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Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. Results: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

Purpose The aim of this study was to produce evidence on quality of life (QoL) among Italian growth hormone deficiency (GHD) children and adolescents treated with growth hormone (GH) and their parents. Methods A survey was conducted among Italian children and adolescents aged 4–18 with a confirmed diagnosis of GHD and treated with GH therapy and their parents. The European Quality of Life 5 Dimensions 3 Level Version (EQ-5D-3L) and the Quality of Life in Short Stature Youth (QoLISSY) questionnaires were administered between May and October 2021 through the Computer-Assisted Personal Interview (CAPI) method. Results were compared with national and international reference values. Results The survey included 142 GHD children/adolescents and their parents. The mean EQ-5D-3L score was 0.95 [standard deviation (SD) 0.09], while the mean visual analogue scale (VAS) score was 86.2 (SD 14.2); the scores are similar to those of a reference Italian population aged 18–24 of healthy subjects. As for the QoLISSY child-version, compared to the international reference values for GHD/ idiopathic short stature (ISS) patients, we found a significantly higher score for the physical domain, and lower scores for coping and treatment; compared to the specific reference values for GHD patients, our mean scores were significantly lower for all domains except the physical one. As for the parents, we found a significantly higher score for the physical domain, and a lower score for treatment; compared to reference values GHD-specific, we found lower score in the social, emotional, treatment, parental effects, and total score domains. Conclusions Our results suggest that the generic health-related quality of life (HRQoL) in treated GHD patients is high, comparable to that of healthy people. The QoL elicited by a disease specific questionnaire is also good, and comparable with that of international reference values of GHD/ISS patients.

Purpose Childhood overweight and obesity associated with insulin resistance and metabolic syndrome represent the new global pandemic and the main causative factors for dysglycemia, prediabetes, and Type 2 Diabetes Mellitus (T2DM). Predictors, such as HOMA-IR, HOMA-β%, and QUICKI lack specific reference values in children. OGTT is a gold standard for glycometabolic assessment. Recently, a glycemic level higher than 155 mg/dl at + 60′ after glucose ingestion has been defined as a risk factor for T2DM in obese adolescents. We aim to analyze and correlate fasting insulin-resistance markers with OGTT results in overweight/obese children and adolescents. Methods We retrospectively evaluated glucose and insulin values during a 2-h OGTT every 30 min in 236 overweight/obese patients. Glucose values and insulin sum during OGTT were compared to glycometabolic indexes and different cut-off values for insulin sum. Results A 1-h glucose > 155 mg/dl and insulin sum > 535 microU/ml at all times during OGTT are the best predictors of diabetes risk in obese youths. A1-h glucose > 155 mg/dl is significantly associated with HbA1c > 5.7%, while no association was observed between HbA1c > 5.7% and glucose levels at baseline and 2 h. The ability of the standardized HOMA-IR to predict the prediabetes status is clearly lower than the total insulin sum at OGTT. Conclusion Our study demonstrates that also 1-h post-OGTT glucose, together with HbA1c, is an effective diabetes predictor.

This paper aims to fill the gap in knowledge about building control testing, thus encouraging control evaluation, to ultimately improve energy efficiency in building operation. A hardware controller and its digital twin are tested in real-time in a separate platform in the cloud, and the results are analyzed to determine what insights can tests on virtual controllers give about the behaviors of their real-life hardware counter-parts. Key performance indicators (KPIs) from literature are used to evaluate the control. It is shown that although the controllers differ in their control output time-series, their overall performance profile along the entire simulation run follows a similar pattern (KPI percent error varies between 3% and 8%). This implies that virtual controller testing can be a good indicator of hardware controller behavior.

PURPOSE: Poor adherence to recombinant human growth hormone (r-hGH) therapy is associated with reduced growth velocity in children with growth hormone deficiency (GHD). This twelve-month observational study was to assess adherence in r-hGH patients treated with the easypod™, an electronic, fully automated injection device designed to track the time, date and dose administered. METHODS: Ninety-seven prepubertal patients receiving r-hGH therapy were included in the study from ten Italian clinical sites and 88 completed the study. To avoid possible confounding effects, only GHD patients (79/88; 89.7 % of the overall study population) were considered in the final analysis. The primary endpoint-adherence to treatment-was calculated as the proportion of injections correctly administered during the observational period out of the expected total number of injections. The relevant information, tracked by the easypod™, was collected at months 6 (V1) and 12 (V2) after baseline (V0). At study termination, adherence data were partially available from 16 patients and fully available from 53 patients. As secondary endpoints, serum IGF-1 levels, fasting serum glucose and insulin levels and key anthropometric characteristics (height, waist circumference and BMI) were also determined. RESULTS: The easypod™ data showed that 56.7 % of the patients were considered to be fully (≥92 %) adherent to their treatment throughout the period V0-V2. Treatment improved stature, significantly increased IGF-1 and produced a non-significant increase in blood glucose and insulin levels. CONCLUSIONS: The injection-recording system and other characteristics of easypod™ could enhance the ability of physicians to monitor adherence to r-hGH treatment.

Background: Bone marrow transplantation (BMT) is associated with bone morbidity. We investigated bone status with quantitative ultrasound (QUS) in pediatric patients with hematological diseases prior to and up to 3 yr following BMT. Methods: Phalangeal QUS measures for amplitude-dependent speed of sound (Ad-SoS) and bone transmission time (BTT) were obtained in 40 hematological patients (25 with malignant, 15 with non-malignant disease; 9.7±4.9 yr) before BMT and 6, 12, 24, and 36 months after BMT. Bone parameters were expressed as Z-scores based on age-sex-matched normal controls. Results: Mean Ad-SoS and BTT Z-scores were normal before BMT and reduced at 36 months (analysis of variance: p=0.0542 and p=0.0233). Ad-SoS and BTT Z-scores remained relatively stable in the first 6 months after BMT and then progressively decreased reaching a plateau at 12–36 months. In non-malignant patients, BTT Z-score decreased at 6–12 months (p=0.029) and subsequently increased, while in malignant patients BTT Z-score showed a decrease at 12–24 months. Pre-pubertal subjects displayed a drop of BTT Z-Score values at both 12 (p=0.023) and 36 months after BMT (p=0.049), while BTT Z-score remained relatively unchanged in pubertal subjects. Early impairment of BTT Z-score was found in patients who suffered acute graft versus host disease (GVHD) compared to patients without this clinical condition; BTT Z-score was lower at 36 months (p=0.045). Conclusions: Longitudinal assessment by QUS of pediatric BMT survivors evidenced that bone status is mildly affected up to 36 months after BMT, mainly in malignant patients, in pre-pubertal subjects at BMT and in patients who suffered acute GVHD.

Objectives: Patients with organic growth hormone deficiency (GHD) or with structural hypothalamic–pituitary abnormalities may have additional anterior pituitary hormone deficits, and are at risk of developing complete or partial corticotropin (ACTH) deficiency. Evaluation of the integrity of the hypothalamic–pituitary–adrenal axis (HPA) is essential in these patients because, although clinically asymptomatic, their HPA cannot appropriately react to stressful stimuli with potentially life-threatening consequences. Design and methods: In this study we evaluated the integrity of the HPA in 24 patients (age 4.2–31 years at the time of the study) with an established diagnosis of GHD and compared the reliability of the insulin tolerance test (ITT), short synacthen test (SST), low-dose SST (LDSST), and corticotropin releasing hormone (CRH) test in the diagnosis of adrenal insufficiency. Results: At a cortisol cut-off for a normal response of 550 nmol/l (20 μg/dl), the response to ITT was subnormal in 11 subjects, 6 with congenital and 5 with acquired GHD. Four patients had overt adrenal insufficiency, with morning cortisol concentrations ranging between 66.2–135.2 nmol/l (2.4–4.9 μg/dl) and typical clinical symptoms and laboratory findings. In all these patients, a subnormal cortisol response to ITT was confirmed by LDSST and by CRH tests. SST failed to identify one of the patients as adrenal insufficient. In the seven asymptomatic patients with a subnormal cortisol response to ITT, the diagnosis of adrenal insufficiency was confirmed in one by LDSST, in none by SST, and in five by CRH tests. The five patients with a normal cortisol response to ITT exhibited a normal response also after LDSST and SST. Only two of them had a normal response after a CRH test. In the seven patients with asymptomatic adrenal insufficiency mean morning cortisol concentration was significantly higher than in the patients with overt adrenal insufficiency. ITT was contraindicated in eight patients, and none of them had clinical symptoms of overt adrenal insufficiency. One of these patients had a subnormal cortisol response to LDSST, SST, and CRH, and three exhibited a subnormal response to CRH but normal responses to LDSST and to SST. Conclusion: We conclude that none of these tests can be considered completely reliable for establishing or excluding the presence of secondary or tertiary adrenal insufficiency. Consequently, clinical judgment remains one of the most important issues for deciding which patients need assessment or re–assessment of adrenal function.

BACKGROUND AND PURPOSE: Midbrain-hindbrain involvement in septo-optic dysplasia has not been well described, despite reported mutations of genes regulating brain stem patterning. We aimed to describe midbrain-hindbrain involvement in patients with septo-optic dysplasia and to identify possible clinical-neuroimaging correlations. MATERIALS AND METHODS: Using MR imaging, we categorized 38 patients (21 males) based on the presence (group A, 21 patients) or absence (group B, 17 patients) of visible brain stem anomalies. We measured height and anteroposterior diameter of midbrain, pons, and medulla, anteroposterior midbrain/pons diameter (M/P ratio), vermian height, and tegmento-vermian angle, and compared the results with 114 healthy age-matched controls. Furthermore, patients were subdivided based on the type of midline anomalies. The associations between clinical and neuroradiological features were investigated. Post hoc tests were corrected according to Bonferroni adjustment (p(B)). RESULTS: Patients with brain stem abnormalities had smaller anteroposterior pons diameter than controls (p(B) < .0001) and group B (p(B) = .012), higher M/P ratio than controls (p(B) < .0001) and group B (p(B) < .0001), and smaller anteroposterior medulla diameter (p(B) = .001), pontine height (p(B) = .00072), and vermian height (p(B) = .0009) than controls. Six of 21 patients in group A had thickened quadrigeminal plate, aqueductal stenosis, and hydrocephalus; 3 also had agenesis of the epithalamus. One patient had a short midbrain with long pons and large superior vermis. There was a statistically significant association between brain stem abnormalities and callosal dysgenesis (P = .011) and developmental delay (P = .035), respectively. CONCLUSION: Midbrain-hindbrain abnormalities are a significant, albeit underrecognized, component of the septo-optic dysplasia spectrum, and are significantly associated with developmental delay in affected patients.

We evaluated the GH-releasing effect of hexarelin (Hex; 2 microg/kg, i.v.) and GHRH (1 microg/kg, i.v.) in 18 patients (11 males and 7 females, aged 2.5-20.4 yr) with GH deficiency (GHD) whose hypothalamic pituitary abnormalities had been previously characterized by dynamic magnetic resonance imaging (MRI). Ten patients had isolated GHD, and 8 had multiple pituitary hormone deficiency. All patients were receiving appropriate hormone replacement therapy. Twenty-four prepubertal short normal children (11 boys and 13 girls, aged 5.9-13 yr, body weight within +/-10% of ideal weight) served as controls. MRI studies revealed an ectopic posterior pituitary at the infundibular recess in all patients. A residual vascular component of the pituitary stalk was visualized in 8 patients with isolated GHD (group 1), whereas MRI showed the absence of the pituitary stalk (vascular and neural components) in the remaining 10 patients (group 2), of whom 8 had multiple pituitary hormone deficiency and 2 had isolated GHD. In the short normal children, the mean peak GH response to GHRH (24.8 +/- 4.4 microg/L) was significantly lower than that observed after Hex treatment (48.1 +/- 4.9 microg/L; P < 0.0001). In the GHD patients of group 2, the mean peak GH responses to GHRH (1.4 +/- 0.3 microg/L) and Hex (0.9 +/- 0.3 microg/L) were similar and markedly low. In the patients of group 1, the GH responses to GHRH (8.7 +/- 1.3 microg/L) and Hex (7.0 +/- 1.3 microg/L) were also similar, but were significantly higher that those observed in group 2 (P < 0.0001). In the whole group of patients, a significant correlation was found between the GH peaks after Hex and those after GHRH (r = 0.746; P < 0.0001). In this study we have confirmed that the integrity of the hypothalamic pituitary connections is essential for Hex to express its full GH-releasing activity and that Hex is able to stimulate GH secretion in patients with GHD but with a residual vascular component of the pituitary stalk.

Recombinant human growth hormone (r-hGH) is indicated for pediatric patients with a variety of growth disorders. Treatment with r-hGH requires long-term daily injections (1). Non-adherence or low adherence to treatment is associated with less favorable clinical outcomes, lower quality of life and higher healthcare costs (2,3). easypodTM has been specifically designed to improve patients’ ease of daily use and to minimize discomfort and pain (4,5). Aim of this observational, national and multicentre study was to monitor the adherence to r-hGH treatment using easypodTM, which records time, date and dose of injections in patients with growth disorders during the 1st year of treatment. 98 pre-pubertal short stature patients with growth disorders (60 male and 37 female, 1 screening failure, median age 10 years) were enrolled in the study. So far data are available for 54 subjects. All subjects underwent a baseline visit, and then after 6 and 12 months. 8 patients were withdrawn from the study prematurely. Data regarding r-hGH administration was uploaded from the autoinjectors. Auxological parameters, routine blood chemistry and hematology values were collected. Adherence during the 1st year has been calculated. Adherence was defined as the proportion of injections correctly administered out of expected total number of injections during the observational period. A patient was considered as adherent if he/she correctly administered >92% of expected total number of injections during the observation period. Data on the 54 available patients show that 25 patients (46.3%) were adherent to treatment while 29 patients (53.7%) were not. The impact of low adherence on clinical and biochemical parameters is under evaluation. The study will run until January 2013. Data obtained from this study will allow to explore the potential impact of adherence to r-hGH on growth outcomes after 1st year of treatment. The long-term adherence will be evaluated in the easypodTM connect observational study, also ongoing in Italy.

Contexte Les HHC/SK sont une cause majeure de retard pubertaire et de maturation osseuse par deficit en steroides sexuels. Les TF/TC n’ont pas ete evaluees dans une grande serie de patients HHC/SK. L’objectif de cette etude a ete de comparer les TF/TC dans une grande cohorte monocentrique. Patients A partir de 410 patients HHC/SK, nous avons selectionne 216 (164/52 hommes/femmes ; 112/104 SK/HHC normosmiques [HHCn]) avec TF/TC disponibles. La taille de la fratrie etait disponible dans un sous-groupe de 162 patients. Resultats La TF des HHC/SK etait superieure a leur TC (hommes : 179 ± 8 vs 175 ± 6 cm, femmes : 166 ± 7 vs 162 ± 5 ; p Conclusions Hors TC, le determinant principal de la TF chez les sujets avec HHC/SK est l’âge de debut du TH. La TF > TC et superieure a la taille de la fratrie montre que l’HHC/SK n’impacte pas negativement l’acquisition staturale et que le TH, debute jeune, a un effet positif. La reduction de gain statural apres 26 ans indique que, au-dela des steroides gonadiques, d’autres mediateurs (hormonaux/non hormonaux) peuvent influencer la soudure epiphysaire et la maturation osseuse.

Pediatric pituitary tumors, albeit relatively infrequent, can significantly alter the quality of life of affected children. Accurate diagnostic differentiation is essential for both safe and effective disease management. Recent advances in neuroimaging have enabled the neuroradiologist to study the pituitary region in greater detail than ever before. Magnetic resonance imaging (MRI) represents the examination method of choice for evaluating hypothalamic-pituitary-related endocrine diseases due to its ability to provide strongly contrasted high-resolution, multiplanar and spatial images. Specifically, MRI allows the detection of the pituitary lesions responsible of the clinical picture and offers useful information about the relationship with adjacent anatomical structures in order to plan the medical or surgical strategy. A rigorous imaging exam technique is necessary in order to obtain images of high diagnostic quality. Advanced MR techniques, including diffusion-weighted imaging and MR spectroscopy, may be helpful in particular cases. Computerized tomography (CT) has a complementary role in the identification of intralesional calcifications or to better evaluate bone structures prior to trans-sphenoidal surgery. The aim of this work is to provide an overview of the most relevant neuroradiological features of pituitary region tumors and to propose an appropriate and accurate differential diagnosis.

Germinoma represents 7.8% of cerebral tumors in pediatric age and 50-65% of germ cell cerebral tumors. Generally it is a definite lesion of the pineal gland or suprasellar region, frequently occurring in the first three decades of life. Clinical presentation depends on tumor localization. Pineal lesions generally determine symptoms due to the compression of cerebral structures, causing Parinaud syndrome, while hypothalamic lesions are often characterized by diabetes insipidus, hypopituitarism and visual defects. In the absence of these classic signs and symptoms, however, the diagnosis of germinoma can be difficult. We presented the case of an 8-year-old boy, referred to our clinic for polyuria and polydipsia. Hormonal evaluations demonstrated central diabetes insipidus (CDI), with normal anterior pituitary function. Magnetic resonance imaging (MRI) showed a lack of posterior pituitary gland and partial pituitary stalk enlargement. The patient started therapy with desmopressin (Minirin) with good hydro-electrolytic balance. During follow-up the pituitary function became insufficient with low growth velocity. A second MRI demonstrated a bifocal lesion with dyshomogeneous and cystic appearance, suggesting the diagnosis of germinoma. On the basis of this case report we would like to point out the importance of an early diagnosis in order to improve the prognosis of the disease and the necessity of a careful follow-up of these patients.

Nijmegen breakage syndrome (NBS) is a rare, autosomal-recessive chromosome instability disorder characterized by growth and developmental defects, immunodeficiency, high susceptibility to lymphoid malignancies, hypersensitivity to ionizing radiation and aberrant cell-cycle checkpoint control. The disease is caused by mutations in the NBS1 gene, which encodes nibrin, a component of the hMre11-Rad50-p95 complex involved in cellular response to DNA double-strand breaks. Genetic heterogeneity has been suggested in at least two patients with the NBS phenotype, but no mutation in the NBS1 gene; recently, mutations in the gene encoding the enzyme ligase IV have been identified in patients with signs of NBS. We describe a boy with an NBS clinical phenotype but no mutation in either the NBS1 or the LIG4 genes. The analysis of his cellular phenotype reveals chromosome instability and radiosensitivity, but normal cell-cycle checkpoint control. In addition, a literature review was carried out to summarize and compare data of all NBS-like patients reported to date. This case confirms genetic heterogeneity for NBS. We believe that dissecting the clinical and cellular phenotypes of this and other NBS-like patients will provide useful information for the research of new genes involved in cellular response to DNA damage and the assessment of cancer risk in NBS-like syndrome.

N . Di Iorgi1, M .C . Salerno2, M . Cappa3, S . Loche4, G . Radetti5, D . Capaldo6, A . Allegri7, F . Napoli8, A . Calcagno7, O .B . Iovovich9, S . Noli7, S . Parodi10, M . Maghnie1 . 1DINOGMI, Endocrine Unit, IRCCS G Gaslini, University of Genova, Genova, Italy, 2Traslational Medical Sciences, Pediatric Endocrinology Unit, University Federico II, Naples, Italy, 3Unit of Endocrinology and Diabetology, Bambino Gesu Children’s Hospital, IRCCS, Rome, Italy, 4Pediatric Endocrine Unit, Ospedale Microcitemico, Cagliari, Italy, 5Pediatrics, Regional Hospital, Bolzano, Italy, 6Traslational Medical Sciences, Pediatric Endocrinology Unit, Federico II, Naples, Italy, 7DINOGMI, Endocrine Unit, University of Genova, Genova, Italy, 8Endocrine Unit, IRCCS, G Gaslini, Genova, Italy, 9Divisione di Laboratorio, IRCCS, G Gaslini, Genova, Italy, 10Institute of Electronics, Computer and Telecommunication Engineering, National Research Council of Italy, Genova, Italy

Hypochondroplasia is characterised by phenotypic and genetic heterogeneity. Differentiation from other conditions with disproportionate short stature is often difficult.To determine the reliability of radiological interpretation in the diagnosis of hypochondroplasia and to evaluate the most typical skeletal abnormalities. These data were correlated with molecular findings.We enrolled 21 patients with suspected hypochondroplasia based on the radiological criteria most often reported in the literature on this disease. Height, sitting height and head circumference were measured in all patients. Radiographs of the lumbar spine, left leg, pelvis and left hand were obtained. The presence of the N540K mutation in the fibroblast growth factor receptor 3 (FGFR3) gene was verified by restriction enzyme digestion. All radiographs which enabled the selection of patients were reviewed a second time by two paediatric radiologists in a blinded examination. Their results were compared.Both radiologists confirmed the diagnosis in 10 out of 21 patients, while in the other 52% of cases they excluded the disease, were uncertain or they did not agree on the final interpretation of the data. The best agreement rate was obtained in the evaluation of the lumbar spine and the legs. The radiological features of the nine patients (43%) carrying the N540K substitution were not remarkably different from the ones reported in the patients without this mutation.Our study shows that the crucial skeletal regions on which to focus the diagnosis of hypochondroplasia are the lumbar spine and legs, while the pelvis and hands seem to be less characteristic. To reduce the risk of misdiagnosis, accurate radiological and clinical evaluation is needed, especially in cases without a defined genetic defect.

The relationship between the hypothalamus-pituitary morphology and the somatotroph responsiveness to maximal provocative tests exploring the GH releasable pool is still unclear. We evaluated the GH-releasing effect of GHRH plus arginine (GHRH plus Arg) in 36 patients with congenital GH deficiency (GHD) according to their pituitary magnetic resonance imaging findings, consisting of anterior pituitary hypoplasia, stalk agenesis (neural and or vascular component), and posterior pituitary ectopia. Seventeen children (12 boys and 5 girls, aged 1--5.2 yr) were evaluated at the time of diagnosis of GHD (mean age, 3.6 +/- 1.4 yr), and 19 adults (13 males and 6 females, aged 15.9-28.6 yr) with childhood-onset GHD were reevaluated after completion of GH treatment (at least 6 months of withdrawal) at a mean age of 20.5 +/- 3.5 yr. Eleven children had isolated GHD, and 6 had multiple pituitary hormone deficiency (MPHD) whereas 7 adults had isolated GHD, and 12 had MPHD. A residual vascular component of the pituitary stalk was visualized in 7 children and 7 adults with isolated GHD, whereas magnetic resonance imaging showed complete pituitary stalk agenesis (both vascular and neural components) in 10 children and 10 adults, including 16 with MPHD (6 children) and 4 children with isolated GHD. In the children, the median peak GH response to GHRH plus Arg (7.6 microg/L; range, 2.4--40.2 microg/L) was significantly higher than that in the adults (1.8 microg/L; range, 0.8--37.4 microg/L; P = 0.0039); it was also significantly higher in the isolated GHD patients (18 microg/L; range, 3.3--40.2 microg/L) than in those with MPHD (1.9 microg/L; range, 0.8--7.6 microg/L; P = 0.00004). In the patients with residual vascular component of the pituitary stalk the median peak GH responses to GHRH plus Arg (19.1 microg/L; range, 1.6--40.2 microg/L) was significantly higher than that in patients with complete pituitary stalk agenesis (2.2 microg/L; range, 0.8--8.8 microg/L; P = 0.00005). There was a trend toward a decrease with age in peak GH response to GHRH plus ARG: Mean serum insulin-like growth factor I (IGF-I) levels were 36 +/- 7.1 microg/L in the children and 63.5 +/- 22.6 microg/L in the adults (P = 0.0001). The mean IGF-I level did not differ between the children with (35.7 +/- 4.8 microg/L) and those without (36.3 +/- 8.7 microg/L) the pituitary stalk; it was much higher in the adults with residual vascular pituitary stalk (81.1 +/- 17.7 microg/L) than in those with complete pituitary stalk agenesis (47.7 +/- 12.5 microg/L; P = 0.0002). The IGF-I level was 36.1 +/- 6.7 microg/L in the isolated GHD children and 36 +/- 8.6 microg/L in those with MPHD; levels were 82.1 +/- 19.4 and 52.7 +/- 16.8 microg/L respectively, in the adults (P = 0.003). In this study we have confirmed that the partial integrity of the hypothalamic pituitary connections is essential for GHRH plus Arg to express its GH-releasing activity and have shown that this provocative test is able to stimulate GH secretion to a greater extent in those patients with GHD, but with a residual vascular component of the pituitary stalk. This test is reliable in the diagnosis of congenital hypopituitarism in both children and adults when associated with complete pituitary stalk agenesis and MPHD. In younger children with congenital GHD but less severe impairment of the pituitary stalk the GH response to GHRH plus Arg may be within the normal range; deterioration of pituitary GH reserve with a GH response of less than 10 microg/L after 20 yr of age makes this test very sensitive in the diagnosis of adult GHD.

Pendred's syndrome is a combination of congenital sensorineural hearing loss and iodine organification defect leading to a positive perchlorate test and goiter. Although it is the commonest form of syndromic hearing loss, the variable clinical presentation contributes to the difficulty in securing a diagnosis. The identification of the disease gene (PDS) prompts the need to reevaluate the syndrome to identify possible clues for the diagnosis. To this purpose, in three Italian families presenting with the clinical features of Pendred's syndrome, the molecular analysis was accompanied by full clinical, biochemical, and radiological examination. A correlation between genotype and phenotype was found in the only patient with enlargement of vestibular aqueduct and endolymphatic duct and sac at magnetic resonance imaging. This subject was a compound heterozygote for a deletion in PDS exon 10 (1197delT, FS400) and a novel insertion in exon 19 (2182-2183insG, Y728X). The present study demonstrates for the first time the value of the combination of clinical/radiological and genetic studies in the diagnosis of Pendred's syndrome. The positivity of a perchlorate discharge test and the malformations of membranous labyrinth fit well with the recent achievements on the role of pendrin in thyroid hormonogenesis and the maintenance of endolymph homeostasis.

Combined pituitary hormone deficiency (CPHD) has been linked with rare abnormalities in genes encoding transcription factors necessary for pituitary development1. We have isolated LHX3, a gene involved in a new syndrome, using a candidate-gene approach developed on the basis of documented pituitary abnormalities of a recessive lethal mutation in mice generated by targeted disruption of Lhx3 (ref. 2). LHX3, encoding a member of the LIM class of homeodomain proteins3, consists of at least six exons located at 9q34. We identified a homozygous LHX3 defect in patients of two unrelated consanguineous families displaying a complete deficit in all but one (adrenocorticotropin) anterior pituitary hormone and a rigid cervical spine leading to limited head rotation. Two of these patients also displayed a severe pituitary hypoplasia, whereas one patient presented secondarily with an enlarged anterior pituitary. These LHX3 mutations consist of a missense mutation (Y116C) in the LIM2 domain at a phylogenetically conserved residue and an intragenic deletion predicting a severely truncated protein lacking the entire homeodomain. These data are consistent with function of LHX3 in the proper development of all anterior pituitary cell types, except corticotropes, and extrapituitary structures.

We describe a mentally retarded 12-year-old girl with ataxia in whom diagnostic evaluation for short stature revealed isolated growth hormone (GH) deficiency and multiple central nervous system (CNS) lesions. Assessment of immunologic status, performed because of the persistence of recurrent respiratory tract infections, showed associated deficiencies of IgG2-IgG4 and specific antibody response; in addition, in vitro lymphocyte response to mitogens was low, in vitro production of interleukin-2 and of IgM was absent, and natural killer activity was decreased. The possibility that association of the CNS lesions, GH deficiency and immune defects could be due to alterations of the neuro-immuno-endocrine network secondary to a disturbance of neurotransmitters induced by precocious CNS damage of a viral or ischemic nature is discussed.

Humoral and cellular immunologic parameters were evaluated in 13 prepuberal cryptorchid boys before, during and 3 months after hCG therapy. Before treatment, all the immunologic parameters were normal except for a higher percentage of T suppressor-cytotoxic cells (CD8+). During therapy, the percentage of CD8+ cells and lymphocyte response to ConA significantly decreased, and returned to the control level after hCG withdrawal. The possible effects of long-term hCG treatment on the immune system remains to be determined.