| Part one:Precocious puberty in boys:a study based on data from a single center in Northern ChinaBackground:Precocious puberty(PP)refers to the development of secondary sexual characteristics in boys before 9 years old.The incidence of PP in boys is about one tenth of that in girls,but the organic disease is much higher than that in girls.PP can be divided into central precocious puberty(CPP)according to whether the hypothalamic pituitary gonadotropin releasing hormone(GnRH)dependent precocious puberty,periphery precocious puberty(PPP),which is GnRH independent precocious puberty.Either CPP or PPP has a wide spectrum of diseases and may have overlapping clinical and biochemical characteristics.At the same time,some diseases can be converted from PPP to CPP before or after treatment.There are few studies with large sample in China or abroad on etiology of male PP,and the disease spectrum varies greatly in different countries and regions.We retrospectively analyzed the clinical characteristics of PP in boys from a single center in northern China for 7 years,to provide evidence for diagnosis and differential diagnosis.Objective:1.To explore the etiological classification and clinical characteristics of PP in boys.2.To establish the diagnosis algorithm of boy with PP.Methods:1.Subjects:Boys who were admitted to Childrn’s Hospital Capital Institute of Pediatrics for PP evaluation from January 2015 to December 2021 were included.2.Methods:(1)Symptoms,signs,age of onset and age of diagnosis were collected.Pubertal stage was conducted according to Tanner stage,and testicular volume was measured by orchidometer.(2)Hormone examinations:luteinizing hormone(LH),follicle-stimulating hormone(FSH),testosterone(T),human chorionic gonadotropin(HCG),adrenocorticotropin(ACTH),human chorionic gonadotropin(HCG),cortisol and 17 hydroxyprogesterone(17-OHP)were tested.(3)CPP is determined by GnRH analogue stimulation test.CPP is considered when LH peak value is higher than 6IU/L and bone age is one year older than chronological age.(4)Imaging examination:Bone age is determined by X-ray,and evaluated by Greulich-Pyle method.Pituitary enhanced MRI and/or cranial MRI to identify pituitary and intracranial lesions;(5)According to the characteristics of different causes of PP in boys,explore the diagnostic process.Results:1.A total of 99 cases of male PP were included in this study.The onset age and diagnosis age of CPP group were higher than PPP group(7.70±2.27 years VS 4.25±2.46 years,P<0.001;8.78±2.07 years VS 5.60±2.16 years,P<0.001).The testicular volume in CPP group was higher than that in PPP group(10(6,12)ml VS 3(2.5,4.5)ml,P<0.001).The pubic hair stage of CPP group was higher than that of PPP group(P=0.042).Among the CPP subgroups,the onset age of idiopathic CPP group(I-CPP)was higher than that of pathological CPP group(P-CPP)(8.59±0.60 years VS 4.17±2.94 years,P<0.001).2.The LH and FSH of CPP group were higher than those of PPP group(4.41(2.81,6.36)IU/L VS 0.15(0.1,0.34)IU/L P<0.001;3.46(2.30,4.77)IU/L VS 0.25(0.11,0.90)IU/L,P<0.001).There was no difference in testosterone between CPP group and PPP group(8.03(4.20,13.78)nmol/L VS 9.84(6.26,20.98)nmol/L,P=0.157).ACTH in CPP group was lower than that in PPP group(47.0(27.8,82.3)pg/mL VS 81.6(39.7,177.5)pg/mL,P=0.020),and cortisol in CPP group was higher than that in PPP group(10.81(7.55,14.3)ug/ml VS 8.07(4.01,12.11)ug/ml,P=0.046).There were no significant differences between I-CPP and P-CPP in LH and testosterone levels(4.19(2.86,6.53)IU/L VS 5.07(1.87,5.96)IU/L,P=0.667;7.75(4.07,13.00)nmol/l VS 10.14(4.20,17.15)nmol/L;P=0.702).3.The level of 17-OHP in children with congenital adrenal hyperplasia(CAH)was significantly higher than that of Familial male-limited precocious puberty(FMPP)and Germ cell tumor(GCT)(45.72(34.40,168)ng/ml VS 2.00(1.00,2.00)ng/ml VS 2.39(1.78,4.23)ng/ml,P<0.001).The level of HCG in GCT patients was significantly higher than that in CAH and FMPP(25.60(0.10,40.20)IU/L VS 0.10(0.10,0.10)IU/L VS 0.10(0.10,0.10)IU/L,P<0.001).4.Etiological composition:99 cases of PP in boys were divided into 10 etiologies,of which CPP was the main reason,accounting for 73.7%(73/99).In CPP group,I-CPP group was dominant,accounting for 80.8%(59/73).In P-CPP group,hypothalamic hamartoma(HH)accounted for 42.6%(6/14),followed by 14.3%(3/14)post bone marrow transplantation(14.3%,3/14)and CAH after treatment(14.3%,3/14).CAH accounted for 42.3%(11/26)in PPP group;GCT accounted for 34.6%(9/26);FMPP accounted for 15.4%(4/26).The proportion of all pathological PP was 40.4%(40/99),of which 14 cases(35.0%)were P-CPP(14/40).PPP accounted for 65.0%(26/40).5.Establish a simplified diagnostic process with testicular volume,GnRHa stimulation test,17-OHP and HCG as the main indicators.Conclusion:The etiology of PP in boys was varied,mainly CPP.The main cause of P-CPP in northern China is I-CPP.The primary cause of P-CPP is HH.The most common etiology of PPP was CAH,the second was intracranial GCT,and the third was FMPP.Part two:Diagnostic model for central precocious puberty in girls Background:Central precocious puberty(CPP)in girls is a common endocrine disease.Early sexual development can lead to early menarche,short stature,psychological problems and anxiety for family members and children.The clinical manifestations of premature thelarche(PT)and peripheral precocious puberty(non-CPP)in girls are sometimes difficult to distinguish from CPP,and the current clinical diagnosis is based mainly on clinical manifestations,basal sex hormones,bone age,pelvic ultrasound,and GnRH stimulation test.GnRH stimulation test involves repeated blood sampling,and usually requires hospitalization.At present,the existing models for diagnosing CPP include many indicators,but their sensitivity or specificity is limited,which cannot meet clinical needs.In order to more accurately improve the diagnostic efficiency of CPP in girls,this study intends to build a diagnostic model of CPP in girls based on the population in northern China.Objective:To establish a simplified and accurate prediction model for girl CPP,which is easy for clinical application.Methods:1.Subjects:163 girls with precocious puberty(PP)who were evaluated.All of the patients were recruited from December 2018 to December 2019 in the Children’s Hosptial Capital Institute of Pediatric.22 girls enrolled in the hospital from October to December 2021,who were used as the external validation population of the model.2.Methods:(1)Basel Data were collected;(2)Laboratory testing included measurements of Luteinizing hormone,follicle-stimulating hormone,estradiol,testosterone,insulin growth factor-1,INHB,anti-Müllerian hormone,thyroid function,25 hydroxyvitamin D and alkaline phosphatase;(3)Imaging data:bone age and pelvic ultrasound examination;(4)CPP is considered when LH peak value is higher than 6IU/L and bone age is one year older than chronological age.3.Statistical Methods:The factors influencing the diagnosis of CPP in girls were summarized by retrieving previous literatures on single-factor and multi-factor prediction models.Combined with the results of single-factor comparison of P<0.05 in this study,single-factor Logistic regression analysis was conducted with disease grouping as the dependent variable and screening variable as the independent variable.The effect size was expressed as OR value and its 95%confidence interval.Multifactor Logistic regression analysis was performed to draw the receiver operating characteristic curve(ROC),area under curve(AUC)and its 95%confidence interval were calculated to evaluate the predictive discrimination ability of the model,and corresponding sensitivity and specificity were calculated respectively.By drawing the correction curve between the predicted probability and the actual probability,the consistency of the prediction ability of the model is evaluated.We use decision curve analysis(DCA)to evaluate the diagnostic efficacy of the prediction model.Based on the results of multi-factor Logistic regression analysis,a disease prediction scoring tool was established according to the regression coefficient β value of each predictor.The prediction ability and calibration ability of the external population regression model were used for external validation.Results:1.A total of 163 girls were recruited in the model,including 92 CPP cases(56.4%,92/163)and 71 non-CPP cases(43.6%,71/163).The CPP group was significantly older than the non-CPP group(8.16±0.82 years vs.7.19± 1.14 years,P<0.001).Breast staging in CPP group was higher than that in non-CPP(P<0.001),but there was no significant difference between pubic hair staging(P=0.665).2.The LH in CPP group was higher than that in non-CPP group(0.76(0.32,2.36)IU/L and 0.16(0.09,0.43)IU/L,P<0.001).INHB in CPP group was higher than that in non-CPP group(57.90±26.56pg/ml VS 31.30±14.93pg/ml,P<0.001).The bone age of the CPP group was higher than that of the non-CPP group(10.11±0.86 years vs.8.66±1.70 years,P<0.001).Uterine volume of the CPP group were larger than those of the non-CPP group,ovarian volume with CPP group were also higher than non-CPP group,with statistical significance(P<0.05).3.Multi-factor Logistic regression model showed that LH(OR=1.238,95%CI:1.067-1.436,P=0.005),INHB(OR=1.066,95%CI:1.032-1.100,P<0.001),bone age(OR=1.563,95%CI:1.037-2.358,P=0.033)and uterine length(OR=1.180,95%CI:1.034-1.348,P=0.014)were the influencing factors for the diagnosis of CPP.Multi-factor Logistic regression prediction model AUC was 0.906(95%CI:0.852-0.959,P<0.001).The correction curve was basically distributed in the diagonals of the graph,and the consistency of prediction ability of the multi-factor Logistic regression model was good.The scoring system based on four variables(LH,INHB,bone age and uterine length)showed:When the total score was 12.5,the sensitivity and specificity of the diagnostic predictive scoring tool were 79.7%and 91.0%,and the AUC of the scoring system was basically consistent with that of the multi-factor Logistic regression prediction model(0.908 vs 0.906).External validation showed that the AUC of the model was 0.958(95%CI:0.887--1.000,P<0.001).Hosmer-lemeshow goodness of fit test shows that P=0.103.Conclusion:The diagnostic prediction model obtained in this study included four indicators including basal LH,INHB,uterine length and bone age.This model has certain reference value for clinical screening of CPP in girls. |
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