Inhibin A production after gonadotropin stimulus: a new method to detect ovarian tissue in ovotesticular disorder of sex development.

BACKGROUND/AIMS: While laboratory methods for the detection of testicular tissue are well standardized, currently there is no available test to demonstrate the presence of ovarian tissue. We evaluated the effectiveness of gonadal stimulation with luteinizing hormone (LH)/follicle-stimulating hormone (FSH) for the detection of ovarian tissue in patients with disorders of sex development (DSD). METHODS: Ten patients with congenital adrenal hyperplasia (CAH) as ovarian-positive controls, 10 with cryptorchidism (ovarian-negative controls), 13 patients with DSD of no defined etiology and 7 patients with ovotesticular DSD (true hermaphroditism, TH) were included in the study. They underwent a daily injection of both LH and FSH on 3 consecutive days. LH, FSH, estradiol, testosterone and inhibin A were measured before treatment, 24 h after the 1st dose and 24 h after the 3rd dose. RESULTS: Estradiol increased in all CAH and TH patients, with a median value of 155.1 and 92.6 pg/ml, respectively, after the 3rd injection. Inhibin A also increased in all CAH and TH patients, with a median value of 70.4 and 32.2 pg/ml, respectively, after the 3rd injection. There was no change in these hormones in the other groups. CONCLUSION: The LH/FSH stimulation test might be a useful method to detect the presence of ovarian tissue.

Evaluation of the hypothalamic-pituitary-adrenal axis in children with leukemia before and after 6 weeks of high-dose glucocorticoid therapy.

Among the adverse effects arising from chronic high-dose glucocorticoid treatment, adrenal insufficiency secondary to suppression of the hypothalamic-pituitary-adrenal (HPA) axis is a cause for concern. Glucocorticoid-induced adrenal suppression is related to the duration of therapy, type of steroid used and dosage, and schedule of glucocorticoid administration. To evaluate the suppression and recovery time of the HPA axis in children with acute leukemia, we performed the ovine CRH (oCRH) stimulation test in 15 patients, who were given high doses of dexamethasone as part of their induction chemotherapy for 42 days. The oCRH tests were performed before, and 7 and 14 days after, discontinuation of the glucocorticoid. The ACTH levels were not significantly different among the 3 tests. The cortisol levels, however, were significantly (albeit mildly) lower, both basally and after oCRH, 1 and 2 weeks post treatment than before therapy. Six patients had cortisol values that remained suppressed 2 weeks after discontinuation of therapy. One of these patients had manifestations of mild adrenal insufficiency, 6-8 days after discontinuation of therapy, but required no glucocorticoid coverage. We conclude that up to 2 weeks after discontinuation of 6 weeks of high-dose dexamethasone administration, the HPA axis of patients with acute leukemia is mildly suppressed but infrequently associated with clinical manifestations of adrenal insufficiency. This may indicate that major stress, when concurrent with glucocorticoid treatment, may prevent clinically significant adrenal suppression.

True hermaphroditism: clinical aspects and molecular studies in 16 cases.

Although true hermaphroditism (TH) accounts for less than 10% of intersex patients, it stands as a diagnostic challenge and has allowed a better understanding of the mechanisms involved in sexual differentiation. In this paper we review the clinical and laboratory data as well as molecular biology findings on 16 TH patients followed up at the Pediatric Endocrine Unit, Instituto da Criança, Hospital das Clínicas. São Paulo University Medical School. They were of a mean age of 3 years 8 months and nine of them were black. All the patients had ambiguous external genitalia as the main complaint. The 46,XX karyotype accounted for 50% of the cases and the ovotestis was the most frequent gonad found (59%). In the eight TH patients with a 46,XX karyotype, the sex-determining region of the Y chromosome (SRY) was negative, posing an intriguing question about the testicular differentiation mechanisms involved in these cases. In 7/19 ovotestes, the ovarian portion of the gonad has been preserved, keeping open the possibility of fertility. The female sex option was made in 10/16 cases (62.5%) and three patients exhibited spontaneous puberty. The mechanism through which testicular tissue develops without SRY has not yet been completely clarified, suggesting the involvement of the X chromosome as well as autosomal genes in the process.

Higher salt consumption, digoxin-like factor, and nifedipine response are associated with salt sensitivity in essential hypertension.

In addition to demonstrating evidences of increased sympathetic nervous system activity and marked left ventricular hypertrophy in salt-sensitive hypertensives, our group has also reported increased weight gain with salt overload in these patients. The increased weight gain suggests volume expansion, a situation already shown to increase plasma levels of a Na, K-ATPase inhibitor. Therefore, in the present study, digoxin-like factor (DLF) serum levels, spontaneous salt ingestion, nifedipine hypotensive effect, and plasma renin activity were evaluated in essential hypertensive subjects. Thirteen essential hypertensive outpatients were studied sequentially on an ad lib diet, a low salt diet (LSD = 30 mEq Na/day), and a high salt diet (HSD = LSD + 171 mmol/L NaCl/day), 1 week each. On the seventh day of LSD and HSD, DLF levels, mean blood pressure (MBP) response to nifedipine (10 mg sublingual), and plasma renin activity were measured. The MBP percent change from the seventh day of LSD to the seventh day of HSD (salt sensitivity) ranged from -13.7 to 20.9%. A positive correlation (r = 0.64, P < .01) was observed between salt sensitivity and 24-h urinary sodium excretion with an ad lib diet. The DLF serum levels correlated with the salt sensitivity both on LSD (r = 0.50, P < .05) and on HSD (r = 0.53, P < .05). Salt sensitivity was positively correlated with the difference of response to nifedipine between HSD and LSD (r = 0.78, P < .001). Plasma renin activity correlated inversely with DLF on LSD (r = -0.51, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Pituitary macroadenoma and Cushing's disease in pediatric patients: patient report and review of the literature.

Cushing's syndrome in pediatric patients has been rarely reported and most of the cases are due to adrenal tumors. When the etiology is an ACTH-secreting pituitary adenoma, most often it is a microadenoma. We report on a 9 year-old girl with an ACTH-secreting macroadenoma, whose surgical removal through transsphenoidal approach was extremely difficult due to invasion of the cavernous sinus as well as adjacent structures. After two surgical approaches and stereotactic radiotherapy, she still suffers from the deleterious effects of hypercortisolism, especially marked osteoporosis with vertebral collapse, which interferes with her walking and causes excruciating pain. Two months after the radiotherapy, we still had doubts about the prognosis regarding the persistence of the hypercortisolism. From six months on, her general health started improving, she lost weight, the backache disappeared and her cortisol level returned to normal.

Persistence of Müllerian remnants in complete androgen insensitivity syndrome.

One of the unusual findings in androgen insensitivity syndrome (AIS) is the persistence of Mullerian derivatives. Several hypotheses have been advanced to explain such persistence: the coincidental occurrence of mutations affecting the androgen receptor (AR) and the synthesis and/or action of anti-Müllerian hormone (AMH); the loss of AMH paracrine action due to early testicular descent; the exposure to drugs such as diethylstilbestrol. We describe a patient with complete AIS for whom surgical and laboratory findings rule out all these hypotheses. She has a missense mutation on the AR gene but no mutations were detected on the genes coding for AMH and AMH receptor. The gonads were found very close to the Mullerian structures (enough to exert a paracrine action), gonadal tissue stained positively for AMH, and yet Mullerian derivatives were present and well developed. These findings indicate the possibility of interactions between the androgen receptor and AMH action.

Primary hyperparathyroidism in children: patient report and review of the literature.

Although primary hyperparathyroidism has rarely been described in pediatric patients, prompt diagnosis can avoid severe CNS and metabolic consequences. The aim of this paper is to report a 6 year-old girl whose first symptoms began at eight days of age with cyanosis, hypotonia, and upward gaze deviation. At 4 months, she was admitted due to neurologic disorders and recurrent infection, but the definite diagnosis was made only six years later. Her serum calcium levels are among the highest ever reported in the medical literature, reaching 25.5 mg/dl (6.36 mmol/l). Hypercalcemia, very high levels of parathormone (1550 ng/l--normal range 10-65) and bone deformities posed no problem to diagnosis when she first came to our attention. Nephrocalcinosis and impaired renal function were detected and this child had to be treated with diuretics (furosemide) and hydration that were able to lower her serum calcium levels. Imaging studies including 99mTc-sestamibi scan were not diagnostic. At surgery, the four parathyroid glands were mildly enlarged, with primary hyperplasia. The four glands were removed, cryopreserved, and 14 fragments (1 mm each) were autotransplanted to the braquioradial muscle of the left forearm. After a first phase of hypocalcemia (hungry-bone syndrome), treated with calcium and calcitriol, the calcium levels stabilized. The question is whether she will experience some degree of recovery from her neurological problems, since her severely high calcium levels have been maintained for such a long time.

Ullrich-Turner syndrome: relevance of searching for Y chromosome fragments.

Forty consecutive patients with Ullrich-Turner syndrome (UTS) were followed-up and investigated for the presence of Y chromosome fragments in their genomes. We used the polymerase chain reaction (PCR) to detect SRY (sex-determining region on the Y chromosome) and the sequence-tagged sites (STS) sY57, sY59, sY85, sY94, sY124 and sY157--which correspond to regions 3C (sY57 and 59), 5C, 5G, 5P, and 6F, respectively, of the Y chromosome--searching for Y fragments that could bear the putative locus (loci) for gonadoblastoma (GBY). It has been shown that the presence of GBY greatly increases the risk of dysgenic gonads to undergo malignant transformation. Among our 40 patients, we found Y-derived sequences--including SRY and the region spanning from sY57 to sY94--in two. These two patients had a marker chromosome detected by conventional cytogenetic analysis (45,X/46,X + mar). Their gonads were excised and found to be streaks. In one of the patients, we found foci of primitive sex cords (amidst the gonadal stroma), oviducts and Wolffian remnants. Fluorescence in situ hybridization (FISH) did not show Y chromosome material in her gonad-derived fibroblasts. The other girl had hyperplastic Leydig cells in the gonadal stroma, oviducts and Wolffian remnants, with signs of epididymal differentiation. PCR assays performed on DNA extracted from paraffin-embedded gonadal tissue were negative for SRY sequences in both patients. These findings show that all UTS patients should be examined for Y chromosome material, and that positive cases should have their dysgenic gonads excised due to the high risk of malignancy.

Proliferating cell nuclear antigen immunoreaction in adrenal tumors.

AIMS AND BACKGROUND: We studied, retrospectively, 33 cases of adrenal tumors of children at the Pediatric Endocrinology Unit, Children's Institute, São Paulo State University Medical School, from 1975 to 1993. All patients had at least 2 years of follow-up with a few exceptions. METHODS: Clinical follow-up data were correlated with histopathologic review, laboratory data and cell kinetic evaluation (based on detection of proliferating cell nuclear antigens). RESULTS: With one exception, all the patients had presented signs of androgen production and had high levels of dehydro-epiandrosterone-sulfate. Tumor weight evaluation represented a good parameter of neoplasm evolution: of 19 cases weighing less than 250 g, 17 had no evidence of disease after surgery, and 2 had an unfavorable prognosis. Of 14 cases weighing more than 250 g, only 1 had no evidence of disease and 13 had an unfavorable evolution. CONCLUSIONS: Proliferating cell nuclear antigen (PCNA) was not helpful to evaluate adrenal neoplasm evolution: our study did not show any correlation between PCNA score and prognosis.

[Childhood hypoglycemia - still a challenge]. / Hipoglicemia na infância - ainda um desafio.

OBJECTIVE: Hypoglycemia in the infant is potentially hazardous to the central nervous system(CNS), and any delay in solving the problem may impose irreversible sequelae. The aim of this review is to provide basic knowledge to the pediatrician to adequately deal with a hypoglycemic patient. METHODS: Bibliographic review was performed in the Medline for the last 10 years, and the most pertinent papers were selected. RESULTS: Even today, there are discrepancies as for the best conduct in the hyperinsulinemic patients. The surgical or clinical approaches have had the support of very important authors. Some state that the best choice is the total pancreatectomy, in which 95% of the pancreas is removed, with all its long-term sequelae, while others emphasize the preservation of the pancreas with drug therapy instead of pancreatectomy. CONCLUSIONS: The doctor who takes care of a hypoglycemic child has to remember that the biggest task is to preserve the CNS integrity, and all the efforts must be made to provide an adequate glucose supply to the brain, otherwise irreversible consequences will ensue.

Effect of long-term blood pressure control on salt sensitivity.

The objective of this study was to reevaluate salt sensitivity (SENS) after a period of antihypertensive treatment (AT). SENS was measured in ten patients, before and after 18 +/- 6 months on AT. The average for all mean blood pressures (MBP) measured during AT was used as an index of blood pressure (BP) control. After at least eight weeks on placebo only, all patients were submitted to an ad libitum diet (ALD), low salt diet (LSD), and high salt diet (HSD) during one week each. SENS was considered as the percent change of the MBP between the seventh day of LSD and HSD. Weight, BP, and daily urinary Na+ and K+ excretion (mean of seven days) on ALD were the same in the first (F) and second (S) evaluation. SENS did not significantly change from the F and S measurement. An inverse correlation was obtained between individual SENS difference and the average mean blood pressure (AMBP) (r = -0.85, p = 0.0018). In conclusion, patients who showed greater decreases in SENS were the ones with the best BP control.

[Persistent hyperinsulinemic hypoglycemia of infancy: case report] / Hipoglicemia hiperinsulinêmica persistente da infância.

OBJECTIVE: To report a case of Persistent Hyperinsulinemic Hypoglycemia in twins which is a situation not yet reported in the literature. METHODS: Report of seizures in identical twins, from consanguineous parents, with persistent hypoglycemia as cause of the seizures. Laboratory tests, performed for etiological investigation of the hypoglycemia, included thyroid hormones (T4/TSH), insulin, cortisol, growth hormone, stimulation test with glucagon (to evaluate the insulin/glucose relation), and histopathological study of the pancreas. RESULTS: Laboratorial investigation revealed a persistent hypoglycemia with hyperinsulinism which were confirmed with the stimulation test with glucagon. The histopathological exam showed a persistence of first generation pancreatic islet, confirming the diagnosis of Persistent Hyperinsulinemic Hypoglycemia in Infancy (the new denomination of Nesidioblastosis). CONCLUSION: Although rare, this condition must be early suspected early in the evaluation of hypoglycemia of the young infant, even out of the neonatal period, specially if the parents are consanguineous. The adequate therapy must be quickly initiated in order to prevent neurological damage.

Salt sensitivity in human essential hypertension: effect of renin-angiotensin and sympathetic nervous system blockade.

We studied the acute effect of oral captopril (25mg) and clonidine(300 micrograms) on blood pressure (BP) in patients with essential hypertension successively maintained on a low (LSD) and high (HSD) salt diet. Seven patients were salt sensitive (SS) and seven were salt resistant (SR). The maximal decrease in diastolic BP caused by captopril in patients on the LSD was greater in SS than SR individuals. Baseline urinary norepinephrine levels did not change from LSD to HSD (p greater than 0.05) in SS patients and decreased in SR patients (p less than 0.05). The maximal decrease in mean BP during the clonidine test was the same for both diets (p greater than 0.05) in SS patients and was lower (p less than 0.05) for the HSD in SR patients. SS patients on the HSD presented a higher decrease in systolic BP than SR patients (p less than 0.05) during the clonidine test. These data suggest overactivity of the renin-angiotensin system in SS patients on the LSD and of the sympathetic nervous system in SS patients on the HSD and that the clonidine test could be a good indicator for identifying SS and SR patients.

Left ventricular hypertrophy is more marked in salt-sensitive than in salt-resistant hypertensive patients.

Besides the duration and severity of hypertension, several other factors have been shown to be related to left ventricular hypertrophy (LVH) in essential hypertension. The present study was conducted to examine the influence of salt sensitivity on LVH. Fifteen essential hypertensive ambulatory patients were submitted to a low-salt (30 mEq of Na/day for 7 days) and a high-salt (200 mEq of Na/day for 7 days) diet after 12 weeks on placebo. Daily urine collection was obtained during the whole study. After the placebo period, all patients were submitted to a complete clinical and laboratory investigation that included an echocardiogram (M-mode and two-dimensional). Five patients were salt-sensitive (mean blood pressure (BP) increase from the seventh day of the low- to the seventh day of the high-salt diet greater than 10%). No differences in weight, sex ratio, and duration of hypertension were obtained between salt-sensitive and -resistant patients. The initial BP was higher in the salt-sensitive patients. However, the difference was small and without statistical significance. The left ventricular weight was higher in the salt-sensitive than in salt-resistant patients (148 +/- 51 vs. 109 +/- 32 g/m2, p less than 0.05). The left ventricular end-diastolic diameter was also higher in the salt-sensitive patients (50 +/- 10 vs. 43 +/- 6 mm, p less than 0.05). The interventricular septum and posterior wall thicknesses were higher in salt-sensitive patients, although they did not reach statistical significance. In conclusion, salt-sensitive essential hypertensive patients are at a higher risk to develop LVH.

CYP21 mutations in Brazilian patients with 21-hydroxylase deficiency.

Congenital adrenal hyperplasia caused by 21-hydroxylase deficiency is a common autosomal recessive disorder resulting from mutations in the 21-hydroxylase (CYP21) gene. To develop a strategy to screen for the most commonly occurring CYP21 mutations in Brazil, we performed molecular genotype analysis on 73 children with CAH representing 71 unrelated families. The techniques used for CYP21 molecular genotype analysis were: restriction fragment length polymorphism, single-strand conformational polymorphism, allele-specific oligonucleotide hybridization, allele-specific polymerase chain reaction amplification, and heteroduplex analyses. Mutations were identified on all but eight affected alleles. The intron 2 splicing mutation was the most frequently identified mutation. Screening for the most common mutations detected at least one mutation on 132/142 (93%) alleles. Multiple CYP21 mutations were detected on 16.2% of alleles. The high frequency of multiple mutations on a single allele emphasizes the importance of thorough and accurate molecular genotype analysis of the complex CYP21 locus.

Rathke's cleft cyst as a cause of growth hormone deficiency and micropenis.

Rathke's cleft cyst has rarely been reported in pediatric patients, and such cysts are usually found by chance, in 2-33% of routine necropsies, as they have not interfered with pituitary function. In general, they are intrasellar with a single layer of ciliated cuboidal or columnar epithelium containing mucoid material. The age range in which symptomatic Rathke's cleft cysts occur is between 30 and 60 years. This paper reports an 8.1-year-old boy presenting with growth hormone deficiency and micropenis attributable to hypogonadotropic hypogonadism (HH), implying altered pituitary function since intrauterine life. At this age (before puberty) the diagnosis of HH can be made by means of the LHRH agonist stimulation test, since conventional LHRH is not able to discriminate HH from a normal prepubertal child. To our knowledge, this is the first case of micropenis caused by Rathke's cleft cyst interfering with gonadotropin and growth hormone secretion since intrauterine life.

[Thyroid carcinoma in children and adolescents - review of six cases] / Carcinoma de tireóide em crianças e adolescentes - revisão de seis casos.

OBJECTIVE: Childhood thyroid carcinoma is a rare entity whose management is controversial. The objective of the present study was to evaluate the characteristics of these patients in terms of diagnosis and evolution. PATIENT AND METHODS: The evolution of six patients with thyroid cancer, followed at a Pediatric Endocrinology Unit during the past 17 years, was retrospectively reviewed. RESULTS: Six female patients with age ranging from 4.5 to 12 years were studied. In all 6 cases, thyroid nodules were present on the initial evaluation. Ultrasonography and 131I scintigraphy showed solid and cold nodules in four patients. Histologic findings indicated four papillary and two follicular carcinomas. All patients were submitted to total thyroidectomy; four were subsequently submitted to radiodine therapy due to the presence metastases and/or residual thyroid tissue. CONCLUSION: Our findings support the notion that children and adolescents with thyroid carcinoma have a positive prognosis; no cases of death occurred after 17 years of follow-up. Our data are in agreement with the literature, which describes low mortality rates for these cases.

Sindrome de Laron: uma causa de baixa estatura grave / Laron's syndrome: a cause of severe small stature

Os autores apresentam dois casos de baixa estatura (BE) do tipo sindrome de Laron em criancas brasileiras e em cujas arvores genealogicas aparecem apenas brasileiros, portugueses e italianos, diferentemente da casuistica do Prof. Laron onde os pacientes sao oriundos do oriente medio. Sao comentados dados relacionados com a evolucao dos valores de hGH (hormonio de crescimento humano) e SmC (somatomedina C) ou IGF-I ("insulin like growth factor"). Em 1966, Laron descreveu um quadro clinico de baixa estatura (BE) grave praticamente superponivel aos aspectos clinicos e metabolicos da deficiencia hipofisaria de hGH porem contrapondo-se a esta por apresentar os niveis basais de hGH muito elevados. Posteriormente, verificou-se que na BE do tipo Laron, alem dos niveis elevados de hGH, sao registrados valores muito baixos de SmC ou IGF-I. A diminuicao da producao de IGF-I seria uma consequencia da falta de receptores celulares de hGH. O receptor de hGH consiste numa sequencia de 620 aminoacidos ancorada a membrana da celula atraves da regiao compreendida pelos aminoacidos 247-72. A porcao extracelular e conhecida como "proteina ligadora do hHG". Quando o hGH se liga a esta "proteina" sucede-se uma serie de reacoes dentro da celula e cuja consequencia principal e a resposta de crescimento....