Prediction of Pubertal Growth at Start of Estrogen Replacement Therapy in Turner Syndrome

In estrogen replacement therapy in Turner syndrome, there is no report which recommends the timing of the start of estrogen therapy in relation to height or adult height prediction. We have established a prediction model for pubertal growth (height difference from the start of estrogen therapy until adult height) at the start of estrogen replacement therapy. Twenty-seven Turner girls without spontaneous puberty were divided into two groups according to birth years; Group I consisted of 16 patients born from 1980–1989 and Group II consisted of 11 patients born before 1980. Using clinical characteristics from Group I, stepwise multiple regression analysis taking pubertal growth as an independent factor, and chronological age, bone age (TW2 RUS method standardized for Japanese children), height and height SDS as dependent factors revealed following formula (p<0.001, R2=0.737): (pubertal growth) = – 1.01x (Chronological age at start of E) – 0.326x (height at start of E) – 1.779x (bone age at start of E) + 90.997. Predicted adult height was obtained by adding predicted pubertal growth to height at the start of estrogen therapy. The mean absolute difference between real adult height (tallest height after height velocity less than 1 cm/yr) and predicted adult height was 1.6 ± 0.9 cm (0.3–2.8 cm) in Group I. When this prediction model was applied to Group II, The mean absolute difference between real adult height and predicted adult height was 1.0 ± 0.7 cm (0.1–2.0 cm). A prediction model for pubertal growth at start of estrogen therapy in Turner syndrome was obtained. Using this prediction model, the timing of the start of estrogen therapy can be decided in consideration of the patient’s desired adult height.     

The Impact of Paternal Alcoholism and Maternal Social Position on Boys' School Adjustment, Pubertal Maturation and Sexual Behavior: A Test of Two Competing Hypotheses

Two competing hypotheses concerning the effects of stressful environments on the onset of puberty were tested using longitudinal data for a sample of boys from low socioeconomic backgrounds. Paternal alcoholism and maternal social position were used as indicators of family stress. School placement was monitored from school entry to 14 years of age. Teachers rated the boys' disruptive and anxious behaviors, while the boys reported on parenting behaviors at 10 years of age. Pubertal maturation, age of first sexual intercourse and sexual behavior were assessed between 11 and 14 years of age. The prepubertal data indicated that boys with an alcoholic father, or a mother from a low social position, were more stressed and had more behavior problems: the boys with alcoholic fathers perceived their parents as being more punitive, and as setting fewer rules concerning their behavior; those who had at least one maladjusted parent were more often placed out of an age-appropriate regular classroom, and were rated more disruptive and more anxious by their teachers. Paradoxically, the results for the onset of puberty gave support to the two rival hypotheses. Paternal alcoholism led to a delay of male pubertal onset, as suggested by the hypothesis that stress activates the hypothalamic-pituitary-adrenal axis, and inhibits the hypothalamic-pituitary-gonadal axis. However, sons of alcoholic fathers had more frequent sexual intereourse and more sexual partners, as suggested by the evolutionary theory of socialization. High maternal social position acted as a protective factor for school placement of boys with an alcoholic father. These results challenged a key hypothesis of the evolutionary theory of socialization for males. They indicated that the link between childhood family environment, behavior development, pubertal maturation and sexual promiscuity are more complex than anticipated.     

Assessment of bone ages: Is the Greulich‐Pyle method sufficient for Turkish boys?

BACKGROUND: The Greulich-Pyle (GP) Atlas of skeletal maturation has been prepared in white children who born between 1917 and 1942 in the USA, and is frequently used for assessment of skeletal maturity. In this study, we investigated whether or not the GP method is sufficient for Turkish children for the determination of the skeletal age. METHODS: Plain radiographies of left hands and wrists of 225 healthy boys between 7 and 17 years of age were taken. Pubic hair (PH) stages of boys were determined by using the Tanner criteria. Mean chronological ages and mean skeletal ages according to GP Atlas were compared for each age groups and each PH stage. RESULTS: Mean skeletal ages were delayed 0.61, 0.72, 0.54, 0.39, 0.25, 0.39, and 0.32 years than the mean chronological ages in the 7-13 years age groups, respectively, and advanced 0.13, 0.01, 0.89, and 0.52 years in the 14-17 years age groups. In PH stages 1, 2, and 3, mean skeletal ages were delayed 0.67, 0.51 and 0.40 years than the mean chronological ages, respectively. In PH stages 4 and 5, mean skeletal ages were advanced 0.66 and 0.76 years than mean chronological ages. CONCLUSION: The results suggest that Turkish boys may have a different tempo of skeletal maturation during pubertal development from that of American children which GP standards were derived. Therefore, GP Atlas is not completely applicable to Turkish boys but can be used with some modification.     

先天性肾上腺皮质增生症的青春发育和治疗进展

21-羟化酶（21-OH）缺陷是先天性肾上腺皮质增生症最常见的类型,理糖和理盐激素分泌不足,雄激素过多分泌和孕激素及相关前体的过多堆积是其主要内分泌异常。21-OH缺陷患儿有青春发育异常、成年身高低下和远期生殖功能受损等表现,其机制涉及青春期皮质醇药代动力学改变,雄激素过多分泌所致下丘脑-垂体-性腺轴调控异常及其对性腺本身的损害和性腺内肾上腺残基瘤。治疗目标除了传统的以皮质醇抑制性替代治疗防止肾上腺危象和抑制雄激素分泌外,还亟需关注保护生长潜能、维护远期的性健康和生殖功能;但对高雄激素的满意控制至今仍是极大的挑战。该文叙述21-羟化酶患儿的青春发育、远期生殖力状况以及传统治疗以外的治疗进展。     

Growth and Maturation in the Male Genitalia From Birth to Adolescence I. Change of Testicular Volume

Testicular volumes of Japanese males from birth to adolescence were studied in cross-sectional series. Maturational events of testicular volumes occurred in the two periods during early infancy and adolescence. The testicular volumes during the first three months of life were slightly greater than later in infancy. Thereafter there was very little increase in testicular volumes from the age 1 to 10 years. After 11 years there was a sudden increase in size. The mean volumes increased from 6.5 cm³ at the age of 11 years to 36.7 cm³ at 14 years. The largest increment was observed between 13 and 14 years of age and between pubic hair stages I and II. Reaching testicular volumes of 6.5 cm³ was found to be a landmark of the earliest sign of puberty. The age at which pubertal development was initiated varied between the ninth and the fourteenth year of life.     

Morphogenesis of the human external male genitalia

The morphogenesis of the external genitalia of human fetuses (16-250 mm crown-rump [CR] length, 6–26 weeks of gestation) obtained after medical termination of pregnancy were studied. Differential development (male/female) started after 50 mm CR length (9 weeks). At that time the external genitalia consisted of a cylindrical genital tubercle 2 mm in length with a visible coronary sulcus and glans and genital swellings on either side. A groove on the ventral aspect of the genital tubercle extended to the coronary sulcus; the lateral boundaries of this groove separated to form the urethral folds. In male fetuses the free edges of the urethral folds fused, starting from the proximal end, to form a tunnel over the ventral aspect of the phallus. The pelvic urethra opened into this tunnel, slightly distal to its origin. The mesodermal tissue forming the genital swellings migrated ventrally and then medially. As medial migrationstarted, the skin in the midline between the genital swellings was raised up as a skin fold, which subsequently, as the genital swellings migrated further, became elevated. The proximal part of the tunnel formed by fusion of the urethral folds (proximal to the point of entry of the pelvic urethra) also was compressed and pushed out as the genital swellings fused in the midline over the root of the phallus. These changes took place at between 80 and 110 mm CR length (12–13 weeks' gestation); at this stage the phallus appeared short and was bent ventrally. With further growth and caudal migration of the scrotum, the phallus lost its ventral curvature. The appearance of the external genitalia at different gestational ages bore a close resemblance to that in children with hypospadias. We therefore conclude that hypospadias can be explained on the basis of an embryological arrest due to the absence of the required stimulus for male phenotypic development at the appropriate time.     

Height, weight, body mass index and pubertal development references for children of Moroccan origin in The Netherlands

AIM: To provide growth and sexual maturation reference data for Moroccan children living in The Netherlands and to compare them with the reference data of children of Dutch origin. METHODS: Cross-sectional growth and demographic data were collected from 2880 children of Moroccan origin and 14,500 children of Dutch origin living in The Netherlands in the age range 0-20 y. Growth references for length, height, weight, weight-for-height, body mass index (BMI) and head circumference were constructed with the LMS method. Predictive variables for height and BMI were assessed by regression analyses. Reference curves for sexual maturation were estimated by a generalized additive model. RESULTS: Moroccan young adults were on average 9 cm shorter than their Dutch contemporaries. Mean final height was 174.7 cm for males and 161.3 cm for females. Height differences in comparison with Dutch children increase from 2 y onwards. Height SDS was predominantly associated with target height. Compared to Dutch children, maturation started 0.2 and 0.9 y later for girls and boys, respectively. Median age at menarche was 12.9 y, 3.6 mo earlier than in Dutch girls (p = 0.001). BMI of Moroccan children was above that of Dutch children, especially for girls. BMI SDS was associated with birthweight in the age group 0 - < or = 5 y. CONCLUSION: Moroccan children living in The Netherlands are substantially shorter than Dutch children. Girls have higher weight-for-height and BMI for age. Median age at menarche occurs earlier. Given these differences, separate growth charts for the Moroccan children are useful.     

A Case Series of Five Sri Lankan Patients with Ovotesticular Disorder of Sex Development

Ovotesticular disorder of sex development (OT-DSD) is a rare disorder of sexual differentiation in which the gonads of an individual are characterized by the presence of both mature ovarian and testicular tissues. The objective of this paper is to report the clinical, cytogenetic and histopathological findings in Sri Lankan patients diagnosed with OT-DSD who were referred to the Human Genetics Unit for cytogenetic evaluation during 2005 to 2011. Five patients had histopathologically confirmed OT-DSD. Their ages at presentation ranged from 2 mo to 47 yr. Clinical symptoms varied from ambiguous genitalia and inguinal hernias at birth to a lower abdominal mass presenting in adulthood. All 5 were reared as phenotypic males. An ovotestis was detected in all cases except one, and the predominant karyotype was 46,XY. The findings in this series of predominantly 46,XY karyotype are in contrast to previously published reports that have reported 46,XX as being the predominant karyotype. It is therefore recommended that individuals with ambiguous genitalia who have the 46,XY karyotype should be thoroughly investigated by ultrasonographic or laparoscopic assessment to determine the exact nature of their internal genital organs. OT-DSD should also be considered in the differential diagnosis of patients with cryptorchidism and inguinal hernia.     

Acquired Cryptorchidism in a Boy with Disorder of Sex Development

Recently, it has been reported that boys with severe hypospadias are at increased risk for acquired cryptorchidism. The reports suggested that prenatal and postnatal androgen disruption might be correlated with this condition. We experienced a case of ovotesticular disorder of sex development (DSD), which was ultimately diagnosed at surgery for acquired cryptorchidism. Ascent of the scrotal contents of the left side was detected in a 7-yr-old boy with the 46, XX karyotype, who had a history of perineal hypospadias repair. Intraoperative findings revealed the left gonad consisted of 2 segments, and this was histologically diagnosed as ovotestis by biopsy specimen. Resection of the ovarian segment was performed simultaneously. Exploration of the contralateral gonad showed the same findings. This is the first report of acquired cryptorchidism observed in a patient with DSD presenting with ambiguous genitalia.     

Evaluation of the Ages and Stages Questionnaires in identifying children with neurosensory disability in the Magpie Trial follow-up study

AIM: To evaluate performance of the Ages and Stages Questionnaires (full ASQ), and a shortened version (short ASQ), in detecting children with severe neurosensory disability in the Magpie Trial follow-up study. METHODS: All children, born to women in the Magpie Trial and selected for follow-up, with a completed full 30 items and/or short 9-items ASQ were included in this analysis. Sensitivity and specificity, corrected for verification bias, were computed to assess detection ability. RESULTS: Of the 2046 children who completed a full ASQ, 406 (19.8%) failed the assessment, 54 of whom had confirmed neurosensory disability. Adjusted sensitivity and specificity (95% confidence intervals) were 87.4% (62.9-96.6%), and 82.3% (80.5-83.9%), respectively. Two of the five domains in the full ASQ (Fine Motor and Problem Solving) contributed little to detection ability. Sensitivity and specificity for the short ASQ were 69.2% and 95.7%, respectively. CONCLUSIONS: Sensitivity of the full ASQ for severe neurosensory disability is generally good, and does not appear to be much reduced by restricting questions to three out of the five domains. The short ASQ reported here reduced performance, although this might be improved by a different choice of questions or scoring system.     

Mutational Analysis of Androgen Receptor (AR) Gene in 46,XY Patients with Ambiguous Genitalia and Normal Testosterone Secretion: Endocrinological Characteristics of Three Patients with AR Gene Mutations

The prevalence of abnormalities in androgen receptor gene (AR) among patients with ambiguous genitalia is unknown. Moreover, endocrinological data from prepubertal patients with AR mutation are very limited. Thus, the aim of this study was to examine the prevalence of abnormalities in AR among patients with both ambiguous genitalia, which was defined as a combination of two or more genital abnormalities (i.e. hypospadias, microphallus (penile length < 25 mm), hypoplastic scrotum, bifid scrotum, undescended testis) in this study, and normal to elevated T levels. We also compared the endocrinological data of prepubertal patients with AR mutation and ambiguous genitalia with that of those without the AR mutation. We screened 26 Japanese prepubertal 46,XY patients (five from three families were included) with both ambiguous genitalia and normal to elevated T levels. Mutations in AR were found in three (two of the three were related). Among the 23 patients without mutation in AR, the steroid 5-alpha-reductase 2 gene (SRD5A2) was also examined in eight patients with elevated T/dehydrotestosterone ratio after the hCG (>10) or with undervirilized family members. No mutation in SRD5A2 was found. Characteristics of the three patients with mutation in AR were compared with the 23 patients without mutation. In two patients, basal T levels (0.3, 0.2 ng/ml) and peak T levels after the hCG tests (8.3, 8.5 ng/ml) tended to be higher, and the peak LH/ peak FSH ratios after the GnRH tests (4.6, 4.0) were higher than in patients without mutation, at the ages of 1 yr and 9 mo and 3 yr and 8 mo, respectively. In conclusion, an abnormality in either AR or SRD5A2 was not common among patients with ambiguous genitalia and normal testosterone secretion. Elevated peak LH/peak FSH ratio (≥4) after the GnRH test in addition to detectable basal T levels and elevated peak T levels after the hCG test may infer AR abnormality in prepubertal patients with ambiguous genitalia at the age of one and over, although further study is needed, because our data were limited.     

分娩方式对儿童神经精神发育影响的出生队列研究

目的评价分娩方式与儿童神经精神发育的关联。方法采用前瞻性母婴队列研究,于2013年和2014年采用年龄与发育进程问卷,从沟通、粗大动作、精细运动、解决问题以及个人-社会5个能区评价651名12和24月龄儿童的神经精神发育状况。以剖宫产为暴露组,阴道分娩为对照组,采用多因素logistic回归分析评估分娩方式与儿童神经精神发育的关联及关联强度。结果 12和24月龄儿童神经精神发育迟缓发生率分别为3.94%和13.12%。剖宫产对12月龄儿童神经精神发育无显著影响。调整妊娠期高血压、妊娠期糖尿病和家庭经济收入等因素后,24月龄剖宫产儿童沟通能区发育迟缓的发生风险显著增加,发病风险为阴道分娩组的3.37倍(95%CI:1.02～10.5,P0.05)。结论剖宫产可能增加24月龄儿童沟通能区发育迟缓的发生风险。     

不同发育时期大鼠肠道黏膜形态与树突状细胞发育活化的研究

目的 探讨不同发育时期SD大鼠肠道黏膜形态发育及树突状细胞发育与活化的关系.方法 25只SD大鼠随机分为五组,分别在3、5、7、9、11周应用图像分析检测技术及流式细胞技术检测幼鼠肠黏膜绒毛与肠集合淋巴结发育状况及肠树突状细胞发育及活化指标.结果 不同发育时期肠绒毛长度、绒毛宽度、绒毛面积、隐窝深度及绒毛长度/隐窝深度差异均有统计学意义(P<0.05);不同发育时期小肠集合淋巴结面积增加差异有统计学意义(P<0.05);随着周龄的增加,肠道OX62 总树突状细胞增加,OX62 /CD4-/OX41-亚型树突状细胞减少,同时,OX62 /CD4 /OX41 亚型树突状细胞增加,变化均有统计学意义(P<0.05).结论 随着周龄的增长,SD大鼠小肠绒毛-隐窝轴增殖分化,肠道树突状细胞逐渐发育与成熟,且两者的发育成熟状况基本同步.SD大鼠肠黏膜形态及黏膜免疫细胞早在断乳期就逐渐成熟,在7～9周时发育幅度最大,并在11周时逐渐达到成熟状态.断乳早期,食物改变会影响SD大鼠肠道黏膜形态发育及树突状细胞发育活化.     

年龄与发育进程问卷（中文版）评估上海市3~66月龄儿童神经精神发育春夏秋季的差异

目的 应用“年龄与发育进程问卷：父母完成的儿童发育监测系统”的标准化翻译中文版（ASQ-C）,研究上海市3～66月龄儿童在春、夏和秋季神经精神发育的差异。方法 于春、夏和秋季,在上海市3～66月龄儿童中分层随机整群抽样。共有8 472名儿童的父母和（或）养育人完成了儿童月龄相应的ASQ-C测试。儿童ASQ-C的量表总分及沟通（CM）、大运动（GM）、精细运动（FM）、解决问题（CG）和个人-社会（PS）能区得分以±s表示;多组样本均数的比较采用完全随机设计的单因素方差分析;两两比较采用SNK法。采用多元线性回归分析以排除混杂因素。结果 ①不同季节测试儿童的ASQ-C量表总分间差异有统计学意义（P＜0.01）,从高至低的排序是秋、夏和春季,秋季显著高于夏和春季（P＜0.05）,夏季与春季间差异无统计学意义;②不同季节测试儿童的ASQ-C 5个能区得分间差异均有统计学意义（P＜0.01或＜0.05）,均以秋季最高;其中CM能区得分从高至低的排序为秋、春和夏季,其他4个能区得分从高至低的排序均为秋、夏和春季。两两比较结果显示,CM能区得分秋季显著高于夏季（P＜0.05）,秋季与春季、春季与夏季间差异无统计学意义;其他4个能区得分均表现为秋季显著高于夏和春季（P＜0.05）。结论 季节对3～66月龄儿童的神经精神发育有影响;进一步研究季节或气候与儿童发育的关系很有必要;在儿童发育评估量表的研究中,建议考虑季节因素的影响。     

Basal Cells of Second Trimester Fetal Breasts: Immunohistochemical Study of Myoepithelial Precursors

The molecular characterization of human mammary myoepithelial cells is incomplete, hindering our understanding of its importance in breast physiology and pathology. Because data on the precursors of this cell lineage remain scarce and often contradictory, basal epithelial cells of second trimester fetal breasts were studied by light microscopy (LM) and immunohistochemistry (IHC). Up to 20 wk of gestational age, the mammary rudiments only comprised roundish primary outgrowths, primary buds, more likely to represent immature nipples than true mammary tissue. At 21 wk secondary outgrowths, projections, extended from enlarged primary buds into well-vascularized layers of dense mesenchyme. Basal projection cells had a partial myoepithelial-like phenotype: they reacted with CD29, CD49f, CD104, keratin 14, vimentin, S100 protein, and p63; furthermore, many became positive for keratin 17, -smooth muscle actin, and CD10 (but not for keratin 19) between wk 21 and 25. The continuous basement membrane associated with the fetal mammary rudiments was strongly positive for collagens type IV and VII, and for laminin 5. Consistently strong and basally polarized staining for hemidesmosomal components suggested that although incompletely differentiated, most second trimester myoepithelial precursors might already mediate local epithelial-mesenchymal interactions, i.e., complex signaling pathways which are crucial for both orderly growth during development and maintenance of homeostasis during adult life. Because they are likely implicated in the phenomenon of menstrual cycle-related growth spurts in the adult resting breast, the strategically positioned cells of the myoepithelial lineage might constitute critical protagonists in defective epithelial-mesenchymal signaling associated with cancer progression.