Auxological and endocrine findings in narcolepsy type 1: seventeen-year follow-up from a pediatric endocrinology center.

Introduction: Narcolepsy Type 1 (NT1) is a rare hypersomnia of central origin linked to hypocretin deficiency, most frequently arising at pediatric age. NT1 could be associated with endocrine comorbidities involving the neuroendocrine axis, predominantly obesity, and Central Precocious Puberty (CPP). The primary aim of this study is the evaluation of endocrine and auxological parameters at diagnosis and during follow-up in patients with NT1, treated with Sodium Oxybate (SO) or not. Methods: We retrospectively evaluated the auxological, biochemical, and radiological parameters of 112 patients referred to our Center between 2004-2022. The design of our study is cross-sectional at the time of diagnosis followed by a longitudinal follow-up. Results: Our study confirms an increased frequency of CPP and obesity in patients with NT1. At first evaluation, obesity was found in 31.3% of patients, while overweight was found in 25.0%. A diagnosis of CPP was made in 19.6% of patients. Interestingly, this group showed a significantly lower level of CSF-hypocretin (hrct-1) at diagnosis compared to others. We found an improvement in BMI SDS in the SO-treated group compared to untreated patients, and this trend persisted also at 36 months of follow-up (0.0 ± 1.3 vs 1.3 ± 0.4; p<0.03). Sixty-three patients reached their final height, with a median SDS of 0.6 ± 1.1 in boys and 0.2 ± 1.2 in girls. Discussion: To our knowledge, these are the first results regarding the final height in a large series of pediatric patients with NT1, with a normal range of IGF1-SDS levels and stature SDS.

Measles virus and cytomegalovirus co-infection, in a child with recent SARS-CoV-2 infection, during COVID-19 pandemic: a case report.

Measles virus (MV) and cytomegalovirus (CMV) may cause pediatric infection. We report the first described case of MV and CMV co-infection in an unvaccinated 13-mo-old girl, with a recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, occurred during coronavirus disease 2019 (COVID-19) pandemic. The COVID-19 pandemic context, combined with patient's complex clinical scenario, presenting symptoms as persistent fever, diarrhea, vomiting, maculopapular rash and edema, in addition to high level of inflammatory markers, led to a suspicion of multisystemic inflammatory syndrome in children (MIS-C). The final diagnosis and the successfully management of the case, discharged after resolution of symptoms, was achieved by a proper virological diagnosis and a close two-way cooperation between pediatricians and clinical microbiologists. The report mainly highlights that awareness about measles should be raised in unvaccinated patients with consistent symptoms, even in the COVID-19 era.

Different Pediatric Acute Care Settings Influence Bronchiolitis Management: A 10-Year Retrospective Study.

Bronchiolitis is the main cause of hospitalization in infants. Diagnosis is clinical, and treatment is based on hydration and oxygen therapy. Nevertheless, unnecessary diagnostic tests and pharmacological treatments are still very common. This retrospective study aimed to evaluate whether the setting of bronchiolitis care influences diagnostic and therapeutic choices. The management of 3201 infants, referred to our Italian Tertiary Care Center for bronchiolitis between 2010 and 2020, was analyzed by comparing children discharged from the pediatric emergency department (PEDd group) undergoing short-stay observation (SSO group) and hospitalization. Antibiotic use in PEDd, SSO, and ward was 59.3% vs. 51.6% vs. 49.7%, respectively (p < 0.001); inhaled salbutamol was mainly administered in PEDd and during SSO (76.1% and 82.2% vs. 38.3% in ward; p < 0.001); the use of corticosteroids was higher during SSO and hospitalization (59.6% and 49.1% vs. 39.0% in PEDd; p < 0.001); inhaled adrenaline was administered mostly in hospitalized infants (53.5% vs. 2.5% in SSO and 0.2% in PEDd; p < 0.001); chest X-ray use in PEDd, SSO, and ward was 30.3% vs. 49.0% vs. 70.5%, respectively (p < 0.001). In a multivariate analysis, undergoing SSO was found to be an independent risk factor for the use of systemic corticosteroid and salbutamol; being discharged at home was found to be a risk factor for antibiotic prescription; undergoing SSO and hospitalization resulted as independent risk factors for the use of CXR. Our study highlights that different pediatric acute care settings could influence the management of bronchiolitis. Factors influencing practice may include a high turnover of PED medical staff, personal reassurance, and parental pressure.

Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics.

Visceral Leishmaniasis (VL) is a vector-borne disease caused by an intracellular protozoa of the genus Leishmania that can be lethal if not treated. VL is caused by Leishmania donovani in Asia and in Eastern Africa, where the pathogens' reservoir is represented by humans, and by Leishmania infantum in Latin America and in the Mediterranean area, where VL is a zoonotic disease and dog is the main reservoir. A part of the infected individuals become symptomatic, with irregular fever, splenomegaly, anemia or pancytopenia, and weakness, whereas others are asymptomatic. VL treatment has made progress in the last decades with the use of new drugs such as liposomal amphotericin B, and with new therapeutic regimens including monotherapy or a combination of drugs, aiming at shorter treatment duration and avoiding the development of resistance. However, the same treatment protocol may not be effective all over the world, due to differences in the infecting Leishmania species, so depending on the geographical area. This narrative review presents a comprehensive description of the clinical picture of VL, especially in children, the diagnostic approach, and some insight into the most used pharmacological therapies available worldwide.

Impact of Guidelines Publication on Acute Bronchiolitis Management: 10-Year Experience from a Tertiary Care Center in Italy.

Bronchiolitis is the most common lower respiratory tract infection in infants. According to evidence-based guidelines, diagnosis is clinical, there is no need for routine use of laboratory or instrumental tests and therapy is primarily supportive, based on oxygen and adequate fluid supplementation. Nevertheless, unnecessary diagnostic tests and pharmacological treatments are still very common. The aim of this retrospective cohort study was to evaluate how the management of bronchiolitis has changed in the last ten years in a Tertiary Care Center in Italy, assessing adherence to national guidelines. Considering the publication of the Italian inter-society consensus document in 2014, we compared patients admitted in the prior four epidemic seasons with patients admitted in the latter six epidemic seasons. The comparison between the two groups showed a significant reduction in the prescription of systemic corticosteroids (58.9% vs. 41.8%, p < 0.001), nebulized epinephrine (73.8% vs. 38.3%, p < 0.001) and antibiotics (59.5% vs. 42.3%, p < 0.001), together with a drastic decrease in the use of chest X-ray (92.2% vs. 54.4%, p < 0.001). On the contrary, the use of inhaled salbutamol remained substantially stable over time (39.4% vs. 37.6%, p = 0.505). Despite the encouraging results, further efforts are needed to limit the prescription of ineffective therapies like antibiotics and inhaled salbutamol.

Oral steroids for reducing kidney scarring in young children with febrile urinary tract infections: the contribution of Bayesian analysis to a randomized trial not reaching its intended sample size.

BACKGROUND: This study aimed to evaluate the effect of oral dexamethasone in reducing kidney scars in infants with a first febrile urinary tract infection (UTI). METHODS: Children aged between 2 and 24 months with their first presumed UTI, at high risk for kidney scarring based on procalcitonin levels (≥1 ng/mL), were randomly assigned to receive dexamethasone in addition to routine care or routine care only. Kidney scars were identified by kidney scan at 6 months after initial UTI. Projections of enrollment and follow-up completion showed that the intended sample size could not be reached before funding and time to complete the study ran out. An amendment to the protocol was approved to conduct a Bayesian analysis. RESULTS: We randomized 48 children, of whom 42 had a UTI and 18 had outcome kidney scans (instead of 128 planned). Kidney scars were found in 0/7 and 2/11 patients in the treatment and control groups respectively. The probability that dexamethasone could prevent kidney scarring was 99% in the setting of an informative prior probability distribution (which fully incorporated in the final inference the information on treatment effect provided by previous studies) and 98% in the low-informative scenario (which discounted the prior literature information by 50%). The probabilities that dexamethasone could reduce kidney scar formation by up to 20% were 61% and 53% in the informative and low-informative scenario, respectively. CONCLUSIONS: Dexamethasone is highly likely to reduce kidney scarring, with a more than 50% probability to reduce kidney scars by up to 20%. TRIAL REGISTRATION NUMBER: EudraCT number: 2013-000388-10; registered in 2013 (prospectively registered) A higher resolution version of the Graphical abstract is available as Supplementary information.

Childhood medical history and psychosis in adult life: Findings from the Bologna EU-GEI incidence and case-control study.

AIM: To estimate the association between the inpatient admissions and Emergency Department (ED) visits before age of 18 years and adulthood-onset first-episode psychosis (FEP). METHODS: We conducted a FEP incidence and case-control study and calculated the odds ratios (ORs) for incident FEP associated with inpatient admissions and ED visits prior to age of 18 years, adjusting our results for cannabis use, parental socio-economic class and childhood trauma. RESULTS: In multivariate logistic regression analysis, odds of FEP increased significantly if the participant had a history of at least one inpatient admission (OR = 3.52; 95% confidence interval [95%CI] 1.07-11.54; P = .04) or at least one ED visit (OR = 8.93; 95%CI 2.41-33.14; P = .001) before age of 18. The associations remained significant adjusting for cannabis use, education, parental socio-economic class and childhood trauma. CONCLUSION: Consistently with the socio-neurodevelopmental model, we found a significant association between a positive history of hospital care in childhood and adulthood-onset psychosis.

Efficacy of adalimumab as second-line therapy in a pediatric cohort of Crohn's disease patients who failed infliximab therapy: the Italian Society of Pediatric Gastroenterology, Hepatology, and Nutrition experience.

BACKGROUND: Adalimumab (Ada) treatment is an available option for pediatric Crohn's disease (CD) and the published experience as rescue therapy is limited. OBJECTIVES: We investigated Ada efficacy in a retrospective, pediatric CD cohort who had failed previous infliximab treatment, with a minimum follow-up of 6 months. METHODS: In this multicenter study, data on demographics, clinical activity, growth, laboratory values (CRP) and adverse events were collected from CD patients during follow-up. Clinical remission (CR) and response were defined with Pediatric CD Activity Index (PCDAI) score ≤10 and a decrease in PCDAI score of ≥12.5 from baseline, respectively. RESULTS: A total of 44 patients were consecutively recruited (mean age 14.8 years): 34 of 44 (77%) had active disease (mean PCDAI score 24.5) at the time of Ada administration, with a mean disease duration of 3.4 (range 0.3-11.2) years. At 6, 12, and 18 months, out of the total of the enrolled population, CR rates were 55%, 78%, and 52%, respectively, with a significant decrease in PCDAI scores (P<0.01) and mean CRP values (mean CRP 5.7 and 2.4 mL/dL, respectively; P<0.01) at the end of follow-up. Steroid-free remission rates, considered as the total number of patients in CR who were not using steroids at the end of this study, were 93%, 95%, and 96% in 44 patients at 6, 12, and 18 months, respectively. No significant differences in growth parameters were detected. In univariate analysis of variables related to Ada efficacy, we found that only a disease duration >2 years was negatively correlated with final PCDAI score (P<0.01). Two serious adverse events were recorded: 1 meningitis and 1 medulloblastoma. CONCLUSION: Our data confirm Ada efficacy in pediatric patients as second-line biological therapy after infliximab failure. Longer-term prospective data are warranted to define general effectiveness and safety in pediatric CD patients.

Growing Up with Type 1 Narcolepsy: Its Anthropometric and Endocrine Features.

STUDY OBJECTIVES: To evaluate the effect of type 1 narcolepsy (NT1) on anthropometric and endocrine features in childhood/adolescence, focusing on patterns and correlates of weight, pubertal development, and growth in treated and untreated patients. METHODS: We collected anthropometric (height, weight, body mass index (BMI) z-scores), pubertal, metabolic, and endocrine data from 72 NT1 patients at diagnosis and all available premorbid anthropometric parameters of patients from their pediatric files (n = 30). New measurements at 1-y reassessment in patients undergoing different treatments were compared with baseline data. RESULTS: We detected a high prevalence of overweight (29.2%), obesity (25%), metabolic syndrome (18.8%), and precocious puberty (16.1%), but no signs of linear growth alterations at diagnosis. According to anthropometric records, weight gain started soon after NT1 onset. At 1-y follow-up reassessment, sodium oxybate treatment was associated with a significant BMI z-score reduction (-1.29 ± 0.30, p < 0.0005) after adjusting for baseline age, sex, sleepiness, and BMI. CONCLUSIONS: NT1 onset in children/adolescents is associated with rapid weight gain up to overweight/obesity and precocious puberty without affecting growth. In our study, sodium oxybate treatment resulted in a significant weight reduction in NT1 overweight/obese patients at 1-y follow-up.

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.

Characterization of deletions at 9p affecting the candidate regions for sex reversal and deletion 9p syndrome by MLPA.

The distal region on the short arm of chromosome 9 is of special interest for scientists interested in sex development as well as in the clinical phenotype of patients with the 9p deletion syndrome, characterized by mental retardation, trigonocephaly and other dysmorphic features. Specific genes responsible for different aspects of the phenotype have not been identified. Distal 9p deletions have also been reported in patients with 46,XY sex reversal, with or without 9p deletion syndrome. Within this region the strongest candidates for the gonadal dysgenesis phenotype are the DMRT genes; however, the genetic mechanism is not clear yet. Multiple ligation-dependent probe amplification represents a useful technique to evaluate submicroscopic interstitial or distal deletions that would help the definition of the minimal sex reversal region on 9p and could lead to the identification of gene(s) responsible of the 46,XY gonadal disorders of sex development (DSD). We designed a synthetic probe set that targets genes within the 9p23-9p24.3 region and analyzed a group of XY patients with impaired gonadal development. We characterized a deletion distal to the DMRT genes in a patient with isolated 46,XY gonadal DSD and narrowed down the breakpoint in a patient with a 46,XY del(9)(p23) karyotype with gonadal DSD and mild symptoms of 9p deletion syndrome. The results are compared with other patients described in the literature, and new aspects of sex reversal and the 9p deletion syndrome candidate regions are discussed.

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.

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.

Emotion recognition and expression in young obese participants: preliminary study.

This study of the presence of alexithymic characteristics in obese adolescents and preadolescents tested the hypothesis of whether they showed impaired recognition and expression of emotion. The sample included 30 obese young participants and a control group of 30 participants of normal weight for their ages. Stimuli, 42 faces representing seven emotional expressions, were shown to participants who identified the emotion expressed in the face. The Level of Emotional Awareness Scale was adapted for children to evaluate their ability to describe their emotions. Young obese participants had significantly lower scores than control participants, but no differences were found in recognition of emotion. The lack of words to describe emotions might suggest a greater prevalence of alexithymic characteristics in the obese participants, but the hypothesis of a general deficit in the processing of emotional experiences was not supported.

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.

Two novel GnRHR gene mutations in two siblings with hypogonadotropic hypogonadism.

OBJECTIVE: Mutations in the gonadotropin-releasing hormone receptor (GnRHR) gene are the cause of isolated hypogonadotropic hypogonadism (HH). We describe the molecular investigations of the GnRHR gene in two siblings affected by HH and their clinical course. DESIGN: The female was referred at age 14 for pubertal delay with no secondary sexual signs, whereas the male had been followed since prepuberty. Hormonal evaluation showed very low levels of gonadotropins, luteinizing hormone-releasing hormone test (LHRH test) and sexual steroids in both patients, suggesting a possible defect in the mechanism of action of the GnRH gene on its receptor. METHODS: The GnRHR gene of the two siblings and their parents were analyzed by PCR followed by direct sequencing. RESULTS: Two new single nucleotide substitutions resulting in the T104I and the Y108C substitutions in the first extracellular loop (ECL1) were identified in both siblings. The molecular analysis confirmed the carrier status of the parents. CONCLUSIONS: We identified two new missense mutations in the GnRHR gene in two siblings with HH. The nature of the substitutions lying in the ECL1 involved in the ligand-receptor interaction, as well as the high conservation of the two residues in all mammalian GnRHR, are suggestive of some implications in the phenotype observed.

An assessment of petrosal sinus sampling for localization of pituitary microadenomas in children with Cushing disease.

CONTEXT: Pituitary adenomas in Cushing disease (CD) are usually small and difficult to visualize. Bilateral inferior petrosal venous sampling (BIPSS) before and after ovine CRH stimulation is reserved for patients who have ACTH-dependent Cushing syndrome and negative magnetic resonance imaging (MRI) or positive MRI but inconsistent biochemical data. OBJECTIVE: The objective of the study was to evaluate the usefulness of BIPSS as a tool for localization of a pituitary adenoma in children with CD. DESIGN: The study was a retrospective review of the records of 141 children who were admitted for evaluation of CD from 1982 to 2004. SETTING: The study was conducted at a tertiary care center. INTERVENTIONS AND OUTCOME MEASURES: Lateralization of ACTH secretion during BIPSS was compared with MRI and surgical findings for the localization of a microadenoma. RESULTS: A total of 94 patients, 49 males and 45 females with an age range of 5.3 to 18.7 yr (13 +/- 3.2 yr), underwent BIPSS. Localization of a microadenoma by BIPSS agreed with surgical location in only 58% of the cases (95% confidence interval, 43-66). The combined use of information from the MRI and inferior petrosal venous sampling did not predict the location of the tumor more frequently than MRI alone (P > 0.1), which in this study localized a lesion in 39% of the patients (95% confidence interval, 28-50). The procedure was completed successfully in all patients, and no serious complications were recorded. CONCLUSIONS: Although BIPSS was safe and well tolerated in an experienced center, lateralization of the ACTH gradient during BIPSS was a poor predictor of the site of the adenoma in children with CD.

SRD5A2 gene analysis in an Italian population of under-masculinized 46,XY subjects.

OBJECTIVE: The differential diagnosis of male under-masculinization, including a wide spectrum of phenotypes and a heterogeneous genetic basis, is crucial for the correct management of the patients. To characterize an Italian population of under-masculinized males, we performed the molecular analysis of the SRD5A2 gene (2p23), encoding the 5alpha-reductase-2 enzyme that converts testosterone (T) to dihydrotestosterone (DHT), and is required for full masculinization of the male foetus. DESIGN AND PATIENTS: Twenty-six Italian patients with 46,XY kariotype and various degrees of ambiguous genitalia were retrospectively selected for this study. Twelve of these patients, 10 of whom were referred for partial androgen insensitivity syndrome (PAIS), were raised as females; 15 were raised as males and all had a severe hypospadias. For most of the patients, the case histories and hormonal findings were incomplete but all could be included in the clinical characteristics of under-masculinization. MEASUREMENT: For hormonal evaluation, T and DHT were measured by means of radioimmunoassay (RIA) and high-performance liquid chromatography (HPLC)-RIA methods, respectively. Genomic DNA of all patients and relatives was extracted from peripheral blood, the five exons of the SRD5A2 gene were amplified by polymerase chain reaction (PCR) and submitted to automatic sequencing. RESULTS: Five known mutations affecting the NADPH binding function and one new mutation affecting the enzyme C-terminus were identified in a total of eight patients (two of whom were sisters). Five families were characterized, and in two patients only one affected allele was observed. The extension of the analysis to the regions flanking exons allowed the identification of a new polymorphism in intron 2, whose frequency was determined. CONCLUSION: This first report of an Italian population underlines the importance of differential diagnoses in patients with under-masculinization. The lack of precise genotype-phenotype correlation in some of the mutations highlights the necessity to improve knowledge about the biochemical aspects of steroid 5alpha-reductase action and about the interactions of genetic and environmental factors.