The causes of intrauterine growth retardation (IUGR) remains a challenge due to the complicated embryonic and fetal growth.More and more researches put their insights into the molecular pathogenesis.In this review,provide recent advances in the molecular pathogenesis of IUGR aimed at further understanding of this vexing medical problem.

Objective:To provide a normal reference range for anogenital distance (AGD) in full-term neonates and to investigate factors possibly affecting neonatal AGD.Methods:Neonates with gestational age ≥37 weeks who were delivered in the Ruijin Hospital Affiliated to Shanghai Jiaotong University School of Medicine from November 2017 to March 2019 were enrolled.General information on mothers and newborns were collected and neonatal AGD were measured.The distance from the male anus center to the base of the scrotum was determined to be the male AGD, and the distance from the female anus center to the posterior labia was recorded as the female AGD.The effects of maternal and neonatal factors on neonatal AGD were analyzed.Results:A total of 1 078 newborns were included, including 586 males and 492 females.Male AGD [(22.90±3.80) mm] was significantly greater than female AGD [(11.80±2.10) mm] ( t=22.316, P<0.05). The AGD of singleton neonates was significantly greater than that of neonatal twins [males: (23.01±3.82) mm vs.(21.18±1.88) mm, females: (11.89±2.08) mm vs.(10.98±1.75) mm, t=26.185, 18.326, all P<0.05]. Neonatal gestational age, birth weight, head circumference and length were significantly associated with AGD (all P<0.05). Maternal factors (including age, height, weight, body mass index, gravidity, parity, occupation, etc.) were not significantly associated with neonatal AGD (all P>0.05). The AGD of 10 children with genital malformation was significantly smaller than that of males with normal genital appearance [(22.89±1.99) mm vs.(23.55±3.78) mm]( t=15.362, P=0.006). Conclusions:The reference ranges of AGD in full-term males and females in Shanghai are(22.90±3.80) mm and (11.80±2.10) mm, respectively.The neonatal gestational age, birth weight, head circumference and length may be the intrinsic factors affecting neonatal AGD.

Objective To observe the final adult height (FAH) outcome and influencing factors in Turner′s Syndrome(TS) children treated with recombinant human growth hormone ( rhGH ).Methods Thirty TS children treated with rhGH were compared with 16 TS children without rhGH treatment and were followed up to achieve their FAH.Comparisons were made regarding predicted adult height (PAH),height standard deviation score for chronological age( HtSDScA ),height SDS for BA( HtSDSRA ),and growth velocity ( GV ) between rhGH treatment and without treatment groups and between the onset and by the end of rhGH treatment group.The factors determining FAH were also evaluated.Results FAH in rhGH treatment group was obviously improved as compared with untreatment group[ ( 149.5±6.3 vs 142.4±5.2) cm,P＜0.01 ].FAH in treatment group was positively correlated with height standard deviation score for chronological age ( Ht0 SDSCA ),Hto SDS for BA ( Hto SDSBA ),height age ( HA0 ) at preliminary diagnosis,and correlated with duration of rhGH therapy,duration of estrogen-free rhGH therapy,and PAH0SDS at preliminary diagnosis.Stepwise regression analysis indicated that duration of estrogen-free rhGH therapy and PAH0 SDS were the variables with the greatest identified influence on FAH (F =11.56 and F =86.91,P＜ 0.01 ).FAH in the 45,XO group was significantly different from the mosaicism group (45,XO/46,XX ) [ ( 147.2 ± 6.3 vs 153.3±6.4) cm,P =0.038].Conclusion rhGH treatment is efficacious in improving FAH of TS children,but a variability in the magnitude of the response to rhGH is recognized.Duration of estrogen-free rhGH therapy and PAH0SDS are the variables with the greatest identified influence on FAH,and karyotype may be one of the influence factors.rhGH treatment should be initiated as early as possible and sufficient course of estrogen-free rhGH therapy is needed to yield a satisfactory FAH.

Objective To assess the efficacy of gonadotropin-releasing hormone analogue(GnRHa)with or without recombinant human growth hormone(rhGH)treatment in Chinese short pubertal children with non-growth hormone deficiency.Methods Of 42 short pubertal children(14 males,28 females)without growth hormone deftcieney,the average age was(11.6±0.8)year.30 children were treated with slow release GnRHa with initial dose (100μg·kg-1·d-1,28d)and maintenance dose(60-80μg·kg-1·d-1,28d)labd rgGH with initial dose(0.15IU·kg-1·d-1)and maintenance dose(0.10-0.15IU·kg-1·d-1)for at least 1year.16 of them were still ongoing till the end of the second year.12 children were treated with GnRHa alone by initial dose(100μg·kg-1·d-1,28d)and maintenance dose (60-80μg·kg-1·d-1,28d),and 7 of them remained on it for 2 years.Dynamic changes including annual growth velocity(GV),bone age(BA)/chronologic age(CA)ratio,Tanner stage,height SDS for CA (HtSDSCA),height SDS for BA(HtSDSBA),and predicted adult height (PAHSDS)were observed.Results By the end of the first year tretment with combination therapy,the following parameters:GV,HtSDSCA,HtSDSBA,and PAHSDS all increased significantly(all P<0.05).Treatment with GnRHa alone did not yield significant changes in GV,HtSDSCA,HtSDSBA,and PAHSDS(all P>0.05).Changes in GV,HtSDSBA,and PAHSDS between these two groups were statistically significant(all P<0.05).By the end of the second year treatment,in the combination group,GV slowed from 6.7 to 5.5 cm/year(P<0.05).HtSDSCA,HtSDSBA,PAHSDS increased(all P<0.05).In the group with GnRHa treatment alone,GV slowed from 4.0 to 3.6 cm/year(P>0.05).HtSDSCA,HtSDSBA,PAHSDS increased(all P>0.05).Changes in GV,HtSDSCA,HtSDSBA,and PAHSDS between these 2 groups were statistically significant respectively(all P<0.05).Conclusion This combined treatment regimen significantly impreved the growth by increasing growth rate and delaying bone matumtion in pubertal chidren without growth hormone deficiency.Further study is needed to verify beneficial effects on the final height gain.

Objective To investigate the efficiency of radiofrequency ablation (RFA) and microwave ablation (MWA) in treating uterine leiomyoma.Methods The clinical data of thermal ablation with RFA and MWA were retrospectively analyzed in 42 patients.All patients were followed up at least 12 months to observe the therapeutic effects after the treatment.The changes of vital signs and the size of uterine leiomyoma,the score of uterine leiomyoma symptom and quality of Iife(UFS-QOL) were compared after RFA or MWA,the two thermal ablations techniques of clinic efficiency and influence on complications were analyzed.Results 23 patients received treatment of RFA and 19 patients received MWA,the visual analogue scale(VAS)during operation and postoperation were statistically significant differences between the two groups(P ＜0.05).The sizes of uterine leiomyoma were significantly reduced after the thermal ablation,the differences of volume within two groups in different time were statistics significance(P ＜0.05),but there were no statistics significance differences between two groups (P ＞0.05).The symptoms in two groups were improved significantly after treatment and the scores of UFS-QOL were no statistics significance differences between two groups (P ＞0.05).Conclusions Both of RFA and MWA have significant clinic efficiency in treating uterine leiomyoma.Compared with MWA,RFA with lower adverse reactions during operation and postoperation.

Objective To investigate the effect of short stature homeobox (SHOX) gene promoter-372G →A mutation on the promoter activity and its mechanism.Methods The luciferase report gene vectors containing human SHOX gene promoter-372G or -372A were contructed.Their transcription activities were detected in chicken chondrocytes.Double-stranded DNA probes containing-372G or-372A were produced by PCR,and used for detecting the affinity with nuclear transcription factors by electrophoretic mobility shift assay(EMSA).Results The transcription activity in a-372A promoter construct was significantly higher than that in the wild type-372G (P<0.01).The result of EMSA showed that-372A gene mutation resulted in loss of the binding affinity to nuclear transcription factors.Conclusion The-372A mutation increases SHOX promoter activity with decreased DNA binding affinity to transcription factors,which may contribute to impaired long bone growth in patients with idio pathic short stature.

Objective To detect the relationship between the molecular defects and their phenotypes in children with growth hormone insensitivity syndrome (GHIS).Methods 21 patients defined as GHIS were enrolled in the study.4 candidate genes (GHR,IGFALS,JAK2,and STAT5B) were analyzed by genomic DNA sequence screening and clinical relevance analysis.Results The statistical descriptions of the patients were showed as an average height standard deviation (SDS)-4.33 ± 1.91 (-9.17 to-2.21),average serum peak values of GH (22.67 ±20.98) tg/L (11.33 to 104.21 μg/L),basal serum insulin-like growth factor-Ⅰ SDS-2.65 ± 0.53 (-3.57 to -1.79),insulin-like growth factor-binding protein 3 SDS-1.77 ± 1.64 (-4.13 to 0.96).Bone age of backward difference (chronological age-bone age) (43.10 ± 19.54) months (6 to 82 months).One of two children with severe growth failure and mid-face hypoplasia was found to a homozygote for G to A gene mutation in the intron 6 splice donor consensus sequences (IVS6 ds+ 1 G-A) in the GHR gene,causing its functional defect.3 cases with mild dwarf were found gene variations as novel finding:c.1097T＞C c.1098C＞T p.V366A pathogenic variant,c.1229C＞T p.S410L and nt1843707 A→G of 5' UTR region in the IGFALS gene.JAK2 and STAT5b genes mutations were not found.Conclusion Molecular pathology of GHIS is considered as involving the defects of GHR and its signal pathway.The mutation of intron 6 splice donor sequences in GHR gene has been reported which affect the function of GHR.The 3 novel type base variants in IGFALS gene,causing non severe dwarfism,might be suspected with pathogenic roles of GHIS.

Objective To explore the causes of ambiguous genitalia.Methods Clinical data of 106 cases with ambiguous genitalia from Ruijin Hospital of Shanghai Jiaotong University School of Medicine were retrospectively analyzed.DNA fragments of related genes from parts of patients were amplified by means of polymerase chain reaction (PCR) and were directly sequenced to detect gene mutations.Results (1)The 106 ambiguous genitalia patients presented a variety of clinical phenotypes.Karyotype of 42 cases(39.6％)were 46,XX,while 62 cases(58.5％)were 46,XY and 2 cases(1.9％)were abnormal.(2)Forty(95.2％)patients with 46,XX were diagnosed with congenital adrenal hyperplasia(CAH) ;one case(2.4％) was adrenal cortical tumor and one case (2.4％) was 46,XX [sex determining region of Y choromosome (SRY) positive] male syndrome.(3) Fifty-three cases (85.5 ％) out of 46,XY karyotype were directly sequenced with steroid-5-alpha-reductase,alpha polypeptide 2 gene (SRD5A2),androgen receptor gene (AR) and steroidogenic factor-1 gene(SF-1).Sequencing analysis of SRD5A2 revealed 8 patients with compound heterozygous or homozygous mutations.A patient carried a novel missense mutation of SF-1 and another patient had a mutation of AR.(4) One abnormal karyotype was 46,XX/46,XY and the other was 46,XX/46,XY/46,X.+ may.ish (DYZ3 +) (DXZ1-).Conclusions (1) CAH is the most common cause of genital ambiguity in 46,XX patients but some rare causes such as adrenal cortical tumors or SRY positive should not be ignored.(2) To find the causes of 46,XY genital ambiguity,direct DNA sequencing analysis of candidate genes would be the better choice because of the complicate pathogenesis.(3)Abnormal karyotype also can lead to ambiguous genitalia.

Objective To explore the value of amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) in evaluating the efficacy of therapy with recombinant human growth hormone ( rhGH ) in patients with idiopathic short stature (ISS) and isolated growth hormone deficiency ( IGHD ).Methods Forty-eight prepubertal children( IGHD n=25,ISS n=23 ) treated for at least 1 year with rhGH were included.Serum insulin-like growth factor- Ⅰ ( IGF- Ⅰ ) and NTproCNP levels were measured before starting treatment and 6 months later.Twelve months after starting treatment,all patients were assessed and annual growth velocity ( GV ),height standard deviation score ( HTSDS),and gained HTSDS (△HTSDS) were recorded.Results In GHD group,positive relationships between GV and change of IGF- ISDS( △IGF- ISDS ),GV and change of NTproCNP concentrations(△NTproCNP) were found( r=0.407,P=0.044 ;r=0.490,P=0.013 ).GH peak value was also positively associated with IGF- ISDS and NTproCNP before therapy ( r =0.558,P =0.004; r =0.630,P =0.001 ).△IGF- ISDS and △NTproCNP were positively associated after therapy ( r =0.466,P =0.019 ).In ISS group,GV was associated with △NTproCNP ( r=0.845,P＜ 0.01 ).Conclusions NTproCNP is a novel biomarker of growth as its level increases during growth-promoting treatment.Furthermore,IGF- Ⅰ is also valuable in evaluating the efficacy of rhGH therapy in short stature patients.

Objectives To evaluate final adult height(FAH), lipid profile, sexual development, and quality of life in individuals with childhood-onset growth hormone deficiency (CO-GHD) during the transition from childhood to adulthood, to reassess the function of GH-IGF-I axis, and to explore effective managements for different types of GHD in each period. Methods Totally 80 CO-GHD patients were divided into 2 groups; 22 patients with isolated growth hormone deficiency ( IGHD) and 58 patients with multiple pituitary hormone deficiencies (MPHD); 62 male (age ≥18 years) and 18 female ( age ≥ 16 years) patients. The clinical and biochemical parameters, education and occupation, rhGH, and other hormones therapy in the past were followed up. Results rhGH replacement improved FAH of patients with GHD. The incidences of either hyperlipidemia (39.0% , 47.4%) or fatty liver disease (26.8%, 31.6%) showed no statistically significant changes between 2 groups with and without rhGH replacement. Mean value of IGF-I SDS was significantly higher in IGHD group than that in MPHD group (-1.43±0. 31,-3. 01 ±0. 66) ,and also IGFBP3(-2. 10±0. 33,-3. 17±0. 19,all P< 0.05 ). Patients with IGHD had normal sexual development, but the incidence of sexual dysfunction accounted for 79.7% in MPHD group. Conclusions rhGH improves FAH of individuals with CO-GHD. Patients with CO-GHD should be followed during the transition period; GHD patients carry a high risk of metabolic abnormalities in the adulthood; IGHD female can give birth to offsprings; patients with MPHD have gonadotrophin deficiency of varying degrees.