Safety and effectiveness of a somatropin biosimilar in children requiring growth hormone treatment: second analysis of the PATRO Children study Italian cohort.

PURPOSE: To investigate the long-term safety (primary endpoint) and effectiveness (secondary endpoint) of the somatropin biosimilar Omnitrope®. METHODS: PATRO Children is an ongoing, multicenter, observational, post-marketing surveillance study. Children who received Omnitrope® for any indication were included. Adverse events (AEs) were evaluated in all study participants. Auxological data, including height standard deviation scores (HSDS) and height velocity standard deviation scores (HVSDS), were used to assess effectiveness. In this snapshot analysis, data from the Italian subpopulation up to August 2017 were reported. RESULTS: A total of 291 patients (mean age 10.0 years, 56.0% male) were enrolled at 19 sites in Italy. The mean duration of Omnitrope® treatment was 33.1 ± 21.7 months. There were 48 AEs with a suspected relationship to the study drug (as reported by the investigator) that occurred in 35 (12.0%) patients, most commonly headache, pyrexia, arthralgia, insulin-like growth factor above normal range, abdominal pain, pain in extremity and acute gastroenteritis. There were no confirmed cases of type 1 or type 2 diabetes; however, two patients (0.7%) had impaired glucose tolerance that was considered Omnitrope® related. The mean HSDS increased from - 2.41 ± 0.73 at baseline (n = 238) to - 0.91 ± 0.68 at 6.5 years (n = 10). The mean HVSDS increased from - 1.77 ± 1.38 at baseline (n = 136) to 0.96 ± 1.13 at 6.5 years (n = 10). CONCLUSIONS: In this sub-analysis of PATRO Children, Omnitrope® appeared to have acceptable safety and effectiveness in the treatment of in Italian children, which was consistent with the earlier findings from controlled clinical trials.

Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients.

BACKGROUND: Autoimmune Polyglandular Syndrome type 1 (APS-1) is a rare recessive inherited disease, caused by AutoImmune Regulator (AIRE) gene mutations and characterized by three major manifestations: chronic mucocutaneous candidiasis (CMC), chronic hypoparathyroidism (CH) and Addison's disease (AD). METHODS: Autoimmune conditions and associated autoantibodies (Abs) were analyzed in 158 Italian patients (103 females and 55 males; F/M 1.9/1) at the onset and during a follow-up of 23.7 ± 15.1 years. AIRE mutations were determined. RESULTS: The prevalence of APS-1 was 2.6 cases/million (range 0.5-17 in different regions). At the onset 93% of patients presented with one or more components of the classical triad and 7% with other components. At the end of follow-up, 86.1% had CH, 77.2% AD, 74.7% CMC, 49.5% premature menopause, 29.7% autoimmune intestinal dysfunction, 27.8% autoimmune thyroid diseases, 25.9% autoimmune gastritis/pernicious anemia, 25.3% ectodermal dystrophy, 24% alopecia, 21.5% autoimmune hepatitis, 17% vitiligo, 13.3% cholelithiasis, 5.7% connective diseases, 4.4% asplenia, 2.5% celiac disease and 13.9% cancer. Overall, 991 diseases (6.3 diseases/patient) were found. Interferon-ω Abs (IFNωAbs) were positive in 91.1% of patients. Overall mortality was 14.6%. The AIRE mutation R139X was found in 21.3% of tested alleles, R257X in 11.8%, W78R in 11.4%, C322fsX372 in 8.8%, T16M in 6.2%, R203X in 4%, and A21V in 2.9%. Less frequent mutations were present in 12.9%, very rare in 9.6% while no mutations in 11% of the cases. CONCLUSIONS: In Italy, APS-1 is a rare disorder presenting with the three major manifestations and associated with different AIRE gene mutations. IFNωAbs are markers of APS-1 and other organ-specific autoantibodies are markers of clinical, subclinical or potential autoimmune conditions.

Disorders of glucose metabolism in Prader-Willi syndrome: Results of a multicenter Italian cohort study.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS) is characterized by a high incidence of altered glucose metabolism (AGM). However, epidemiological data on impaired fasting glucose (IFG), impaired glucose tolerance (IGT) and type 2 diabetes mellitus (T2DM) are still discordant. METHODS AND RESULTS: We performed a multicenter study based on 274 PWS patients [144 females, aged 20.3 ± 10.4 yrs (range: 8.1-50.1 years)] evaluating the prevalence for AGM in the entire group, and according to age (children <10 yrs; adolescents 10-18 yrs, and adults >18 yrs), Body Mass Index (BMI = kg/m(2)), gender, genotypes (deletion or uniparental disomy for chromosome 15), and GH therapy (GHT) (untreated, previously or currently treated). Altogether, AGM was detected in 67 (24.4%) of patients (0.7% IFG, 10.2% IGT, 13.5% T2DM). The prevalence of AGM was correlated to age (p = 0.001), BMI (p = 0.001) and HOMA-IR (p = 0.001). However, gender, genotype, and GHT did not influence AGM development in univariate analysis. These data were confirmed as positive predictors when inserted in a multivariate analysis model. CONCLUSION: This study is the first report on the prevalence of AGM in a large population of PWS. Overall, PWS subjects show a high prevalence of AGM that appears more common in obese and adult subjects. Our data confirm the main role of obesity on the individual metabolic risk clustering in PWS, and thus reinforce the concept that improvement in weight control remains the most important goal of any PWS treatment program.

Brain anatomical substrates of mirror movements in Kallmann syndrome.

Among male patients affected by Kallmann syndrome, a genetically determined disease due to defective neural migration leading to hypogonadropic hypogonadism and hypo/anosmia, about 40% present the peculiar phenomenon of mirror movements, i.e. involuntary movements mirroring contralateral voluntary hand movements. Several pathogenic hypotheses have been proposed, but the ultimate neurological mechanisms are still elusive. The aim of the present study was to investigate brain anatomical substrates of mirror movements in Kallmann syndrome by means of a panel of quantitative MRI analyses. Forty-nine male Kallmann syndrome patients underwent brain MRI. The study protocol included 3D-T1-weighted gradient echo, fluid attenuated inversion recovery and diffusion tensor imaging. Voxel-based morphometry, sulcation, curvature and cortical thickness analyses and tract based spatial statistics were performed using SPM8, Freesurfer and FSL. All patients underwent a complete physical and neurological examination including the evaluation of mirror movements (according to the Woods and Teuber criteria). Kallmann syndrome patients presenting with mirror movements (16/49, 32%) displayed the following brain changes: 1) increased gray matter density in the depth of the left precentral sulcus behind the middle frontal gyrus; 2) decreased cortical thickness in the precentral gyrus bilaterally, in the depth of right precentral sulcus and in the posterior portion of the right superior frontal gyrus; and 3) decreased fractional anisotropy in the left hemisphere involving the temporal lobe and peritrigonal white matter. No differences were shown by cortical curvature and sulcation analyses. The composite array of brain changes observed in Kallmann syndrome patients with mirror movements likely represents the anatomical-structural underpinnings leading to the peculiar derangement of the complex circuitry committed to unilateral hand voluntary movements.

Effects of saltwater intrusion on pinewood vegetation using satellite ASTER data: the case study of Ravenna (Italy).

The San Vitale pinewood (Ravenna, Italy) is part of the remaining wooded areas within the southeastern Po Valley. Several studies demonstrated a widespread saltwater intrusion in the phreatic aquifer caused by natural and human factors in this area as the whole complex coastal system. Groundwater salinization affects soils and vegetation, which takes up water from the shallow aquifer. Changes in groundwater salinity induce variations of the leaf properties and vegetation cover, recognizable by satellite sensors as a response to different spectral bands. A procedure to identify stressed areas from satellite remote sensing data, reducing the expensive and time-consuming ground monitoring campaign, was developed. Multispectral Advanced Spaceborne Thermal Emission and Reflection Radiometer (ASTER) data, acquired between May 2005 and August 2005, were used to calculate Normalized Difference Vegetation Index (NDVI). Within the same vegetation type (thermophilic deciduous forest), the areas with the higher vegetation index were taken as reference to identify the most stressed areas using a statistical approach. To confirm the findings, a comparison was conducted using contemporary groundwater salinity data. The results were coherent in the areas with highest and lowest average NDVI values. Instead, to better understand the behavior of the intermediate areas, other parameters influencing vegetation (meteorological data, water table depth, and tree density) were added for the interpretation of the results.

Medical treatment in gender dysphoric adolescents endorsed by SIAMS-SIE-SIEDP-ONIG.

PURPOSE: Despite international guidelines being available, not all gender clinics are able to face gender dysphoric (GD) youth population needs specifically. This is particularly true in Italy. Centers offering specialized support are relatively few and a commonly accepted Italian approach to GD youth has still not been defined. The aim of the present Position Statement is to develop and adhere to Italian guidelines for treatment of GD adolescents, in line with the "Dutch Approach", the Endocrine Society (ES), and the World Professional Association for Transgender Health (WPATH) guidelines. METHODS: An in-depth brainstorming on the application of International guidelines in the Italian context was performed by several dedicated professionals. RESULTS: A staged approach, combining psychological support as well as medical intervention is suggested. In the first phase, individuals requesting medical help will undergo a psycho-diagnostic procedure to assess GD; for eligible adolescents, pubertal suppression should be made available (extended diagnostic phase). Finally, from the age of 16 years, cross-sex hormonal therapy can be added, and from the age of 18 years, surgical sex reassignment can eventually be performed. CONCLUSIONS: The current inadequacy of Italian services offering specialized support for GD youth may lead to negative consequences. Omitting or delaying treatment is not a neutral option. In fact, some GD adolescents may develop psychiatric problems, suicidality, and social marginalization. With access to specialized GD services, emotional problems, as well as self-harming behavior, may decrease and general functioning may significantly improve. In particular, puberty suppression seems to be beneficial for GD adolescents by relieving their acute suffering and distress and thus improving their quality of life.

Alström syndrome is associated with short stature and reduced GH reserve.

INTRODUCTION: Alström syndrome (ALMS) is a rare autosomal recessive monogenic disease included in an emerging class of genetic disorders called 'ciliopathies' and is likely to impact the central nervous system as well as metabolic and endocrine function. Individuals with ALMS present clinical features resembling a growth hormone deficiency (GHD) condition, but thus far no study has specifically investigated this aspect in a large population. MATERIAL AND METHODS: Twenty-three patients with ALMS (age, 1-52 years; 11 males, 12 females) were evaluated for anthropometric parameters (growth charts and standard deviation score (SDS) of height, weight, BMI), GH secretion by growth hormone-releasing hormone + arginine test (GHRH-arg), bone age, and hypothalamic-pituitary magnetic resonance imaging (MRI). A group of 17 healthy subjects served as controls in the GH secretion study. Longitudinal retrospective and prospective data were utilized. RESULTS: The length-for-age measurements from birth to 36 months showed normal growth with most values falling within -0·67 SDS to +1·28 SDS. A progressive decrease in stature-for-age was observed after 10 years of age, with a low final height in almost all ALMS subjects (>16-20 years; mean SDS, -2·22 ± 1·16). The subset of 12 patients with ALMS tested for GHRH-arg showed a significantly shorter stature than age-matched controls (154·7 ± 10·6 cm vs 162·9 ± 4·8 cm, P = 0·009) and a mild increase in BMI (Kg/m(2) ) (27·8 ± 4·8 vs 24·1 ± 2·5, P = 0·007). Peak GH after GHRH-arg was significantly lower in patients with ALMS in comparison with controls (11·9 ± 6·9 µg/l vs 86·1 ± 33·2 µg/l, P < 0·0001). Severe GHD was evident biochemically in 50% of patients with ALMS. The 10 adult ALMS patients with GHD showed a reduced height in comparison with those without GHD (149·7 ± 6·2 cm vs 161·9 ± 9·2 cm, P = 0·04). MRIs of the diencephalic and pituitary regions were normal in 11 of 12 patients. Bone age was advanced in 43% of cases. CONCLUSIONS: Our study shows that 50% of nonobese ALMS patients have an inadequate GH reserve to GHRH-arg and may be functionally GH deficient. The short stature reported in ALMS may be at least partially influenced by impairment of GH secretion.

Polypoid lesion of the gallbladder in childhood: case report and literature review.

Gallbladder polypoid lesions are rare in the pediatric patient and sometimes represent an incidental finding. A 13 year old male was referred to the Padua Hospital Pediatric Department for an obesity. A routine abdominal ultrasound (US) detected a gallbladder polypoid lesion 6 mm in diameter, initially considered a gallbladder adenoma. Investigation did not detect any other biliary tract abnormality. After seven months, the asymptomatic patient underwent a follow-up US which revealed the disappearance of the polypoid mass. The following concerns are raised: what is the size of the polypoid mass that should be considered for surgery? How does the presence of symptoms worsen the diagnosis and lead to preferring a surgical approach (cholecystectomy) over an echographic follow-up?

Cardiovascular risk factors and ultrasound evaluation of intima-media thickness at common carotids, carotid bulbs, and femoral and abdominal aorta arteries in patients with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

CONTEXT: In congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency, a tendency for obesity, high insulin, and high 24-h blood pressure levels has been reported in children and adolescents. Increased intima-media thickness (IMT) is considered a measure of subclinical atherosclerosis and a predictor of myocardial infarction and stroke. OBJECTIVE: The objective of the study was to evaluate glucose metabolism, lipid profile, IMT of the abdominal aorta, right and left common carotids, carotid bulbs, and common femoral arteries in adult CAH patients. SUBJECTS: Nineteen (10 females, nine males; 28 +/- 3.5 yr) patients (12 salt wasting and seven simple virilizing) and 19 (10 females, nine males) healthy subjects matched for anthropometric parameters (age, sex, body mass index, smoking habit, waist to hip ratio, and blood pressure). METHODS: Glucose metabolism was studied using the oral glucose tolerance test and the homeostasis model assessment-insulin resistance. The echo-Doppler was used for arterial ultrasound. 17-Hydroxyprogesterone, androstenedione, testosterone, ACTH, plasma renin activity, total and high-density lipoprotein cholesterol, and triglycerides were measured. RESULTS: CAH patients had significantly higher fasting plasma insulin (11.6 +/- 6.20 microU/ml vs 5.18 +/- 2.4 microU/ml; P < 0.0001) and homeostasis model assessment-insulin resistance than controls (2.46 +/- 1.92 vs 1.12 +/- 0.58; P = 0.0033). IMT of the studied arteries was higher in CAH patients than controls. There was no correlation between IMT and cumulative glucocorticoid doses and androgen levels. CONCLUSION: A reduced insulin sensitivity and increased IMT were demonstrated in adults with CAH, who consequently need a follow-up for cardiovascular risk.

Oil spill hazard from dispersal of oil along shipping lanes in the Southern Adriatic and Northern Ionian Seas.

An assessment of hazard stemming from operational oil ship discharges in the Southern Adriatic and Northern Ionian (SANI) Seas is presented. The methodology integrates ship traffic data, the fate and transport oil spill model MEDSLIK-II, coupled with the Mediterranean Forecasting System (MFS) ocean currents, sea surface temperature analyses and ECMWF surface winds. Monthly and climatological hazard maps were calculated for February 2009 through April 2013. Monthly hazard distributions of oil show that the zones of highest sea surface hazard are located in the southwestern Adriatic Sea and eastern Ionian Sea. Distinctive "hot spots" appear in front of the Taranto Port and the sea area between Corfu Island and the Greek coastlines. Beached oil hazard maps indicate the highest values in the Taranto Port area, on the eastern Greek coastline, as well as in the Bari Port area and near Brindisi Port area.

I. Adrenal cortex and steroid 21-hydroxylase autoantibodies in adult patients with organ-specific autoimmune diseases: markers of low progression to clinical Addison's disease.

Adrenal cortex antibodies (ACA) were measured by immunofluorescence in 8840 adult patients with organ-specific autoimmune diseases without overt hypoadrenalism. Sixty-seven (0.8%) patients were ACA-positive, with the highest prevalence in those with premature ovarian failure (8.9%). Forty-eight ACA-positive and 20 ACA-negative individuals were enrolled into a prospective study. Antibodies to steroid 21-hydroxylases (21-OH), steroid 17 alpha-hydroxylase (17 alpha-OH) and cytochrome P450 side chain cleavage enzyme (P450scc) were measured by immunoprecipitation assay. Human leucocyte antigens D-related (HLA-DR) genotyping was also carried out and adrenal function assessed by ACTH test. On enrollment, 75% of ACA-positive patients had a normal adrenal function, while 25% revealed a subclinical hypoadrenalism. 21-OH antibodies were positive in 91% of ACA-positive sera. Eleven patients were positive for steroid-cell antibodies by immunofluorescence, and 9 revealed a positivity for antibodies to 17 alpha-OH and/or P450scc. During the prospective study, overt Addison's disease developed in 21% and subclinical hypoadrenalism in 29% of ACA-positive patients, while 50% maintained normal adrenal function. Progression to Addison's disease was more frequent in patients with subclinical hypoadrenalism, high titers of ACA and higher levels of 21-OH antibodies, complement-fixing ACA and HLA-DR3 status. All 20 persistently ACA-negative patients were also negative for antibodies to 21-OH, 17 alpha-OH, and P450scc, and all maintained normal adrenal function during follow-up. In conclusion, the detection of ACA/21-OH antibodies in adults is a marker of low progression toward clinical Addison's disease.

II. Adrenal cortex and steroid 21-hydroxylase autoantibodies in children with organ-specific autoimmune diseases: markers of high progression to clinical Addison's disease.

Adrenal cortex autoantibodies (ACA) were measured by immunofluorescence in 808 children with organ-specific autoimmune diseases without adrenal insufficiency. ACA were found in 14 children (1.7%), mostly in hypoparathyroidism (48%). Ten ACA-positive and 12 ACA-negative children were followed up for a maximum of 10 yr by evaluation of adrenocortical function (ACTH test) and autoantibody status. In all patients steroid-producing cell autoantibodies were assessed by immunofluorescence and autoantibodies to steroid 21-hydroxylase, 17 alpha-hydroxylase, and cytochrome P450 side-chain cleavage enzyme by immunoprecipitation assay. All 10 ACA-positive patients were positive for 21-hydroxylase autoantibodies. Six were positive for steroid-producing cell autoantibodies and 5 also for autoantibodies to 17 alpha-hydroxylase and/or P450 side-chain cleavage enzyme. Overt Addison's disease developed in 9 (90%) ACA/21-OH-antibody-positive children after 3-121 months, and 1 remaining child had subclinical hypoadrenalism. By contrast, all ACA/21-OH antibody-negative children maintained normal adrenal function. Adrenal failure was not related to ACA titres, sex, adrenal function, type of preexisting autoimmune disorder, or human leucocyte antigens D-related status. In conclusion, in children with autoimmune endocrine diseases, ACA/21-hydroxylase autoantibodies are important predictive markers for the development of Addison's disease.

DNA HLA-DRB1 analysis in children of positive mothers and estimated risk of vertical HIV transmission.

RFLP HLA-DRB1 analysis was performed on a total of 83 children born from HIV-infected mothers, 35 of whom were shown to be HIV-infected, while 48 reverted from seropositivity to seronegativity, indicating that they were not infected. Moreover, 89 healthy children were used as controls. It has been found that DRB1-14a and DRB1-13a.4 alleles were not present in the HIV-infected children, but were found in the sero-reverted (HIV-uninfected) children (in the proportion of 9.6 per cent and 5.3 per cent, respectively), and in the controls (5.6 per cent and 3.9 per cent, respectively). The possible correlation between DR and risk of HIV transmission from mother to baby was analysed considering every single allele, estimated by the ratio between the number of infected children and the number of all children born from seropositive mothers. There was also introduced a statistic G for the control of 'statistical validity' of data.

The number of markers of pancreatic autoimmunity is proportional to the risk for type 1 diabetes mellitus in Italian and English patients with organ-specific autoimmune diseases.

An 11-year prospective study was carried out in 226 patients with organ-specific autoimmune disease (OSAD) coming from northern Italy and southern England. Patients were investigated for diabetes-related autoantibodies (ICAs, GADAbs, and IA2Abs) in order to evaluate the best immunological combination in predicting type 1 DM. One hundred twenty-eight patients were ICA positive (77 Italian and 51 English), and 98 were ICA negative. ICAs were detected by immunofluorescence technique on human pancreas, whereas GADAbs and IA2Abs were found by immunoprecipitation assay. During follow-up, 33 of 128 (25.8%) ICA(+) (26% of Italian and 25.5% of English) and 2 of 98 (2%) ICA(-) patients developed type 1 DM (17 with acute-onset, and 18 with non-acute-onset disease). Among ICA(+) patients, three subgroups were considered: ICA(+) alone; ICA and GADAb(+); ICA, GADAb, and IA2Ab(+). Patients who were only ICA(+) had a predictive value for type 1 DM of 4.7%, with an annual incidence of 0.7%, and a cumulative risk of 6%. ICA and GADAb(+) patients had a predictive value of 17.5%, with an annual incidence of 2%, and a cumulative risk of 20%. ICA, GADAb, and IA2Ab(+) patients had a predictive value of 72, with an annual incidence of 13%, and a cumulative risk of 87%. Patients having three immunological markers revealed a prevalence increased in HLA-DR3 and/or -DR4, but reduced in HLA-DR2 haplotypes. The risk for type 1 DM increased proportionally with the number of diabetes-related antibodies, which were also related to the presence of genetic markers of disease susceptibility.

Prenatal sexing and sex determination in infants with ambiguous genitalia by polymerase chain reaction.

Sex determination in both fetuses and infants with ambiguous external genitalia usually necessitates time-consuming and costly karyotyping. We propose a simple, rapid, and reliable method of prenatal and postnatal sex determination by means of the PCR, a technique currently used to identify gender for forensic purposes. DNA was extracted from 20 samples of whole blood from infants with ambiguous genitalia and from five samples of amniotic fluid. Three markers were amplified from each specimen: a Y chromosome alphoid repeat sequence and two homologous genes, amelogenin (AME) and zinc finger protein (ZFP). All three were detected in under 10 hr. A comparison of the results obtained with those of cytogenetic analysis of the same samples showed a perfect sex match, demonstrating that this PCR technique provides an accurate means of determining gender.

Sex chromosome analysis in Turner Syndrome by a pentaplex PCR assay.

In this study, we describe a pentaplex PCR to determine the parental origin of the X chromosome and the presence of mosaicism, via amplification of four polymorphic markers located along the X chromosome (DXS10011, DXS6807, HUMARA, DXS101) and the X-Y amelogenin marker, in 41 families having a daughter with Turner Syndrome. Our results confirmed the cytogenetic findings and we found that the parental origin of the single X chromosome to be maternal in 84% of cases.

Unresolved problems concerning optimal therapy of puberty in children with chronic renal diseases.

Many children with chronic renal insufficiency (CRI) show growth retardation and severely delayed pubertal development. Successful renal transplantation (RTx) also rarely results in full growth rehabilitation. Pubertal height gain in CRI patients is only 58% and 48% of that observed in late-maturing boys and girls, respectively. Growth retardation in both CRI and RTx patients is not the result of abnormal GH secretion or decreased levels of IGF-I, but rather of elevated levels of IGFBPs inhibiting the bioavailability of the IGFs. In RTx patients prednisone may also inhibit growth directly via inhibition of bone matrix formation. Several studies have convincingly shown that GH therapy at a dose of 4 IU/m2/day results in a sustained improvement of growth in prepubertal and pubertal children with CRI and in growth-retarded prepubertal and pubertal post-transplant patients. The following consensus was reached concerning optimal therapy of puberty in children with chronic renal disease. GH therapy does not lead to an earlier start of puberty. It is safe to give GH to RTx patients if transplant function is stable. GH therapy will not accelerate bone maturation and can improve the final height of children with CRI and after RTx. Increasing the GH dose above 4 IU/m2/day in pubertal RTx patients does not increase height gain or final height and is not advised as it may increase insulin resistance. GH should best be started before the start of the pubertal growth spurt but will still be effective in RTx patients with advanced bone age. GH testing should not be a prerequisite for starting GH therapy. It is important to optimise other therapies during puberty. During GH therapy of RTx patients use minimum daily, not alternate-day, steroid dosing. Further research is still required on the possible long-term effects of GH therapy in children with chronic diseases. Two studies demonstrated improved long-term growth and final height within the target height range, without significant side effects. Renal graft function did not deteriorate more than in matched controls. A GH dose of 4 IU/m2/day proved adequate.

Current concepts in tall stature and overgrowth syndromes.

In this overview an update is given on the pathogenesis, classification and differential diagnosis of overgrowth syndromes. In addition, height prognosis and therapeutic modalities available for managing mainly constitutional tall stature are discussed. Constitutional tall stature comprises normal variants in which one or both parents are tall. Primary disorders may have a prenatal onset and may be of chromosomal or genetic origin. Secondary overgrowth syndromes are most often the result of hormonal disturbances. Height prediction plays a key role in the management of tall children. Prediction equation models have been developed based on the growth data of healthy tall children. There is general agreement that a favourable effect on reducing ultimate height is obtained using high doses of sex steroids (girls 100-300 microg ethinyloestradiol; boys testosterone (T) ester depot preparations 250-1000 mg/month), the height reduction being greater when the treatment is started at a lower chronological and/or bone age. An alternative is the induction of puberty with low doses of sex steroids (girls 5-50 microg ethinyloestradiol; boys T esters 25-50 mg/m2/3 wk). In addition orthopaedic procedures have been suggested, but there is limited experience. Although psychosocial factors constitute the main reason for treating tall stature, extensive psychological investigations before or during height limiting therapy are lacking. Moreover, there are no objective data indicating lifelong psychosocial damage resulting from being tall.

Autoimmunity in isolated Addison's disease and in polyglandular autoimmune diseases type 1, 2 and 4.

Sera from 300 Italian patients with Addison's disease were collected over a 30 year period. Among these patients, 82% had autoimmune disease, 13% had tuberculosis and 5% had another causal condition. In 59% of the cases, autoimmune disease was associated with the autoimmune manifestations contributing to the description of polyglandular autoimmune disease (PGAD). In PGAD type 1, the disease was associated with chronic candidiasis and/or chronic hypoparathyroidism. In PGAD type 2, the patients had autoimmune thyroid disease and/or diabetes mellitus type 1, and in PGAD type 4, they presented a combination with other autoimmune diseases excluding those previously mentioned. Finally, the autoimmune disease was apparently isolated in 41% of the cases. In addition, patients with these four forms of disease exhibited a different genetic pattern, sex distribution, and age at presentation in addition to minor frequency of autoimmune diseases. Adrenal cortex autoantibodies directed against 21-hydroxylase were common serological markers for these four main clinical forms, showing a very high frequency at clinical onset of adrenal insufficiency. In some patients, steroid-producing cell autoantibodies were also present and correlated with gonadal failure and they recognize of 17alpha-hydroxylase or P450 side chain cleavage enzymes as target antigens.

Short-term bisphosphonate therapy could ameliorate osteonecrosis: a complication in childhood hematologic malignancies.

Osteonecrosis (ON) is a critical complication in the treatment of childhood leukemia and lymphoma. It particularly affects survivors of acute lymphoblastic leukemia and non-Hodgkin lymphoma reflecting the cumulative exposure to glucocorticosteroid therapy. ON is often multiarticular and bilateral, specially affecting weight-bearing joints. A conventional approach suggests a surgical intervention even if pharmacological options have also recently been investigated. We reported two cases of long time steroid-treated patients who underwent Bone Marrow Transplantation (BMT) for hematological disease. Both patients developed femoral head osteonecrosis (ON) that was diagnosed by magnetic resonance imaging (MRI) and the ON was also accompanied with pain and a limp. Despite of the conventional strategies of therapy, we successfully started a short-term treatment with bisphosphonates in order to decrease the pain and the risk of fracture.