Rossella Gaudino

Prevalence of polycystic ovary syndrome in young women who had idiopathic central precocious puberty

OBJECTIVE To assess the prevalence of polycystic ovary syndrome (PCOS) in a cohort of young women with previous idiopathic central precocious puberty (ICPP) at least 3 years after menarche, and to look for any predictive factors of PCOS at the time ICPP was diagnosed. DESIGN Longitudinal study. SETTING Pediatrics unit, Verona, Italy. PATIENT(S) Forty-six young women (18.1 +/- 3.0 years) who had been treated with GnRH analogues during childhood, observed at gynecologic age of 6.23 +/- 3.3 years. INTERVENTION(S) Semistructured interview concerning cycles, physical exam, blood sampling, and transabdominal pelvic ultrasound. MAIN OUTCOME MEASURE(S) Oligomenorrhea, LH, FSH, E(2), T, DHEAS, free T, delta4-androstenedione, 17-OHP, P, polycystic ovary morphology (PCOM). RESULT(S) Fifteen percent of the young women had oligomenorrhea, 28% clinical hyperandrogenism, 48% biochemical hyperandrogenism, and 37% PCOM. A total of 32% of the patients had PCOS according to the Rotterdam definition and 30% had PCOS according to the Androgen Exess Society. The prevalent phenotype of PCOS was characterized by clinical and/or biochemical hyperandrogenism and PCOM. We did not find any predictive factors for PCOS at the time ICPP was diagnosed. CONCLUSION(S) Patients with ICCP are prone to developing PCOS. The prominent phenotype in this cohort was PCOM associated with clinical and/or biochemical hyperandrogenism. Further follow-ups of these young adult patients will clarify whether this phenotype persists and if it will have important long-term implications regarding increased risk of infertility or metabolic complications.

Neonatal screening for glucose-6-phosphate dehydrogenase deficiency fails to detect heterozygote females.

We examined glucose-6-phosphate dehydrogenase (G6PD) deficiency in north-eastern Italian Caucasian neonates detected by neonatal screening, in order to measure the incidence of heterozygote females detected by neonatal screening, and to estimate the near-true total incidence. A total of 85,437 Caucasian neonates, born between January 2000 and December 2001, have been enclosed in the study. The total incidence of the disease, measured by fluorescent method, is 0.9‰ the total incidence, calculated by Hardy–Weinberg law, is 4.8‰. The frequency of missed females is 93% of total females expected with G6PD deficiency; most of them are very likely heterozygous females. The sensitivity of the fluorescent method might be not sufficient to detect all females. Since heterozygote females might develop the symptoms of G6PD deficiency later, these results suggest that the G6PD neonatal screening may not be helpful in preventing disease in females.

Prepubertal serum inhibin B in cryptorchid infants and in monorchid boys with compensatory testicular hypertrophy

OBJECTIVE To investigate the prepubertal serum inhibin B levels in monorchid boys with compensatory testicular hypertrophy (CTH) and in surgically treated cryptorchid boys with normal testicular volume. DESIGN Prospective study. SETTING Pediatric Division, University of Verona, Italy. PATIENT(S) Thirty-two prepubertal boys: 11 monorchids with CTH and 21 cryptorchids. For comparison we analyzed 15 healthy boys. MAIN OUTCOME MEASURE(S) All patients underwent a GnRH agonist test. Inhibin B measurement was performed at basal time. RESULT(S) There was a significant difference in mean testicular volume between monorchid and cryptorchid or healthy children, with boys with CTH evidencing larger testicle volume. There was no significant difference in inhibin B levels between boys with CTH and cryptorchid, but the levels were significantly lower in both groups than in the control group. Boys with CTH had significantly higher serum levels of basal FSH than children with cryptorchid. The FSH peak response to GnRH agonist stimulation was significantly higher in boys with CTH than in those with cryptorchid. CONCLUSION(S) Monorchid infants with CTH showed low inhibin B and high FSH levels. Our finding may confirm the hypothesis that CTH is unable to prevent testicular insufficiency in adulthood. We suggest an early hormonal evaluation of boys with CTH at puberty, together with early sperm analysis.

Diagnostic effectiveness of simultaneous thyroxine and thyroid-stimulating hormone screening measurements. Thirteen years' experience in the Northeast Italian Screening Programme.

Objectives: To evaluate the effectiveness of thyroid-stimulating hormone (TSH) and thyroxine [T4) measurements at neonatal screening for congenital hypothyroidism, we compared our false-negative results with those we would have obtained if we had used TSH screening alone. Subjects and methods: Between January 1989 and December 2001 745,258 newborns were screened (98.3% of total born) for congenital hypothyroidism in northeast Italy. T4 and TSH were measured simultaneously on blood spots collected after birth. Between 1989 and 1998, semiquantitative total T4 (tT4) and TSH concentrations were measured by radiolabelled immunological assay and, from 1999 to 2001, using time-resolved fluorometer Delfia instruments (EG&G Wallac Oy, Finland) and fluoroimmunometric assay (Delfia neonatal hTSH and T4 kits). Results: Ten neonates were missed by our screening programme (normal tT4 and TSH) and classified as false negatives; these infants were diagnosed later in life with central hypothyroidism. If we had measured TSH alone in our screening programme, we would have missed an additional 21 patients with low tT4 and normal TSH; of these, four were affected by central hypothyroidism and 17 were diagnosed within the second month of life as affected by primary hypothyroidism with delayed TSH rise. Conclusions: Simultaneous T4 and TSH measurements at neonatal screening can miss patients affected by central hypothyroidism. However, this screening procedure allows identification of cases of central hypothyroidism with low T4 values and those neonates affected by primary hypothyroidism with delayed TSH rise who we would have missed by using the TSH measure alone.

Congenital hypothyroidism with delayed TSH elevation in low-birth-weight infants: incidence, diagnosis and management

OBJECTIVE To evaluate the incidence of congenital hypothyroidism (CH) with delayed TSH elevation among low-birth-weight (LBW) newborns in North-Eastern Italy and to verify if they need a second or third screening. DESIGN Analysis of clinical and biochemical data of newborns affected by CH with delayed TSH elevation identified by neonatal screening. METHODS Data of all newborns with birth weight (BW) <2500 g and evidence of delayed TSH elevation at newborn screening were collected between 2011 and 2014. Confirmatory tests were based on serum TSH and FT4 levels. All their clinical signs at diagnosis were reported. RESULTS 57.5% of LBW newborns with delayed TSH increase at neonatal screening presented a CH with delayed TSH elevation and began a treatment with l-thyroxine. The incidence of this condition in North-Eastern Italy is therefore 1:908. The remaining infants presented a subclinical hypothyroidism (21.25%) or a complete normal serum thyroid function (21.25%). These data could be drawn only from a retesting strategy of neonatal screening. CONCLUSIONS Our report describes the incidence of CH with delayed TSH rise in North-Eastern Italy and differentiates this clinical condition from other thyroid dysfunctions of preterm or LBW newborns. The second-screening strategy for CH in neonates with BW < 2500 g proved useful in detecting newborns who otherwise would not be identified at the first screening.

Body size and early growth in appropriate- and large-for-gestational-age infants

Aims: To study weight, length, body composition, sleeping energy expenditure (SEE), and respiratory quotient (RQ) at birth and at 5 mo of age in both adequate‐for‐gestational‐age (AGA) and large‐for‐gestational‐age (LGA) subjects; to compare the changes in body weight and body composition adjusting for gender, age, SEE, RQ and several maternal factors; to investigate the contribution of initial SEE and RQ to changes in body weight and body composition. Methods: Sixty‐nine neonates were recruited among term infants in the University Hospital of Verona, Italy. Forty‐nine subjects participated until follow‐up. At birth and follow‐up, weight and length were measured and arm‐fat area and arm‐muscle area were calculated from triceps and subscapular skinfolds. SEE and RQ were measured by indirect calorimetry. Results: At birth, weight, length, arm‐muscle and arm‐fat areas were significantly higher in LGA subjects than in AGA subjects. Weight status, SEE and RQ at birth did not explain the relative weight change after adjusting for gestational weight, placental weight, age at follow‐up and gender. Arm‐fat area and weight/length ratio at birth were negatively associated with relative changes in body weight after adjusting for the above variables (p < 0.05).

Sleep-disordered breathing is associated with blood pressure and carotid arterial stiffness in obese children.

Introduction: Both sleep-disordered breathing (SDB) and high blood pressure (BP) occur more frequently among obese children than among normal weight children, and this may be due to endothelial dysfunction and worsened arterial stiffness. The aim of this study was to evaluate the possible association between SDB and BP, and the possible role of endothelial function and local and systemic arterial stiffness in a sample of obese children asymptomatic for sleep disturbances. Materials and methods: Thirty-nine obese children were included in the study. Children underwent overnight limited channel polysomnography, and the vascular measurements included the following: office and 24-h ambulatory BP; brachial flow-mediated dilatation, carotid intima–media thickness and carotid distensibility measured using ultrasound; and systemic arterial stiffness index measured using digital volume pulse analysis. Results: Significant correlations between different BP measurements (both office and ambulatory BP monitoring and estimated by Z score) and SDB were found, including correlations involving the respiratory disturbance index, the apnea–hypopnea index (AHI), the number of desaturations per hour and the mean peripheral saturation (r ranging between 0.330 and 0.474). Carotid distensibility was correlated with the AHI (r = −0.367; P = 0.030) and with the mean oxygen saturation (r = 0.401; P = 0.017). In contrast, there was no relationship among flow-mediated dilatation, stiffness index, carotid intima–media thickness and all the tested respiratory markers. In the multivariate analysis, the supine Z SBP remained independently associated with the number of desaturations per hour and the AHI, even after correction for carotid distensibility and BMI. Conclusion: Our data suggest that in obese children asymptomatic for sleep respiratory problems, SDB might worsen BP, in part, through an increase in arterial stiffness.

Serum inhibin B levels before and after varicocelectomy in early adolescence

Background: Whereas no clear relationship has been observed between varicocelectomy and serum inhibin B levels in men, in adolescents comparison between inhibin B levels before and after varicocelectomy is lacking. Aim: To evaluate the effect of varicocele surgical treatment on inhibin B levels in adolescents at the beginning of puberty compared to a group of healthy adolescents. Subjects and methods: We studied 28 adolescents in Tanner 2 pubertal stage with a grade III left-sided varicocele (patients) compared to 13 age- and pubertal stage-matched healthy adolescents (controls). All patients underwent blood tests to determine serum inhibin B levels before and 6 months after varicocelectomy by Palomo procedure. For comparison we investigated inhibin B levels in controls and repeated this test 6 months later. Testicular ultrasound was performed for patients only. Results: Baseline inhibin B concentrations of patients and controls were 109.90±40.26 and 109.33±38.34 pg/ml, respectively. No significant changes were observed in patients’ inhibin B concentrations after varicocelectomy (116.00±42.65 pg/ml), or in controls during the 6 months’ follow-up (99.12±30.09 pg/ml). Doppler examination after treatment shows a complete resolution of varicocele in all the patients without alterations in testicular parenchyma. Conclusions: Varicocelectomy performed on adolescents at T2 pubertal stage might be useful to avoid alteration in inhibin B production and consequently in testicular function. Further studies are necessary to confirm the prognostic value of inhibin B levels and the benefit of early varicocelectomy in preserving the fertility of these adolescents.

Identification of a novel pax8 gene sequence variant in four members of the same family: from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism.

BackgroundCongenital hypothyroidism is often secondary to thyroid dysgenesis, including thyroid agenesis, hypoplasia, ectopic thyroid tissue or cysts. Loss of function mutations in TSHR, PAX8, NKX2.1, NKX2.5 and FOXE1 genes are responsible for some forms of inherited congenital hypothyroidism, with or without hypoplastic thyroid. The aim of this study was to analyse the PAX8 gene sequence in several members of the same family in order to understand whether the variable phenotypic expression, ranging from congenital hypothyroidism with thyroid hypoplasia to mild subclinical hypothyroidism, could be associated to the genetic variant in the PAX8 gene, detected in the proband.MethodsWe screened a hypothyroid child with thyroid hypoplasia for mutations in PAX8, TSHR, NKX2.1, NKX2.5 and FOXE1 genes. We studied the inheritance of the new variant R133W detected in the PAX8 gene in the proband’s family, and we looked for the same substitution in 115 Caucasian European subjects and in 26 hypothyroid children. Functional studies were performed to assess the in vitro effect of the newly identified PAX8 gene variant.ResultsA new heterozygous nucleotide substitution was detected in the PAX8 DNA-binding motif (c.397C/T, R133W) in the proband, affected by congenital hypothyroidism with thyroid hypoplasia, in his older sister, displaying a subclinical hypothyroidism associated with thyroid hypoplasia and thyroid nodules, in his father, affected by hypothyroidism with thyroid hypoplasia and thyroid nodules, and his first cousin as well, who revealed only a subclinical hypothyroidism. Functional studies of R133W-PAX8 in the HEK293 cells showed activation of the TG promoter comparable to the wild-type PAX8.ConclusionsIn vitro data do not prove that R133W-PAX8 is directly involved in the development of the thyroid phenotypes reported for family members carrying the substitution. However, it is reasonable to conceive that, in the cases of transcriptions factors, such as Pax8, which establish several interactions in different protein complexes, genetic variants could have an impact in vivo.

Lung Function in Women with Idiopathic Central Precocious Puberty: A Pilot Study

Background: Studies have reported that women with early menarche (≤10 years) have lower lung function. Aim: To investigate lung function in women with a history of idio pathic central precocious puberty (ICPP) treated during childhood with gonadotropin-releasing hormone agonist (GnRHa). Methods: ICPP women (n = 23) were compared with healthy age-matched controls (n = 23). Subjects were clinically evaluated by means of a questionnaire, baseline and post-β2 agonist spirometry, impulse oscillometry (a measure of airway resistance), and measurement of fractional exhaled nitric oxide (FeNO). Results: Patients had lower lung function values than controls: forced expiratory volume in 1 s (FEV1) (median 97.90 vs. 109.45; p = 0.011), FEV1 after β2 agonist (100.80 vs. 114.10; p = 0.013), peak expiratory flow (92.90 vs. 97.95; p = 0.031), and maximum mid-expiratory flow (MMEF) (80.80 vs. 106.30; p = 0.008). FeNO was significantly lower in the patients (p < 0.001). Significant reversibility of FEV1 after β2 agonist was observed in 8.7% of the patients. FEV1/forced vital capacity and MMEF after β2 agonist correlated negatively with hysterometry at diagnosis (p = 0.009 and p = 0.03, respectively). There was a negative correlation between age at diagnosis and airway resistance. Conclusions: Women with ICPP seem to have lower lung function despite treatment with GnRHa. Further research on the effects of sex hormones on the airways should take into account potential interplay with factors affecting the start of puberty.