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Genital abnormalities and disorders of pubertal development such as hypogonadism are common in Prader-Willi Syndrome (PWS). Depending on age, PWS patients present genital hypoplasia and delayed or incomplete gonadal maturation. Nevertheless, only a few evaluations have been made of these findings in this syndrome; in the cases previously reported the diagnosis of PWS has often been based only on clinical criteria and not confirmed by genetic analysis. In this paper we describe both external genital findings and spontaneous pubertal development in 84 patients aged from 2.1 to 35.4 (42 males, 42 females) affected by PWS. Diagnosis was made using the Holm and Cassidy criteria and was confirmed by genetic analysis (methylation test and/or FISH). We evaluated the presence of cryptorchidism, scrotal development, length of penis and volume of testis in males and outlook of labia minora and/or clitoris, age of menarche and features of menses (when present) in females; in both sexes we also evaluated the onset of puberty. All recruited males showed cryptorchidism, which was bilateral in 36 out of 42 patients (86%); 38 patients (90%) underwent orchidopexy. Small testes and scrotal hypoplasia were present in 76% and 69% of cases, respectively. In 76% of females, hypoplasia or absence of labia minora and/or clitoris was described. Spontaneous menarche occurred only in 14/32 cases (44%) over the age of 15 years, but menstrual cycles were often a periodical vaginal spotting. Primary amenorrhea was diagnosed in 56% of cases. Isolated premature pubarche was present in six males and in six females (14% of cases) while one male and two females were affected by precocious puberty (3.6%). Conclusion: Hypogonadism represents a common clinical feature in PWS, confirming the importance of such a major diagnostic criterion. Cryptorchidism was consistently present in all our cases. Patients with PWS commonly fail to spontaneously complete puberty, although some patients may have early pubarche or, more rarely, precocious puberty. In older subjects, hormonal replacement therapy is not always necessary and it must be reserved for selected patients.

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.

Twenty-five medical centers and the Prader-Willi Syndrome (PWS) Association collaborated on a study which attempted to identify all people with genetically confirmed diagnosis of PWS living in Italy. Investigators of the participating centers contacted PWS subjects and/or their family, filled in a specially developed form with the required data and forwarded this information by email. The study identified 425 subjects (209 males and 216 females, between the ages of 0.4-46.7). Two hundred thirty-eight patients had del15, 104 had UPD15, 4 demonstrated a translocation affecting chromosome 15 and 79 showed a positive methylation test. There were fewer subjects found over the age of 35, probably due to the low rate of identification of older PWS patients as well as the high mortality rate. There were a greater number of male children and adolescents with PWS whilst, amongst adults, there were more females. As expected, the majority of subjects with PWS were obese, especially in adult life. Nevertheless, it is noteworthy that 26% of patients aged between 6 and 17 were normal weight. A total of 212 subjects had received GH treatment, of which 141 were still receiving therapy, while the remaining 71 had stopped. In children and adolescents (233 cases), 89 subjects had never undergone GH therapy. Eighteen PWS patients had died in the past 20 years. Obesity-related cardiovascular and respiratory diseases were the cause of death, both during childhood and after 18 years of age. Three children died suddenly whilst undergoing GH therapy. Respiratory infection and cardiac illness were the causes of death in two cases. There was no definitive cause of death found in the third case. Overall, there was no increase in number of deaths during GH treatment, suggesting that GH administration in patients with PWS, as a group, does not increase the risk of death. ß

Objective: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 mg/l based on a cohort of subjects with a mean age of 45 years. Design and methods: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic -pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8^2.3 years, range 17 -25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2^4.4 years, range 15.1 -30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals. Results: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8^2.0 mg/l, range 0.1-6.1 mg/l) compared with the 39 controls (18.5^15.5 mg/l, range 6.1-84.0 mg/l; P , 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 mg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 mg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of 2 1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I # 2 2.0 SDS showed a sensitivity of 62%. Conclusion: Our data show that the cut-off value of the peak GH response to ITT of less than 3 mg/l or 5 mg/l and of IGF-I of less than 22.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic -pituitary abnormalities.

Aims/hypothesisThe aim of this study was to investigate the genetic aetiology of permanent diabetes mellitus with onset in the first 12 months of age.MethodsWe 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.ResultsIn 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/interpretationGenetic 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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-011-2094-8) contains supplementary material, which is available to authorised users.

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.

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