A Gender-, Age-, and Weight Status-Specific Analysis of the High Prevalence of Hyperuricemia Among Chinese Children and Adolescents with Obesity.

Objective: To explore the gender-, age-, and weight status-specific prevalence of hyperuricemia (HUA) and its associated risk factors among Chinese children and adolescents with obesity. Methods: A total of 1329 children aged 2-17 years, who were diagnosed with obesity and hospitalized in our center from January 2016 to December 2022 were recruited. They were divided into mild obesity, moderate obesity, and severe obesity groups. HUA was defined as fasting serum uric acid level >420 µmol/L for boys and >360 µmol/L for girls. Multivariate logistic regression analyses were performed to identify risk factors for HUA. Results: The highest proportion of hospitalized obese children was aged 10-13 years comprising 677 (50.9%) followed by those aged 6-9 years comprising 348 (26.2%) whereas the least proportion was aged 2-5 years comprising 76 (5.7%). The above differences in age distribution were still present in subgroup analyses according to weight status. Most hospitalized obese children were boys (64.7%), especially in the severe obesity group (75.0%). The overall estimated prevalence of HUA in obese children was 54.8%. It presented a gradual increase trend over the last 7 years, with more rapidly in boys than in girls. Subgroup analysis by weight status showed that the prevalence of HUA was higher in children with moderate obesity (64.3%) and severe obesity (64.2%) when compared with mild obesity (48.2%) (P all<0.01). Boys reached a relatively high HUA incidence level (≥60%) at age 12, which occurred about 2 years later than in girls (age 10). With 12 years as the cut-off point, a high prevalence of HUA (≥60%) was observed in both genders. Multivariable logistic regression analyses showed that boy (OR=2.844, 95% CI 2.024-3.998), age (OR=1.253, 95% CI 1.155-1.360), BMI-Z score (OR=2.132, 95% CI 1.438-3.162), fasting blood glucose (OR=0.907, 95% CI 0.860-0.956), phosphorus (OR=4.123, 95% CI 2.349-7.239), alkaline phosphatase (OR=1.002, 95% CI 1.001-1.004), creatinine (OR=1.067, 95% CI 1.037-1.098), urea nitrogen (OR=1.193, 95% CI 1.032-1.378), aspartate aminotransferase (OR=1.016, 95% CI 1.002-1.030), triglycerides (OR=1.339, 95% CI 1.075-1.667), and high-density lipoprotein cholesterol (OR=0.381, 95% CI 0.160-0.910) were independently associated with odds of HUA (P all<0.05). Conclusion: The prevalence of HUA in Chinese obese children and adolescents is unexpectedly high. Childhood HUA was significantly associated with obesity. Gender and age differences were observed in the association between childhood obesity and HUA. Obese children aged ≥12 years should be focused on screening the risk of HUA.

Altered gut microbiota and its metabolites correlate with plasma cytokines in schizophrenia inpatients with aggression.

BACKGROUND: The pathophysiological mechanisms of aggression are manifold and they may closely interconnect. Current study aimed to determine the gut microbiota and its metabolites, and clarify their correlations with inflammation, oxidation, leaky gut and clinical profiles underlying aggression in schizophrenia (ScZ). METHODS: Serum and stool specimens from ScZ inpatients with (ScZ-Ag, 25 cases) and without aggression (NScZ-Ag, 25 cases) were collected. Systemic inflammation, oxidation and leaky gut biomarkers were determined by ELISA, gut microbiota by 16S rRNA sequencing, short-chain fatty acids (SCFAs) by gas chromatography-mass spectrometry analysis and neurotransmitters by liquid chromatograph mass spectrometry analysis. RESULTS: Significantly higher systemic pro-inflammation, pro-oxidation and leaky gut biomarkers were observed in ScZ-Ag than NScZ-Ag group (all P<0.001). Compared to NScZ-Ag group, the alpha-diversity and evenness of fecal bacterial community were much lower, the abundance of fecal genera Prevotella was significantly increased, while that Bacteroides, Faecalibacterium, Blautia, Bifidobacterium,Collinsella and Eubacterium_coprostanoligenes were remarkably reduced in ScZ-Ag group (all corrected P<0.001). Meanwhile, 6 SCFAs and 6 neurotransmitters were much lower in ScZ-Ag group (all P<0.05). Finally, a few strongly positive or negative correlations among altered gut microbiota, SCFAs, systemic pro-inflammation, leaky gut, pro-oxidation and aggression severity were detected. CONCLUSIONS: These results demonstrate that pro-inflammation, pro-oxidation and leaky gut phenotypes relating to enteric dysbacteriosis and microbial SCFAs feature the aggression onset or severity in ScZ individuals.

Growth Curves of Chinese Children with Androgen Insensitivity Syndrome: A Multicenter Registry Study.

Objective: To provide new information about androgen insensitivity syndrome (AIS), we studied growth patterns in Chinese children with AIS. Subjects: Data are from 118 untreated AIS patients who were admitted to eight pediatric endocrine centers from January 2010 to December 2019. Methods: In this retrospective cohort study, clinical data were collected from a multicenter database. We compared physical assessment data among AIS patients and standard growth charts for Chinese pediatric population. Results: 1. Children with AIS grew slightly less than the mean before 6 months of age, and then, height gradually increased before 12 years of age, from the median to +1 standard deviation (SD), according to the standard reference for Chinese pediatric population. After 12 years of age, height showed differently in profiles: The mean height in AIS patients gradually decreased from the mean to −1 SD, according to the standard for Chinese boys, and increased from the mean to +2 SD, according to the standard for Chinese girls. 2. The weights of children with AIS were greater than the mean standards of Chinese pediatric population from newborn to 11 years of age. From 12−16 years of age, the mean weight of children with AIS showed different profiles, from the mean to −1 SD, according to the standard for Chinese boys and from the mean to +1.5 SD, according to the standard for Chinese girls. 3. Weight standard deviation (WtSDS) and target height (THt) in northern Chinese AIS patients were significantly higher than those from the southern region (p = 0.035, 0.005, respectively). Age in northern Chinese AIS patients was significantly younger than those from the southern region (p = 0.034). No difference was found among birth weight (BW), birth length (BL), height standard deviation (HtSDS) and body mass index (BMI) in AIS patients from different regions (p > 0.05). 4. HtSDS and WtSDS in complete AIS (CAIS) patients were higher than those in partial AIS (PAIS) patients without significant difference (p > 0.05). Conclusions: Growth of children with AIS varied to different degrees. AIS patients seemed not to experience a puberty growth spurt. CAIS and PAIS patients show little difference in their growth. Regional differences have no effect on the height but influence the weight of AIS patients.

Whole Exome Sequencing Uncovered the Genetic Architecture of Growth Hormone Deficiency Patients.

Purpose: Congenital growth hormone deficiency (GHD) is a rare and etiologically heterogeneous disease. We aim to screen disease-causing mutations of GHD in a relatively sizable cohort and discover underlying mechanisms via a candidate gene-based mutational burden analysis. Methods: We retrospectively analyzed 109 short stature patients associated with hormone deficiency. All patients were classified into two groups: Group I (n=45) with definitive GHD and Group II (n=64) with possible GHD. We analyzed correlation consistency between clinical criteria and molecular findings by whole exome sequencing (WES) in two groups. The patients without a molecular diagnosis (n=90) were compared with 942 in-house controls for the mutational burden of rare mutations in 259 genes biologically related with the GH axis. Results: In 19 patients with molecular diagnosis, we found 5 possible GHD patients received known molecular diagnosis associated with GHD (NF1 [c.2329T>A, c.7131C>G], GHRHR [c.731G>A], STAT5B [c.1102delC], HRAS [c.187_207dup]). By mutational burden analysis of predicted deleterious variants in 90 patients without molecular diagnosis, we found that POLR3A (p = 0.005), SUFU (p = 0.006), LHX3 (p = 0.021) and CREB3L4 (p = 0.040) represented top genes enriched in GHD patients. Conclusion: Our study revealed the discrepancies between the laboratory testing and molecular diagnosis of GHD. These differences should be considered when for an accurate diagnosis of GHD. We also identified four candidate genes that might be associated with GHD.

Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature.

PURPOSE: ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms. METHODS: We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined. RESULTS: We identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro. The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2. CONCLUSION: We expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.

Exome sequencing reveals genetic architecture in patients with isolated or syndromic short stature.

Short stature is among the most common endocrinological disease phenotypes of childhood and may occur as an isolated finding or in conjunction with other clinical manifestations. Although the diagnostic utility of clinical genetic testing in short stature has been implicated, the genetic architecture and the utility of genomic studies such as exome sequencing (ES) in a sizable cohort of patients with short stature have not been investigated systematically. In this study, we recruited 561 individuals with short stature from two centers in China during a 4-year period. We performed ES for all patients and available parents. All patients were retrospectively divided into two groups: an isolated short stature group (group I, n = 257) and an apparently syndromic short stature group (group II, n = 304). Causal variants were identified in 135 of 561 (24.1%) patients. In group I, 29 of 257 (11.3%) of the patients were solved by variants in 24 genes. In group II, 106 of 304 (34.9%) patients were solved by variants in 57 genes. Genes involved in fundamental cellular process played an important role in the genetic architecture of syndromic short stature. Distinct genetic architectures and pathophysiological processes underlie isolated and syndromic short stature.

Efficacy and safety of human chorionic gonadotropin combined with human menopausal gonadotropin and a gonadotropin-releasing hormone pump for male adolescents with congenital hypogonadotropic hypogonadism.

BACKGROUND: Compared to adult studies, studies which involve the treatment of pediatric congenital hypogonadotropic hypogonadism (CHH) are limited and no universal treatment regimen is available. The aim of this study was to evaluate the feasibility of human chorionic gonadotropin (hCG)/human menopausal gonadotropin (hMG) therapy for treating male adolescents with CHH. METHODS: Male adolescent CHH patients were treated with hCG/hMG (n = 20) or a gonadotropin-releasing hormone (GnRH) pump (n = 21). The treatment was divided into a study phase (0-3 months) and a follow-up phase (3-12 months). The testicular volume (TV), penile length (PL), penis diameter (PD), and sex hormone levels were compared between the two groups. The TV and other indicators between the groups were analyzed using a t-test (equal variance) or a rank sum test (unequal variance). RESULTS: Before treatment, there was no statistical difference between the two groups in terms of the biochemistry, hormones, and other demographic indicators. After 3 months of treatment, the TV of the hCG/hMG and GnRH groups increased to 5.1 ±â€Š2.3 mL and 4.1 ±â€Š1.8 mL, respectively; however, the difference was not statistically significant (P > 0.05, t = 1.394). The PL reached 6.9 ±â€Š1.8 cm and 5.1 ±â€Š1.6 cm (P < 0.05, t = 3.083), the PD reached 2.4 ±â€Š0.5 cm and 2.0 ±â€Š0.6 cm (P < 0.05, t = 2.224), respectively, in the two groups. At the end of 6 months of treatment, biomarkers were in normal range in the two groups. Compared with the GnRH group, the testosterone (T) level and growth of PL and PD were significantly greater in the hCG/hMG group (all P < 0.05). While the TV of both groups increased, the difference was not statistically significant (P > 0.05, t = 0.314). After 9 to 12 months of treatment, the T level was higher in the hCG/hMG group. Other parameters did not exhibit a statistical difference. CONCLUSIONS: The hCG/hMG regimen is feasible and effective for treating male adolescents with CHH. The initial 3 months of treatment may be a window to optimally observe the strongest effects of therapy. Furthermore, results from the extended time-period showed positive outcomes at the 1-year mark; however, the long-term effectiveness, strengths, and weaknesses of the hCG/hMG regimen require further research. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02880280; https://clinicaltrials.gov/ct2/show/NCT02880280.

Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial.

Treatment of severe Coronavirus Disease 2019 (COVID-19) is challenging. We performed a phase 2 trial to assess the efficacy and safety of human umbilical cord-mesenchymal stem cells (UC-MSCs) to treat severe COVID-19 patients with lung damage, based on our phase 1 data. In this randomized, double-blind, and placebo-controlled trial, we recruited 101 severe COVID-19 patients with lung damage. They were randomly assigned at a 2:1 ratio to receive either UC-MSCs (4 × 107 cells per infusion) or placebo on day 0, 3, and 6. The primary endpoint was an altered proportion of whole lung lesion volumes from baseline to day 28. Other imaging outcomes, 6-minute walk test (6-MWT), maximum vital capacity, diffusing capacity, and adverse events were recorded and analyzed. In all, 100 COVID-19 patients were finally received either UC-MSCs (n = 65) or placebo (n = 35). UC-MSCs administration exerted numerical improvement in whole lung lesion volume from baseline to day 28 compared with the placebo (the median difference was -13.31%, 95% CI -29.14%, 2.13%, P = 0.080). UC-MSCs significantly reduced the proportions of solid component lesion volume compared with the placebo (median difference: -15.45%; 95% CI -30.82%, -0.39%; P = 0.043). The 6-MWT showed an increased distance in patients treated with UC-MSCs (difference: 27.00 m; 95% CI 0.00, 57.00; P = 0.057). The incidence of adverse events was similar in the two groups. These results suggest that UC-MSCs treatment is a safe and potentially effective therapeutic approach for COVID-19 patients with lung damage. A phase 3 trial is required to evaluate effects on reducing mortality and preventing long-term pulmonary disability. (Funded by The National Key R&D Program of China and others. ClinicalTrials.gov number, NCT04288102.

Clinical characteristics and genotype-phenotype correlations of 130 Chinese children in a high-homogeneity single-center cohort with 5α-reductase 2 deficiency.

BACKGROUND: Patients with steroid 5α-reductase 2 deficiency (5α-RD) caused by SRD5A2 (OMIM #607306) variants present variable genotypes and phenotypes. The genotype-phenotype correlations remain unclear. METHODS: We investigated genotype-phenotype correlations of SRD5A2 variants in a large Chinese single-center cohort. Phenotypes were categorized using the external masculinization score (EMS), urethral meatus and gonad position, and penile length-standard deviation score. RESULTS: Of the 130 included patients, 113 had hypospadias, and 17 had a normal urethral meatus position. Testosterone/dihydrotestosterone (T/DHT) values were not significantly associated with phenotypic severity (p = 0.539-0.989). Of the 31 SRD5A2 variants, including 10 novel variants, p.R227Q was the most prevalent (39.62%), followed by p.Q6* (16.92%), p.R246Q (13.46%), and p.G203S (10.38%). Compared to biallelic missense mutations, biallelic nonsense mutations were associated with a lower EMS and urethral meatus score (p = 0.009 and p = 0.024, respectively). Patients homozygous for p.R227Q exhibited mild and variable phenotypes, while those homozygous for p.Q6*, p.R246Q, or p.G203S showed consistently severe phenotypes. The phenotypes were variable and milder in patients with compound heterozygosity for p.R227Q and these mutations. CONCLUSION: T/DHT does not predict phenotype severity. The most prevalent SRD5A2 variant in Han Chinese is p.R227Q, which is associated with milder phenotypes and greater phenotypic variability. SRD5A2 variants may significantly influence phenotypic variation.

New insights into 5α-reductase type 2 deficiency based on a multi-centre study: regional distribution and genotype-phenotype profiling of SRD5A2 in 190 Chinese patients.

BACKGROUND: The 5α-reductase type 2 (5α-RD2) deficiency caused by mutations in the steroid 5α-reductase 2 (SRD5A2) gene results in variable degrees of undervirilisation in patients with 46,XY disorders of sex development. This study aims to profile the regional distribution and phenotype-genotype characteristics of SRD5A2 in a large Chinese 5α-RD2 deficiency cohort through multi-centre analysis. METHODS: 190 subjects diagnosed with 5α-RD2 deficiency were consecutively enrolled from eight medical centres in China. Their clinical manifestations and genetic variants were analysed. RESULTS: Hypospadias (isolated or combined with microphallus and/or cryptorchidism) was fairly common in the enrolled subjects (66.32%). 42 variants, including 13 novel variants, were identified in SRD5A2. Homozygous and compound heterozygous mutations presented in 38.42% and 61.58% of subjects, respectively, and predominated in exons 1, 4 and 5. The most prevalent variant was c.680G > A (52.37%), followed by c.16C > T, (10.79%), c.607G > A, (9.21%) and c.737G > A, (8.95%). However, their distributions were different: c.680G > A was more common in South China than in North China (62.62% vs 39.16%, p < 0.001), whereas the regional prevalence of c.16C > T was reversed (6.07% vs 16.87%, p = 0.001). Furthermore, c.680G > A prevailed in cases with normal meatus (68.75%) or distal hypospadias (66.28%), compared with those with proximal hypospadias (35.54%, p < 0.001). However, cases with proximal hypospadias showed a higher frequency of c.16C > T (20.48%) than those with normal meatus (3.13%) or distal hypospadias (3.49%, p < 0.001). CONCLUSIONS: This study profiled variable phenotypic presentation and wide mutational spectrum of SRD5A2, revealing its distinctive regional distribution in Chinese patients and further shaping the founder effect and genotype-phenotype correlation of SRD5A2.

Growth Pattern in Chinese Children With 5α-Reductase Type 2 Deficiency: A Retrospective Multicenter Study.

BACKGROUND: 5α-reductase type 2 deficiency (5αRD) is an autosomal recessive hereditary disease of the group of 46, XY disorders of sex development (DSD). OBJECTIVE: To study the growth pattern in Chinese pediatric patients with 5αRD. SUBJECTS: Data were obtained from 141 patients with 5αRD (age: 0-16 years old) who visited eight pediatric endocrine centers from January 2010 to December 2017. METHODS: In this retrospective cohort study, height, weight, and other relevant data were collected from the multicenter hospital registration database. Baseline luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), and dihydrotestosterone (DHT) after human chorionic gonadotropin (HCG) stimulation test were measured by enzyme enhanced chemiluminescence assay. Bone age (BA) was assessed using the Greulich-Pyle (G-P) atlas. Growth curve was constructed based on λ-median-coefficient of variation method (LMS). RESULTS: The height standard deviation scores (HtSDS) and weight standard deviation scores (WtSDS) in 5αRD children were in the normal range as compared to normal boys. Significantly higher HtSDS was observed in patients with 5αRD who were <1 year old (t = 3.658, 2.103, P = 0.002, 0.048, respectively), and higher WtSDS in those <6 months old (t = 2.756, P = 0.012). Then HtSDS and WtSDS decreased gradually and fluctuated near the median of the same age until 13 years. WtSDS in 5αRD children from northern China were significantly higher than those from the south (Z = -2.670, P = 0.008). The variation tendency of HtSDS in Chinese 5αRDs was consistent with the trend of stimulating T. HtSDS and stimulating T in the external masculinization score (EMS) <7 group were slightly higher than those in EMS ≥ 7 group without significant difference. Additionally, the ratio of BA over chronological age (BA/CA) was significantly <1 in children with 5αRD. CONCLUSION: Children with 5αRD had a special growth pattern that was affected by high levels of T, while DHT played a very small role in it. Their growth accelerated at age <1 year, followed by slowing growth and fluctuating height near normal median boys' height. The BA was delayed in 5αRD children. Androgen treatment, which may be considered anyway for male 5αRD patients with a micropenis, may also be beneficial for growth.

Variant analysis of the chromodomain helicase DNA-binding protein 7 in pediatric disorders of sex development.

IMPORTANCE: This study investigated the role of the chromodomain helicase DNA-binding protein 7 (CHD7) in disorders of sex development (DSD). OBJECTIVE: We aimed to present the potential pathogenicity of CHD7 variants in pediatric patients with DSD. METHODS: Choosing cases with CHD7 variants from DSD patients in Beijing Children's Hospital to assess for the study. Prediction software tools were used to predict variant pathogenicity in these subjects. RESULTS: Among the 113 DSD patients, 22 cases had CHD7 variants. Twenty-four different CHD7 variants were identified in the 22 DSD patients. Prediction software combined with ClinVar database information and their clinical manifestations revealed that, of the 18 patients with 46, XY DSD, two had CHARGE syndrome and two had Kallmann syndrome. Seven of the variants were highly categorized as "likely to be pathogenic" and seven as "suspected to be pathogenic". Of the four patients with 46, XX DSD, three had ovotesticular DSD (c.305A>G, c.2788G>A, and c.3098G>A) and one had testicular DSD (c.2831G>A). INTERPRETATION: A high frequency of CHD7 variants was found in the DSD patients, especially those with 46, XY DSD. Thus, the detection of a pathogenic CHD7 variant could suggest a diagnosis of hypogonadotropic hypogonadism for 46, XY DSD patients, but pre-pubescent patients should be reassessed in adolescence to confirm this diagnosis. This study also suggests that DNA sequencing could help to identify pre-pubescent DSD patients. Further data are required to determine the connection between CHD7 variants and sex-reversal in patients with 46, XX DSD, and the accumulation of these data is essential and necessary for DSD research.

Novel phenotypes and genotypes in Antley-Bixler syndrome caused by cytochrome P450 oxidoreductase deficiency: based on the first cohort of Chinese children.

BACKGROUND: Antley-Bixler syndrome (ABS) caused by P450 oxidoreductase deficiency (PORD) is a congenital adrenal hyperplasia with skeletal malformations and disordered sex development in both sexes. There have been no reports of ABS caused by PORD in Chinese children. METHODS: We described the clinical and genetic characteristics of eight Chinese children with ABS caused by PORD and compared them with those of subjects in previous studies. RESULTS: Eight patients, aged 6 months-17.8 years, showed strikingly similar craniofacial malformations. We first described four unreported features: lower eyelid fat pads (4/8), prominent lower eyelid-zygoma transverse line (4/8), underdeveloped or absent antihelix (5/8) and single earlobe crease (5/8). Five 46, XY patients presented various degrees of undervirilization, while three 46, XX cases showed masculinization. Basal endocrine measurements revealed the following consistent results: normal cortisol; elevated adrenocorticotropic hormone, progesterone, pregnenolone, 17-hydroxypropgesterone, and corticosterone; and decreased or normal testosterone/oestradiol. We identified three previously reported variants and four novel variants (c.51719_51710delGGCCCCTGTGinsC, p.D210G, p.Y248X and p.R554X) of POR. The most prevalent variant was p.R457H (8/16). The hydrocortisone dosages of patients differed because of variable degrees of adrenal insufficiency. CONCLUSIONS: We described novel phenotypes and genotypes of ABS caused by PORD. The variant p.R457H was the most prevalent in this cohort. All subjects had combined characteristics of 17-hydroxylase and 21-hydroxylase deficiency. Steroid replacement therapy for patients with PORD requires individually tailored dosing.

Phenotype and Molecular Characterizations of 30 Children From China With NR5A1 Mutations.

Background: Patients harboring NR5A1 mutations have a wide spectrum of phenotypes. Objective: To investigate the phenotype of patients with NR5A1 gene mutations from a 30 Chinese patient cohort. Methods: We reported the clinical features of children with NR5A1 gene mutations and compared them between two groups of patients with social genders of male (boys group) and female (girls group). Results: Thirty patients with NR5A1 mutations ranging from 2 months to 17 years of age were studied. There were 11 boys and 19 girls who were identified when they visited the hospital. The patients were verified as having testes without a uterus and ovaries by B-mode ultrasound. There was no difference between boys and girls in terms of the Prader stage (p = 0.086), but the position of the testes was higher in girls than in boys (p = 0.013). The patients' average height is -0.43 SDS according to the normal boys' height with SDS (while their average target height was 0.07 SDS). However, there was no such difference between boys and girls (p > 0.05). Although the basal LH and post-hCG testosterone (T) levels were not different (p > 0.05), but the basal FSH level, LH/FSH ratio, and INHB level were decreased in girls (p = 0.002; p = 0.001; p = 0.006). All of the mothers of the patients reported to have normal pregnancies. We found 24 patients (80%) with de novo mutations in the NR5A1 gene; 5 patients had inherited mutations from their mothers, and one inherited from the father. Only the mothers of patients 16 and 18 showed premature ovarian failure at the time of reporting. Among 26 disease associated mutations, 14 novel mutations that have been reported the first time and p.R87C is the most common Among the other 12 had had been reported,the p.R313C is the most common. Conclusion: Patients with 46, XY NR5A1 mutations presented a wide spectrum of external genitalia characteristics and severe Sertoli cell impairment. The p.R87C and p.R313C mutations appeared to be common (10%) in this group, and 14 new mutations were identified, improving our understanding the genotype phenotype correlations.

Novel pathogenic RECQL4 variants in Chinese patients with Rothmund-Thomson syndrome.

BACKGROUND: Rothmund-Thomson syndrome (RTS) is a rare autosomal recessive disorder mainly characterized by cutaneous poikiloderma, sparse hair, short stature and skeletal defects. Deleterious mutations in the RecQ-like DNA helicase type 4 (RECQL4) gene have been detected in approximately two-thirds of RTS cases. METHODS: Three Chinese patients from two unrelated families were enrolled for clinical evaluation. Targeted next-generation sequencing (NGS) using a custom panel consisting of 705 short-stature-related genes was performed for the probands. Variants detected by NGS were confirmed by Sanger sequencing and examined in family members. RESULTS: The probands presented with characteristic features of severe growth delay, poikiloderma mostly on the face, buttocks and extremities, sparse or absent hair, eyelashes, and eyebrows, forearm reduction defects, small hands with hypoplasia of the middle phalanx (little finger) in one of the probands, epicanthus, hypertelorism, and dental abnormalities. In addition, novel auricle features and other rare facial features, including narrow palpebral fissure, depressed nasal bridge, and small chin were exhibited. Four novel RECQL4 variants were identified, including three pathogenic frameshift variants, c.1724_1725delAC, p.His575fs*7; c.2421dupT, p.Asp808*; c.1770_1807del, p.Pro591fs*2, and one likely pathogenic missense variant, c.691G>A, p.Gly231Ser. CONCLUSION: Our study expands the mutational spectrum of RECQL4 gene and reveals novel phenotypes observed in Chinese RTS patients.

Prenatal and early diagnosis of Chinese 3-M syndrome patients with novel pathogenic variants.

BACKGROUND: 3-M syndrome is a clinically recognizable yet under-diagnosed primordial growth retardation disorder. Molecular testing for CUL7, OBSL1 or CCDC8 genes can provide confirmed diagnosis for patients at prenatal or early age. So far, the clinical and molecular features of Chinese 3-M syndrome patients have not been reported. METHODS: In this article, the authors performed prenatal and early diagnosis of Chinese patients with 3-M syndrome by Next-Generation Sequencing. RESULTS: The authors reported six unrelated Chinese 3-M syndrome patients. Five of the six patients were diagnosed before two years of age including one prenatal case. The authors identified six novel pathogenic variants and five previously reported pathogenic variants. The authors' clinical evaluations indicated that Chinese 3-M syndrome patients share similar recognizable features as those reported in patients of other ethnic background. The authors noticed some uncommon features in this small cohort of Chinese patients such as delayed motor development at early ages, undelayed bone age and presence of lower eyelid fat pads. CONCLUSION: The authors' study of Chinese 3-M syndrome patients revealed novel mutations and clinical phenotypes.

New iron(III) phosphate phases: crystal structure and electrochemical and magnetic properties.

Two new iron(III) phosphates, FePO(4), have been synthesized from the dehydration of hydrothermally prepared monoclinic and orthorhombic hydrated phosphates FePO(4).2H(2)O. The structures of both hydrates were redetermined from single crystal data. On dehydration, a topotactic reaction takes place with only those bonds associated with the water molecules being broken, so that both FePO(4) phases have essentially the same Fe-P backbone frameworks as the corresponding hydrates. They are, respectively, monoclinic FePO(4), space group P2(1)/n, a= 5.480(1) A, b = 7.480(1) A, c= 8.054(1) A, beta = 95.71(1) degrees, and Z = 4; and orthorhombic FePO(4), space group Pbca, a = 9.171(1) A, 9.456(1) A, c = 8.675(1) A, and Z = 8. Both of these phases are thermally unstable relative to the trigonal quartz-like FePO(4). The electrochemical studies find that the orthorhombic iron phosphate is more active than the monoclinic phase, while both are more active than trigonal FePO(4). Both phases approach Curie-Weiss behavior at room temperature, with the monoclinic phase exhibiting stronger antiferromagnetic interactions due to Fe-O-Fe interactions. The electrochemical and magnetic data are consistent with the structures of these two compounds. The properties of these new iron phosphate structures are compared with other iron phosphate phases.