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Type II 3β-hydroxysteroid dehydrogenase/Δ(5)-Δ(4)-isomerase (3β-HSD2), encoded by the HSD3B2 gene, is a key enzyme involved in the biosynthesis of all the classes of steroid hormones. Deleterious mutations in the HSD3B2 gene cause the classical deficiency of 3β-HSD2, which is a rare autosomal recessive disease that leads to congenital adrenal hyperplasia (CAH). CAH is the most frequent cause of ambiguous genitalia and adrenal insufficiency in newborn infants with variable degrees of salt losing. Here we report the molecular and structural analysis of the HSD3B2 gene in a 46,XY child, who was born from consanguineous parents, and presented with ambiguous genitalia and salt losing. The patient carries a homozygous nucleotide c.665C>A change in exon 4 that putatively substitutes the proline at codon 222 for glutamine. Molecular homology modeling of normal and mutant 3β-HSD2 enzymes emphasizes codon 222 as an important residue for the folding pattern of the enzyme and validates a suitable model for analysis of new mutations.

In 2004, Costa-Santos and cols. reported 24 patients from 19 Brazilian families with 17α-hydroxylase deficiency and showed that p.W406R and p.R362C corresponded to 50% and 32% of CYP17A1 mutant alleles, respectively. The present report describes clinical and molecular data of six patients from three inbred Brazilian families with 17α-hydroxlyse deficiency. All patients had hypogonadism, amenorrhea and hypertension at diagnosis. Two sisters were found to be 46,XY with both gonads palpable in the inguinal region. All patients presented hypergonadotrophic hypogonadism, with high levels of ACTH (> 104 ng/mL), suppressed plasmatic renin activity, low levels of potassium (< 2.8 mEq/L) and elevated progesterone levels (> 4.4 ng/mL). Three of them, including two sisters, were homozygous for p.W406R mutation and the other three (two sisters and one cousin) were homozygous for p.R362C. The finding of p.W406R and p.R362C in the CYP17A1 gene here reported in additional families, confirms them as the most frequent mutations causing complete combined 17α-hydroxylase/17,20-lyase deficiency in Brazilian patients.

The Y-chromosome-located SRY gene encodes a small testis-specific protein containing a DNA-binding motif known as the HMG (high mobility group) box. However, mutations in SRY are not frequent especially in cases of 46,XY partial gonadal dysgenesis. Several sex-determining genes direct the fate of the bipotential gonad to either testis or ovary. In addition, heterozygous small deletions in 9p can cause complete and partial XY gonadal dysgenesis without other symptoms. Human DMRT1 gene, which is located at 9p24.3, is expressed in testis and ovary and has been considered, among others, a candidate autosomal gene responsible for gonadal dysgenesis. In this report we describe a nucleotide insertion in DMRT1 3'UTR in a patient of XY partial gonadal dygenesis. The 3'UTR+11insT is located within a conserved motif important for mRNA stabilization.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary cancer syndrome characterized mostly by parathyroid, enteropancreatic, and anterior pituitary tumors. We present a case of an 8-year-old boy referred because of hypoglycemic attacks. His diagnosis was pancreatic insulinoma. Paternal grandmother died due to repeated gastroduodenal ulcerations and a paternal aunt presented similar manifestations. At a first evaluation, the father presented only gastric ulceration but subsequently developed hyperparathyroidism and lung carcinoid tumor. During almost 15 years of follow-up, three brothers and the index case presented hyperparathyroidism and hyperprolactinemia. Molecular study showed a G to A substitution in intron 4, at nine nucleotides upstream of the splicing acceptor site, causing a splicing mutation. All affected members of the family have the same mutation. Paternal grandmother and aunt were not studied and the mother does not carry any mutation. MEN1 is a rare condition that requires permanent medical assistance. Early clinical and genetic identification of affected individuals is essential for their own surveillance and also for genetic counseling.

X-linked adrenoleukodystrophy (X-ALD) is an inherited disease with clinical heterogeneity varying from presymptomatic individuals to rapidly progressive cerebral ALD forms. This disease is characterized by increased concentration of very long chain fatty acids (VLCFAs) in plasma and in adrenal, testicular and nervous tissues. Affected individuals can be classified in different clinical settings, according to phenotypic expression and age at onset of initial symptoms. Molecular defects in X-ALD individuals usually result from ABCD1 gene mutations. In the present report we describe clinical data and the ABCD1 gene study in two boys affected with the childhood cerebral form that presented with different symptomatic manifestations at diagnosis. In addition, their maternal grandfather had been diagnosed with Addison's disease indicating phenotypic variation for X-ALD within this family. The mutation p.Trp132Ter was identified in both male patients; additionally, three females, out of eleven family members, were found to be heterozygous after screening for this mutation. In the present report, the molecular analysis was especially important since one of the heterozygous females was in first stages of pregnancy. Therefore, depending on the fetus outcome, if male and p.Trp132Ter carrier, storage of the umbilical cord blood should be recommended as hematopoietic stem cell transplantation could be considered as an option for treatment in the future.

Objective: To estimate body composition by evaluating skinfold thickness (ST) and electric bioimpedance (EB) in a group of women with congenital adrenal hyperplasia due to classical 21-hydroxylase deficiency (CAH-C-21OHD) in relation to a control group., Subjects and Methods: Sixteen patients and 26 controls were evaluated, all female, with age varying from 8 to 18 years. Fat (FM) and lean (LM) masses were evaluated by ST and EB. FM and LM data were analyzed in relative (%) and absolute (kg) values, and in relation to stature (FMI and LMI)., Results: There were no observed significant differences between the two methods in each group. In relation to the control group, CAH-C-21OHD patients showed higher values for FM (%) EB, FMI EB and LMI ST but lower values for FM (%) EB. Positive and high correlation values were observed for all parameters analyzed., Conclusion: ST and EB results observed were similar in this sample of females with CAH-C-21OHD, but controversial in relation to the control group, suggesting caution when using these methods to evaluate body composition in this population.

The objective of this study was to describe the change in diagnosis and prognosis of a child with testicular dysgenesis and 46,XY karyotype after detection of a 45,X cell line and to discuss the difficulties caused by the terms mixed gonadal dysgenesis (MGD) and XY partial gonadal dysgenesis (XYPGD). One case was reported including clinical and laboratory findings of a child of 41-day-old infant with 1.3-cm phallus, penoscrotal hypospadias and left prepubertal testis. Karyotype 46,XY (16 cells), normal hormone levels. Right streak gonad, epididymis and müllerian remnants were removed; initial diagnosis was XYPGD. Persistent growth retardation led to further cytogenetic analysis (50 cells) and detection of a 45,X cell line. Detection of a 45,X lineage changed both the diagnosis to MGD and also the prognosis.The number of cells analyzed in karyotyping is critical. Use of MGD and XYPGD to designate both a histological picture and a syndromic diagnosis, results in lack of emphasis on clinical differences between 46,XY and 45,X/46,XY subjects.

Objective: To evaluate clinical and laboratory profiles of patients with type 1 diabetes mellitus in three public hospitals in São Paulo, Brazil, since type 1 diabetes mellitus is a chronic illness that occurs mainly in the pediatric age group in the Brazilian population., Methods: Cross-sectional study with patients followed up in reference centers in São José do Rio Preto (FAMERP), Campinas (UNICAMP) and São Paulo (Conjunto Hospitalar do Mandaqui). Data about gender, age, diabetes duration, daily insulin dose, number of daily insulin injections, and glycosylated hemoglobin (HbA1c) were analyzed., Results: Two hundred and thirty-nine patients (131 females) were evaluated; mean age was 13.1+/-4.7 years and mean diabetes duration was 6.6+/-4.2 years. Daily insulin doses ranged from 0.1 to 1.78 units/kg/day (0.88+/-0.28), and 180 (74.7%) patients had two daily injections. HbA1c ranged from 4.6 to 17.9% (10.0+/-2.3%)., Conclusions: Although the hospitals included in this study are excellence centers for the follow-up of patients with diabetes in three municipalities in the state of São Paulo, one of the most developed states in Brazil, blood glucose control evaluated according to HbA1c was not adequate. Findings confirm that, despite the efforts of all the professionals involved, great challenges still lie ahead.

Aim: To evaluate body composition of black and white schoolchildren in Brazil., Methods: The study included 1,443 children aged 6-11 years, both genders, black and white skin colors. The measures of weight, height, BMI, brachial perimeter, tricipital and subscapular skinfolds, lean and fat area of the arm were transformed into standard deviation scores (SDS)., Results: As to frequency of variables under -2 SDS, only arm perimeter and lean area of the arm in both white and black schoolchildren showed results over 7%, but tricipital and subscapular skinfolds, fat area of the arm, sum of skinfolds and fat percentage, in both skin colors, presented results close to zero. As to frequency of variables over +2 SDS, only fat percentage presented results over 5% in both skin colors., Conclusion: The present study did not find important differences in body composition between black and white schoolchildren in this group of the Brazilian population.

Objective: To evaluate age of menarche and anthropometric data of schoolgirls of different socioeconomic levels in Cascavel, state of Parana, in Southern Brazil., Methods: A cross-sectional study was carried out in 2006 with 2,761 girls evaluated in 27 private and public schools. Age at menarche was obtained by the status quo method. Sexual maturity was assessed by self evaluation, according to Tanner's criteria. Socioeconomic level was obtained through the ABEP (2003) questionnaire. Data of weight, stature and Body Mass Index (BMI) were obtained. Data were analyzed by descriptive statistics and Mann-Whitney test at 5% significance., Results: Age at menarche was 12.2+/-1.2 years in the whole sample, and was 12.1+/-1.1; 12.3+/-1.2 and 12.4+/-1.2 in girls from high, medium and low socioeconomic levels, respectively. Post-menarche girls aged 10-17 years had higher values of stature and weight and girls aged 11-14 years had higher BMI., Conclusions: Age at menarche was lesser in girls from a higher socioeconomic level. Although these differences had been found in distinct socioeconomic levels, they were considered biologically small.

Objective: To evaluate the nutritional status of pupils from public schools of two cities in the western part of the state of Parana according to socioeconomic status and race., Methods: 1,443 children (aged 6 - 11 years) of both genders, classified as white or black and with different socioeconomic status were evaluated by weight, height and body mass index, transformed into the z score. A descriptive analysis of the data was performed, and the chi-square test, Fisher's exact test, variance analysis and linear regression with significance of 5% were used., Results: In the low socioeconomic status black pupils were predominant. Black boys presented lower values in weight and height in relation to white boys. When values of the z score lower than -2 were considered, white girls predominated in weight and height and black boys in height. No significant difference was found in values above +2. Low interaction of socioeconomic status and age was observed to predict weight, as well as for socioeconomic status, age and color of the skin, for height., Conclusion: Despite socioeconomic and racial differences found, there was no important variation of the nutritional status in the group of schoolchildren evaluated.

Objective: To verify the influence of programmed physical activity on body composition among adolescent students during 1 school year., Methods: The sample included 383 students (age range: 10 to 15 years) separated into two groups: 186 cases (96 male and 90 female) and 197 controls (108 male and 89 female). This was an intervention study with pre- and post-test assessments in which interventions consisted of programmed physical activity; the control group had conventional school physical education. Body composition was assessed by anthropometric measurements, body mass index (BMI), body fat percentage and fat and lean body mass., Results: In the case group, subscapular skinfold thickness, BMI, body fat percentage and fat body mass remained stable; there were significant reductions in tricipital skinfold thickness and in abdominal perimeter among girls and significant increases in arm, waist and calf perimeters and in lean body mass. In the control group, there were significant increases in BMI, tricipital skinfold thickness, abdominal perimeter and fat body mass among girls. At post-test, overweight and obesity significantly decreased among case group subjects, but not among controls., Conclusion: Programmed physical activity resulted in improvement or maintenance of body composition parameters and in reduction of overweight and obesity in the intervention group.

Aim: To present phenotypic variability of WT1-related disorders., Methods: Description of clinical and genetic features of five 46,XY patients with WT1 anomalies., Results: Patient 1: newborn with genital ambiguity; he developed Wilms tumor (WT) and chronic renal disease and died at the age of 10 months; the heterozygous 1186G>A mutation compatible with Denys-Drash syndrome was detected in this child. Patients 2 and 3: adolescents with chronic renal disease, primary amenorrhea and hypergonadotrophic hypogonadism; patient 2 had a gonadoblastoma. The heterozygous IVS9+4, C>T mutation, compatible with Frasier syndrome was detected. Patient 4: 9-year-old boy with aniridia, genital ambiguity, dysmorphisms and mental deficiency; a heterozygous 11p deletion, compatible with WAGR syndrome was detected. Patient 5: 2 months old, same diagnosis of patient 4; he developed WT at the age of 8 months., Conclusions: Constitutional abnormalities of WT1 cause gonadal and renal anomalies and predisposition to neoplasia and must be investigated in patients with ambiguous genitalia, chronic renal disease and(or) Wilms tumors; primary amenorrhea with chronic renal disease; and aniridia, genital ambiguity and dysmorphisms.

Objective: To evaluate the profile of children with diabetic ketoacidosis (DKA) treated at the UNICAMP 'Hospital de Clínicas'., Methods: Retrospective and descriptive study of clinical and laboratory variables of 74 admissions related to 49 patients bearers of DKA, between January 1994 and December 2003., Results: Twelve patients were admitted more than once, 27 were females and ages ranged from 0.9 to 14.5 years. The mean time from DM1 diagnosis to admission was 3+/-3.1 years and 20 cases presented with DKA at the onset of DM1. DKA was severe in 51% and moderate in 30%, at admission 17 patients presented with shock and 13 coma. The time needed for normalization of glycemia, pH, and bicarbonate had a significant positive correlation with the initial value. Intravenous bicarbonate was administered in only 3 admissions. The initial potassium value ranged from 3.1 to 5.9 mEq/l; in 8% the value was lower than 3.5 and in 62% higher than 4.5. Hypoglycemia occurred in 10 admissions and cerebral edema and death in one. The total time of treatment had a significant correlation with the time of fluid replacement, place of admission and time needed for pH normalization., Conclusion: The analyzed sample showed a predominance of female patients, less than ten years of age with a severe manifestation of the disease. However, evolution was good with few complications. Most of the admissions refer to a small number of patients.

Objectives: To estimate the prevalence of type 1 diabetes mellitus (DM1) and celiac disease association and to verify the existence of celiac disease symptoms, as well as the occurrence of other autoimmune diseases among the patients, their first-degree relatives and the possible influences of celiac disease in diabetes control., Methods: It was done a cross-sectional study with 195 patients that answered a questionnaire about gastrointestinal symptoms and the occurrence of autoimmune diseases in their first-degree relatives. IgA was measured and antiendomysial antibody (EMA) was screened. The patients with positive EMA were submitted to intestinal biopsy. Those with celiac disease confirmed by biopsy (case group) were paired with DM1 patients without celiac disease (control group) according to age on diabetes diagnosis, diabetes duration and gender., Results: EMA was positive in nine patients. In seven of them the biopsy has confirmed celiac disease (4.0%). Comparing the cases with controls, the gastrointestinal symptoms were significantly more frequent in the first group, but there was no difference between the groups regarding to the occurrence of autoimmune disease among the first-degree relatives and regarding to the control of diabetes (z weight, z height, insulin dose, HbA1c)., Conclusions: The prevalence found was 4.0%. This sample of celiac patients showed a predominance of gastrointestinal symptoms, although the celiac disease did not influence the diabetes control.

Context: Differentiation of testicular tissue in 46,XX individuals is seen either in XX males, the majority of them with SRY gene, or in individuals, usually SRY(-), with ovotesticular disorder of sex development (OT-DSD). Although they are sporadic cases, there are some reports on familial recurrence, including coexistence of XX maleness and OT-DSD in the same family., Objective: We report on a case of SRY(-) 46,XX monozygotic twins with genital ambiguity., Methods: Hormonal evaluation included testosterone, FSH, and LH measurements. SRY gene was investigated by PCR and two-step PCR in peripheral leukocytes and gonadal tissues, respectively. Direct DNA sequencing of the DAX-1 coding sequence was performed. Real-time PCR for SOX9 region on chromosome 17 was obtained., Results: Both twins had a 46,XX karyotype. Twin A had a 1-cm phallus with chordee, penoscrotal hypospadias, and palpable gonads. Serum levels of FSH (2.34 mIU/ml), LH (8.8 mIU/ml), and testosterone (1.6 ng/ml) were normal, and biopsies revealed bilateral testes. Twin B had a 0.5-cm phallus, perineal hypospadias, no palpable gonad on the right, and a left inguinal hernia. Hormonal evaluation revealed high FSH (8.2 mIU/ml) and LH (15 mIU/ml) and low testosterone (0.12 ng/ml). Upon herniotomy, a right testis (crossed ectopia) and a small left ovotestis were found. SRY gene was absent in both peripheral leukocytes and gonadal tissue samples. Neither DAX-1 mutations nor SOX9 duplication was identified., Conclusions: This case provides evidence that both XX maleness and XX OT-DSD are different manifestations of the same disorder of gonadal development.

Objective: To present the diagnostic criteria of genital ambiguity, the initial medical management and the attitude expected of pediatricians., Sources: Review of the scientific literature in the form of articles indexed on MEDLINE, in English and Portuguese, published between 1990 and 2007 and dealing with the pediatric age group., Summary of the Findings: Pediatricians have a fundamental role to play in the assessment of genital ambiguity, the purpose of which is to arrive at an etiologic diagnosis in the shortest possible time in order to define the patient's sex and plan treatment. There are specific diagnostic criteria, but, in general, genitalia are ambiguous whenever there is difficulty in attributing gender to a child. The pediatrician should inform the patient's family that assignment of their child's sex will depend upon detailed laboratory investigations, preferably carried out by a multidisciplinary team at a tertiary service. The 46,XX or 46,XY karyotypes are not alone sufficient to define the gender of rearing, although the test is fundamental to guide the investigation. When there are no palpable gonads, the first hypothesis should be congenital adrenal hyperplasia. Other causes included partial androgen insensitivity, 5alpha-reductase deficiency, partial gonadal dysgenesis and hermaphroditism. The family should be provided with support and information throughout the assessment process, and their participation is fundamental in the decision of which gender to rear the child in., Conclusions: Although cases of genital ambiguity are relatively rare for pediatricians, they should be well-informed on the subject and the correct management of these conditions, since they will often be responsible for the initial guidance that families receive and for maintaining contact between them and the multidisciplinary team.

Disorders of sex development have posed a tremendous challenge not only in the diagnosis but also in the treatment, placing the patient, the family members, and the health team in the difficult task of attributing the best sex of rearing for that specific patient. A confusing and stigmatizing nomenclature has been employed and the Chicago Consensus tried to minimize the discomfort with modifications of the current terminology. The authors perform a critical analysis of the Consensus, raising the question that the new terminology does not solve the problems and persist being stigmatizing to the patient and to the family. First of all, the inclusion of the karyotype in the name of the disease holds the false premise that the patients do not know the meaning of a 46,XY or a 46,XX karyotype. A child raised in the female sex will not understand that her disease holds a "male" karyotype in its name (46,XY DSD). The substitution of ovotesticular DSD for true hermaphroditism maintains the stigma of the name since ovotesticular is easily perceived as ovarian and testicular tissues. If, on one hand, the recognition of using terms like intersex and hermaphroditism are stigmatizing, on the other hand, we need terms that are really neutral to not create problems of sexual identification. One point in which there is consensus is that the change of the term "intersex" for "disorder of sex development" is highly desirable and eliminates the idea of an "intermediate sex".

Patients with Turner syndrome (TS) frequently exhibit transient, recurrent and asymptomatic variations of TSH and/or thyroid hormones (TH). This work was carried out to evaluate thyroid function and structure in patients with TS who had had such variations in hormone concentrations. Our sample comprised 24 patients, 17 less than 20-years old. Evaluation included serum levels of TSH, free T4, total T3, TPO and Tg autoantibodies, thyroid ultrasound (US) and scintigraphy with 99mTc-pertechnetate. Thirteen patients had abnormal TSH and/or TH levels; 23 exhibited US features compatible with chronic thyroid disorder, particularly thyromegaly (established according to volume expected for stature) and heterogeneous echogenicity. Uptake was normal in 21 cases and tracer distribution was homogeneous in 22. The finding of abnormal hormone concentrations was independent of age, length of time since the first similar finding, thyroid autoantibodies, number of abnormalities at US and abnormal scintigraphic findings. Patients aged more than 20 years had higher frequency of thyroid antibodies and heterogeneous echogenicity, and thyroid volume was significantly correlated to length of time since detection of the first hormone variation, indicating progressive thyroid disease. These results suggest that subclinical thyroid dysfunction in TS is due to chronic autoimmune thyroid disease.

Adrenal involvement by Paracoccidioides brasiliensis was described at necropsies and in many clinical studies, but only in adults. Therefore, the aim of this study was to evaluate adrenal function in children with paracoccidioidomycosis. Twenty-three children with the systemic form of paracoccidioidomycosis were evaluated and divided in two Groups: Group A (n = 8) included children before treatment and Group B (n = 15) children after the end of treatment. Plasma cortisol (basal and after ACTH test), ACTH, renin activity, aldosterone, sodium and potassium were measured. They were within normal range in all cases, except for renin activity and aldosterone, which were elevated in some cases. Group A patients showed basal and post-ACTH cortisol levels significantly greater than Group B patients. The results showed that adrenal function was not compromised in these children with paracoccidioidomycosis.

Objective: To evaluate the growth and body composition of pre-pubertal diabetic children, and to check for influence of the age of diabetes onset and length, sex, insulin requirement and glycosylated hemoglobin., Patients and Methods: 59 diabetic children (39 M; 29 F), age 1.2-11.5 years, and 67 controls (36 M; 31 F), age 1.2-11.7 years were included. Weight, height, body mass index (BMI), arm circumference, skin folds, fat mass and muscle areas were evaluated and transformed into standard deviation scores (SDS)., Results: Among the diabetic children the mean height SDS was -0.13 (+/- 0.97) while in the control group it was 0.28 (+/- 0.86) (p= 0.013). The difference between the first and the current height SDS showed that the height SDS decreased significantly (p< 0.001) and multiple regression analysis indicated correlation with the duration of the disease. The mean arm fat SDS also revealed difference (p< 0.001). The means for weight, BMI, addition of 3 skinfolds and muscle mass did not demonstrate difference between the groups., Conclusions: The diabetic children showed reduction of height SDS during the period studied and they were significantly shorter than the controls, even though their statures were within the population standards. The arm fat area also showed an increase in relation with the controls.

Aim: To analyze the changes in IGF-1, IGFBP-3, leptin and insulin after replacement doses of recombinant human growth hormone (rhGH) in short prepubertal children with chronic renal failure (CRF)., Patients and Methods: Eleven children (3F:8M), with mean age of 9.6 years, were treated with rhGH (0.23 mg/Kg weekly for 12 months). Serum leptin, insulin, glucose, IGF-1 and IGFBP-3 were measured before, 6 and 12 months after beginning rhGH treatment., Results: The serum levels of leptin, insulin and glucose did not vary during the treatment; normal leptin and glucose levels and high insulin were observed. There was a significant increment of IGF-1 and IGFBP-3 during the use of rhGH., Conclusions: The replacement doses of rhGH during 12 months in a selected group of CRF children determined an increment in IGF-1 and IGFBP-3, associated to normal serum leptin and insulin resistance.

Objective: To determine final height (FH) in congenital adrenal hyperplasia (CAH) patients and investigate conditions allowing better height outcome., Methodology: 13 salt-wasting (SW) and 14 simple virilizing (SV) patients were studied. FH and target height (TH) were transformed into standard deviation score (z). Data were analyzed according to sex, clinical form, age at treatment onset and length of treatment before attaining FH., Results: zFH (n = 27) was -1.57 +/- 1.01. FH (-1.50 +/- 1.03) was below TH (-0.78 +/- 0.84) (n = 25, p < 0.001). FH has not differed according to sex, clinical form and age at therapy onset although there was a trend towards better FH in SW patients and in early treated cases; there was significant difference (p = 0.018) between patients treated for less than 5 years (-2.49 +/- 1.03) and those accompanied longer than 10 years (-1.21 +/- 0.88) before attaining FH., Conclusions: There was a FH impairment and adult height improvement seems to depend mainly on early diagnosis and treatment.

Evidence from in vitro and animal studies suggests that members of the insulin-like growth factors (IGFs) system, including IGF-I, IGF-II, the IGF-I receptor (IGF-IR), and the IGF-binding proteins (IGFBPs) play a central role in the development and progression of cancer. More specifically, IGFs may promote cell cycle progression and inhibition of apoptosis either by directly associating with other growth factors or indirectly by interacting with other molecular systems, which have an established role in carcinogenesis and cancer promotion. In addition, a growing number of epidemiologic studies suggest that increased serum levels of IGFs and/or altered levels of their binding proteins are associated with increased risk for developing several malignancies. This review aims to summarize and to show the role of IGF system in tumor regulation, a revision of epidemiologic studies and the risk of neoplasia in patients (with or without personal history of previous neoplasia) who received growth hormone (rhGH). It is important to emphasize that the clinical use of rhGH, in the indications internationally approved, is secure, and there are not evidences, at this moment, of the association with neoplasias development.

Objective: The first Brazilian study aimed to evaluate body proportions in patients with Turner Syndrome (TS) with no growth hormone treatment., Methods: A cross-sectional study with 50 TS patients (5 to 43 years) evaluating age, karyotype, pubertal development, height, sitting height, arm span, weight, BMI, head circumference, length of hand, foot and leg, waist to hip ratio, biacromial and biiliac diameters. The data were transformed in score z. A descriptive analysis was done and Mann-Whitney test and analysis of variance was applied., Results: Twenty-eight patients were pubertal and 22 nonpubertal, and all of the absolute measurements were significantly increased in the former. There were no significant differences of the anthropometric findings according to the karyotype and puberty, in relation to score z data. The SD scores of all variables showed means above -2, except height and arm span in the nonpubertal patients and also sitting height and hand in the pubertal patients. The same result was observed when only the patients > 20 years were analyzed, being only weight, BMI, and biacromial and biiliac diameters significantly smaller in relation to the Danish data of Gravholt and Naeera from 1997., Conclusion: The retardation of growth in TS occurs mainly on the longitudinal axis, and the results showed in this study are similar to the Danish report.

Objective: Type 1 diabetes mellitus (DM1), the most important chronic endocrine-metabolic disease in children and adolescents, may lead to delayed growth and puberty. In this study we analyzed the influence of DM1 on growth spurt and puberty of patients whose onset of the disease was before or at the beginning of this phase., Patients and Methods: Data from 40 patients, 25 females, who had attained final height were retrospectively obtained, including duration of disease, patient's height and weight SDS at each consultation, parental target height, yearly growth velocities (GV), peak of growth spurt, duration of puberty, magnitude of growth spurt and glycated hemoglobin (HbA1C) levels., Results: 37 patients had an adequate final height to parental target height, and only 3 were below the lower limit. There was no significant association among the variables and the appropriate final height to the target height, except for GV on growth spurt, when it was lower than or equal to 6 cm/year. The age of onset of DM1 and the age of peak of growth spurt was similar to previously data reported; regarding the age of the onset of puberty, there was no delay. However, the magnitude of the growth spurt and the peak of GV were lower. According to HbA1C levels, all patients exhibited a bad chronic control of DM1., Conclusions: In this group of inadequately controlled patients, the final height was lower than expected when compared to the height at onset of DM1, probably due to a slow GV during puberty, which however had no influence on the final height to parental target height.

Objective: To evaluate the anatomical and cosmetic results of feminizing genitoplasty in girls with ambiguous genitalia due to Congenital Adrenal Hyperplasia (CAH)., Casuistic and Method: Twenty-seven females with genital ambiguity (Prader III-V) due to CAH underwent an one-stage feminizing genitoplasty and were followed for a mean time of 4 years. In twelve girls, two cutaneous labioscrotal island-flaps were associated with the conventional genitoplasty, to decrease the excess of labia majora and to enlarge the vaginal introitus. Urinary tract infections were observed in sixteen girls in the preoperative and in only seven in the postoperative period. The cosmetic results were obtained by the systematic anatomical evaluation of the different structures that compose the genitalia., Results: The results of clitoroplasty were considered good in 63% of the cases; however, 4 girls developed clitoral atrophy. An excess of labia majora was present in 25% and persistence of the urogenital sinus occurred in 11% (three children without labioscrotal island flap). The labioscrotal island flap was considered technically feasible and reproducible. Five girls had to be re-operated. The cosmetic results were considered excellent or good in 63% of the cases, satisfactory in 18.5% and unsatisfactory or bad in 18.5%., Conclusions: The anatomical and cosmetic results were good in majority of the cases; however, some technical aspects should be adjusted, to avoid irreversible sequels and re-operations.

Aim: To show data on true hermaphrodites (TH) followed in two reference centers in the state of São Paulo., Patients: Twenty-six TH patients have been followed from 1975 to 2004 in the Pediatric Endocrinology Unit, São Paulo University Medical School, and the other 10 patients from 1989 to 2004 in the GIEDDS-UNICAMP., Methods: Clinical and pathological data were retrospectively analyzed, as well as the decision about the sex of rearing., Results: Genital ambiguity was the most frequent complaint (34/36 cases) and the age at the first appointment was 20 mo (median). In 55.6% of the patients the female option was taken. The most frequent karyotype was 46,XX (47.2%), followed by mosaicisms (27.8%). SRY was negative in all 46,XX TH patients and the prevalent gonad was ovotestis (OT-47%), followed by ovary (OV-27%) and testis (TT-24%). The prevalent gonadal associations were OV+TT (30.5%), OT+OT (22.2%) and OT+OV (22.2%). The decision about the sex of rearing did not depend on karyotype, phallus size, and testosterone levels. However, the location of the urethral meatus was taken into account in this decision: 20 (80%) patients out of the 25 with perineal urethra were reared as females while all 11 with "non-perineal" urethra were reared as males. In five 46,XX patients reared as females it was possible to maintain the ovarian portion of the ovotestis., Conclusion: TH keeps on defying clinicians and investigators since most patients are 46,XX and SRY-negative, and yet they are able to develop testicular and ovarian tissues. The female sex of rearing seems to be the most adequate, and it is important to try to preserve, in these cases, the ovarian portion of the ovotestis, allowing the patient to have normal puberty and fertility.

Objective: To report the experience regarding patients with steroid 5alpha-reductase type 2 deficiency from three different clinical services in Brazil., Casuistic and Methods: Twenty five patients with clinical and hormonal features of 5alpha-reductase deficiency from 23 families (15 from Bahia, 7 from São Paulo and 1 from Minas Gerais) were included in this study. Clinical, hormonal and molecular data were evaluated. The molecular analysis of the five exons of the SRD5A2 gene was done by automatic or manual sequencing of PCR products., Results: In ten families, SRD5A2 mutations were found in homozygosis (5 with G183S, 2 with R246W, 1 with G196S, 1 with del642T, 1 with 217&#95;218insC), in three in compound heterozygosis (1 with Q126R/IVS3+1G>A, 1 with Q126R/del418T, 1 with Q126R/G158R) while other three were heterozygous, with only one deleterious mutation (1 with G196S, 1 with A207D, and 1 with R246W). In seven cases, no sequencing abnormalities were detected. The G183S substitution was the most frequently found among miscegenated patients (Afro-Euro-Brazilians) from Bahia. Hormonal and clinical findings did not differ between patients with or without mutations, exception made to a higher frequency of consanguinity and greater severity of genital ambiguity in the first group., Conclusion: Our results reinforce the importance of molecular investigation for the diagnosis of this disease and point out to the finding of a very frequent mutation (G183S) in our series, especially in patients with mixed ethnic background from Bahia, and the description of mutations that have only been reported in Brazilian patients so far.

We report on three patients with the clinical condition known as "XX male", which is uncommon in the pediatric age group. Patients have a male phenotype (usually without ambiguous genitalia) and testes; however, the karyotype is 46,XX. The diagnosis is usually made in adult life due to infertility; it may also be done by the pediatrician when there is ambiguous genitalia or gynecomastia. The SRY gene (Sex-determining Region of the Y chromosome) is detected in most cases, thus explaining the origin of testicular development; however, it is absent in 20% of the cases, thus indicating that gonadal determination is a complex process which depends on the interaction of many genes and transcription factors. The finding of only 3 cases in two reference services in a 30-year period indicates the rarity of this disorder among intersex cases.

The authors report a case of a virilizing adrenal tumor that developed in a 2-year-old child with Beckwith-Wiedemann syndrome (BWS). He had a fetal diagnosis of omphalocele and a history of neonatal adrenal cysts. The importance of prenatal diagnosis of BWS and postnatal follow-up of tumors is discussed. The differential diagnosis of adrenal pathologies occurring in BWS also is reviewed.

Investigation of the origin of sexual ambiguity is complex. Although testicular function has traditionally been assessed only by examining the steroidogenic capacity of Leydig cells and spermatogenesis, it has recently been shown that the measurement of serum anti-Müllerian hormone (AMH) as a marker of Sertoli cell function may also help clinicians. The aim of this study was to evaluate both Leydig and Sertoli cell functions in 46,XY patients with intersex states in order to establish biochemical patterns that would help to reach an etiologic diagnosis. We measured serum androgens, AMH and gonadotropins in 24 patients with sexual ambiguity and XY karyotype: 8 with gonadal dysgenesis (GD), 3 with 3beta-hydroxysteroid dehydrogenase deficiency (3betaHSD), 5 with androgen insensitivity syndrome (AIS), 4 with 5alpha-reductase 2 (SRD5A2) deficiency, and 4 were of unknown origin or idiopathic. Our results showed that while testosterone was low and gonadotropins elevated in patients with either GD or 3betaHSD, AMH was low in the former and high in the latter. Serum AMH and gonadotropins were normal or high in patients with 3betaHSD or AIS, but these could be distinguished by testosterone levels. Serum testosterone and gonadotropins were normal or high in AIS and SRD5A2 deficiency patients; however, while AMH was elevated in AIS, it was not the case in SRD5A2 deficiency patients, indicating that testosterone is sufficient to inhibit AMH within the testis. In idiopathic cases gonadotropins and testosterone were normal, and AMH was normal or low. We conclude that the combined measurement of androgens, AMH and gonadotropins helps to establish the diagnosis in intersex patients.

Sex ambiguity may be due to several disorders of gonadal differentiation, including true hermaphroditism (TH), as well as male and female pseudohermaphroditism. Although TH is a rare cause of intersex in Europe and North America, in Africa it presents one of the highest frequencies. The 46,XX karyotype has been found in the majority of the reported patients (70.6%), and aberrations in the sex chromosomes have been observed in about 22% of the cases. The 46,XY karyotype has been described as less frequent. Herein we describe ten cases of TH which have been diagnosed over the last 7 years, six lateral TH, two unilateral TH, and two cases of ovotestes with absent contralateral gonad. From a total of 18 gonads analyzed, there were 8 testes, 6 ovaries and 4 ovotestes. Nine subjects had originally a male sex assignment, and in three cases this was reverted to female. Four cases had a 46,XY karyotype. Additional sex chromosome aberrations had been found in four different cases [two 46,XX/46,XY, one 45,X/47,XYY, one 46,X,del(Yq)]. A 46,XX karyotype was found in only two individuals, and both were SRY negative. Our preliminary data, especially on the constitution of chromosomes and gonads, indicate marked differences from those in the literature.

Hypogonadotrophic hypogonadism can result from different abnormalities in the central nervous system. The clinical picture depends upon the time of onset the deficiency, the magnitude of the gonadotropins deficiency and whether there are other pituitary hormone deficiencies as well. We report on a 18-year-old boy, who was investigated because of pubertal and growth delay. He also had learning disabilities. On physical examination he exhibited mild eunuchoid aspect, 162 cm height (z score = 2.17), pubertal development on stage G II, P II, and 4 cm3 testis. Laboratory investigation revealed pre-pubertal levels of testosterone and normal results of the combined test of anterior pituitary function, except for in GnRH acute and prolonged test. Brain CT showed an arachnoid cyst on left middle fossa with expansion to suprasellar cisterna. He was diagnosed as having hypogonadotrophic hypogonadism secondary to compression by the cyst, and a cyst-peritoneal derivation was performed. After surgery there was no improvement of the pubertal state and bilateral anosmia was discovered, so Kallmann's syndrome was then diagnosed and was confirmed by MRI, even though the hormonal results are not totally matched with the referred syndrome. We did not find in the literature any description of the association between Kallmann's syndrome and arachnoid cyst and we believe that in this case the results of the hormonal measurement may be due to such association that provoked an additional hypophysis dysfunction.

This study reports on the usefulness of skin mast cell quantification (mast cells(mm2) as a parameter for the diagnosis of atopic dermatitis (AD) and for determining the efficacy of the therapeutic measures employed. Fifteen children with AD of moderate to extreme severity, and which started within the first two years of life, were studied. The therapeutic measures were limited to advice regarding the choice of adequate living conditions and of an appropriate diet in conjunction with the oral administration of hydroxyzine. Before treatment, 11 children with active AD were submitted to biopsies of both affected and non-affected skin. After treatment, in six children who were asymptomatic for at least one month, another biopsy was performed at a site of previous skin disease. A biopsy of a previously affected site was also performed in the other four children with a personal history of AD and who had no symptoms for more than one year. Treatment with hydroxyzine significantly reduced the number of papillar and reticular mast cells/mm3 of affected skin. In children who had been asymptomatic for one month, the number of papillar dermis mast cells/mm3 was greater than in those who had been asymptomatic for 12 months. In both groups of asymptomatic children, the number of mast cells/mm3 of affected skin was greater than in non-affected skin.(ABSTRACT TRUNCATED AT 250 WORDS)

We report on a 5-year-old girl with a male karyotype (46,XY), severe psychomotor and physical retardation, minor anomalies, and female external genitalia with a blindly ending vagina. She has normal adrenal function, prepubertal serum gonadotropin and testosterone levels, which did not rise after hCG stimulation. On abdominal exploration no gonads were found, and only mesonephric and Müllerian remnants. She was HY positive, and no deletion was detected in the Y chromosome using 5 different probes. Although a genetic defect is not excluded, pregnancy complications suggest an environmental insult to the developing testes.