Cell Cycle Kinetics and Sister Chromatid Exchange in Mosaic Turner Syndrome.

Turner syndrome (TS) is caused by a complete or partial absence of an X or Y chromosome, including chromosomal mosaicism, affecting 1 in 2500 female live births. Sister chromatid exchange (SCE) is used as a sensitive indicator of spontaneous chromosome instability. Cells from mosaic patients constitute useful material for SCE evaluations as they grow under the influence of the same genetic background and endogenous and exogenous factors. We evaluated the proliferation dynamics and SCE frequencies of 45,X and 46,XN cells of 17 mosaic TS patients. In two participants, the 45,X cells exhibited a proliferative disadvantage in relation to 46,XN cells after 72 h of cultivation. The analysis of the mean proliferation index (PI) showed a trend for a significant difference between the 45,X and 46,X+der(X)/der(Y) cell lineages; however, there were no intra-individual differences. On the other hand, mean SCE frequencies showed that 46,X+der(X) had the highest mean value and 46,XX the lowest, with 45,X occupying an intermediate position among the lineages found in at least three participants; moreover, there were intra-individual differences in five patients. Although 46,X+der(X)/der(Y) cell lineages, found in more than 70% of participants, were the most unstable, they had a slightly higher mean PI than the 45,X cell lineages in younger (≤17 years) mosaic TS participants. This suggests that cells with a karyotype distinct from 45,X may increase with time in mosaic TS children and adolescents.

Body composition, but not insulin resistance, influences postprandial lipemia in patients with Turner's syndrome.

OBJECTIVE: The aim of the present study was to examine the influence of body composition and insulin resistance on the magnitude of postprandial lipemia in patients with Turner's syndrome receiving oral versus transdermal estrogen replacement. METHODS: Twenty-five patients with Turner's syndrome receiving oral or transdermal estrogen replacement were evaluated for body mass index, waist-to-hip and waist-to-height ratios, fasting glycemia, insulin, body composition (dual-energy X-ray absorptiometry), and postprandial lipid metabolism. For statistical analysis, we used parametric tests to compare numeric variables between the two subgroups. RESULTS: We observed no difference in postprandial triglyceride levels between patients receiving oral versus transdermal hormone replacement therapy. The postprandial triglycerides increment correlated positively with the percentage of total fat mass (p=0.02) and android fat mass (p=0.02) in the transdermal group. In the oral estrogen group, a positive correlation was observed between the increment in postprandial triglycerides and waist-to-hip (p=0.15) and waist-to-height (p=0.009) ratios. No association was observed between the estrogen replacement route and insulin resistance evaluated by the homeostatic model assessment-insulin resistance (HOMA-IR) index (p=0.19 and p=0.65 for the oral and transdermal groups, respectively). CONCLUSION: We concluded that body composition and anthropometric characteristics possibly affect the extent of postprandial lipemia independently from the route of estrogen replacement.

Body composition, but not insulin resistance, influences postprandial lipemia in patients with Turner's syndrome

ABSTRACT Objective: The aim of the present study was to examine the influence of body composition and insulin resistance on the magnitude of postprandial lipemia in patients with Turner's syndrome receiving oral versus transdermal estrogen replacement. Subjects and methods: Twenty-five patients with Turner's syndrome receiving oral or transdermal estrogen replacement were evaluated for body mass index, waist-to-hip and waist-to-height ratios, fasting glycemia, insulin, body composition (dual-energy X-ray absorptiometry), and postprandial lipid metabolism. For statistical analysis, we used parametric tests to compare numeric variables between the two subgroups. Results: We observed no difference in postprandial triglyceride levels between patients receiving oral versus transdermal hormone replacement therapy. The postprandial triglycerides increment correlated positively with the percentage of total fat mass (p=0.02) and android fat mass (p=0.02) in the transdermal group. In the oral estrogen group, a positive correlation was observed between the increment in postprandial triglycerides and waist-to-hip (p=0.15) and waist-to-height (p=0.009) ratios. No association was observed between the estrogen replacement route and insulin resistance evaluated by the homeostatic model assessment-insulin resistance (HOMA-IR) index (p=0.19 and p=0.65 for the oral and transdermal groups, respectively). Conclusion: We concluded that body composition and anthropometric characteristics possibly affect the extent of postprandial lipemia independently from the route of estrogen replacement.

Hiperplasia adrenal congênita / Congenital adrenal hyperplasia

A hiperplasia adrenal congênita (HAC) é um grupo de doenças de transmissão autossômica recessiva, em que os defeitos enzimáticos levam à síntese deficiente do cortisol e excesso de androgênios adrenais. A deficiência da 21?-hidroxilase é a forma mais frequente. Na HAC clássica o excesso de androgênios resulta em virilização e desenvolvimento de genitália ambígua no recém-nascido do sexo feminino e, quando não diagnosticada, alta mortalidade no sexo masculino. É necessário um diagnóstico preciso e urgência no início do tratamento para prevenir a mortalidade e as morbidades que acompanham esta doença. Os autores apresentam de forma prática e concisa como diagnosticar, tratar e prevenir complicações.

Pubertal development profile in patients with Turner syndrome.

INTRODUCTION: Puberty can be divided into two independent events: adrenarche and gonadarche. In healthy children, adrenarche is followed by gonadarche, but in patients with gonadal dysgenesis there is partial or complete dissociation between these two events. OBJECTIVE: To evaluate the age and chronology of the development of secondary sexual characteristics and occurrence of these events and their relationship to the induction of puberty in patients with Turner syndrome (TS). MATERIALS AND METHODS: A descriptive analysis with historical records of the patients with clinical and cytogenetic TS was conducted. The following variables were recorded: karyotype; age of thelarche, pubarche, and menarche; occurrence of spontaneous puberty; maintenance of puberty or secondary failure; and the onset of hormone replacement therapy (HRT) with estrogen. RESULTS: We evaluated 123 medical charts. Seven (5.7%) patients were prepubertal, 10 (8.1%) had only pubarche, and 5 (4%) had only thelarche. Forty-seven (38.2%) patients entered puberty spontaneously. Among these, 35 (28.5%) remained in puberty, and 12 (9.8%) required subsequent HRT; 54 (44%) had puberty induced. Sixty-six (56.9%) patients had pubarche started before thelarche. Menarche occurred in 67 patients, spontaneously in 19. Pubarche spontaneously presented in 91 (78.4%) patients, and in 25 (21.5%) after HRT introduction. CONCLUSIONS: Spontaneous puberty occurred in approximately one-third of the patients. Pubarche was the first feature in most patients and about 20% showed pubarche only after estrogen therapy.

Hipotireoidismo na criança / Childhood hypothyroidism

Hipotireoidismo é uma doença causada pela disfunção da glândula tireoide ou por deficiência do hormônio hipofisário estimulador da tireoide (TSH). Os autores apresentam as diversas etiologias e as peculiaridades da clínica, da investigação diagnóstica e das complicações da doença nas várias fases da vida da criança. Enfatizam detalhes da triagem neonatal, assim como a necessidade do tratamento precoce no hipotireoidismo congênito para prevenir o retardo mental irreversível...

Turner syndrome patients' ultrasound profile.

OBJECTIVE: Evaluate the uterus and ovary by ultrasonography, considering the genotype, pubertal development and hormonal levels. MATERIALS AND METHODS: Cross-sectional study of 53 (7-53 years old) patients with Turner syndrome considering pubertal development by Tanner stage, puberty induced or not and the ultrasound examination. RESULTS: The patients were 10 prepubertal and 43 with pubertal signs. Uterus was found adequate in 12 (57.1%) patients and all had spontaneous puberty. Hypoplasic uterus was found in all prepubertal patients and in 28 (52.8%) patients pubescent. The ovaries were visualized bilaterally in 32 (60%) patients and unilaterally in 15 (27.7%). Ovaries were appropriate bilaterally in eight (15.1%). In pubertal patients, the average volume being significantly higher in those with spontaneous puberty (p = 0.04 and 0.03, respectively). We found no significant difference in uterine volume, when considered estrogen route and karyotype. CONCLUSION: The ultrasonographic pattern in patients with spontaneous puberty without secondary failure was appropriate. The karyotype and the route estrogen therapy were not related to the standard of ultrasound study of the uterus and ovary.

Leydig cell tumour in a 46,XX child with congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CASE REPORT: A 10-year-old male was referred to our institution due to short stature and bilateral cryptorchidism and reported pubic hair development and acne since the age of 4 years. Laboratory and molecular genetic tests indicated congenital adrenal hyperplasia due to 21-hydroxylase deficiency. After treatment with prednisone, adrenal hormones normalised but testosterone remained elevated. Magnetic resonance imaging of the abdomen due to cryptorchidism revealed uterus and adnexal attachments, a prostate and poorly defined nodules on the iliac chains. Upon exploratory laparotomy, a hysterectomy, bilateral oophorectomy and resection of a peri-adnexal nodular lesion on the patient's right side were performed. Histopathology of the nodule mass was compatible with a Leydig cell tumour with a low proliferation rate according to Ki67.

Endocrine diseases, perspectives and care in Turner syndrome / Doenças endócrinas, perspectivas e cuidados na síndrome de Turner

Turner syndrome is a frequent chromosome disorder in clinical practice. It is characterized by short stature, gonadal dysgenesia and multisystemic involvement, responsible for a high morbidity and reduced life expectancy. The aim of the present paper is to describe the endocrinopathies and major problems at different ages, and to present suggestion for follow-up care in these patients.

A síndrome de Turner é uma doença cromossômica frequente na prática clínica. É caracterizada pela baixa estatura, disgenesia gonadal e alterações em diversos sistemas, o que leva a uma alta morbidade e diminuição da expectativa de vida. O objetivo do presente estudo é descrever as endocrinopatias e outros problemas em cada idade e apresentar uma sugestão de cuidados e segmentos dessas pacientes.

Endotelium in Turner syndrome with capillaroscopy / Endotélio na síndrome de Turner com capilaroscopia

OBJECTIVE: The aim of this study was to assess the endothelium function in patients with Turner syndrome using videocapillaroscopy and to compare the results with healthy control. METHODS: Subjects and controls were studied in a temperature-controlled room, 20 days after no nailfold manipulations. The capillaries were visualized by a microscope connected to a television and a computer. The test of post-occlusive reactive hyperemia was performed using a sphygmomanometer attached to the fourth left finger, 20mmHg above maximum arterial pressure during 1 minute, and the following patterns were studied: area of transverse segment, maximal post-ischemia area and time to reach maximal post-ischemia area. RESULTS: The value of measure of transverse segment projected area , the maximal postischemia area of hand nailfold capillary loops using computerized videophotometry and the time to reach maximal post ischemia area were studied in 40 patients with Turner syndrome and 26 healthy women controls of comparable age (20±7.5 versus 18±8.1 years old; p=0.57). There were differences between transverse segment area (706.8±139.1 versus 548.8±117.2; p=0.001). Maximal post-ischemia area (891.3±226.1 versus 643.5±134.3; p=0.001) and the time to reach it (10.8±4.3 versus 5.5±2.5; p=0.001) were different between patients and controls. CONCLUSIONS: Changes of capillary response to ischemia could be observed in patients with Turner syndrome using videocapillaroscopy when they were compared to a healthy control group.

OBJETIVOS: O objetivo deste estudo foi avaliar a função endotelial de pacientes com síndrome de Turner, utilizando a videocapilaroscopia e comparar os resultados com grupo controle saudável. MÉTODOS: Pacientes e controles foram estudados em sala com temperatura controlada, após 20 dias, sem a manipulação das cutículas. Os capilares foram visualizados por microscópio conectado a televisão e computador. O teste de hiperemia reativa pós-oclusiva foi realizado utilizando-se esfigmomanômetro fixado no quarto quirodáctilo da mão esquerda, 20mmHg acima da pressão arterial máxima durante 1 minuto, e os seguintes parâmetros foram estudados: área do segmento transverso, área máxima pós-hiperemia e tempo para alcançar a área máxima pós-hiperemia. RESULTADOS: O valor da área do segmento transverso, área máxima pós-hiperemia dos capilares da região da mão usando-se a videocapilaroscopia computadorizada e o tempo para alcançar a área pós-hiperemia foram estudadas em 40 pacientes com síndrome de Turner e 26 controles do sexo feminino pareados para idade (20±7,5 versus 18±8,1 anos; p=0,57). Houve diferenças nos grupos quanto à área do segmento transverso (706,8±139,1 versus 548,8±117,2; p=0,001). A área máxima pós-hiperemia (891,3±226,1 versus 643,5±134,3; p=0,001) e o tempo para alcançá-la (10,8±4,3 versus 5,5±2,5; p=0,001) foram significativamente diferentes entre pacientes e controles. CONCLUSÃO: Houve alterações na resposta do capilar à isquemia em pacientes com síndrome de Turner utilizando-se videocapilaroscopia quando comparados ao grupo controle saudável.

Isolated premature pubarche: report of anthropometric and metabolic profile of a Brazilian cohort of girls.

AIMS: Isolated premature pubarche (PP) is commonly caused by premature adrenarche (PA), and links between PA, children born small for gestational age (SGA) and insulin resistance have already been made in some populations. SUBJECTS AND METHODS: We assessed anthropometric data, pubertal landmarks and metabolic profile at diagnosis and during the study in 52 girls with the diagnosis of isolated PP from a Brazilian cohort. RESULTS: The prevalence of obesity (25%), dyslipidemia (63.5%) and born SGA children (21.2%) was greater among PP girls than in the reference population (4, 46.8 and 10%, respectively). There was no increase in the prevalence of insulin resistance and no correlation with birth weight, onset of PP or other pubertal signs. The Z score of heights at PP diagnosis was greater than the Z score of mid-parental height, but achieved final height (n = 16 girls, p = 0.002) was similar to normal population standards and to the predicted final height based on bone age at PP diagnosis (p = 0.08). Thelarche and menarche occurred at normal age, just earlier than expected. CONCLUSION: The prevalence of children born SGA, obese and dyslipidemic, but not of hyperinsulinemic children, was high in our cohort of PP girls. Puberty started earlier than usual but within the normal range.

Endocrine diseases, perspectives and care in Turner syndrome.

Turner syndrome is a frequent chromosome disorder in clinical practice. It is characterized by short stature, gonadal dysgenesia and multisystemic involvement, responsible for a high morbidity and reduced life expectancy. The aim of the present paper is to describe the endocrinopathies and major problems at different ages, and to present suggestion for follow-up care in these patients.

Septo-optic dysplasia.

Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction. We report 5 children with SOD, originally referred to be evaluated due to short stature, who also presented bilateral optic nerve hypoplasia, nystagmus and development delay. In 4 of the patients, we identified neuroimaging abnormalities of the hypothalamo-pituitary axis such as anterior pituitary hypoplasia (3/5), ectopic posterior pituitary (4/5), thin or absent stalk (3/5) and empty sella (1/5). We also encountered diverse pituitary deficiencies: growth hormone (3/5), adrenocorticotropic hormone (3/5), thyroid-stimulating hormone (2/5) and antidiuretic hormone (1/5). Only one child presented intact pituitary function and anatomy. Although rare, SOD is an important cause of congenital hypopituitarism and it should be considered in children with optic nerve hypoplasia or midline brain abnormalities for early diagnosis and treatment.

Septo-optic dysplasia / Displasia septo-óptica

Septo-optic dysplasia (SOD), also referred to as de Morsier syndrome, is a rare congenital condition, characterized by two of the classic triad features: midline brain abnormalities, optic nerve hypoplasia (ONH) and pituitary endocrine dysfunction. We report 5 children with SOD, originally referred to be evaluated due to short stature, who also presented bilateral optic nerve hypoplasia, nystagmus and development delay. In 4 of the patients, we identified neuroimaging abnormalities of the hypothalamo-pituitary axis such as anterior pituitary hypoplasia (3/5), ectopic posterior pituitary (4/5), thin or absent stalk (3/5) and empty sella (1/5). We also encountered diverse pituitary deficiencies: growth hormone (3/5), adrenocorticotropic hormone (3/5), thyroid-stimulating hormone (2/5) and antidiuretic hormone (1/5). Only one child presented intact pituitary function and anatomy. Although rare, SOD is an important cause of congenital hypopituitarism and it should be considered in children with optic nerve hypoplasia or midline brain abnormalities for early diagnosis and treatment.

A displasia septo-óptica (DSO, síndrome de Morsier) é uma condição congênita rara definida por dois critérios da tríade: defeitos de linha média, hipoplasia de nervo óptico e insuficiência hipotálamo-hipofisária. Descrevemos 5 casos de DSO, encaminhados por baixa estatura, com hipoplasia dos nervos ópticos, nistagmo e atraso global do desenvolvimento. Destes, 4 possuem alteração na ressonância magnética de sela túrcica e insuficiência hipotálamo-hipofisária, tendo sido observada adeno-hipófise hipoplásica (3/5), neuro-hipófise ectópica (4/5), haste afilada/ausente (3/5) e sela vazia (1/5), além de déficit dos eixos somatotrófico (3/5), adrenocorticotrófico (3/5), tireotrófico (2/5) e do hormônio antidiurético (1/5). Apenas um paciente não apresenta alteração anatômica ou funcional do eixo hipotálamo-hipofisário. Embora rara, a DSO é causa importante de hipopituitarismo congênito, devendo ser considerada em crianças com hipoplasia de nervo óptico ou defeito de linha média para seu diagnóstico e tratamento precoces, evitando seqüelas graves.

Indução da puberdade e terapia de reposição hormonal na síndrome de Turner / Puberty induction and hormone replacement therapy in Turner's syndrome

O objetivo da indução da puberdade com estrogênio em meninas hipogonádicas é alcançar o desenvolvimento físico e psicológico semelhante ao que ocorre na puberdade natural. Neste trabalho, descrevem-se os principais protocolos para indução da puberdde e de terapia de reposição hormonal (TRH) utilizados na síndrome de Turner. Revisão da literatura, associada à experiência dos autores, serve de base para a elaboração deste artigo, que propõe diretrizes no manuseio dessas pacientes. Constatou-se na literatura que os tipos de estrogênio mais utilizados foram o etinilestradiol e os estrogênios eqüinos conjugados. O estrogênio percutâneo na forma de gel foi o tipo de reposição mais aceito pelas pacientes do nosso ambulatório de Endocrinologia. Considerando a importância do uso de estrogênio nas adolescentes com hipogonadismo, propõe-se um protocolo de indução de puberdade e de acompanhamento às pacientes com síndrome de Turner

The aim of pubertal induction with estrogen in hypogonadal girls is to achieve physical and psychological development similar to that in the natural puberty. In this study we describe the main protocols for puberty induction and hormonal replacement therapy (HRT) used in Turner syndrome. A review of the literature, associated with the authors'experience, is the basis of this paper which proposes guidelines for the treatment of these patients. We have observed in the literature that the estrogens most commonly used are ethinylestradiol and conjugated equine estrogens. Moreover, percutaneous estrogen gel was the type of replacement most frequently accepted by the patients in our Ambulatory of Endocrinology Clinic. Considering the importance of the use of estrogen for teenagers with hypogonadism, we propose a protocol for puberty induction and follow-up of patients with Turner syndrome

IGF-I, IGFBP-3 and ALS generation test in Turner syndrome.

OBJECTIVES: The pathophysiology of the short stature in girls with Turner syndrome (TS) is not well understood. The "IGF-I generation test" is used to assess the sensitivity to growth hormone. We compared the biochemical response to four days of growth hormone of TS and controls. STUDY DESIGN: Pre-pubertal TS were recruited to participate in the study. Their siblings served as controls. IGF-I, IGFBP-3 and ALS were measured before and 5 days after using hGH (0.05mg/kg/day). Student-t test was used to compare the differences in their responses. RESULTS: Eleven TS (mean age of 8.5+/-2.4) and 11 siblings (6 females and 5 males) (mean age of 7.0+/-2.0) participated in the study. The basal serum levels of IGF-I, IGFBP-3 and ALS were normal and not different between groups (p=0.62 for IGF-I, p=0.91 for IGFBP-3 and p=0.51 for ALS). The IGF-I generation test was positive in all controls and in 10/11 TS. The IGFBP-3 generation test was positive in 6/11 controls and 4/11 TS. After hGH the mean IGFBP-3 was lower in TS than in controls (p=0.08). The ALS response to hGH was not uniform between groups. CONCLUSIONS: The IGF-I and ALS generation test results were not different between controls and TS. The IGFBP-3 results were higher in the control group but more than 50% of tested children did not pass. The IGF-I/IGFBP-3 generation tests, as presently done, did not help in the understanding of the short stature in TS. The use of different GH dosages and number of doses need to be investigated.

Insulin resistance and body composition in Turner syndrome: Effect of sequential change in the route of estrogen administration.

The aim of the present study was to examine the impact of sequential change in the route of estrogen administration on body composition and insulin resistance in patients with Turner syndrome (TS) using cyclical hormone replacement therapy (HRT) with conjugated equine estrogens (CEE) plus medroxyprogesterone acetate (MPA). We carried out a self-controlled study of nine non-obese patients with TS, with an average age of 23 +/- 4.9 years. Body mass index (BMI), waist-to-hip ratio (WHR), fasting glycemia, insulin tolerance (glucose disappearance constant during an insulin tolerance test, kITT) and body composition (dual-energy X-ray absorptiometry) were studied after 1 year's use of CEE plus MPA and repeated after 1 year's use of 17beta-estradiol gel with the same schedule of MPA administration. We did not observe any difference between the oral and percutaneous HRT with regard to BMI, WHR and insulin tolerance (kITT: 4.9 +/- 1.5 vs. 5.3 +/- 1.5%/min, p = 0.8). During administration of the 17beta-estradiol gel a tendency to increased total lean mass (p = 0.054) was observed. We conclude that sequential change in the route of estrogen administration in TS patients using cyclical HRT with CEE and MPA does not affect insulin resistance, although use of percutaneous 17beta-estradiol gel seems to exert favorable changes in body composition.

Decreased serum inhibin B/FSH ratio as a marker of Sertoli cell function in male survivors after chemotherapy in childhood and adolescence.

OBJECTIVE: Inhibin B produced by Sertoli cells may be an important marker of seminiferous tubule function in patients treated with chemotherapy (CT). The aim of this study was to evaluate the inhibin B/FSH ratio to detect male gonadal dysfunction in cancer survivors treated in childhood and adolescence. PATIENTS: Twenty-one male patients (group A) treated with 6-10 courses of CT for Hodgkin's disease during childhood and adolescence were examined 3-11 years after the conclusion of treatment. Twenty healthy young men (18-23 years old) were used as controls (group B). METHODS: Serum samples for the determination of inhibin B, follicle-stimulating hormone (FSH), luteinizing hormone (LH), testosterone (T), sex hormone-binding globulin (SHBG) and semen for analysis were collected. RESULTS: The median testicular volume of patients of group A was lower than those of group B (p = 0.001) and a positive correlation was found between testicular size and sperm count (r = -0.5, p = 0.01). Semen analysis revealed azoospermia in 11 patients, severe oligospermia in four and normal sperm count in three. No significant difference was found in the median of T, LH, SHBG, inhibin B concentrations and T/LH ratio between the groups. Serum inhibin B was correlated with the serum FSH levels (r = -0.5, p = 0.02). Median FSH was significantly higher (p = 0.0001), and median inhibin B/FSH ratio was significantly lower in group A than in controls (p = 0.0002), but the inhibin B/FSH ratio was higher in the patients with normal sperm count than in those with oligospermia (p = 0.00004). CONCLUSIONS: These results show that the cytotoxic effects of CT cause severe damage to the germinal epithelium with subtle effects on Sertoli cells. To assess Sertoli cell function in men with primary testicular damage after treatment with CT in childhood and adolescence, the inhibin B level needs to be interpreted in the context of the circulating FSH, especially when normal FSH levels are observed.