High prevalence of precocious puberty and obesity in childhood narcolepsy with cataplexy.

STUDY OBJECTIVES: We analyzed the potential predictive factors for precocious puberty, observed in some cases of childhood narcolepsy with cataplexy (NC) and for obesity, a much more common feature of NC, through a systematic assessment of pubertal staging, body mass index (BMI), and metabolic/endocrine biochemical analyses. DESIGN: Cross-sectional on consecutive recruitment. SETTING: Hospital sleep center and pediatric unit. PATIENTS: Forty-three children and adolescents with NC versus 52 age-matched obese children as controls. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Patients underwent clinical interview, polysomnographic recordings, cerebrospinal fluid hypocretin-1 measurement, and human leukocyte antigen typing. Height, weight, arterial blood pressure, and Tanner pubertal stage were evaluated. Plasma lipid and glucose profiles were analyzed. When an altered pubertal development was clinically suspected, plasma concentrations of hypothalamic-pituitary-gonadal axis hormones were determined. Children with NC showed a high prevalence of overweight/obesity (74%) and a higher occurrence of precocious puberty (17%) than obese controls (1.9%). Isolated signs of accelerated pubertal development (thelarche, pubic hair, advanced bone age) were also present (41%). Precocious puberty was significantly predicted by a younger age at first NC symptom onset but not by overweight/obesity or other factors. In addition, overweight/obesity was predicted by younger age at diagnosis; additional predictors were found for overweight/obesity (short disease duration, younger age at weight gain and lower high-density lipoprotein cholesterol), which did not include precocious puberty. NC symptoms, pubertal signs appearance, and body weight gain developed in close temporal sequence. CONCLUSIONS: NC occurring during prepubertal age is frequently accompanied by precocious puberty and overweight/obesity, suggesting an extended hypothalamic dysfunction. The severity of these comorbidities and the potential related risks require a multidiagnostic approach and a tailored therapeutic management.

Early corticosteroid treatment in 4 Duchenne muscular dystrophy patients: 14-year follow-up.

INTRODUCTION: Corticosteroid treatment is the standard of care in Duchenne muscular dystrophy (DMD), but the optimal age to initiate treatment and dosage pattern remain a matter of discussion. METHODS: We performed a long-term study of alternate-day corticosteroids in five 2- to 4-year-old DMD patients. The primary outcome measure was prolongation of the ability to walk. RESULTS: One patient lost ambulation at age 10. Four patients, aged 16 to 18 were fully ambulant, and 3 of them could still climb stairs. Respiratory function was moderately reduced in 2. Left ventricular ejection fraction was > 45%. Short stature and delayed puberty were the most relevant side effects. Although the negative impact of corticosteroid treatment on growth rate remained their major concern, parents and patients stated that they preferred corticosteroid therapy. CONCLUSIONS: Long-term corticosteroid treatment is effective in prolonging function but not in recovering lost function, and its early use seems appropriate.

Onset of type 1 diabetes mellitus in two patients with maturity onset diabetes of the young.

The association between maturity onset diabetes of the young (MODY) and type 1 diabetes mellitus (T1DM) has been rarely described. We report two patients affected by MODY who developed T1DM. Case 1: a 4-yr-old girl referred for glycosuria presented hemoglobin A1c (HbA1c) of 6.6%. Islet cell antibodies (ICA) and anti-glutamic acid decarboxylase (GADA) were initially negative. As her father, uncle and grandmother showed mild hyperglycemia, they were screened for MODY 2. A novel mutation in glucokinase gene was found in the family. Few months later, her glycemic control worsened consistently and she required insulin treatment. A high titer of GADA and ICA was then detected. Six years afterwards insulin requirement is 0.8 U/kg and HbA1c 6.7%. Case 2: a 15-yr-old boy treated for growth hormone deficiency was found with a blood glucose level of 106 mg/dL. HbA1c was 7.2%, ICA and GADA were negative. Family history was positive for autoimmune diseases and type 2 diabetes mellitus. The patient was investigated for MODY 2 and MODY 3, and a mutation of hepatocyte nuclear factor-1 alpha gene was found. The same mutation was found in the mother who had never been referred for hyperglycemia. After 1 yr, due to an unjustified worsening of the metabolic control, autoimmunity was again investigated and a mild positivity was found. He then required insulin therapy and after 5 yr current HbA1c was 8.2%. The diagnosis of MODY does not exclude the risk of developing T1DM. Therefore autoimmunity should be investigated when ordinary treatments fail and metabolic control unexpectedly worsens.

Comparison between sensor-augmented insulin therapy with continuous subcutaneous insulin infusion or multiple daily injections in everyday life: 3-day analysis of glucose patterns and sensor accuracy in children.

BACKGROUND: Sensor-augmented continuous subcutaneous insulin infusion (CSII) therapy is superior to CSII therapy alone, but little is known on the effectiveness of sensor-augmented multiple daily injections (MDI) therapy. METHODS: We compared during everyday life mean glucose control and several variability indexes recorded for 3 days by a real-time glucose sensor (Medtronic, Northridge, CA) in two groups of children treated with either CSII or MDI. Fifty-five consecutive subjects were examined: 17 receiving CSII and 38 receiving MDI basal-bolus therapy (age range, 7-22 years). All subjects wore the sensor for 4 days, and 3 days were used for statistical analysis. Mean glucose and SD, coefficient of variation (CV), mean amplitude of glucose excursion (MAGE), mean of daily differences (MODD), continuous overall net glycemic action (CONGA) at 2 and 4 h, blood glucose (BG) rate, area under the curve (AUC) above 180 mg/dL and below 70 mg/dL, Low BG Index (LBGI), and High BG Index (HBGI) were calculated. RESULTS: Patients receiving CSII administered more daily boluses than patients receiving MDI (5.2±1.5 vs. 3.2±0.3, respectively; P=0.001). Mean glucose was lower in the CSII group. AUC above 180 mg/dL and HBGI were higher in the MDI group. CV, CONGA at 2 h, CONGA at 2 h during the day, and HBGI were worse in the MDI group, whereas MODD, LBGI, BG rate, and MAGE were similar. A positive correlation (r=0.95; P<0.05) was found between the paired sensor-meter values. For the glucose values <70 mg/dL, sensitivity was 40%, and specificity was 99%. CONCLUSIONS: In our pediatric patients during everyday life sensor-augmented CSII therapy seemed more effective than sensor-augmented MDI therapy, in terms both of glucose mean values and of intraday variability. Mild hypoglycemic episodes and indexes of low BG values were similar in the two groups, although the latter results may be inaccurate because of low sensor sensitivity at low glucose value.

High rate of regression from micro-macroalbuminuria to normoalbuminuria in children and adolescents with type 1 diabetes treated or not with enalapril: the influence of HDL cholesterol.

OBJECTIVE: To evaluate the frequency of normalization, the persistence of remission, and the impact on normalization of glycemic control and lipid profile, we analyzed data from a retrospective observational cohort study of type 1 diabetic children and adolescents with abnormal urinary albumin excretion (UAE). RESEARCH DESIGN AND METHODS: All diabetic children and adolescents (n = 41) who had persistent abnormal UAE in the period of 1984 to 2008 and followed up until 2009 (follow-up duration = 13.1 ± 6.2 years) were included in the study. Nine patients progressed to macroalbuminuria; 24 patients were administered ACE inhibitor treatment. RESULTS: The cumulative prevalence of abnormal UAE was 9%. During follow-up, 14 of 17 untreated and 19 of 24 treated patients reverted to normoalbuminuria. In the remission group compared with the nonremission group, A1C levels during follow-up decreased (7.5 ± 1.0 vs. 9.4 ± 1.2%, P < 0.0001) and serum HDL cholesterol increased (52.7 ± 11.3 vs. 42.7 ± 8.6 mg/dL, P < 0.05). The micro-macroalbuminuric patients had lower HDL cholesterol (51.0 ± 11.4 vs. 62.4 ± 13.6 mg/dL, P < 0.0001) than 134 normoalbuminuric diabetic patients. CONCLUSIONS: Microalbuminuria and macroalbuminuria were not permanent in most of our diabetic children and adolescents. If abnormal UAE values are high and persist for >1 year, only long-lasting treatment with ACE inhibitors seems able to induce persistent remission, especially when associated with good metabolic control and high HDL cholesterol levels.

Psychological and behavioural aspects in children and adolescents with congenital hypothyroidism diagnosed by neonatal screening: comparison between parents' and children's perceptions.

OBJECTIVE: To compare the psychological adjustment and behaviour of congenital hypothyroidism (CH) children and their parents with a control group. STUDY DESIGN: A cross-sectional study was carried out with 84 CH subjects diagnosed by neonatal screening (range 2.7-18.6 years), subdivided into four age groups: group 1 (2-5 years); group 2 (6-10 years); group 3 (11-13 years); and group 4 (14-18 years) and was compared with an age-matched control group. Patients were assessed using two questionnaires: Child Behaviour Checklist for parents and Youth Self-Report for children over 11 years of age. RESULTS: In groups 1, 3 and 4, total score (TS), internalising score (IS=problems within the self) and externalising score (ES=conflicts with other people) as reported by parents were not significantly different in CH patients and in controls. In group 2, parents of CH children showed values of TS (P<0.05), IS (P<0.05), ES (P<0.05) and scores on other scales significantly higher than controls. In self-reports of groups 3 and 4, the behavioural scales were not significantly different in CH patients and in controls. CONCLUSIONS: Paediatricians should be informed about the increased risk of the development of behavioural problems at primary school age in CH patients. At this age special attention should be paid to parental worries and anxiety. However, it can be reassuring for the patients and parents to know that the problems may be related to CH, and that they may spontaneously disappear.

Update on age at menarche in Italy: toward the leveling off of the secular trend.

PURPOSE: To update the information on age at menarche in the Italian population and to verify the influence of genetic, nutritional, and socioeconomic factors on menarcheal age. Recent studies suggest that the magnitude of the secular trend toward an earlier age at menarche is slackening in industrialized countries. METHODS: This multicenter study was conducted on a large, population-based sample of Italian high school girls (n = 3,783), using a self-administered questionnaire. The questionnaire was used to gather information on the girls, including demography, anthropometry, menarcheal date, regularity of menses, behavioral habits, and physical activity. The questionnaire was also used to gather information on parents, including demography and mothers' and sisters' menarcheal ages. The median age at menarche and its 95% confidence interval were estimated by means of Kaplan-Meier survival analysis. To identify the independent predictive factors of age at menarche, multivariate mixed-effects models were applied. RESULTS: The median age at menarche of the subjects was 12.4 years (95% confidence interval: 12.34-12.46). The girls had their first menses approximately one-quarter of a year (median-0.13) earlier than did their mothers (p < .0001). Among all variables, parents' birth area, body mass index, family size, and the mother's menarcheal age were significantly and independently associated with age at menarche. CONCLUSIONS: This study confirmed the reduction in the trend toward earlier menarche in Italy. The results also confirmed that genetic and nutritional factors are strong markers for early menarche. Currently, socioeconomic factors do not seem to play as significant a role as in the past.

Long-term clinical significance of thyroid autoimmunity in children with celiac disease.

OBJECTIVE: To evaluate the long-term outcome of thyroid function and autoimmunity in a large series of children with celiac disease. STUDY DESIGN: This longitudinal, retrospective study (duration of follow-up, 8.9 +/- 4.0 years) was conducted at the Pediatric Department, University of Bologna, Italy. One hundred thirty-five consecutive patients diagnosed between June 1990 and December 2004 and followed on a gluten-free diet were examined. Inclusion criteria were good dietary compliance and duration of follow-up for at least 3 years. RESULTS: Of 101 patients who never showed positive antithyroid titers during the follow-up, 86 remained euthyroid; 15 showed high thyroid-stimulating hormone values at diagnosis that normalized in 11 cases after 12 to 18 months of gluten withdrawal. Of 31 patients with persistently positive antibody titers, 23 (74%) remained consistently euthyroid during the follow-up and 8 (26%) had a subclinical hypothyroidism. The prevalence of cases with positive antibodies was similar in children with growth retardation or gastroenterological symptoms at diagnosis and different durations of gluten exposure. CONCLUSIONS: The presence of antithyroid antibodies in children with celiac disease has a low predictive value for the development of thyroid hypofunction during the indicated surveillance period. Longer follow-up is needed.

Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism.

CONTEXT: Mutations in TSH receptor (TSHR) are notoriously associated with congenital hypothyroidism as well as with non-autoimmune subclinical hypothyroidism, a mild form of TSH resistance that is not as well characterized by diagnostic procedures. OBJECTIVE: The genetic analysis of the TSHR gene was performed to determine the prevalence of TSHR gene mutations in non-autoimmune subclinical hypothyroidism during the pediatric age. The new mutations were studied for genotypic-phenotypic correlation. PATIENTS: Thirty-eight children (ages 0.5-18.0 yr) affected by non-autoimmune subclinical hypothyroidism diagnosed in our center (follow-up from 1 to 11.5 yr) and normal at neonatal screening were enrolled in the genetic study. In 11 cases, the relatives were included in the genetic analysis. RESULTS: Eleven different mutations of the TSHR gene were identified in 11 of the 38 patients. Two are new: the nonsense mutation C31X and the missense mutation P68S, which shows a decrease in TSH binding capacity but not in biological activity. In all cases the carrier parent was identified. CONCLUSIONS: To date, this study demonstrates the highest prevalence (29%) of TSHR gene mutations in children and adolescents with non-autoimmune subclinical hypothyroidism not selected by neonatal screening. Functional studies show that some mutations cause a slight inactivation of the TSHR. This reveals a possible limit of the in vitro study or of the knowledge of mechanisms involving TSHR, or that other candidate genes must be considered.

Correlations of phenotype and genotype in relation to morphologic remodelling of the aortic root in patients with Turner's syndrome.

BACKGROUND: Patients with Turner's syndrome are at risk of aortic dilation and dissection. Currently, it is not known whether such dilation is related to associated cardiovascular abnormalities, or to the genetic anomaly itself. METHODS: We studied echocardiographically 107 patients with genetically proven Turner's syndrome, with heterogeneous underlying karyotypes, and without associated cardiac lesions. Their average age was 19.6 plus or minus 8.4 years. We compared the finding with those from 71 age-matched healthy female volunteers. The diameter of the aorta was measured at the level of the basal attachments of the aortic valvar leaflets, the sinuses of Valsalva, the sinutubular junction, and its ascending component. RESULTS: Compared to control subjects, the patients with Turner's syndrome had larger diameters of the aorta at the level of the sinuses of Valsalva, at 23.4+/-4.8 versus 25.5+/-4.1 millimetres (p = 0.0014), the sinutubular junction, at 19.9+/-3.8 versus 23.3+/-4.1 millimetres (p < 0.0001), and the ascending aorta, at 22.3+/-4.9 versus 24.6+/-4.4 millimetres (p = 0.0011). Dilation of the sinutubular junction, found in just over one-quarter of the patients, was more common than dilation of the ascending aorta, the latter found in less than one-tenth. The patients with Turner's syndrome, therefore, presented with remodelling of the aortic root, with relative dilation of the sinutubular junction. The underlying karyotype influenced both the dimensions of the sinutubular junction (p = 0.0054), and the ascending aorta (p = 0.0064), so that patients with the karyotype 45X had larger aortas. The karyotype was the strongest predictor by multivariate analysis for dilation at both these sites (p = 0.0138 and 0.0085, respectively). CONCLUSIONS: Dilation at the sinutubular junction is frequent in patients with Turner's syndrome, and is more common than dilation of the ascending aorta. The syndrome is associated with a remodelling of the aortic root, with prominent dilation of the sinutubular junction. There seems to be a relation between aortic dilation and the underlying genotype.

Developmental syndromes: growth hormone deficiency and treatment.

Developmental syndromes are characterized by numerous phenotypical signs and malformations. In most of them such as Turner, Noonan, Prader-Willi, Silver-Russel, Williams, Kabuki, Leri-Weill syndrome and skeletal dysplasias, short stature is a common feature. Growth defect is very often related to a defect in cellular growth, but some unknown abnormality in GH action is possible. Recently, the greater availability of recombinant GH has expanded the interest towards GH secretion and therapy also in developmental syndromes. We recognize syndromes associated with GH deficiency (GHD), showing a developmental midline defect such as Pallister-Hall syndrome, septo-optic dysplasia, but many of these conditions do not have a convincing link with GHD. Moreover, some conditions, in particular the well-studied Turner syndrome, that do not have a real GHD, have proven to benefit from GH therapy at supra-physiological doses obtaining a higher final height than the expected one according to the natural history. This has expanded the indications for GH therapy. The aim of our paper is to review the literature on GH secretion, on the effects and costs-benefits of GH therapy in many dysmorphic syndromes, presenting some results of GH secretion and therapy obtained in our experience.

Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy.

We report on the outcome of intravenous high-dose immunoglobulin (IVIg) treatment in four children with narcolepsy and cataplexy, in whom the early diagnosis and the extreme disease severity were indications for this potentially efficacious therapy. One of four patients showed an objective and persistent improvement in clinical features during and after IVIg treatment. Our data partially support the recent report of the efficacy of IVIg treatment in early diagnosed narcolepsy with cataplexy and support the need for a controlled multicenter clinical trial on IVIg in narcolepsy.

Three novel AMH gene mutations in a patient with persistent mullerian duct syndrome and normal AMH serum dosage.

BACKGROUND: Persistentmullerian duct syndrome (PMDS) is characterized by the presence of uterus, fallopian tubes and the upper part of the vagina in 46,XY patients with perfectly virilized external genitalia. It is mostly caused by mutations of the AMH or AMH type 2 receptor (AMHR2) gene. The AMH serum level is very often low or undetectable in the AMH gene defect and normal in the AMHR2 gene defect. AIM: We investigate an Italian patient, genotypically and phenotypically male, observed at 1 month of age for a right inguinal hernia that at surgery showed the presence of both testes in the same hernial sac and uterus and fallopian tubes in the abdomen. RESULTS: Genetic tests first showed the absence of the common 27-bp deletion in the AMHR2 gene, then the presence of three new sequence variations in the AMH geneleading to the following variants: the p.A405P carried by the paternal allele; the p.G326V plus the p.V508A carried by the maternal allele. CONCLUSIONS: The determination of serum AMH, performed after the genetic analysis, showed a normal level for age, suggesting that these mutations may affect the function and the bioactivity of the hormone and not the secretion rate.

Quality of life, psychological adjustment and metabolic control in youths with type 1 diabetes: a study with self- and parent-report questionnaires.

OBJECTIVE: To evaluate self and parent reports on quality of life (QoL) and psychological adjustment of youths with type 1 diabetes, in comparison to a general paediatric population, and identify relationships between disease duration, metabolic control and psychological parameters. RESEARCH DESIGN AND METHODS: Participants included 70 youths with type 1 diabetes and their parents. They were compared with 70 non-diabetic subjects. Data were analyzed in the whole group and in subgroups aged 6-10, 11-13 and 14-18 yr. All cases performed pediatric QoL, Child Behaviour Checklist, filled in by parents, and Youth Self-Report, filled in by youths. Data were compared with haemoglobin A1c (HbA1c) values and disease duration. RESULTS: Self-reports showed a psychological adjustment of youths with type 1 diabetes similar to that of controls. Parent reports showed that parents of children with type 1 diabetes were more worried than those of controls (p < 0.01). Adolescents showed a worse QoL and more frequent psychological disturbances. In this group, for youth and parent reports, HbA1c levels correlated positively with psychological problems (p < 0.05) and negatively with QoL (p < 0.05). Only for parent reports, in the whole group and in subgroups aged 6-10 and 11-13 yr, disease duration correlated positively with psychological adjustment (p < 0.05). CONCLUSIONS: Before adolescence, youths with type 1 diabetes showed only slight problems in psychological adjustment and QoL, with an association with disease duration reported by parents. In adolescence, both youths and their parents reported more emotional and behavioural problems, independent of disease duration. Better metabolic control and psychological well-being seemed directly related.

Prevalence of celiac disease in children with type 1 diabetes mellitus increased in the mid-1990 s: an 18-year longitudinal study based on anti-endomysial antibodies.

Between 1987 and 2004, 331 consecutive children, all newly diagnosed with type 1 diabetes mellitus in our pediatric clinic, underwent repeated serological screening for celiac disease (CD) by means of anti-endomysial antibodies, measured prospectively between 1994 and 2004, and retrospectively, using frozen banked serum, between 1987 and 1993. There were 22 cases (6.6%) of biopsy-proven CD among the 331 diabetic children. The prevalence of CD was significantly (P = 0.015) higher after 1994 (10.6%) than before 1994 (3.3%). The rapid change in the risk of CD among Italian diabetic children that occurred in the mid-1990 s could be related to changes in environmental factors, namely, eating habits and viral infections.

A novel PRKAR1A mutation associated with hepatocellular carcinoma in a young patient and a variable Carney complex phenotype in affected subjects in older generations.

CONTEXT: Carney complex (CNC) is an autosomal dominant multiple endocrine neoplasia syndrome (OMIM 160980). About 70% of cases are familiar; most have mutations of the PRKAR1A gene on chromosome 17q22-24. There is little phenotype-genotype correlation known to date. OBJECTIVE: To study the genotype-phenotype correlation in a family with newly diagnosed CNC and three generations of subjects bearing the same PRKAR1A mutation. The proband was diagnosed with hepatocellular carcinoma, a tumour that appears to be associated with CNC. DESIGN: The study consisted of clinical and genetic analysis of a total of 10 individuals belonging to a large Italian family. PATIENTS: The index case was referred for PRKAR1A gene mutation analysis because he met the diagnostic criteria for a clinical diagnosis of CNC. RESULTS: The PRKAR1A-inactivating mutation c.502 +1G > A in the intron 5 splice-donor site was detected after bidirectional sequencing of germline DNA. The mutation causes a frameshift in the transcribed sequence and a nonsense mRNA that was shown to be degraded; this leads to PRKAR1A haploinsufficiency in all tissues. All available relatives were screened first by DNA testing and, if the latter was positive, by clinical, biochemical and imaging means. CONCLUSIONS: A novel PRKAR1A mutation with an apparently low penetrance and variable expression is reported; the same mutation is also associated with a hepatocellular carcinoma. This is the first time a PRKAR1A mutation is reported in individuals who were diagnosed with CNC after retrospective family screening and following the identification of a proband; the finding has implications for genetic counselling on PRKAR1A and/or CNC.

Airway inflammation and lung function decline in childhood post-infectious bronchiolitis obliterans.

Post-infectious bronchiolitis obliterans (PBO) is a rare form of chronic obstructive lung disease in children with few data on the pulmonary function outcome and underlying inflammatory process. The aim of this study was to determine the change in lung function over time and to investigate by bronchoalveolar lavage (BAL) the inflammatory characteristics of pulmonary involvement. Eleven Caucasian children with PBO were evaluated to estimate the average rate of change in lung function indices using a mixed model. The differential cytology and lymphocyte subsets of BAL fluid were analyzed. The median follow-up was 10.2 (IQR 3.2-12) years. The estimated forced expiratory volume in 1 sec (FEV1) had a baseline intercept of 57% predicted (62% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.01% per year whereas the estimated forced expiratory flow 25-75 (FEF25-75) had a baseline intercept of 36% predicted (42% predicted after bronchodilator) at 10 years of age which fell at a rate of 1.04% per year. The estimated FEV1/FVC ratio had a baseline intercept of 70% (74% after bronchodilator) at 10 years of age which declined with an average slope of 1.02% per year (-1.10% per year after bronchodilator). Although the baseline and post-bronchodilator level of estimated FVC was abnormal (68% and 69% predicted, respectively) it did not change significantly with time. The median disease duration at BAL evaluation was 3.7 (IQR 0.7-8) years. The percentage differential cell counts were characterized by a significant increase in neutrophils (median 50%, IQR 1-66%), and a slight increase of lymphocytes (median 14%, IQR 7.5-15%). In conclusion, pulmonary function in childhood PBO is characterized by significant airway obstruction which deteriorates over time. The presence of an ongoing inflammatory process could explain the decline in lung function over time.

Functional characterization of naturally occurring NR3C2 gene mutations in Italian patients suffering from pseudohypoaldosteronism type 1.

OBJECTIVE: The renal form of pseudohypoaldosteronism type 1 (PHA1) is a rare disease caused by mutations in the human mineralocorticoid receptor gene (NR3C2). DESIGN: Aim of the study was to analyze the NR3C2 gene in three Italian patients with clinical signs of renal PHA1 and to evaluate the distribution of the -2G > C, c.538A > G, and c.722C > T single nucleotide polymorphism (SNP) pattern in the PHA1 patients and in 90 controls of the same ethnic origin. METHODS: Analysis of the NR3C2 gene sequence and of the polymorphic SNP markers. Functional characterization of the detected novel NR3C2 mutations utilizing aldosterone-binding assays and reporter gene transactivation assays. RESULTS: One novel nonsense (Y134X) and one novel frameshift (2125delA) mutation were detected. They exhibited no aldosterone binding and no transactivation abilities. No mutation was detected in the third patient. Haploinsufficiency of NR3C2 was ruled out by microsatellite analysis in this patient. The c.722T SNP was detected in 97% of alleles in the Italian population which is significantly different from the general German or US population. CONCLUSIONS: Molecular analysis of the NR3C2 gene in PHA1 patients is warranted to detect novel mutations in order to clarify the underlying genetic cause, which may extend the insight into relevant functional regions of the hMR protein. The effect the different distribution of the c.722T SNP is not clear to date. Further studies are necessary to provide evidence as to a possible advantage of a less sensitive hMR in southern countries.

Reproductive outcome in patients treated and not treated for idiopathic early puberty: long-term results of a randomized trial in adults.

OBJECTIVE: To evaluate the adult reproductive outcome in girls with early puberty who participated in a previous random study. STUDY DESIGN: A total of 22 subjects treated with triptorelin 3.75 mg every 4 weeks (group 1), 18 subjects not treated (group 2), and 22 age-matched normal volunteers (control group) underwent a physical examination, serum hormone level determination, and pelvic ultrasonography. RESULTS: The characteristics of menstrual cycles, serum hormone levels, and ultrasound results did not differ significantly among the 3 groups examined. The mean ovarian volume and the uterine volume tended to increase in the subjects of group 2, but the differences were not significant. The percentage of subjects who reported being sexually active at the time of the examination was greater in the 2 groups with previous early puberty than in the controls (76% of cases in group 1, 72% in group 2, and 59% in the control group). CONCLUSIONS: Neither early puberty nor its treatment seems to significantly affect the normal adult function of the pituitary-gonadal axis.

Effect on adult height of pubertal growth hormone retesting and withdrawal of therapy in patients with previously diagnosed growth hormone deficiency.

CONTEXT: GH replacement therapy in GH-deficient (GHD) patients is usually continued until adult height despite the fact that most of these subjects display a normal secretion when retested at the end of growth. Puberty is the most likely time for normalization of GH secretion. OBJECTIVES: The objectives of this study are to establish the characteristics and the percentage of the subjects with isolated GHD who normalized secretion at puberty and to compare their statural outcomes with those of the subjects with persistent deficiency treated also after retesting. DESIGN AND SETTING: This was a prospective, nonrandomized, open-label study conducted in a university research hospital. PATIENTS AND INTERVENTION: Sixty-nine subjects (40 male, 29 female) with a diagnosis before puberty of isolated GHD by means of arginine and l-dopa tests were reevaluated with the same tests after at least 2 yr of therapy and after puberty onset. If GH peak at retesting was more than 10 microg/liter, therapy was withdrawn. MAIN OUTCOME MEASURES: Percentage and characteristics of normalized subjects at retesting, outcome of treatment in the subjects treated or untreated to adult height, and factors predictive of growth outcome were measured. RESULTS: At retesting, 44 subjects (63.7%) confirmed a GH peak less than 10 microg/liter (24 of 40 male and 20 of 29 female). Apart from a less delayed bone age at diagnosis in females, the subjects with confirmed GHD were not different at diagnosis from the other group for height deficit at diagnosis, first year growth response to GH, age and height at puberty onset, height, and IGF-I at retesting. Mean adult height was 165.1 +/- 4.5 cm in the male group treated until adult height vs. 164.0 +/- 3.4 cm in the group who suspended therapy at retesting. Mean adult height was 153.2 +/- 4.1 cm in the female group treated until adult height vs. 152.9 +/- 5.2 cm in the group that suspended therapy at retesting. As regards the parameters expressing the final outcome, the only difference was found in the mean increment adult height-target height sd score in favor of the male group treated until adult height. In both sexes, therapy duration and GH levels at diagnosis and at retesting were unrelated to adult height parameters and to height increments during the period of observation. CONCLUSIONS: One third of our GHD subjects diagnosed before puberty presented a normal secretion at puberty. The withdrawal of GH therapy in these subjects after retesting was not associated with a catch down growth, and they obtained an adult height similar to those obtained by the GHD subjects treated until adult height. It seems convenient, in subjects with nonsevere GHD, to retest GH secretion at midpuberty and to withdraw treatment for the subjects that are no longer deficient.