OBJECTIVE: To explore the genetic basis for a child with Rothmund-Thomson syndrome (RTS). METHODS: The child has featured poikeloderma, short stature, cataract, sparse hair and skeletal malformation. Peripheral blood samples of the child and her family members were collected and subjected to whole exome sequencing. Candidate variants were verified by Sanger sequencing. RESULTS: The child was found to harbor compound heterozygous variants of the RECQL4 gene, namely c.1048_1049delAG and c.2886-1G>A, among which c.2886-1G>A was unreported previously. According to the ACMG guidelines, the c.1048_1049delAG was predicted to be pathogenic (PVS1+PM3_Strong+PM2), while the c.2886-1G>A was predicted to be likely pathogenic (PVS1+PM2). CONCLUSION The compound heterozygous variants of the RECQL4 gene probably underlay the pathogenesis of RTS in this patient. Above finding has enriched the mutational spectrum of the RECQL4 gene.
Child ; Family ; Female ; Humans ; Mutation ; RecQ Helicases/genetics* ; Rothmund-Thomson Syndrome/genetics* ; Whole Exome Sequencing

To report the process of diagnosis and treatment of 1 case with SRY gene mutation of 46, XY complete gonadal dysplasia, and to discuss the clinical characteristics, diagnosis and treatment of the disease.Due to clitoral enlargement for 8 months, a 9 years old girl was admitted to the Children′s Hospital Affiliated to Zhejiang University School of Medicine.Previously, she had early breast development, and suffered from high gonadotropin expression when she was 6 years and 4 months old.Physical examination: breast B3 stage, female vulva, clitoris hypertrophy, normal urethra, normal vaginal opening, slightly thick hymen ring, the development of pubic hair was 2 stages, and Prader score level 1.Laboratory data showed elevated levels of estradiol, testosterone, and human chorionic gonadotrophin.Genetic examination revealed that the chromosome karyotype was 46, XY and SRY gene detection was positive.Therefore, the patient was diagnosed with 46, XY complete gonadal dysplasia.Bilateral gonadectomy was performed, and the posto-perative pathological diagnosis was bilateral gonadoblastoma with left dysgerminoma.The tumor did not recur after che-motherapy.The etiology of early breast development needs to be carefully identified.Patients with sexual characteristics dysplasia need to accept the chromosome karyotype analysis and gene detection, and surgical exploration should be performed when necessary for a correct diagnosis as soon as possible.

To report the clinical, imaging, and pathological feature of a rare case of central precocious puberty with primary pigmented nodular adrenocortical disease(PPNAD), and to conduct a retrospective analysis of PPNAD with relevant literatures. The pubic hair was found in the child for more than one year. Physical examination showed Cushing′s syndrome. ACTH in blood decreased, cortisol rhythm was disordered, 24-hour urine free cortisol increased and the paradoxical increase of urine free cortisol after high dose dexamethasone suppression test. Adrenal enhancement computed tomography(CT)showed multiple small nodular shadows in bilateral adrenal glands. Gonadotropin releasing hormone(GnRH)stimulation test supported central precocious puberty and GnRH analogue was used to control the sexual development. PPNAD was supported by pathology result. The symptoms of Cushing′s syndrome were relieved partially after left adrenalectomy.

Congenital lipoid adrenal hyperplasia (CLAH) is a rare autosomal recessive disorder, which is characterized by adrenal insufficiency and 46, XY sex reversal. Two cases of CLAH with 46, XY karyotype exhibited male external genitalia were reported to explore the clinical and genetic features. A retrospective analysis of CLAH with relevant literatures was performed.

Objective:To analyze the patients′ clinical and genetic characteristics with pseudohypoparathyroidism (PHP) and investigate the correlation between clinical phenotypes and genotypes.Methods:Twenty PHP patients were ascertained at Children′s Hospital Zhejiang University School of Medicine from January 2011 to July 2020. Clinical manifestation, laboratory examination and gene test results were retrospectively analyzed.Results:In these twenty patients, eighteen cases showed resistance to parathyroid hormone (PTH) and thirteen cases had Albright′s hereditary osteodystrophy (AHO) phenotype. Gene abnormalities were found in all the twenty PHP patients, which included seven patients with GNAS gene variations (six frameshifts and one missense) and thirteen patients with GNAS gene methylation defects. Moreover, twelve children with both PTH resistance and AHO phenotype were clinically diagnosed as PHP-Ⅰa, meanwhile, seven carried GNAS variations and five had methylation abnormalities with a correct diagnosis of PHP-Ⅰb.Conclusions:Patients with AHO phenotype and PTH resistance may have a high genetic diagnosis rate. Because PHP-Ⅰb clinical phenotype may be similar to PHP-Ⅰa, early genetic detection is required for the differential diagnosis. In addition, children without PTH resistance should also be followed up regularly, which may help the early diagnosis.

Objective:To analyze the trends of overweight and obesity prevalence in Chinese children, aged from 6 to 15 years old among 4 provinces and cities from 2009 to 2019.Methods:Reviewed the national multi-center epidemiological survey data of children from the National Key Technology R&D Program of China during the Eleventh Five-Year Plan (2009 to 2010) and the National Key Research and Development Program of China during the Thirteenth Five-Year Plan (2017 to 2019). The participants′ data were selected from four provinces,municipalities and autonomous region,including Beijing, Tianjin (Northern region), Zhejiang (Eastern region), and Guangxi (Southern region). Totally 14 597 pairs of 6-15 year-old children were surveyed. According to the body mass index (BMI) and standard deviation score (SDS) of children among different genders, ages, and regions, t test or chi-square test was used to evaluate the changes in overweight and obesity over a 10-year span. Results:Totally 7 721 pairs of boys and 6 876 pairs of girls were collectted in this study, whose mean age was (10.7±2.5) years. In the past 10 years, the overall BMISDS were 0.39±1.24 and 0.36±1.31 and the overall obesity rate were 11.8% ( n=1 773) anel 12.5% ( n=1 813) of children in the 4 administrative regions did not have statistically significant differences (all P>0.05). However, the overall overweight rate rose from 17.1% ( n=2 496) to 19.1% ( n=2 781) (χ2=18.657, P<0.01), and the average annual growth rate was 0.20%. The BMISDS in the Eastern region increased from 0.10±1.07 to 0.19±1.22 ( t=-4.095, P<0.01), and the overweight rate and obesity rate increased by 3.8% ( n=202) and 3.1% ( n=169) respectively (both P<0.01); the BMISDS in the Northern region and the obesity rate did not have statistically significant differences(all P>0.05), but the overweight rate rose from 20.5% ( n=1 233) to 22.8% ( n=1 365) significantly (χ2=7.431, P<0.01); BMISDS in the Southern region was significantly decreased from 0.30±1.19 to 0.09±1.25 ( t=1.426, P<0.01), and the rate of obesity decreased from 9.8% ( n=315) to7.9% ( n=256) (χ2=6.46, P<0.05), the overweight rate was not stafistically significant ( P=0.10), respectively. The obesity rate of boys had risen from 16.4% ( n=1 265) to 18.2% (1 407) (χ2=8.997, P<0.01) in the past 10 years, and the overweight rate had risen from 18.0% ( n=1 393) to 20.5% ( n=1 579) (χ2=14.26, P<0.01). The overweight+obesity rate rose from 34.4% ( n=2 658) to 38.7% ( n=2 986) (χ2=29.859, P<0.01), and the weight problem in the age group of 8 to 11 years was particularly severe (all P<0.01). The obesity rate of girls dropped from 6.8% ( n=468) to 5.9% ( n=406) (χ2=4.546, P<0.05), the overweight rate rose from 16.0% ( n=1 103) to 17.5% ( n=1 202) (χ2=5.006, P<0.05), and the overall overweight+obesity rate rose from 22.8% ( n=1 571) to 23.4% ( n=1 608) (χ2=0.53, P>0.05). Conclusions:The growth rate of obesity among children in China had slowed down from 2009 to 2019, but the overweight rate was still on the rise. The overall base of overweight and obesity population continued to expand. The weight problem of peri-adolescent boys was particularly prominent. The current status of obesity epidemics in different regions, ages, and genders are significantly different and had their own characteristics. It is necessary to establish a personalized prevention and control strategy.

Objective: To explore the feasibility of gender assignment in 46,XY disorders of sex development (DSD) with severe undermasculinisation mainly based on molecular diagnosis. Methods: A retrospective study of 45 patients of 46, XY DSD with severe undermasculinisation were admitted between November 2015 and October 2018 at Children′s Hospital, Zhejiang University School of Medicine. The initial social gender were all female, of whom the external genital manifestations were Prader 0 to 2; the degree of masculinity was scored using external masculinisation score (EMS); the position and development of the gonads were examined by ultrasound, cystoscopy and laparoscopy, also including assessing the development of the Wolffian tube and the Müllerian tube. The level and ratio of testosterone to dihydrotestosterone before and after hCG stimulation were evaluated for the function of Leydig cell and 5α-reductase-2. Gender role scales and sandbox games were used to assess gender role behavior. Genital sensitivity to androgen stimulation was assessed; A panel including 163 genes related to gender development were determined by second-generation sequencing in all 45 patients. Finally, a multidisciplinary team (MDT) makes a gender assignment after a comprehensive analysis mainly based on the molecular etiological diagnosis. Results: Thirty-nine out of 45 patients (87%) had an identifiable genetic etiology, and the remaining 6 (13%) were negative for genetic testing. Forty-five patients had EMS less than or equal to 3 points. Sexual psychological assessment was performed in 39 patients, with male dominance in 24 (62%) and female dominance in 15 (38%). The gender assignment was 23 cases (51%) for male and 19 cases (42%) for female, and 3 cases (7%) were not completely determined. Conclusions Molecular diagnosis provides a strong basis for appropriate gender assignment of 46, XY DSD children with severe undermasculinisation. Based on molecular diagnosis, each DSD should be analyzed by professional MDT to analyze the clinical symptoms/signs, gonadal development, gonad tumor risk, external genital morphology, sexual psychological assessment, potential fertility opportunities, parental views, Social and cultural factors, etc. make appropriate gender assignment.

Objective: To investigate the associations between genetic variations of DNA polymerase kappa (POLK) and treatment response to platinum-based chemotherapy of small cell lung cancer (SCLC), and to analyze the influencing factors on survival. Methods: Five haplotype-tagging single nucleotide polymorphisms (htSNPs) of POLK were genotyped by Sequenom MassARRAY methods in 1 030 SCLC patients who received platinum-based chemotherapy, and had different response and survival time. The associations between SNPs and treatment response were analyzed by computing the odds ratios (ORs) and 95% confidence intervals (CIs) from logistic regression model. Cox regression was used for survival analysis between SNPs and overall survival by computing the hazard ratios (HRs) and 95% CIs. Results: Among 1 030 cases, 558 (54.2%) cases received cis-platinum and etoposide treatment while others treated with carboplatin and etoposide. Seven hundred and eighty eight patients were chemotherapy responders in the study with a response rate of 76.5%. The median follow-up time of these patients was 22.0 months. Patients were followed up to get their survival information. The median survival time of these patients was 22.5 months. Six hundred and seventy three patients (65.3%) had died by the last date of follow-up to get their survival information (Dec 21, 2017). Five htSNPs of POLK were not associated with the chemotherapy response of SCLC patients who received platinum-based chemotherapy (all P>0.05). Multivariate Cox proportional hazards regression model analysis showed that, rs73120833 of POLK was significantly associated with the overall survival (OS) of SCLC patients, compared with POLK rs73120833 T allele, C allele can prolong OS (adjusted HR=0.87, 95% CI=0.77-0.97, P=0.021). The remaining 4 SNPS, including rs10077427, rs3756558, rs4549504 and rs5744545, were not significantly associated with overall survival. Age≤56, KPS> 80, limited-stage, chemotherapy response and radiation therapy can remarkably prolong OS (all P<0.05). Conclusion These results suggest that POLK genetic polymorphism rs73120833 plays an important role on the prognosis of SCLC patients, which can be potential genetic biomarker for SCLC personalized treatment.

Objective To evaluate the efficacy of computed tomography ( CT ) image?guided 125 I radioactive seed implantation for locally recurrent rectal cancer ( LRRC ) , and to analyze the relationship between the dosimetry and prognosis. Methods A retrospective analysis was performed on the clinical data of 36 patients with LRRC who received CT image?guided 125 I seed implantation in our hospital from 2003 to 2011. Dosimetric verification was performed using CT scan immediately after 125 I seed implantation. The D90 , D100 , V100 , and V150 values were evaluated. In all the patients, the median activity of seeds was 0?7 mCi (0?4?0?8 mCi) and the median number of implanted seeds was 74(33?137). The local control (LC) and overall survival ( OS ) rates were calculated using the Kaplan?Meier method. The log?rank test and Cox regression model were used for the univariate and multivariate analyses, respectively. Results The median OS time was 16?2 months ( 95% CI= 13?5?18?9 months ) . The median LC time was 10?0 months (95% CI=6?2?13?8 months). The D90 and V100 values were (118.6±25?1) Gy and (90.0±0?3)%, respectively. The univariate analysis suggested that D90 was correlated with the LC time ( P=0?048) and V100 was correlated with the OS time ( P=0?035) . The multivariate analysis showed that a V100 value higher than 90% was a prognostic factor of OS (P=0?044). Conclusions In the treatment of LRRC using CT image?guided 125 I radioactive seed implantation, a D90 value larger than 140 Gy and a V100 value higher than 90% in the postoperative verification plan help improve the LC and OS rates. The D90 and V100 values in the postoperative verification plan may predict treatment outcomes in patients.

Objective To evaluate the efficacy and adverse reactions of CT-guided 125I radioactive seed implantation in treatment of locally recurrent rectal cancer (LRRC).Methods Thirty patients with LRRC who refused operation or were unable to endure pelvic radiotherapy received 125I seed implantation under CT guidance.Three-dimensional treatment planning system was used to calculate the number,activity,and dose of the seeds needed.The activity of seeds ranged from 14.8 to 29.6 MBq with a median of 25.9 MBq,the seed numbers ranged from 33 to 137 with a median of 74.5,the prescription doses ranged from120-160 Gy,and the actual verification dose D90 ranged from 75.91 to 159.32 Gy with a median of 119.77 Gy.Dosimetric verification by CT scanning was conducted immediately after the treatment.Follow-up was conducted for 15.2 months(4.2-35.0 months).Results The follow-up rate was 93.3％.The pain relief rate was 95.2％.The overall response rate was 50.0％,including a complete response rate of 13.3％ and a partial response rate of 36.7％.The 1-and 2-year local control rates were 30.0％ and 8.0％ respectively.The median local control survival time was 7.8 month.The 1-and 2-year survival rates were 66.5％ and 32.9％ respectively.The median overall survival time was 21.5 months.Complications,mainly adverse effects of skin and urinary system (frequent urination,urgent urination,and dysuria) occurred in 6 patients with a rate of 20.0％.Conclusions Minimally invasive and with satisfying efficacy and tolerable complications,CT-guided 125I radioactive seed implantation is a favorable option for treatment of LRRC,especially for the patients who have undergone previous pelvic radiation.