed in the Medical Biology and Genetic Department Laboratory in Zhejiang DIAN Diagnostics. We evaluated the variants of clinical indications, and incidence and types of chromosomal abnormalities among groups. During the study period, 4129 samples were collected and analyzed. Among them, 769 children were detected with chromosome abnormalities, accounting for 18.62% of all referral cases. The ratio of sex-linked chromosomal abnormalities to autosomal ones was 1:3.2. The detection rates were 19.66% (365/1857) for boys and 17.78% (404/2272) for girls. Most of trisomy 21 were found before the age of 1 year old, while most of children with Turner syndrome were found after 6 years old. The group presenting with specific clinical stigmata had highest detection rate of 59.1%. We demonstrated the detection rates of chromosome abnormalities in children who were suspected with chromosomal disorders. Combined with previous report, we established a database of common chromosomal anomalies and the clinical features that could be useful for genetic counseling and remind the medical professionals what kind of patients should be transferred to genetic analysis.

Sonic hedgehog (Shh) functions as a conserved morphogen in the development of various organs in metazoans ranging from Drosophila to humans. Here, we have investigated the potential roles and underlying mechanisms of Shh signaling in murine placentation. Immunostaining revealed the abundant expression of the main components of Shh pathway in both the trophectoderm of blastocysts and developing placentas. Disruption of Shh led to impaired vascularogenesis of yolk sac, less branching and malformation of placental labyrinth, thereby leading to a robust decrease in capacity of transplacental passages. Moreover, placenta-specific gene incorporation by lentiviral transduction of mouse blastocysts and blastocyst transplantation robustly knocked down the expression of Gli3 and Gli2 in placenta but not in embryos. Finally, Gli3 knockdown in Shh−/− placentas partially rescued the defects of both yolk sac and placental labyrinth, and robustly restored the capacity of transplacental passages. Gli2 knockdown in Shh+/− placentas affected neither the capacity of tranplacental passages nor the vascularogenesis of yolk sac, however, it partially phenocopied the labyrinthine defects of Shh−/− placentas. Taken together, these results uncover that both Shh/Gli2 and Shh/Gli3 signals are required for proper development of murine placentas and are possibly essential for pregnant maintenance.

Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near complete absence of adipose tissue since birth and insulin resistance. The diagnosis is made on the basis of lack of body fat, muscular hypertrophy, acanthosis nigricans, hirsutism, hepatomegaly with fatty liver, hyperlipidemia and hyperglycemia with insulin resistance. We describe a 4-year-old Chinese girl with the clinical features of CGL.

To determine whether lead affects brainstem auditory evoked potentials (BAEPs) in low-to-moderate lead exposed children.BAEPs were recorded from 114 asymptomatic children aged 1 - 6 years. Average values were calculated for peak latency (PL) and amplitude (Amp). Whole blood lead (PbB) levels were assessed by graphite furnace atomic absorption spectroscopy. Based on their PbB levels, subjects were divided into low lead (PbB100 micro g/L) and high lead subgroups (PbBor = 100 micro g/L).The PbB levels of the 114 subjects ranged from 32.0 to 380.0 micro g/L in a positively skewed distribution. The median of PbB levels was 90.0 micro g/L while the arithmetic average was 88.0 micro g/L. Of the subjects, 43.0% (49/114) had levels equal to or greater than 100 micro g/L. Bilateral PLs I, V, and III of the left ear in the high lead subgroup were significantly longer than those in the low lead subgroup (P0.05). A positive correlation was found between PbB levels and bilateral PLs I, V and III of the left ear (P0.05), after controlling for age and gender as confounding factors. A significant and positive correlation between PbB levels and PL I of the left ear, even when PbB levels were lower than 100 micro g/L, in the low subgroup (r = 0.295, P = 0.019) was also found.Lead poisoning in children younger than 6 years old is a very serious problem to which close attention should be paid. The indications that lead prolongs partial PLs may imply that lead, even at PbB levels lower than 100 micro g/L, impairs both the peripheral and the central portions of the auditory system. BAEPs may be a sensitive detector of subclinical lead exposure effects on the nervous system in children.