Metabolic syndrome in adult patients with Prader-Willi syndrome.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most common genetic cause of obesity, is characterized by elevated morbility and mortality in all ages. In this context, non-obese PWS children showed low frequency of metabolic syndrome (MetS), while a comparable prevalence was observed in obese PWS and obese controls. Aim of this study was to estimate the occurrence of MetS and its components in a large group of PWS adults, according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 108 PWS aged 18.0-43.2 years (87 obese and 21 non-obese) and in 85 controls with nonsyndromic obesity matched for age, gender, and BMI with obese PWS. Non-obese PWS showed lower waist circumference, insulin, HOMA-index, triglycerides, diastolic blood pressure, and higher HDL-C than both obese PWS and obese controls (p < 0.017). Obese PWS showed higher glucose and systolic blood pressure than both non-obese PWS and obese controls (p < 0.017). MetS was found in 1/21 (4.8%) non-obese PWS, 36/87 (41.4%) obese PWS and 39/85 (45.9%) obese controls. Non-obese PWS showed lower frequency for each MetS component as compared with obese PWS and obese controls. PWS patients with deletion of the chromosome 15q11-13 showed a lower risk for low HDL-C (p < 0.01) and a trend towards a lower MetS risk (p < 0.06) compared to subjects without deletion. CONCLUSION: Our findings suggest the main role that obesity status plays on the individual metabolic risk clustering in PWS adults. Early identification of MetS could be helpful to improve morbidity and prevent mortality in such patients.

Permanent diabetes during the first year of life: multiple gene screening in 54 patients.

AIMS/HYPOTHESIS: The aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age. METHODS: We studied 46 probands with permanent, insulin-requiring diabetes with onset within the first 6 months of life (permanent neonatal diabetes mellitus [PNDM]/monogenic diabetes of infancy [MDI]) (group 1) and eight participants with diabetes diagnosed between 7 and 12 months of age (group 2). KCNJ11, INS and ABCC8 genes were sequentially sequenced in all patients. For those who were negative in the initial screening, we examined ERN1, CHGA, CHGB and NKX6-1 genes and, in selected probands, CACNA1C, GCK, FOXP3, NEUROG3 and CDK4. The incidence rate for PNDM/MDI was calculated using a database of Italian patients collected from 1995 to 2009. RESULTS: In group 1 we found mutations in KCNJ11, INS and ABCC8 genes in 23 (50%), 9 (19.5%) and 4 (8.6%) patients respectively, and a single homozygous mutation in GCK (2.1%). In group 2, we identified one incidence of a KCNJ11 mutation. No genetic defects were detected in other loci. The incidence rate of PNDM/MDI in Italy is estimated to be 1:210,287. CONCLUSIONS/INTERPRETATION: Genetic mutations were identified in ~75% of non-consanguineous probands with PNDM/MDI, using sequential screening of KCNJ11, INS and ABCC8 genes in infants diagnosed within the first 6 months of age. This percentage decreased to 12% in those with diabetes diagnosed between 7 and 12 months. Patients belonging to the latter group may either carry mutations in genes different from those commonly found in PNDM/MDI or have developed an early-onset form of autoimmune diabetes.

Metabolic syndrome in children with Prader-Willi syndrome: the effect of obesity.

BACKGROUND AND AIMS: Prader-Willi syndrome (PWS), the most frequent syndromic obesity, is associated with elevated morbidity and mortality in pediatric and adult ages. In PWS, the presence of metabolic syndrome (MS) has not yet been established. The aim of the study was to estimate the frequency of MS and its components in pediatric subjects according to obesity status. METHODS AND RESULTS: A cross-sectional study was performed in 109 PWS children aged 2-18 years (50 obese and 59 non-obese) and in 96 simple obese controls matched for age, gender, and also for BMI with obese PWS. Obesity was defined when SDS-BMI was >2. Non-obese PWS showed significantly lower frequency of hypertension (12%) than obese PWS (32%) and obese controls (35%)(p=0.003). The same was observed for low HDL-cholesterol (3% vs 18% and 24%, p=0.001) and high triglycerides (7% vs 23% and 16%, p=0.026). Frequency of altered glucose metabolism was not different among groups (2% vs 10% and 5%), but type 2 diabetes (four cases) was present only in obese PWS. Non-obese PWS showed lower insulin and HOMA-index respect to obese PWS and obese controls (p ≤ 0.017). Overall MS frequency in PWS was 7.3%. None of the non-obese PWS showed MS compared with 16% of obese PWS and controls (p<0.001). When obesity was excluded from the analysis, a significantly lower frequency for clustering of ≥ 2 factors was still found in non-obese PWS (p=0.035). CONCLUSION: Non-obese PWS showed low frequency of MS and its components, while that observed in obese PWS was very close to those of obese controls, suggesting the crucial role of obesity status. Prevention of obesity onset remains the most important goal of PWS treatment. Early identification of MS could be helpful to improve morbidity and mortality in such patients.

A survey on Prader-Willi syndrome in the Italian population: prevalence of historical and clinical signs.

Clinical criteria for the diagnosis of Prader-Willi Syndrome (PWS) were established by consensus in 1993 (Holm et al.). Specific molecular testing is now available and the purpose of diagnostic criteria has shifted to identify individuals to test, thus avoiding the expense of unnecessary analysis. The aim of this study was to find clinical indicators to select patients with suspected PWS for laboratory testing. We analyzed the prevalence of clinical signs and symptoms in 147 genetically diagnosed Italian patients with PWS (67 males and 80 females), aged from 9 months to 34.6 years (13.6 +/- 8.3 years), using the consensus diagnostic criteria, and according to age, sex and type of genetic abnormality. The prevalence of several clinical features changed significantly with age, but very few with sex. According to genetic subtypes (deletion vs UPD), only hypopigmentation and acromicria were more frequent in patients with deletion. Some criteria considered as minor or supportive by Holm et al. have higher prevalence than some major criteria. In conclusion, in order to identify patients with suspected PWS to submit to laboratory testing, we recommend a classification of clinical criteria according to age, giving more attention to those so-called minor or supportive criteria.

Immunochemotherapy with in vivo purging and autotransplant induces long clinical and molecular remission in advanced relapsed and refractory follicular lymphoma.

BACKGROUND: To evaluate the clinical outcome of patients with relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and high-dose therapy with autotransplant. PATIENTS AND METHODS: Sixty-four patients were enrolled in the trial. Primary end point was progression-free survival (PFS). Secondary end points were the in vivo purging effect on stem-cell harvest and the impact of molecular response on the outcome. RESULTS: At enrollment, 59% of patients were PCR+ for bcl-2 rearrangement in bone marrow (PCR-informative). After the immunochemotherapy, before mobilization, 97% obtained complete response or partial response and 87% of patients informative for bcl-2 were molecularly negative. Sixty-one patients proceeded to in vivo purging and peripheral blood stem cell (PBSC) mobilization with rituximab and high-dose AraC. The median number of CD34+ cells collected was 16.6 x 10(6)/kg. Of 33 PCR-informative patients, the harvests resulted in PCR- in all. Fifty-eight patients received high-dose therapy and autotransplant of in vivo purged PBSC. After a median follow-up of 3.5 years, 41 patients are in complete remission. Five-year PFS is 59%. CONCLUSION: This study demonstrates that patients with advanced relapsed or refractory follicular lymphoma treated with immunochemotherapy, in vivo purging and autotransplant may obtain long-lasting PFS. In bcl-2-positive patients, in vivo purging allows the harvest of lymphoma-free PBSC. Absence of the bcl-2 rearrangement after autotransplant is associated with persistent clinical remission.

Efficacy of single dose pegfilgrastim in enhancing the mobilization of CD34+ peripheral blood stem cells in aggressive lymphoma patients treated with cisplatin-aracytin-containing regimens.

Systematic data on the ability of pegfilgrastim to mobilize stem cells after chemotherapy are scarce. We evaluated the efficacy of a single 6 mg dose of pegfilgrastim for mobilizing peripheral blood stem cells (PBSC) in aggressive lymphoma patients. Between July 2004 and October 2005, 17 aggressive non-Hodgkin's lymphoma and 11 poor-risk Hodgkin's lymphoma were treated with cycles containing cisplatin-aracytin. At the end of chemotherapy, the patients received 6 mg of pegfilgrastim. Duration of grade 4 neutropenia, adverse events, time to neutrophil recovery, peak and harvest of CD34+ cells were recorded. Twenty-seven out of 28 patients harvested a median of 17.3 x 10(6)/CD34+ cells (range 2.5-28.9) after a median of 9 days (range 8-12 days), with a single apheresis procedure in 25 cases. All patients had grade 3-4 neutropenia, median duration 3 days. The only adverse event was mild bone pain. To date, 13 patients have been autografted with a median of 15.4 x 10(6) CD34+ pegfilgrastim-mobilized cells per kg (range 2.5-28.9) with rapid and sustained engraftment. Mobilization, harvesting and autografting of pegfilgrastim-mobilized PBC can be successfully achieved in pretreated patients with aggressive lymphoma.

Treatment outcome and prognostic factors for primary mediastinal (thymic) B-cell lymphoma: a multicenter study of 106 patients.

PURPOSE: To define clinicopathologic features, response to treatment, and prognostic factors of primary mediastinal B-cell lymphoma (MBL), a CD20+ tumor recognized as a distinct entity among non-Hodgkin's lymphomas (NHL). PATIENTS AND METHODS: One hundred six patients presented with disease confined to thorax (86%), bulky mediastinum (73%), superior vena cava syndrome (47%), and contiguous infiltration (57%). Ninety-nine received doxorubicin-containing chemotherapy (CHT). RESULTS: Thirty-five of 99 patients were primarily CHT-resistant, and 64 responded: 23 achieved complete response (CR) and 41 achieved response with residual mediastinal abnormality. Seventy-seven percent of responders received mediastinal radiotherapy (RT). Of 64 responders, 18 (28%) relapsed: none of 23 CR patients and 18 of 41 (44%) with residual mediastinal abnormality. Relapse-free survival rate of responders was 71% at 3 years. Actuarial 3-year survival rate was 52% for all patients and 82% for responders. Predictive factors of poor outcome were identified by logistic regression; Cox survival analysis was performed on death and relapse. Pericardial effusion (P < .001) and Eastern Cooperative Oncology Group (ECOG) performance status > or = 2 (P = .009) predicted nonresponse (NR) and affected survival. Less than partial midway response to CHT predicted NR to subsequent therapies. Bulky disease was related to persistent mediastinal abnormality and risk of relapse (P = .025). CONCLUSION: MBL is an aggressive NHL with unique clinicopathologic aspects, often refractory to current CHT designed for high-grade NHL. Poor performance status and pericardial effusion predict NR and poor survival. Inadequate response after the first courses of front-line CHT predicts failure of subsequent treatment. Responders with bulky mediastinum or residual mediastinal abnormality after CHT are at risk of relapse. These factors should help to select high-risk patients for intensive treatments.

Glucagon response to arginine stimulation in obese and diabetic children.

The effect of arginine infusion on blood sugar and plasma levels of growth hormone and glucagon has been studied in children with clinical diabetes mellitus and in obese children with normal carbohydrate tolerance. Basal levels of plasma GH are significantly lower in obese children than in diabetics and controls; in obese subjects the increment of GH is significantly lower than in diabetics and controls. Basal plasma glucagon levels are comparable in all three groups despite the high sugar levels in diabetic patients. After arginine infusion there is a significant rise in glucagon levels without significant differences between the three groups.

Effect of physical exercise on secretion of growth hormone, glucagon, and cortisol in obese and diabetic children.

The effect of muscular exertion of moderate intensity on blood sugar (BS), plasma levels of growth hormone (GH), glucagon, and cortisol (F) has been studied in endocrinologically normal children with short stature and compared with children with clinical diabetes mellitus and obese children with normal and diminished carbohydrate tolerance. In diabetic children, physical exertion induces a rise in plasma GH levels comparable to that in controls; in obese children with normal or with diminished glucose tolerance, the rise is considerably smaller. Physical exertion caused no change in F levels in the groups tested, although basal level in the obese children was significantly higher than in the controls. Basal glucagon levels were similar in all groups and showed no change on physical exertion. The behavior of GH and glucagon in diabetic children was comparable to that in the controls even where blood sugar level was high.

Effect of somatostatin on blood sugar, plasma growth hormone, and glucagon levels in diabetic children.

In nine children with clinically overt insulin-dependent diabetes mellitus the authors injected cyclic somatostatin (3 mug./kg. bolus, followed by infusion of 13 mug./kg. in 60 minutes) and measured blood glucose, plasma growth hormone, and glucagon concentrations throughout the infusion. The rapid administration produced no significant changes of these parameters. With the prolonged infusion there was a significant reduction of blood glucose from a mean of 148 +/- 19.7 to a mean of 88.5 +/- 18.1 mg./100 ml. (P less than 0.005) and of plasma glucagon from a basal mean of 33.3 +/- 2.4 to a minimum mean of 22.1 +/- 1.7 pg./ml. (P less than 0.01). There was a statistically significant correlation between the two parameters (0.01 less than P less than 0.05). Plasma GH values also diminished during the infusion, but the reduction was not statistically significant. These results show that somatostatin lowers blood glucose concentrations as a secondary effect of inhibition of glucagon secretion. Somatostatin is not suitable for therapy in diabetes. We speculate that a similar substance with a more prolonged and specific action on glucagon might prove of practical value in the treatment of diabetes mellitus.

Genetic and hormonal characterization of cryptic 21-hydroxylase deficiency.

Cryptic 21-hydroxylase deficiency has been previously described in asymptomatic family members of patients with classical congenital adrenal hyperplasia (CAH). These family members were detected by high baseline 17-hydroxyprogesterone levels found in the course of family studies. The hormonal responses to ACTH of the family members with cryptic 21-hydroxylase deficiency were determined and compared to the responses of patients with CAH, patients with acquired adrenal hyperplasia, family members predicted to be heterozygous for CAH, family members predicted to be unaffected, and the general population. The ACTH-stimulated levels of 17-hydroxyprogesterone and delta 4-androstenedione in the cryptic family members were elevated above the level of the general population or family members heterozygous for classical CAH, but below that of patients with CAH. The hormonal profile of patients with cryptic 21-hydroxylase deficiency is similar to that of patients with acquired adrenal hyperplasia. The response of family members heterozygous for the cryptic gene (21-OH CRYPTIC/21-OH NORMAL) was indistinguishable from that of family members heterozygous for the classical CAH gene (21-OH CAH/21-OH NORMAL). These studies support our previous proposal that patients with cryptic 21-hydroxylase deficiency are genetic compounds, having one gene for a severe enzyme deficiency and one gene for a mild 21-hydroxylase deficiency. Thus, the 21-hydroxylase genotype in cryptic 21-hydroxylase deficiency is 21-OH CAH/21-OH CRYPTIC.

Cryptic 21-hydroxylase deficiency in families of patients with classical congenital adrenal hyperplasia.

Serum androgens and 17-hydroxyprogesterone concentrations and HLA genotypes were determined in 124 families of patients with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH). In 8 pedigrees, we discovered 16 pubertal or postpubertal family members of either sex who had biochemical evidence of 21-hydroxylase deficiency but were without clinical symptoms of excess virilism, amenorrhea, or infertility. We designated these family members as individuals with cryptic 21-hydroxylase deficiency. Within each generation, the family members with cryptic 21-hydroxylase deficiency were HLA identical. It is proposed that these family members are genetic compounds, having 21-hydroxylase deficiency as a result of two recessive gene defects: 1) a severe 21-hydroxylase gene defect present in the index case with classical CAH (21-OHCAH) and 2) a mild 21-hydroxylase gene defect (21-OHCRYPTIC). Thus, the CAH genotype in the family members with cryptic 21-hydroxylase deficiency is 21-OHCAH/21-OHCRYPTIC. Lod score analysis for linkage between the cryptogenic 21-OH trait and HLA gave a combined Lod score for males and females of theta = 0.00 of 3.409. Close genetic linkage between HLA and 21-OHCRYPTIC was thus established. This study provides support for the previously reported heterogeneity of 21-hydroxylase deficiency which may result from allelic variability at the locus for steroid 21-hydroxylase.

Treatment of patients with high-grade non-Hodgkin's lymphoma aged over 70 years with an all-oral regimen combining idarubicin, etoposide and alkylators.

In elderly patients age-specific comorbidity often reduces the possibility of administering intensive chemotherapy and of obtaining response to treatment. Therefore, chemotherapy must differ from that for non-elderly patients, while maintaining the primary goal of a complete clinical response. We treated 19 patients over the age of 70 years (median age 75 years, range 70-86) with stage II-IV high-grade non-Hodgkin's lymphoma (NHL) with a combination regimen including idarubicin plus etoposide and prednimustine (or chlorambucil+prednisone), all administered orally on an outpatient basis. The therapeutic schedule included six 5-day courses of idarubicin 20 mg/sqm on day 1 (or 10 mg/sqm on days 1 and 3 in the nine patients last treated), etoposide 60 mg/sqm/12 h days 2-5, prednimustine 60 mg/sqm days 2-5, G-CSF 300 microg/day from day+7 until PMN>1000/microl. In ten patients prednimustine was replaced by chlorambucil 10 mg/sqm, days 2-5, and prednisone 50 mg days 2-5, because of non-availability of the drug. Of the 19 patients submitted to this regimen 15 (79%) obtained a clinical response: eight reached a complete response (CR), and seven a partial response (PR). Hematologic toxicity was generally mild. Only three patients had to be hospitalised for infection. Except alopecia, non-hematologic toxicities were negligible. At a median follow-up of 16 months, five of eight patients who obtained CR relapsed (median CR duration 7 months). The actuarial median survival is 34 months (range 6-46). This study demonstrates the feasibility and efficacy of an all-oral regimen including idarubicin, plus etoposide and prednimustine (or chlorambucil+prednisone) in NHL patients aged over 70 years.

The possible influences of B2A2 and B3A2 BCR/ABL protein structure on thrombopoiesis in chronic myeloid leukaemia.

The Philadelphia chromosome, t(9;22)(q34;q11) gives rise more frequently, in chronic myeloid leukaemia (CML), to two BCR/ABL chimeric transcripts differing only by the absence of 75 nucleotides and defined as b2a2 and b3a2 types, encoding two 210-kDa tyrosine kinase proteins differing only by the absence of 25 amino acids coded by the b3 exon. In the present study the two transcripts, detected by RT-PCR in 88 consecutive unselected CML patients, were correlated with haematological findings at diagnosis and with the megakaryocyte size and frequency by morphometric evaluation of 45 bone marrow biopsies. The secondary structure prediction and hydrophobicity of the b2a2 and b3a2 type BCR/ABL protein were also obtained. The prediction results for the b3 exon amino acids using GOR IV and NnPredict methods showed a short beta strand corresponding to the hydrophobic portion of the peptide. Significantly higher values were found in the platelet count of patients carrying b3a2 transcripts. The megakaryocyte size and frequency in bone marrow biopsies did not show significant differences between the two groups of patients. Stratifying the patients on the basis of white blood cell (WBC) count below or above 100x10(9)/l we still had, in both groups, a significant difference in the platelet count between the b2a2 and b3a2 patients. The possible relationships between the structure of b2a2 and b3a2 types of BCR/ABL fused protein and thrombopoiesis are discussed.

Nonreciprocal and jumping translocations of 15q1----qter in Prader-Willi syndrome.

We analyzed 33 cases of Prader-Willi syndrome (PWS) (including 2 personal observations) with translocations of 15q1----qter onto the terminals of different, apparently whole chromosomes. In all but one of the 23 informative cases the translocations was de novo. Thirty of the patients were unbalanced and 27 had a 45-chromosome constitution compatible with a 3:1 segregation. One balanced and 2 unbalanced translocations were jumping ones. The possible existence of actual non-reciprocal translocations in man is indicated by the following considerations about these and other PWS-associated rearrangements: 1) The observed excess of de novo translocations; 2) the relatively frequent familial occurrence of reciprocal 15q translocations; 3) the concurrence in 3 terminal translocation cases of an idic (15); 4) the visualization of jumping terminal translocations as simple transpositions rather than as successive reciprocal exchanges; 5) the predominance of true isodicentrics in PWS patients with extra inv dup(15) chromosomes; and 6) the rarity of extra derivatives resulting in 15q proximal tertiary trisomy. Additional findings in the present series were normal parental age in the de novo 45-chromosome cases, an apparently random distribution of telomeric breakpoints, and the occurrence of different breakpoints within the 15q1 region.

Efficacy of an early intensification treatment integrating chemotherapy, autologous stem cell transplantation and radiotherapy for poor risk primary mediastinal large B cell lymphoma with sclerosis.

The aim of our study was to evaluate the impact of an early intensification programme including chemotherapy (CHT), autologous stem cell transplantation (ASCT) and radiation therapy (RT) in patients with primary mediastinal large B cell lymphoma (MLCL) with sclerosis presenting with adverse prognostic factors. Between 1993 and 1999, 19 patients with MLCL were referred to our institution. Four patients were classified as low risk according to the age-adjusted International Prognostic Index (AA-IPI). Fifteen (79%) were categorised in the high-intermediate or high risk group and were considered eligible for ASCT. Induction therapy consisted of VACOP-B (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone and bleomycin) for 12 weeks. After induction therapy the four low risk patients achieved a complete remission (CR) and did not undergo ASCT. Of the 15 poor risk patients, five achieved CR, seven partial remission (PR), and three showed refractory disease (RD). All these patients received mobilising therapy consisting of high-dose cyclophosphamide. After peripheral stem cell (PSC) collection, to obtain a greater tumor mass reduction before transplantation, the seven patients in PR underwent further treatment with high-dose etoposide and those with RD received two cycles of DHAP (dexamethasone, cytarabine and cisplatin). At the time of ASCT, seven patients were in CR, six in PR and two had RD. After transplantation using BEAM as preparative regimen, all patients but one achieved a CR. Seven patients with minimal (<25%) residual mass at computed tomography scan received further mediastinal RT even if they had a negative Ga(67) scan. At a median follow-up of 35 months from transplantation the disease free survival is 93%. The outcome following this programme of early intensification in poor prognosis MLCL results in a high incidence of durable remissions even in patients with refractory disease.

Final height in congenital adrenal hyperplasia due to 21-hydroxylase deficiency: the Italian experience.

OBJECTIVE: To investigate the influence of target height (TH), gender, phenotype, glucocorticoid formulation and age at onset of treatment on final height (FH) in patients with 21-hydroxylase deficiency (21OHD). PATIENTS: Clinical data of 93 patients--46 simple virilizing (SV), 35 salt-wasting (SW) and 12 late onset (LO)--were collected in six pediatric endocrinology units in Italy. RESULTS: FH and TH were always below the mean height of the general population (mean FH, SDS: SW patients -1.3 +/- 1.2, SV patients -1.8 +/- 0.9, LO patients -1.7 +/- 1.1; mean TH, SDS: SW patients -0.6 +/- 0.8, SV patients -0.7 +/- 0.9, LO patients -1.4 +/- 1.3). FH was significantly below TH in patients with classic form (SW and SV, p <0.001), but not in LO patients. In classic form, TH seems to be related to FH, followed by age at onset of therapy and by steroid formulation, these variables explaining 30% of FH variance. CONCLUSIONS: In the classic form, substitutive therapy started before 21 months of age improved the long-term outcome. Lower TH in LO patients could be due to undiagnosed non-classic 21OHD in some of their parents. FH in LO patients seems not to benefit from corticosteroid therapy, even if late diagnosis may partly account for this result.

Etiology and age incidence of precocious puberty in girls: a multicentric study.

We review the etiology and age incidence of precocious puberty in 438 girls examined between 1988-1998; 428 (97.7%) had central precocious puberty (CPP), the remaining 10 (2.3%) gonadotropin-independent precocious puberty (GIPP) of ovarian origin. The majority of CPP girls (59.6%) were aged between 7-7.9 yr, 22.4% were 6 year olds, and only 18% were under 6 years old. Cranial CT and/or MRI performed in 304/428 girls, showed neurogenic abnormalities in 56/304 (18.4%) CPP girls; 30 (9.9%) were due to previously diagnosed intracranial abnormalities and the remaining 26 (8.5%) were detected at the diagnosis of CPP. The frequency of neurogenic CPP tended to be higher in girls under 4 years of age while the frequency of idiopathic CPP tended to be higher in girls aged between 7-7.9 years, but no statistically significant differences were found. Interestingly, some CNS anomalies either of tumoral or congenital origin were detected at presentation in 7% of the girls aged over 7 years. Other related or coincidental clinical anomalies, mainly due to genetic diseases, were observed in 22/304 (7.2%) patients. History of precocious maternal menarche was found in 12/304 (4%) girls. In conclusion, idiopathic CPP was observed in 74% of the girls in this study. Neurogenic anomalies or other coincidental or related clinical findings were observed in the remaining 26%. The increased frequency of idiopathic CPP in girls aged over 7 years may suggest an early, but otherwise normal onset of puberty in many of these girls as a consequence of the trend towards earlier maturation. Nonetheless, the finding of CNS anomalies also in the older patients, raises the question of whether these patients should undergo a complete diagnostic work-up.

Etiology of central precocious puberty in males: the results of the Italian Study Group for Physiopathology of Puberty.

We reviewed the hospital records of 45 boys, followed in 13 pediatric departments throughout Italy, who had undergone computed tomography and/or magnetic resonance imaging for central precocious puberty (CPP). Twenty-seven patients (60%) had idiopathic CPP and 18 (40%) neurogenic CPP. A hamartoma of the tuber cinereum was found in six patients (33%). All patients with hypothalamic hamartoma had earlier onset of symptoms than patients with idiopathic CPP. Five patients (27%) were affected by type 1 neurofibromatosis, two had ependymoma and five patients had an intracranial anomaly. Basal LH and basal and peak LH/FSH ratio were greater, but not significantly, in boys with neurogenic CPP than in boys with idiopathic CPP. The highest LH peak levels were observed in patients with hamartoma; however, no correlation was observed between LH peak and the size of the hamartomas. In addition, bone age at diagnosis was more advanced in patients with hamartoma than in patients with other conditions. In conclusion, gonadotrophin-dependent precocious puberty may be of idiopathic origin or may occur in association with any CNS disorder. Further studies are needed in order to evaluate the effects of nutritional, environmental and psychosocial factors on the timing of sexual maturation, to explain the high incidence of idiopathic CPP in our male patients.

[Adrenal neoplasms in childhood. Description of a clinical case and review of the literature]. / Neoplasia surrenalica in età pediatrica. Descrizione di un caso clinico e review della letteratura.

Hyperadrenocorticism caused by tumors of adrenal cortex is uncommon in children; it occurs more frequently in girls and on the left side. The clinical manifestations depend upon age and sex of patients; virilization is the predominant sign in about two thirds of the cases, and Cushing's syndrome in the others. Diagnosis is made by hormonal and instrumental evaluations. Therapy is surgical eradication. Histology has not proved to be useful because pleiomorphism and capsular invasion have been found in clinically benign tumors. High mortality rate in older literature may have been due to post-operative complications and inadequate steroid replacement; in more recent issues good prognosis is referred in pediatric patients. Early diagnosis and therapy are important to prevent adverse effect on growth and development. After an up-to-date review of the literature, a case of adrenocortical tumor is reported. We present a 3 years old boy with pseudoprecocious puberty (accelerated growth and bone age, sexual hair, facial acne, penile enlargement, hoarse voice) and a diagnosis of testosterone-producing adrenal tumor was confirmed by endocrine and radiological investigations. Removal of functioning adrenal tumor was followed by rapid regression of most of the clinical signs of the disease; plasma and urinary steroids returned to normal values. Twelve months after eradication of the tumor the patient is in good health; long-term-follow-up is necessary to exclude any relapse.