Objective:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.Methods:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).Results:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c. 1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright′s hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c. 2T>C (p.Met1? ) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. Conclusion:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of comorbid genetic diseases.

OBJECTIVE: To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously. METHODS: Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01). RESULTS: Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c.1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright's hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c.2T>C (p.Met1?) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. CONCLUSION When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of co-morbid genetic diseases.
Child, Preschool ; Female ; Humans ; Male ; Class Ia Phosphatidylinositol 3-Kinase/genetics* ; Comorbidity ; Exome Sequencing ; Mutation ; Rare Diseases/genetics* ; Retrospective Studies ; Adolescent

Objective:To explore the clinical and genetic characteristics of two children diagnosed with two rare genetic diseases simultaneously.Methods:Two children with comorbidity of two genetic diseases due to dual genetic mutations diagnosed at the Third Affiliated Hospital of Zhengzhou University respectively in May 2022 and March 2023 were selected as the study subjects. Clinical and genetic data of the two children were retrospectively analyzed. This study has been approved by the Ethics Committee of the Third Affiliated Hospital of Zhengzhou University (Ethic No. 2021-062-01).Results:Child 1 was a 2-year-and-4-month-old boy whose clinical manifestations included facial dysmorphism, developmental delay, short stature, microcephaly, cleft palate, cryptorchidism, hypospadias, recurrent infections and immunological abnormalities. Whole exome sequencing revealed that he had harbored a heterozygous c.6595delT (p.Y2199Ifs*65) variant of the KMT2D gene and a heterozygous c. 1892G>A (p.R631Q) variant of the PIK3R1 gene. This has led to a dual genetic diagnosis of Kabuki syndrome and PI3Kδ-related immunodeficiency type 36. Child 2 was a 15-year-old girl whose clinical manifestations included epilepsy, Albright′s hereditary osteodystrophy, long body trunk, short limbs, hypocalcemia, hyperphosphatemia and hyperparathyroidism. The child also had a family history of short stature. Whole exome sequencing revealed that she had harbored a heterozygous c. 2T>C (p.Met1? ) variant of the GNAS gene and deletion of exons 2 to 6 of the SHOX gene. The two variants have led to dual diagnose of pseudohypoparathyroidism and X-linked idiopathic short stature. Conclusion:When the clinical phenotype of a genetic disease is complex and cannot be fully explained with a single genetic variant, multiple pathogenic variants should be considered, and this may lead to the diagnosis of co-morbid genetic diseases. To adopt or supplement corresponding genetic testing in time and re-analyze the genetic data may facilitate accurate diagnosis of comorbid genetic diseases.

Objective To investigate the associations between thyroid hormone sensitivity indices in euthyroid patients with hypertension and the risk of ischemic stroke,as well as gender difference in this association.Methods We selected 760 hypertensive patients admitted to the Geriatric Neurology Department and outpatient clinic in The Second Affiliated Hospital of Xi'an Jiaotong University between April 2021 and May 2022.We collected their basic characteristics,blood biochemical parameters,thyroid indices,and brain magnetic resonance imaging information.All the patients were divided into two groups based on the clinical manifestations and brain magnetic resonance imaging:hypertension combined with ischemic stroke(n=526)and control(n=234)groups.Independent sample t-tests or non-parametric tests were used to compare the differences in thyroid hormone sensitivity indicators between the two groups.Spearman correlation analysis was used to analyze the correlation between serum thyroid indices and ischemic stroke.Multivariate conditional Logistic regression analysis was made to estimate odds ratios(ORs)and 95％confidence intervals(CIs)for thyroid indices and ischemic stroke.Results There were statistically significant differences between the two groups in terms of age,gender,TC,LDL-c,HDL-c,systolic blood pressure,FT3/FT4,TFQI,and PTFQI(all P＜0.05).However,there was no statistically significant difference between the two groups in weight,smoking,drinking,history of diabetes,TG,FBG,diastolic blood pressure,TSHI,or TT4RI(all P＞0.05).The results of Spearman correlation analysis showed a negative correlation between FT3/FT4 and ischemic stroke(P＜0.05),but a positive correlation of TFQI and PTFQI with ischemic stroke(P＜0.05)in euthyroid patients with hypertension.Logistic regression analysis showed that FT3/FT4 was significantly associated with ischemic stroke in euthyroid patients with hypertension(P=0.001),with OR(95％CI)of 0.001(0.000,0.058).After stratifying by gender,Logistic regression analysis found that FT3/FT4,TFQI,and PTFQI were associated with an increased risk of ischemic stroke in female patients,with OR(95％CI)of 0.000(0.000,0.001),3.132(1.415,6.930),and 3.010(1.406,6.445),respectively.Conclusion Lower serum FT3/FT4 ratio is associated with an increased risk of ischemic stroke in euthyroid patients with hypertension,and the significant association of TFQI and PTFQI with the risk of ischemic stroke is found in females.

Objective:To find a method for fertility preservation through oocytes retrieval during gynecological operation and provide an experimental basis for patients who are not suitable for fertility preservation by transvaginal oocyte retrieval.Methods:The objects of the study were patients with polycystic ovary syndrome (PCOS) who underwent laparoscopic surgery in the Affiliated Reproductive Hospital of Shandong University from April to June 2020 and patients with tumors who underwent fertility preservation during gynecological surgery. This was a retrospective study. Totally 23 patients with PCOS infertility who were to undergo laparoscopy surgery underwent ovarian surface follicle puncture for oocyte retrieval, and the oocytes were obtained and sent to the assisted reproduction laboratory for in vitro culture, and mature oocytes were inseminated by intracytoplasmic sperm injection (ICSI), and high-quality embryos were obtained for cryopreservation. Gynecological surgery and ovarian surface follicle puncture were performed for oocytes retrieval in tumor patients ( n=6) with fertility preservation. The feasibility of simultaneous gynecological surgery with oocytes retrieved was evaluated according to the indexes of the number of oocytes retrieval, maturation, fertilization and embryo culture. Results:In PCOS patients, oocytes retrieved rate was 52.17% (12/23) per cycle. The number of oocytes retrieved was 2.00±1.48, among which the number of culturable oocytes was 1.50±1.00. The oocyte maturation rate was 22.22% (4/18). Two oocytes got fertilization and one zygote got cleavage. In contrast, the fertility-preserving oncology patients undergoing gynecologic surgery had a 100.00% (6/6) oocytes retrieved rate per cycle, with 3.00±1.27 oocytes retrieved. Oocyte maturation rate was 38.46% (5/13). Three oocytes got fertilization and one blastocyst formed. Three patients got oocytes or embryos cryopreservation.Conclusion:For patients who are not suitable for transvaginal oocyte retrieval for fertility preservation, follicle puncture during the gynecologic operation can yield available oocytes.

【Objective】 To investigate the association between remnant cholesterol (RC) and triglyceride and glucose (TyG) index in young and middle-aged patients with ischemic stroke. 【Methods】 A total of 268 patients were divided into two groups, namely low TyG index group (n=134) and high TyG index group (n=134). Characteristics of the study population and metabolism risk factors (TC, TG, HDL-C, LDL-C, UA) were collected from biochemical test results. Spearman correlation analysis was used to analyze the correlation between metabolism risk factors and TyG index. Multivariate conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for RC and TyG index. 【Results】 Compared with the low TyG index group, significant differences were observed for BMI, history of diabetes, history of hypertension, SBP, DBP, FBG, TC, TG, LDL-C, RC, UA, and TyG index in high TyG index group. No significant differences were observed in age, gender, smoking status, or drinking status, HDL-C between the two groups. Spearman correlation analysis indicated that significant linear associations were observed between BMI, SBP, DBP, FBG, TC, TG, HDL-C, LDL-C, RC, UA and TyG index. Logistic regression analysis revealed that the RC, BMI, hypertension, diabetes, TC, LDL-C, and UA were significantly associated with the risk of increased level of TyG index. After adjusted analysis by RC, BMI, hypertension, diabetes, TC, LDL-C, and UA, only RC was significantly associated with an increased risk of increased level of TyG index. 【Conclusion】 Remnant cholesterol was associated with an increased risk of elevated TyG index level in young and middle-aged patients with ischemic stroke.

【Objective】 To investigate the association of thyroid indices with the prevalence of ischemic stroke in young and middle-aged euthyroid population. 【Methods】 For this retrospective study, 620 euthyroid patients aged from 18 to 65 years were divided into ischemic stroke group (n=308) and non-ischemic stroke group (n=312). The characteristics of the study population; serum thyroid indices, i.e., free triiodothyronine (FT3), free thyroxine (FT4) and thyroid-stimulating hormone (TSH), were collected from biochemical test results. Multivariate conditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for thyroid indices and ischemic stroke. 【Results】 Compared with non-ischemic stroke group, significant differences were observed in age, gender, weight, smoking status, drinking status, history of hypertension and diabetes, SBP, DBP, FBG, TC, HDL-C, LDL-C, FT3, FT4, FT3/FT4, TFQI, and PTFQI in ischemic stroke patients (all P<0.05). No significant differences were observed for TG, TSH, TSHI, or TT4RI between the two groups (all P>0.05). Logistic regression analysis revealed that lower FT3 [OR (95% CI) =0.722 (0.547~0.955) , P=0.022] and FT3/FT4 ratio [OR (95% CI) =0.723 (0.600~0.870) , P=0.001] , FT4 [OR (95% CI) =1.099 (1.011~1.194) , P=0.026] were significantly associated with an increased risk of ischemic stroke. After stratified analysis by hypertension, FT4 [OR (95% CI) =1.133 (1.021~1.257) , P=0.019] , lower FT3/FT4 ratio [OR (95% CI) =0.723 (0.600~0.870) , P=0.003] , TFQI [ OR (95% CI) =1.854 (1.026~3.350) , P=0.041] , and PTFQI [OR (95% CI) =1.871 (1.065~3.288) , P=0.029] were significantly associated with an increased risk of ischemic stroke in patients combined with hypertension, while after stratified analysis by diabetes, we only found that lower FT3/FT4 ratio [OR (95% CI) =0.730 (0.559~0.953) , 0.704 (0.536~0.944) , P=0.021] and FT4 [OR (95% CI) =1.170 (1.025~1.335) , P=0.026] were significantly associated with an increased risk of ischemic stroke in patients combined with diabetes. 【Conclusion】 FT3, FT4, and FT3/FT4 ratio are associated with an increased risk for ischemic stroke in young and middle-aged euthyroid population; TFQI and PTFQ are associated with an increased risk for ischemic stroke in patients combined with hypertension.

Objective:To find a method for fertility preservation through oocytes retrieval during gynecological operation and provide an experimental basis for patients who are not suitable for fertility preservation by transvaginal oocyte retrieval.Methods:The objects of the study were patients with polycystic ovary syndrome (PCOS) who underwent laparoscopic surgery in the Affiliated Reproductive Hospital of Shandong University from April to June 2020 and patients with tumors who underwent fertility preservation during gynecological surgery. This was a retrospective study. Totally 23 patients with PCOS infertility who were to undergo laparoscopy surgery underwent ovarian surface follicle puncture for oocyte retrieval, and the oocytes were obtained and sent to the assisted reproduction laboratory for in vitro culture, and mature oocytes were inseminated by intracytoplasmic sperm injection (ICSI), and high-quality embryos were obtained for cryopreservation. Gynecological surgery and ovarian surface follicle puncture were performed for oocytes retrieval in tumor patients ( n=6) with fertility preservation. The feasibility of simultaneous gynecological surgery with oocytes retrieved was evaluated according to the indexes of the number of oocytes retrieval, maturation, fertilization and embryo culture. Results:In PCOS patients, oocytes retrieved rate was 52.17% (12/23) per cycle. The number of oocytes retrieved was 2.00±1.48, among which the number of culturable oocytes was 1.50±1.00. The oocyte maturation rate was 22.22% (4/18). Two oocytes got fertilization and one zygote got cleavage. In contrast, the fertility-preserving oncology patients undergoing gynecologic surgery had a 100.00% (6/6) oocytes retrieved rate per cycle, with 3.00±1.27 oocytes retrieved. Oocyte maturation rate was 38.46% (5/13). Three oocytes got fertilization and one blastocyst formed. Three patients got oocytes or embryos cryopreservation.Conclusion:For patients who are not suitable for transvaginal oocyte retrieval for fertility preservation, follicle puncture during the gynecologic operation can yield available oocytes.

Lingguizhugan Decoction (LGZG) has been investigated in basic studies, with satisfactory effects on insulin resistance in non-alcoholic fatty liver disease (NAFLD). This translational approach aimed to explore the effect and underlying mechanism of LGZG in clinical setting. A randomized, double-blinded, placebo-controlled trial was performed. A total of 243 eligible participants with NAFLD were equally allocated to receive LGZG (two groups: standard dose and low dose) or placebo for 12 weeks on the basis of lifestyle modifications. The primary efficacy variable was homeostasis model assessment of insulin resistance (HOMA-IR). Analyses were performed in two populations in accordance with body mass index (BMI; overweight/obese, BMI ⩾ 24 kg/m²; lean, BMI < 24 kg/m²). For overweight/obese participants, low-dose LGZG significantly decreased their HOMA-IR level compared with placebo (-0.19 (1.47) versus 0.08 (1.99), P = 0.038). For lean subjects, neither dose of LGZG showed a superior effect compared with placebo. Methylated DNA immunoprecipitation sequencing and real-time qPCR found that the DNA N6-methyladenine modification levels of protein phosphatase 1 regulatory subunit 3A (PPP1R3A) and autophagy related 3 (ATG3) significantly increased after LGZG intervention in overweight/obese population. Low-dose LGZG effectively improved insulin resistance in overweight/obese subjects with NAFLD. The underlying mechanism may be related to the regulation of DNA N6-methyladenine modification of PPP1R3A and ATG3. Lean subjects may not be a targeted population for LGZG.
Humans ; Non-alcoholic Fatty Liver Disease/drug therapy* ; Overweight/drug therapy* ; Insulin Resistance ; Obesity/drug therapy* ; China ; DNA/therapeutic use*

Objective:To summarize the clinical characteristics of drug-resistant epilepsy (DRE) in children and to analyze the efficacy of lamotrigine (LTG) add-on therapy for DRE in children of different seizure type, syndrome and etiological category.Methods:All cases of DRE patients treated with LTG or other antiseizure medication (ASM) adjunctive therapy in the Third Affiliated Hospital of Zhengzhou University from May 2019 to April 2020 were collected.The LTG add-on therapy group was treated with LTG add-on therapy, and the control group was treated with other ASM add-on therapy.The therapeutic effects of the two groups were compared.Results:A total of 134 cases meeting the requirement of research were collected, including 98 cases in the LTG add-on therapy group and 36 cases in the control group.For seizure of focal onset and unknown origin, there was statistical difference in efficacy between the LTG add-on therapy group and the control group ( Z=-2.48、-2.11, P<0.05), but for generalized DRE in children, there was no statistical difference in efficacy between the two groups ( Z=-0.39, P>0.05). There was a significantly statistical difference in curative effect between the LTG add-on therapy group and the control group for childhood DRE which could not be classified as any epileptic syndrome ( Z=-3.99, P<0.01), but there was no statistical difference in efficacy between the two groups for West syndrome and benign epilepsy accompanied by central temporal spikes ( Z=-0.94、-1.22, P>0.05). For childhood intractable epilepsy with unknown etiology, there was statistical difference in efficacy between the LTG add-on therapy group and the control group ( Z=-1.96, P<0.05), and for childhood intractable epilepsy with structural etiology, there was significantly statistical difference in efficacy between the two groups ( Z=-3.07, P<0.01), but there was no statistical difference in the efficacy for childhood intractable epilepsy with genetic etiology between the two groups ( Z=-1.02, P>0.05). Conclusion:The efficacy of LTG add-on therapy is significantly better than others for childhood DRE with seizure of focal onset or unknown origin, childhood DRE unclassified to any syndrome, and childhood DRE with structural etiology and unknown origin, especially with structural etiology.