Ductopenia and fetal liver-like architecture as unique and evocative sign of Turner syndrome.

BACKGROUND: Turner syndrome is the most common genetic disorder in females. In most subjects, with a normal physical appearance at birth, the diagnosis is suspected long after birth because of short stature, delayed puberty, primary or secondary amenorrhea or infertility. Abnormalities of liver function tests are reported in literature, with a prevalence ranging from 20% to 80%. In most subjects liver diseases are self-limiting, associated with obesity, hormonal therapy and autoimmune diseases. An association between Turner syndrome and cryptogenic liver disease has been reported. Abnormalities of liver function tests could be the unique sign of Turner syndrome in subjects with normal phenotypes. The histological picture of "fetal liver-like architecture" and "ductopenia" is of fundamental importance for the diagnosis of chromosomopathy. AIM: Review the causes of hypertransaminasemia by focusing on more rare as metabolic and genetic diseases. MATERIALS AND METHODS: We evaluated a 10 year old girl with a normal phenotype affected by chronic hypertransaminasemia and cholestasis, in whom a needle liver biopsy was performed after the most common causes of hypertransaminasemia were excluded. RESULTS: Liver histological evaluation revealed a smoldering colangiopathy with mild ductopenia and a fetal liver-like architecture. Turner syndrome, suspected on the basis of this histological picture, was confirmed by a pelvic ultrasound and a chromosome analysis. CONCLUSIONS: The histological features of "fetal liver-like architecture" and "ductopenia" represent an evocative sign that could indicate the diagnostic suspicion of Turner syndrome in a subject lacking in signs or symptoms of this disease. It is important to perform a pelvic ultrasound and an endocrinological evaluation in all females with chronic asymptomatic hypertransaminasemia even though they have normal phenotypes.

Infections occurring in adult patients receiving mechanical circulatory support: the two-year experience of an Italian National Referral Tertiary Care Center.

OBJECTIVE: Infection during mechanical circulatory support is a frequent adverse complication. We analyzed infections occurring in this population in a national tertiary care center, and assessed the differences existing between the setting of extracorporeal membrane oxygenation (ECMO) and ventricular assist devices (VADs). DESIGN, SETTING, AND PARTICIPANTS: An observational study was made of patients treated with ECMO or VAD in the San Raffaele Scientific Institute (Italy) between 2009 and 2011. INTERVENTIONS: None. RESULTS: Thirty-nine percent of the 46 patients with ECMO and 69% of the 15 patients with VAD developed infection. We observed a mortality rate of 36.1% during mechanical circulatory support and of 55.7% during the global hospitalization period. Although Gram-negative infections were predominant overall, patients with ECMO were more prone to develop Candida infection (29%), and patients with VAD tended to suffer Staphylococcus infection (18%). Patients with infection had longer ECMO support (p=0.03), VAD support (p=0.01), stay in the intensive care unit (p=0.002), and hospital admission (p=0.03) than patients without infection. Infection (regression coefficient=3.99, 95% CI 0.93-7.05, p=0.02), body mass index (regression coefficient=0.46, 95% CI 0.09-0.83, p=0.02), fungal infection (regression coefficient=4.96, 95% CI 1.42-8.44, p=0.009) and obesity (regression coefficient=10.47, 95% CI 1.77-19.17, p=0.02) were predictors of the duration of ECMO support. Stepwise logistic regression analysis showed the SOFA score at the time of implant (OR=12.33, 95% CI 1.15-132.36, p=0.04) and VAD (OR=1.27, 95% CI 1.04-1.56, p=0.02) to be associated with infection. CONCLUSIONS: Infection is a major challenge during ECMO and VAD support. Each mechanical circulatory support configuration is associated with specific pathogens; fungal infections play a major role.

Effects of chronic elevation of atrial natriuretic peptide and free fatty acid levels in the induction of type 2 diabetes mellitus and insulin resistance in patients with mitral valve disease.

BACKGROUND AND AIMS: The relationship between atrial natriuretic peptide (ANP), increased free fatty acid (FFA) and insulin resistance in patients with mitral valve disease (MVD), a group characterised by elevated atrial pressure and increased ANP levels, is not defined. The present study was performed to evaluate, in MVD patients, the relationship between increased ANP and FFA levels and insulin resistance and the role of mitral valve replacement/repair in ameliorating these metabolic alterations. Conversely, coronary heart disease (CHD) patients were evaluated before and after coronary artery bypass grafting (CABG), since they are known to be insulin resistant in the presence of chronic FFA increase. METHODS AND RESULTS: Fifty MVD patients and 55 CHD patients were studied before and 2 months after surgery and compared with 166 normal subjects. Before surgery, 56% of MVD patients had impaired glucose tolerance or newly diagnosed type 2 diabetes after a standard oral glucose load and this percentage decreased to 46% after surgery. In CHD, impaired glucose tolerance (IGT) or newly diagnosed type 2 diabetic patients were 67% of patients before and after CABG. In MVD, left atrial (LA) volume, ANP, FFA incremental area and insulin levels were higher and Insulin Sensitivity (IS) index significantly reduced while after surgery, LA volume, ANP and FFA significantly decreased and IS index significantly improved. In CHD, insulin resistance and hyperinsulinaemia were present both before and after surgery with increased tumour necrosis factor (TNF)-α and interleukin (IL)-6 levels. CONCLUSION: In MVD, a higher degree of abnormal glucose tolerance and insulin resistance are associated to increased levels of ANP and FFA, while these metabolic alterations are improved by mitral valve replacement/repair surgery. Clinical Trial.gov registration number NCT 00520962.

Evaluation of Kisspeptin levels in prepubertal obese and overweight children: sexual dimorphism and modulation of antioxidant levels.

OBJECTIVE: Kisspeptin, neuropeptide involved in puberty beginning and regulation of pituitary-gonadal axis, has been shown to stimulate antioxidant defenses in murine models. Its levels are greater in females than males and also in obese prepubertal girls. Therefore, our aim was to evaluate sex-related differences in prepubertal obese patients and the relationships of Kisspeptin with metabolic/hormonal parameters. PATIENTS AND METHODS: We studied Kisspeptin concentrations in 54 children (22 males and 32 females, Tanner stage 1), 5-12 ys, classified according to Cole's criteria into 17 overweight and 37 obese; 25 normal-weight children, aged 6-12 years, were studied as controls. We evaluated metabolic (glucose and insulin levels after oral glucose load, total- LDL- HDL-cholesterol, triglycerides, uric acid) and hormonal (fT3, fT4, TSH, IGF-1, leptin) parameters. Moreover, total antioxidant capacity (TAC) was evaluated by spectrophotometric method, using the system H202-metmyoglobin-ABTS. Kisspeptin levels were measured by RIA. RESULTS: We did not find significant differences between obese and normal-weight children, but obese males presented significantly lower levels than females. Kisspeptin did not correlate with BMI, HOMA-IR, Insulin peak levels and TAC; a significant correlation was found between Kisspeptin and fT3 (r2=0.25; p=0.003) in the obese group; leptin levels, significantly greater in obese vs. overweight and control children, significantly correlated with TAC (r2=0.39; p=0.03). CONCLUSIONS: These data suggest that both hormones could modulate antioxidants, Kisspeptin indirectly via influence on thyroid hormones, and Leptin by a direct effect. This mechanism seems to be sex-related, not attributable to peripheral steroid levels. Further studies can clarify the complex interrelationship between central and peripheral Kisspeptin secretion and oxidative stress in children obesity.

Unilateral cervical mass as a main clue raising the diagnostic suspicion of Kawasaki syndrome.

Unilateral cervical mass and fever were firstly misdiagnosed as bacterial lymphadenitis in a 6-year-old child and empirically treated with antibiotics. Later the child developed the additional features of Kawasaki syndrome and received intravenous immunoglobulins at the eighth day since fever onset with progressive disappearance of the cervical mass and no cardiac sequel. Kawasaki syndrome should be considered in childhood as a relevant cause of cervical lymphadenopathy unresponding to antibiotics: its recognition at an early stage might contribute to anticipate a proper treatment and abate heart complication rate.

Frailty of Obese Children: Evaluation of Plasma Antioxidant Capacity in Pediatric Obesity.

Background: Obese children are subject to the same chronic oxidative and inflammatory stress, responsible for the onset of all the complications typical of adult age, such as insulin resistance, type 2 diabetes, dyslipidemia and cardiovascular disease. Objectives: Since few studies are reported in prepubertal obese children, we investigated the relationship between oxidative stress, body composition and metabolic pattern in childhood obesity in comparison with adult obese patients. Methods: We enrolled 25 prepubertal children (12 males and 13 females) aged 5-12 years with a mean value of standard deviation of BMI (SDS-BMI)±SEM of 1.96±0.09. We performed oral glucose tolerance test, hormonal and metabolic evaluation, bioimpedentiometry, evaluation of total antioxidant capacity using spectroscopical method using a radical cation, 2,2I- azinobis(3-ethylbenzothiazoline-6 sulphonate) (ABTS), as indicator of radical formation, with a latency time (LAG) proportional to antioxidant in the sample. Results: LAG values significantly correlate with % fat mass, waist circumference and waist/hip ratio. However mean LAG values were significantly lower than in obese adults. Conclusions: We suggest that children are more susceptible to oxidative stress than adults, possibly to incomplete development of antioxidant system. Prognostic and therapeutical implications need to be further investigated.

The impact of insulin secretion on the ovarian response to exogenous gonadotropins in polycystic ovary syndrome.

The aim of the study was to evaluate the influence of insulin level on the ovarian response to FSH when inducing ovulation in patients affected by polycystic ovarian syndrome (PCOS). To evaluate the presence of hyperinsulinemia, 34 patients affected by PCOS were studied by an oral glucose tolerance test, then patients were stimulated for 52 cycles using FSH to induce ovulation. The ovarian response to therapy was evaluated by ultrasounds and as estradiol (E2) and androstenedione (A) plasma level determinations. On the basis of the insulinemic response to the glucose challenge, 20 patients were considered to be hyperinsulinemic and 14 normoinsulinemic. The hormonal features of each group were similar. The ovulation rate was similar in hyperinsulinemic and normoinsulinemic subjects, whereas the incidence of ovarian hyperstimulation was significantly higher in the hyperinsulinemic group. The increase in ovarian dimensions observed in hyperinsulinemic subjects after gonadotropin stimulation was more marked than that observed in normoinsulinemic ones. This was caused by the development of a larger number of immature follicles. E2 levels gradually increased after gonadotropin stimulation in both groups of subjects; however, higher levels were observed in hyperinsulinemic patients. During stimulation, the higher E2/A ratio suggests the presence of a greater aromatization activity in hyper-insulinemic patients. In conclusion, the present study suggests that, in PCOS, the insulinemic pattern may influence the ovarian response to gonadotropin administration; thus, hyperinsulinemic subjects may be at greater risk of ovarian hyperstimulation syndrome than normoinsulinemic subjects.

Short stature in a patient with Klinefelter syndrome and growth hormone deficiency.

We report on a child with Klinefelter syndrome and short stature due to idiopathic growth hormone deficiency (IGHD). His height was below the mid-parental height, with a significant delay in bone age. Height velocity increased from 4.5 to 8.2 cm/year during 1 year of GH therapy and typical catch-up growth was observed. No adverse reactions to the treatment were observed. We wish to emphasize the rare association between Klinefelter syndrome and IGHD and the apparent effectiveness and safety of recombinant somatotropin treatment in aneuploid patients.

Effects of oral glucose administration on plasma growth hormone levels in women with polycystic ovary syndrome.

OBJECTIVE: To evaluate the sensitivity of GH secretion to the suppressive effect of oral glucose administration in women with polycystic ovary syndrome (PCOS). DESIGN: Comparison of the GH response to an oral glucose load in women with PCOS and in weight-matched normally menstruating women (controls). SETTING: Reproductive endocrinology unit. PATIENT(S): Eighteen obese and 11 nonobese patients and 10 obese and 10 nonobese controls. INTERVENTION(S): After an overnight fast, each woman underwent a 75-g, 3-hour oral glucose tolerance test (OGTT). MEAN OUTCOME MEASURE(S): Growth hormone, glucose, and insulin responses to OGTT. RESULT(S): No significant differences in the glycemic and insulinemic responses were found between the patients and the weight-matched controls. No decrease in plasma GH was observed in both obese and nonobese patients and in obese controls during the OGTT, whereas a significant GH decrease occurred in nonobese controls 60 and 120 minutes after glucose intake. CONCLUSION(S): Oral glucose administration was unable to suppress GH levels in nonobese as well as in obese women with PCOS and in obese control women. These data suggest that both PCOS and obesity are associated with a reduced sensitivity of GH secretion to glucose suppression.

Dopamine DA-2 receptor sites in the rat renal cortex: a light microscope autoradiographic study.

The binding of the DA-2 receptor antagonist [3H]-spiroperidol, in the presence of appropriate concentrations of ketanserin to avoid the possible labelling of 5-HT-2 sites, was studied in sections of rat kidney using combined radioreceptor assay and light microscope autoradiography. [3H]-Spiroperidol was bound by sections of rat kidney in a manner consistent with the labelling of a single class of high affinity of DA-2 sites. Scatchard analysis of the binding isotherms showed a Kd value of 2.5 +/- 0.2 nmol/l and a Bmax value of 129.5 +/- 6.8 fmol/mg protein. Light microscope autoradiography, centered on the renal cortex, revealed the development of silver grains within cortical convoluted tubules. Silver grains were rather homogeneously distributed to both proximal and distal convoluted tubules, with no specific glomerular localization. These findings do not support the assumption of the existence of glomerular DA-2 receptors in the rat kidney.

Radioligand binding and autoradiographic analysis of dopamine receptors in the human heart.

The effects of dopamine on the 3',5-'cyclic adenosine monophosphate (cAMP) generating system were analyzed in membrane particles from the human right and left cardiac ventricle. In addition, the pharmacological profile and the anatomical localization of dopamine receptors were assessed on frozen sections of human cardiac atrial or ventricular tissue. Dopamine increased cAMP levels, in a concentration-dependent manner, in membranes of the right and the left ventricle. These effects were abolished by the beta-adrenoceptor antagonist (-)-propranolol, but not by the D1 receptor antagonist SCH 23390 or by the non selective D1/D2 receptor antagonist haloperidol. No specific binding of the D1 receptor antagonist [3H]-SCH 23390 was noticeable within the atrial or ventricular portions of the heart examined using either radioligand binding or autoradiographic techniques. The D2 receptor antagonist [3H]-spiroperidol, in the presence of concentrations of ketanserin sufficient to block possible binding to 5-HT2 sites, was specifically bound to sections of human heart with a dissociation constant value of about 2.6 nmol/l. The highest density of [3H]-spiroperidol binding occurred in the right ventricle followed, in descending order, by the right atrium, the upper part of the left ventricle, the lower part of the left ventricle, the left atrium and the interventricular septum. The binding profile of [3H]-spiroperidol to sections of human heart was consistent with the labeling of dopamine D2 sites. Light microscope autoradiography revealed silver grains throughout the atrial and ventricular walls and these were frequently accumulated in clusters.(ABSTRACT TRUNCATED AT 250 WORDS)

IGF-I levels in prepubertal and pubertal children with Down syndrome.

BACKGROUND: Growth retardation is a main feature of Down syndrome but it is still unclear whether an alteration of the GH/IGF-I axis is present in this condition. Concerning IGF-I levels, they have been found reduced by some authors but normal by others. METHODS: On these bases, IGF-I levels have been assessed from prepubertal to late pubertal stages of gonadal maturation in a large group of children and adolescents with Down syndrome (DS, 68 M, 45 F, 12.5 +/- 0.6 yr; prepubertal n = 39, pubertal n = 74) with those in a group of normal children and adolescents (NS, 75 M, 87 F; 11.1 +/- 0.4 yr; prepubertal n = 94, pubertal n = 68). RESULTS: Within each group, IGF-I levels were gender-independent while showed age-related variations with positive association with pubertal stage--peaking up in pubertal stage IV--(DS: r = 0.6, NS: r = 0.4, both p < 0.0001) and testosterone (DS: r = 0.6, NS: r = 0.5, p < 0.001) or estradiol (DS: r = 0.6, NS: r = 0.5, p < 0.001) levels. Considering whole groups, mean IGF-I levels in DS were slightly but significantly lower than those in NS (257.9 +/- 12.5 vs 310.8 +/- 12.6 micrograms/l, p < 0.02). Analyzing individual IGF-I levels in DS with respect to normal ranges per pubertal stage, more than 85% of IGF-I levels resulted within the normal limits. These results demonstrate that IGF-I levels in DS patients are generally within the normal range--though a slight reduction of mean IGF-I levels is present--and follow normal age-related variations with clear cut increase at puberty and positive association with gonadal steroid levels. CONCLUSIONS: This evidence points toward the need to clarify the GH/IGF-I axis function and activity in DS patients.

Structural variants of chromosome 9: a possible association with hypogonadotropic hypogonadism.

We report two cases of structural variations of chromosome 9 associated with hypogonadotropic hypogonadism and azoospermia in adolescent boys. One patient also had a partially imperforated urethral meatus. Histological examination revealed that both had hypotrophic and underdeveloped testes. There was no LH and FSH response to LH-RH stimulation nor was there any response to naloxone tests. Basal and HCG stimulated plasma testosterone values were below normal prepubertal levels. As the administration of gonadotrophins did not improve the clinical and hormonal findings, alternative androgen therapy was necessary to achieve secondary sexual characteristics. Although they reached a good level of androgenization, their testes were still very small and azoospermia remained, as confirmed by repeated semen analyses. A possible association between chromosome 9 polymorphisms and hypothalamo-pituitary axis abnormalities is suggested. It is hypothesized that structural variants of chromosome 9 are not unrelated occurrences. Furthermore, and in view of the fact that they can lead to a high risk of azoospermia and infertility, such variants call for clinical investigation.

Gonadotropin-dependent sexual precocity in a boy affected by pseudohypoparathyroidism.

Pseudohypoparathyroidism (PHP) is characterized by hypocalcemia and hyperphosphatemia due to PTH resistance. PHP type Ia is due to diminished G(s)alpha activity in several tissues, causing resistance to hormones whose action is mediated by cAMP. Only two cases of males with PTH type Ia who paradoxically showed sexual precocity have been described in the literature. We describe an 11.5 year-old boy affected by PHP without AHO but with associated true precocious puberty, who came to the I.C.U. for tetanic seizures and drowsiness due to severe hypocalcemia. Hyperphosphatemia, increased PTH levels and normal 25-OH-vitamin D values were present. Skeletal X-ray showed mild osteopenia. Brain MRI revealed symmetric calcifications in basal ganglia and in frontal areas. Thyroid and thyreotropinic function were normal. Testosterone levels were in the adult range, as well as basal and stimulated gonadotropin levels. Tanner stage P4, G4; testicular volume 12-15 mi. Molecular cytogenetics studies are now underway to further elucidate the etiology of this form of PHP.

Which treatment options should be used in adolescents with polycystic ovary syndrome?

Several studies have hypothesized a peripubertal onset of polycystic ovary syndrome (PCOS). This syndrome affects different pathogenetic pathways and includes endocrine-metabolic abnormalities such as hyperandrogenism, hyperinsulinism and insulin resistance. The therapeutic approaches must be addressed to individualization of therapy, considering the major clinical manifestations of the syndrome during adolescence. While the treatment of hyperandrogenism makes use of different drugs already studied, the debate about the use of insulin sensitizing drugs is still open. It will be more and more necessary to define the phenotypic and genotypic milieu in which all treatments will be as safe and effective as possible.

Treatment of undescended testes with hMG and hMG plus hCG: clinical, hormonal and sonographic evaluation.

20 children (mean age 4, 6 yrs), of whom 13 had unilateral and 7 had bilateral cryptorchidism were treated with hMG: 40 I.U. three i.m. injections per week for six or eight weeks. Where there was no descent of testis, treatment was continued with hMG at the same dosage plus hCG 500 I.U. one i.m. injection per week for an additional four weeks. The children were tested for FSH, LH and Testosterone serum levels at the beginning of treatment and after 6, 8 and 14 weeks. We obtained testicular descent in 10 out of 20 cases treated. Ultrasonography enabled us to locate the undescended testes in all cases and to follow the response to treatment.

[Evaluation of the testicular function using the HCG test in normal and cryptorchid children]. / Valutazione della funzione testicolare mediante hCG-test in bambini normali e criptorchidi.

The testicular function has been evaluated by a single dose hCG-test in normal and cryptorchid prepubertal boys using three different protocols. No remarkable difference has been observed using different posologic protocols. Testicular function in boys affected by cryptorchidism was similar to the testicular function in normal controls. However cryptorchid boys older than 6 years of age showed a significant reduction in testicular response to hCG-test in comparison to cryptorchid boys younger than 6 years of age.

[Intracranial hemorrhage in congenital factor II deficiency]. / Emorragia endocranica nel deficit congenito del fattore II.

A case of congenital defect of factor II is reported. It concerns a newborn with a not traumatic haematoma due to congenital hypoprothrombinaemia, which is rarely described in scientific literature.