Sorahia Domenice

Sleep characteristics of adolescents: A longitudinal study

The aim of the present research was to study sleep/wake cycle parameters of adolescents and to examine biologic and social influences on their changing sleep patterns. This was a longitudinal study of sleep characteristics of a group of 66 adolescents (mean age, 13 years and 6 months). The adolescents underwent a physical examination, had their pubertal development classified according to Tanner stages, and answered a sleep questionnaire on three timepoints at 6-month intervals. Sleep onset occurred about 1.0 hr later, wake-up time about 3.0 hr later, and sleep length was 1.0-1.5 hr longer on weekends when compared with weekdays. About 60% of the adolescents reported daytime sleepiness, mainly from 8:00 a.m. to 10:00 a.m. and from 2:00 p.m. to 4:00 p.m. on school days. Morning sleepiness on school days occurred at a time of the day that corresponded to sleep on non-school days. Additionally, there was a displacement toward later hours of the wake-up time and a sleep-length increase during weekends from the first to the third timepoint. Social factors such as home conditions and scheduling of school and non-school activities did not change throughout the period of pubertal development studied. Changes of sleep patterns detected may therefore represent an ontogenetic trend along puberty.

Clinical, Hormonal and Pathological Findings in a Comparative Study of Adrenocortical Neoplasms in Childhood and Adulthood

PURPOSE We reviewed clinical and laboratory findings in 6 male and 32 female patients with functional adrenocortical neoplasms, and compared pediatric and adult data. MATERIALS AND METHODS Hormonal measurements were performed by radioimmunoassay, histological analysis was based on Weiss criteria and staging was done according to previously established guidelines. RESULTS Children had a higher incidence of virilization (72%), whereas in adults the predominant feature was Cushings syndrome (60%). A high testosterone level was the most common finding in adults and children with virilization followed by high dehydroepiandrosterone sulfate, androstenedione and dehydroepiandrosterone levels. High 11-deoxycortisol levels were frequently associated with tumor recurrence. Cortisol suppression after dexamethasone was altered in 93% of patients with virilization and no clinical features, suggesting autonomous cortisol secretion. CONCLUSIONS No statistically significant relation was noted between tumor weight and prognosis but there was a negative correlation between patient age and prognosis since children had a more favorable followup than adults. Mixed features in both groups resulted in the worst prognosis. A Weiss criteria grade IV or greater correlated well with a poor prognosis in adults but not children, while staging was more reliable in children.

Founder effect for the highly prevalent R337H mutation of tumor suppressor p53 in Brazilian patients with adrenocortical tumors

The incidence of adrenocortical tumors in children from the Southern region of Brazil is higher than in other parts of the world. This fact has been related to the identification of an inherited missense mutation of the p53 (R337H) at high frequency (78-97%) in Brazilian children with adrenocortical tumors. Given the high frequency of this germline mutation in the Brazilian population, it is very likely that the R337H mutation has arisen from a common origin. In this study, we analyzed two highly polymorphic intragenic markers (VNTRp53 and p53CA) in 22 patients (16 children and 6 adults) with adrenocortical tumors carrying the germline R337H mutation and 60 normal individuals using GeneScan Fragment Analysis software. We found six and sixteen different alleles for the VNTRp53 and p53CA polymorphic markers, respectively. Two distinct alleles, both with 122 bp, were found in 56.8% (VNTRp53) and 54.5% (p53CA) of the 44 alleles from patients with adrenocortical tumors associated with the R337H mutation. Differently, these same VNTRp53 and p53CA alleles were found in 18.3% and 14.2% of 120 alleles from normal individuals, respectively (p<0.01, Chi-square test). An identical haplotype for p53 locus was also identified in 95% of the apparently unrelated Brazilian patients with adrenocortical tumors carrying the R337H mutation. In conclusion, we demonstrated a strong evidence of co-segregation between two intragenic polymorphic p53 markers and the germline R337H mutation, indicating that this mutation has originated from a single common ancestral in the great majority of the Brazilian patients with adrenocortical tumors.

46,XY disorders of sex development (DSD)

The term disorders of sex development (DSD) includes congenital conditions in which development of chromosomal, gonadal or anatomical sex is atypical.

A novel missense mutation (S18N) in the 5' non-HMG box region of the SRY gene in a patient with partial gonadal dysgenesis and his normal male relatives

Abstract Mutations in the sex-determining region of the Y chromosome (the SRY gene) have been reported in low frequency in patients with 46,XY gonadal dysgenesis. We investigated 21 Brazilian 46,XY sex-reversed patients, who presented either complete or partial gonadal dysgenesis or embryonic testicular regression syndrome. Using Southern blotting, polymerase chain reaction, denaturing gradient gel electrophoresis and direct sequencing, we analyzed deletions and point mutations in the SRY gene. We found a missense mutation at codon 18 upstream of the 5′ border of the HMG box of the SRY gene in one patient with partial gonadal dysgenesis. This variant sequence was also found in DNA obtained from blood and sperm cells of his father and in blood cells of his normal brother. The S18N mutation was not found in 50 normal males, ruling out the possibility of a common polymorphism. We identified a novel familial missense mutation (S18N) in the 5’ non-HMG box of the SRY gene in 1 of 21 patients with 46,XY sex reversal.

Treatment of gonadotropin dependent precocious puberty due to hypothalamic hamartoma with gonadotropin releasing hormone agonist depot

The gonadotropin releasing hormone (GnRH) secreting hypothalamic hamartoma (HH) is a congenital malformation consisting of a heterotopic mass of nervous tissue that contains GnRH neurosecretory neurons attached to the tuber cinereum or the floor of the third ventricle. HH is a well recognised cause of gonadotropin dependent precocious puberty (GDPP). Long term data are presented on eight children (five boys and three girls) with GDPP due to HH. Physical signs of puberty were observed before 2 years of age in all patients. At presentation with sexual precocity, the mean height standard deviation (SD) for chronological age was +1.60 (1.27) and the mean height SD for bone age was −0.92 (1.77). Neurological symptoms were absent at presentation and follow up. The hamartoma diameter ranged from 5 to 18 mm and did not change in six patients who had magnetic resonance imaging follow up. All patients were treated clinically with GnRH agonists (GnRH-a). The duration of treatment varied from 2.66 to 8.41 years. Seven of the eight children had satisfactory responses to treatment, shown by regression of pubertal signs, suppression of hormonal levels, and improvement of height SD for bone age and predicted height. One patient had a severe local reaction to GnRH-a with failure of hormonal suppression and progression of pubertal signs. It seems that HH is benign and that GnRH-a treatment provides satisfactory and safe control for most children with GDPP due to HH.

The role of desmopressin in bilateral and simultaneous inferior petrosal sinus sampling for differential diagnosis of ACTH-dependent Cushing's syndrome

Objective   Bilateral inferior petrosal sinus sampling (BIPSS) with corticotrophin‐releasing hormone (CRH) stimulation is currently the gold standard test for the differential diagnosis of ACTH‐dependent Cushings syndrome. Reports on the use of desmopressin in this approach are limited. The aim of this study was to evaluate the use of desmopressin during BIPSS in a cohort of patients with ACTH‐dependent Cushings syndrome.

Disorders of sex development: effect of molecular diagnostics

Disorders of sex development (DSDs) are a diverse group of conditions that can be challenging to diagnose accurately using standard phenotypic and biochemical approaches. Obtaining a specific diagnosis can be important for identifying potentially life-threatening associated disorders, as well as providing information to guide parents in deciding on the most appropriate management for their child. Within the past 5 years, advances in molecular methodologies have helped to identify several novel causes of DSDs; molecular tests to aid diagnosis and genetic counselling have now been adopted into clinical practice. Occasionally, genetic profiling of embryos prior to implantation as an adjunct to assisted reproduction, prenatal diagnosis of at-risk pregnancies and confirmatory testing of positive results found during newborn biochemical screening are performed. Of the available genetic tests, the candidate gene approach is the most popular. New high-throughput DNA analysis could enable a genetic diagnosis to be made when the aetiology is unknown or many differential diagnoses are possible. Nonetheless, concerns exist about the use of genetic tests. For instance, a diagnosis is not always possible even using new molecular approaches (which can be worrying for the parents) and incidental information obtained during the test might cause anxiety. Careful selection of the genetic test indicated for each condition remains important for good clinical practice. The purpose of this Review is to describe advances in molecular biological techniques for diagnosing DSDs.

46,XY DSD due to impaired androgen production

Disorders of androgen production can occur in all steps of testosterone biosynthesis and secretion carried out by the foetal Leydig cells as well as in the conversion of testosterone into dihydrotestosterone (DHT). The differentiation of Leydig cells from mesenchymal cells is the first walk for testosterone production. In 46,XY disorders of sex development (DSDs) due to Leydig cell hypoplasia, there is a failure in intrauterine and postnatal virilisation due to the paucity of interstitial Leydig cells to secrete testosterone. Enzymatic defects which impair the normal synthesis of testosterone from cholesterol and the conversion of testosterone to its active metabolite DHT are other causes of DSD due to impaired androgen production. Mutations in the genes that codify the enzymes acting in the steps from cholesterol to DHT have been identified in affected patients. Patients with 46,XY DSD secondary to defects in androgen production show a variable phenotype, strongly depending of the specific mutated gene. Often, these conditions are detected at birth due to the ambiguity of external genitalia but, in several patients, the extremely undervirilised genitalia postpone the diagnosis until late childhood or even adulthood. These patients should receive long-term care provided by multidisciplinary teams with experience in this clinical management.

DSD Due to 5 alpha-Reductase 2 Deficiency - from Diagnosis to Long Term Outcome

Most of the patients with 5α-RD 2 deficiency are reared in the female social sex due to their severely undervirilized external genitalia but ~60% who have not been submitted to orchiectomy in childhood undergo male social sex change at puberty. In our cohort of 30 cases from 18 families, all subjects were registered in the female social sex except for two children-one who had an affected uncle and the other who was diagnosed before being registered. The majority of the patients were satisfied with the long-term results of their treatment and surprisingly, penile length was not associated with satisfactory or unsatisfactory sexual activity. Steroid 5α-RD2 deficiency should be included in the differential diagnosis of all newborns with 46,XY DSD with normal testosterone production before gender assignment or any surgical intervention because these patients should be considered males at birth.