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Background: Re-testing for GH secretion is needed to confirm the diagnosis of GH deficiency (GHD) after adult height achievement in childhood-onset GHD (COGHD).Aim: To define the cut-off of GH peak after retesting with GH-releasing hormone plus arginine (GHRHarg) in the diagnosis of permanent GHD in COGHD of different etiology.Patients and methods: Eighty-eight COGHD (median age 17.2 y), 29 idiopathic GHD (IGHD), 44 cancer survivors (TGHD) and 15 congenital GHD (CGHD) were enrolled in the study; 54 had isolated GHD (iGHD) and 34 had multiple pituitary hormone deficiencies (MPHD). All were tested with insulin tolerance test (ITT) and GHRHarg. IGHD with a GH response to ITT >= 6 mu g/L were considered true negatives and served as the control group, and patients with a GH response = 6 mu g/L and 42 with GH peak = 6 mu g/L. ROC analysis based on the etiology indicated the best diagnostic accuracy for peak GH cutoffs after GHRHarg of 25.3 mu g/L in CGHD, 15.7 in TGHD, and 13.8 in MPHD, and for IGF-1 SDS at -2.1 in CGHD, -1.5 in TGHD, and -1.9 in MPHD.Conclusions: Our findings indicate that the best cut-off for GH peak after retesting with GHRHarg changes according to the etiology of GHD during the transition age. Based on these results the diagnostic accuracy of GHRHarg remains questionable.

Central adrenal insufficiency (CAI) is a life-threatening condition caused by either pituitary disease (secondary adrenal insufficiency) or impaired hypothalamic function with inadequate CRH production (tertiary adrenal insufficiency). ACTH deficiency may be isolated or, more frequently, occur in conjunction with other pituitary hormone deficiencies and midline defects. Genetic mutations of the TBX19 causing isolated CAI are rare but a number of genes encoding transcription factors involved in hypothalamic-pituitary gland development, as well as other genes including POMC and PC1, are associated with ACTH deficiency. CAI is frequently identified in congenital, malformative, genetic, and epigenetic syndromes as well as in several acquired conditions of different etiologies. The signs and symptoms vary considerably and depend on the age of onset and the number and severity of associated pituitary defects. They may include hypoglycemia, lethargy, apnea, poor feeding, prolonged cholestatic jaundice, jitteriness, seizures, and sepsis in the neonate, or nonspecific signs such as fatigue, hypotension, vomiting and hyponatremia without hyperkalemia in children. The diagnosis of CAI relies on the measurement of morning cortisol concentrations along with dynamic test for cortisol release with different stimulating agents. Early recognition of CAI and its correct management are mandatory in order to avoid both morbidity and mortality in affected neonates, children and adolescents.

Following the increased awareness about the central role of the pediatric age in building bone for life, clinicians face more than ever the necessity of assessing bone health in pediatric subjects at risk for early bone mass derangements or in healthy children, in order to optimize their bone mass accrual and prevent osteoporosis. Although the diagnosis of osteoporosis is not made solely upon bone mineral density measurements during growth, such determination can be very useful in the follow-up of pediatric patients with primary and secondary osteoporosis. The ideal instrument would give information on the mineral content and density of the bone, and on its architecture. It should be able to perform the measurements on the skeletal sites where fractures are more frequent, and it should be minimally invasive, accurate, precise and rapid. Unfortunately, none of the techniques currently utilized fulfills all requirements. In the present review, we focus on the pediatric use of dual-energy X-ray absorptiometry (DXA), quantitative computed tomography (QCT), peripheral QCT (pQCT), and magnetic resonance imaging (MRI), highlighting advantages and limits for their use and providing indications for bone densitometry interpretation and of vertebral fractures diagnosis in pediatric subjects.

Growth hormone (GH) is essential not only for normal growth during childhood, but also for the acquisition of bone mass and muscle strength in both sexes. This process is completed after the achievement of adult height in the phase of transition from adolescence to adulthood. Adolescents with childhood onset GH deficiency (GHD) show reduction of bone mineral density, decrease in lean body mass, increase in fat mass, and deterioration of the lipid profile. For this reason, continuation of GH replacement therapy in the transition age is recommended in all patients with a confirmed diagnosis of GHD. To confirm the diagnosis of GHD, GH treatment should be discontinued for at least 1 month after the attainment of adult height, and the patient should be re-evaluated for GH secretion. Current guidelines indicate that retesting is not required for those with a transcription factor mutation, more than 3 pituitary hormone deficits, or isolated GHD associated with an identified mutation. The key predictors of persistent GHD are its severity, the presence of additional pituitary hormone deficits, low insulin-like growth factor I (IGF-I) concentration, and the presence of structural hypothalamic-pituitary abnormalities Treatment should be initiated with a low dose (0.2-0.5 mg/day s.c.) and then adjusted according to IGF-I concentrations.

PURPOSE: The improvement in survival rates of pediatric patients with brain tumors (BT) has raised questions on the endocrinological, neurocognitive and psychological late effects of long-term survivors. MATERIALS AND METHODS: We retrospectively collected data from 53 children treated at our Institution for BT between 2005-2015 who received psychological and quality of life (QoL) evaluation at a median age of 12.5 years (range,4.7-18) after a median time of 34 months (range,1-152) from diagnosis. Data regarding treatment and Neuro-Endocrinological Sequelae (NES): hypothyroidism, hypoadrenalism, hypogonadism, growth hormone deficiency and diabetes insipidus were analyzed. Fatigue was assessed by Facit-F-Peds-Revised (FACIT). QoL was assessed by Pediatric-Quality-of-Life-Inventory. Psychological assessment was carried out using the Child-Behavior-CheckList. RESULTS: Twenty-one patients received neurosurgery,3 5 patients chemotherapy, 36 patients radiotherapy. Thirty-five patients were NES-free. Four patients developed 1 NES, 12 patients at least 2 NES, 2 patients all 5 NES;t here were no significant differences in terms of FACIT score among these three groups. However the increasing of the number of NES corresponded with worsening of QoL. Fatigue was reported in 25 patients, 7 of them also showed low level of psychosocial and school QoL. The psychological assessment showed clinical levels of emotional distress in 10 children due to increase in anxiety, depression and social problems. CONCLUSIONS: Our preliminary data regarding late effects in childhood BT survivors show that fatigue affects 47% of them. This symptom, not always can be predicted by NES status. QoL was overall good although it worsens with the increase of NES. Further studies will be performed in order to better comprehend the relationship among risk factors and psychosocial outcome.

Objective To investigate the role of T2-DRIVE MRI sequence in the accurate measurement of pituitary stalk (PS) size and the identification of PS abnormalities in patients with hypothalamic–pituitary disorders without the use of gadolinium. Design This was a retrospective study conducted on 242 patients who underwent MRI due to pituitary dysfunction between 2006 and 2015. Among 135 eligible patients, 102 showed eutopic posterior pituitary (PP) gland and 33 showed ‘ectopic’ PP (EPP). Methods Two readers independently measured the size of PS in patients with eutopic PP at the proximal, midpoint and distal levels on pre- and post-contrast T1-weighted as well as T2-DRIVE images; PS visibility was assessed on pre-contrast T1 and T2-DRIVE sequences in those with EPP. The length, height, width and volume of the anterior pituitary (AP), PP height and length and PP area were analyzed. Results Significant agreement between the two readers was obtained for T2-DRIVE PS measurements in patients with ‘eutopic’ PP; a significant difference was demonstrated between the intraclass correlation coefficient calculated on the T2-DRIVE and the T1-pre- and post-contrast sequences. The percentage of PS identified by T2-DRIVE in EPP patients was 72.7% compared to 30.3% of T1 pre-contrast sequences. A significant association was found between the visibility of PS on T2-DRIVE and the height of AP. Conclusion T2-DRIVE sequence is extremely precise and reliable for the evaluation of PS size and the recognition of PS abnormalities; the use of gadolinium-based contrast media does not add significant information and may thus be avoided.

Central diabetes insipidus (CDI) is a complex and heterogeneous clinical syndrome affecting the hypothalamic-neurohypophyseal network and water balance. A recent national surveillance in Denmark showed a prevalence rate of twenty-three CDI patients per 100 000 inhabitants in five years. The differential diagnosis between several presenting conditions with polyuria and polydipsia is puzzling, and the etiological diagnosis of CDI remains a challenge before the identification of an underlying cause. For clinical practice, a timely diagnosis for initiating specific treatment in order to avoid central nervous system damage, additional pituitary defects and the risk of dissemination of germ cell tumor is advisable. Proper etiological diagnosis can be achieved via a series of steps that start with careful clinical observation of several signs and endocrine symptoms and then progress to more sophisticated imaging tools. This review summarizes the best practice and approach for the diagnosis and treatment of patients with CDI.

Magnetic resonance imaging (MRI) has proved to be an essential tool in the assessment of pituitary stalk lesions including lymphocytic infundibulo-hypophysitis, Langerhans cell histiocytosis (LCH), germ cell tumours, nongerminomatous germ cell tumours, pituicytomas and other tumours, metastases from lymphoma or breast cancer, Wegener's hypophysitis, neurosarcoidosis and inflammatory infiltrations by infectious diseases. The diagnosis of lesions determining pituitary stalk thickness is challenging, and the identification of the underlying condition may require a long-term follow-up. Thus, clinicians should readily recognize that, when the diagnosis of central diabetes insipidus has been established, specific MRI sequences should be used in the assessment of the hypothalamic-pituitary region, and whole-brain evaluation is recommended. For clinical practice, a timely diagnosis is advisable to avoid central nervous system damage, pituitary defects and the risk of dissemination of germ cell tumours or organ involvement by LCH. Proper aetiological diagnosis can be achieved via a series of steps that start with careful observation of several neuroimaging predictors and endocrine dysfunction and then progress to more sophisticated and advanced imaging techniques.

ObjectiveIdiopathic early-onset central diabetes insipidus (CDI) might be due to mutations of arginine vasopressin–neurophysin II (AVP–NPII (AVP)) or wolframin (WFS1) genes.Design and methodsSequencing of AVP and WFS1 genes was performed in nine children with CDI, aged between 9 and 68 months, and negative family history for polyuria and polydipsia.ResultsTwo patients carried a mutation in the AVP gene: a heterozygous G-to-T transition at nucleotide position 322 of exon 2 (c.322G>T) resulting in a stop codon at position 108 (p.Glu108X), and a novel deletion from nucleotide 52 to 54 (c.52_54delTCC) producing a deletion of a serine at position 18 (p.Ser18del) of the AVP pre-prohormone signal peptide. A third patient carried two heterozygous mutations in the WFS1 gene localized on different alleles. The first change was A-to-G transition at nucleotide 997 in exon 8 (c.997A>G), resulting in a valine residue at position 333 in place of isoleucine (p.Ile333Val). The second novel mutation was a 3 bp insertion in exon 8, c.2392_2393insACG causing the addition of an aspartate residue at position 797 and the maintenance of the correct open reading frame (p. Asp797_Val798insAsp). While similar WFS1 protein levels were detected in fibroblasts from healthy subjects and from the patient and his parents, a major sensitivity to staurosporine-induced apoptosis was observed in the patient fibroblasts as well as in patients with Wolfram syndrome.ConclusionsEarly-onset CDI is associated with de novo mutations of the AVP gene and with hereditary WFS1 gene changes. These findings have valuable implications for management and genetic counseling.

Magnesium (Mg2+) plays a crucial role in many biological processes especially in the brain, heart and skeletal muscle. Mg2+ homeostasis is regulated by intestinal absorption and renal reabsorption, involving a combination of different epithelial transport pathways. Mutations in any of these transporters result in hypomagnesemia with variable clinical presentations. Among these, CNNM2 is found along the basolateral membrane of distal tubular segments where it is involved in Mg2+ reabsorption. To date, heterozygous mutations in CNNM2 have been associated with a variable phenotype, ranging from isolated hypomagnesemia to intellectual disability and epilepsy. The only homozygous mutation reported so far, is responsible for hypomagnesemia associated with a severe neurological phenotype characterized by refractory epilepsy, microcephaly, severe global developmental delay and intellectual disability. Here, we report the second homozygous CNNM2 mutation (c.1642G > A,p.Val548Met) in a Moroccan patient, presenting with hypomagnesemia and severe epileptic encephalopathy. Thus, we review and discuss the phenotypic spectrum associated with CNNM2 mutations.

Context There is little information on the long-term natural history of Silver-Russell syndrome (SRS). Objective To describe the phenotypes and metabolic status in adults with SRS. Design Clinical and metabolic evaluations in adults with a molecular diagnosis of SRS. Participants Seven patients (aged 18 to 46 years; mean age, 26.9 years) were studied. Two had chromosome 7 maternal uniparental disomy, three had 11p15 loss of methylation, and two had 11p15 duplication. Setting Single tertiary university center. Main outcome measures Netchine-Harbison (NH) clinical score, oral glucose tolerance test, lipid profiles, bone mineral density (BMD; lumbar spine at L1 to L4 and total body), lean body mass (LBM), absolute fat mass (kg), fat mass percentage, fat mass index (FMI), and trunk/limb fat ratio were evaluated. Results The NH score declined in all but two patients during adulthood, and all patients but one displayed relative macrocephaly. Two patients were underweight, four patients had a normal body mass index, and one was obese. Two patients had glucose intolerance and hyperinsulinemia; two showed a high total cholesterol level with low high-density lipoprotein (HDL) cholesterol levels. BMD was within the normal range, whereas a high fat mass percentage, FMI, and trunk/limb fat ratio and a low LBM were found. The trunk/limb fat ratio showed an inverse relation with HDL cholesterol levels. Conclusions The diagnosis of SRS seems to be reliable in adults, although some clinical signs become less pronounced with age. Glucose, lipids, and body composition should be monitored over time.

Growth hormone (GH) is essential not only for normal growth during childhood, but also for the acquisition of bone mass and muscle strength in both sexes. This process is completed after the achievement of adult height in the phase of transition from adolescence to adulthood. Adolescents with childhood onset GH deficiency (GHD) show reduction of bone mineral density, decrease in lean body mass, increase in fat mass, and deterioration of the lipid profile. For this reason, continuation of GH replacement therapy in the transition age is recommended in all patients with a confirmed diagnosis of GHD. To confirm the diagnosis of GHD, GH treatment should be discontinued for at least 1 month after the attainment of adult height, and the patient should be re-evaluated for GH secretion. Current guidelines indicate that retesting is not required for those with a transcription factor mutation, more than 3 pituitary hormone deficits, or isolated GHD associated with an identified mutation. The key predictors of persistent GHD are its severity, the presence of additional pituitary hormone deficits, low insulin-like growth factor I (IGF-I) concentration, and the presence of structural hypothalamic-pituitary abnormalities Treatment should be initiated with a low dose (0.2-0.5 mg/day s.c.) and then adjusted according to IGF-I concentrations.

Neonatal severe primary hyperparathyroidism (NSHPT) is a rare autosomal recessive disorder of calcium homeostasis, characterized by striking hyperparathyroidism, marked hypercalcemia and hyperparathyroid bone disease. We report the case of a newborn with a novel homozygous mutation of the CaSR, treated by successful subtotal parathyroidectomy, who had an acute presentation of the disease, i.e. out-of hospital cardiorespiratory arrest. .A 8-day-old female newborn was admitted to the NICU of University of Bari "Aldo Moro" (Italy) after a cardiorespiratory arrest occurred at home. Severe hypercalcemia was found and different drug therapies were employed (Furosemide, Cinacalcet and bisphosphonate), as well as hyperhydration, until subtotal parathyroidectomy, was performed at day 32. Our patient's mutation was never described before so that a strict and individualized long-term follow-up was started.This case of NSHPT suggests that a near-miss event, labelled as a possible case of SIDS, could also be due to severe hypercalcemia and evidentiates the difficulties of the neonatal management of NSHPT. Furthermore, the identification of the specific CaSR mutation provides the substrate for prenatal diagnosis.

Purpose Female survivors of childhood, adolescent, and young adult (CAYA) cancer who were treated with alkylating agents and/or radiation, with potential exposure of the ovaries, have an increased risk of premature ovarian insufficiency (POI). Clinical practice guidelines can facilitate these survivors’ access to optimal treatment of late effects that may improve health and quality of survival; however, surveillance recommendations vary among the existing long-term follow-up guidelines, which impedes the implementation of screening. Patients and Methods The present guideline was developed by using an evidence-based approach and summarizes harmonized POI surveillance recommendations for female survivors of CAYA cancer who were diagnosed at age < 25 years. The recommendations were formulated by an international multidisciplinary panel and graded according to the strength of the evidence and the potential benefit gained from early detection and intervention. The harmonized POI surveillance recommendations were developed by using a transparent process and are intended to facilitate care for survivors of CAYA cancer. Results and Conclusion The harmonized set of POI surveillance recommendations is intended to be scientifically rigorous, to positively influence health outcomes, and to facilitate the care for female survivors of CAYA cancer.

ObjectiveThe diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents.DesignRetrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests.MethodsSeventy four patients with organic GHD (GH peak 10μg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS.ResultsThe optimal GH cut-off for arginine resulted 6.5μg/L, 5.1μg/L for ITT and 6.8μg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity.ConclusionsThe results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

Magnetic resonance imaging (MRI) is the radiological examination method of choice for evaluating hypothalamo-pituitary-related endocrine disease and is considered essential in the assessment of patients with suspected hypothalamo-pituitary pathology. Physicians involved in the care of such patients have, in MRI, a valuable tool that can aid them in determining the pathogenesis of their patients' underlying pituitary conditions. Indeed, the use of MRI has led to an enormous increase in our knowledge of pituitary morphology, improving, in particular, the differential diagnosis of hypopituitarism. Specifically, MRI allows detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI recognition of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding in the diagnosis and understanding of certain forms of 'idiopathic' and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient's endocrine profile. Indeed, several trends have emerged and have been confirmed: (i) a normal MRI or anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement; (ii) patients with multiple pituitary hormone deficiencies (MPHD) seldom show a normal pituitary gland; and (iii) the classic triad of ectopic posterior pituitary, pituitary stalk hypoplasia/agenesis and anterior pituitary hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have also been reported in patients with hypopituitarism carrying mutations in several genes encoding transcription factors. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Going forward, neuroimaging techniques are expected to progressively expand and improve our knowledge and understanding of pituitary diseases.

Few studies have addressed the diagnostic role of the glucagon test in children with suspected GH deficiency (GHD).The objective of the study was to investigate the diagnostic value of the glucagon test as an alternative test to insulin tolerance test (ITT) and arginine in GHD children younger than 6 yr.This study was conducted in two pediatric endocrinology centers.Forty-eight children (median age 4.2 yr, median height -3.0 sd score) with GHD confirmed by a peak GH to ITT and arginine less than 10 microg/liter (median 4.7 and 3.4 microg/liter, respectively) underwent a glucagon stimulation test. Magnetic resonance imaging showed normal hypothalamic-pituitary anatomy in 24 children, isolated anterior pituitary hypoplasia in seven, and structural hypothalamic-pituitary abnormalities in 17.Median GH peak response to glucagon (13.5 microg/liter) was significantly higher than that observed after ITT and arginine (P0.0001). GH peak after glucagon was less than 10 microg/liter in 20 subjects (group 1) and greater than 10 microg/liter in 28 subjects (group 2) without significant clinical or biochemical differences between the two groups. Median GH peak after glucagon was similar between patients with multiple pituitary hormone deficiency and those with isolated GHD and between subjects with and without structural hypothalamic-pituitary abnormalities. The magnitude of the GH peak after glucagon was negatively correlated to age at diagnosis (rho = -0.636, P0.0001).This study shows that glucagon has an effective GH-releasing activity and can be used to evaluate somatotroph function in young children with short stature. Normative data for this test in young children need to be established before its use in clinical practice.

Lo studio dell’ipotalamo-ipofisi e fondamentale per la diagnosi delle patologie endocrine. La risonanza magnetica e la modalita d’elezione per valutare la morfologia ipotalamo-ipofisaria. Con l’avvento della biologia molecolare e delle tecniche di neuroimmagine e stato dimostrato che le differenze della morfologia ipofisaria alla RMN sono l’espressione di una gamma di patologie dell’adenoipofisi con prognosi diversa.

Introduction The availability of pediatric age- and sex-matched reference curves for bone markers is essential for appropriate assessment of bone turnover and treatment follow-up of bone disorders. The aim of this work was to obtain updated reference equations for collagen type I C-telopeptides (CTX-1) and bone alkaline phosphatase (BAP) by using an alternative statistical approach. The study included 1502 Italian pediatric subjects from 6 months to 16 years of age (686 females and 816 males) subjected to CTX-1 and BAP measurement during a six-year period. Methods The unselected population of patients was used for the calculation of age- and sex-matched reference curves by using a multivariate statistical analysis after an appropriate validation with a selected population of 184 healthy subjects (6 months-16 years; 88 females and 96 males). The effect of age, sex, puberty based on Tanner stage evaluation and anthropometrics on the variations of the two bone markers was then studied. Results Pediatric reference curves were obtained for CTX-1 and BAP from 3465 results retrieved by our Laboratory Information System. The equations for the calculation of reference values were obtained for boys and girls. The two bone markers markedly varied according to age, sex and pubertal stage with females displaying higher values during Tanner stages II and III and males during stages III and IV. Conclusions The application of a novel statistical approach provided reference curves for CTX-1 and BAP. This method, moreover, could be applied in pediatrics to obtain reference intervals for other biomarkers.

Background The efficacy and safety of various modes of medical treatment for primary hyperparathyroidism in pregnancy are largely unknown. Case presentation We report the case of a 34-year-old white woman with primary hyperparathyroidism symptomatic for nephrolithiasis. Her serum calcium was 3.15 mmol/l and parathyroid hormone was 109.0 ng/L. Neck imaging found no pathological parathyroid tissue. Cinacalcet and cholecalciferol were started. She became pregnant 17 months later. The calcimimetic was stopped. During pregnancy, she was admitted for hydration administered intravenously two to three times per week. In her 24th week of pregnancy, cinacalcet was restarted. In her 32nd week, a cesarean section was carried out as planned. Conclusions Only three cases of primary hyperparathyroidism in women on cinacalcet therapy in pregnancy have been published in the literature. In the present case, hydration was useful in controlling serum calcium. Cinacalcet therapy helped to control serum calcium.

MRI imaging is the technique of choice in the diagnosis of children with hypopituitarism. Marked differences in MRI pituitary gland morphology suggest different etiologies of growth hormone deficiency (GHD) and different prognoses. Pituitary stalk agenesis and ectopic posterior pituitary (EPP) are specific markers of permanent GHD, and patients with these MRI findings show a different clinical and endocrine outcome compared to those with isolated hypoplastic pituitary or normal pituitary anatomy. T2 DRIVE images aid in the identification of the pituitary stalk without the use of contrast medium administration. Future developments in imaging techniques will undoubtedly reveal additional insights. Mutations in a number of genes have been associated with pituitary dysfunction and abnormal pituitary gland development; the correlation of genetic mutations to endocrine and MRI phenotypes has improved our knowledge of pituitary development.

Context: The current criteria for definition of partial GHD in young adults are still a subject of debate. Objectives: The objective of the study was to reinvestigate anterior pituitary function in young adults with congenital childhood-onset GHD associated with structural hypothalamic-pituitary abnormalities and normal GH response at the time of first reassessment of GH secretion. Design and Setting: This was a prospective explorative study conducted in a university research hospital. Patients and Methods: Thirteen subjects with a mean age of 17.2 ± 0.7 yr and a peak GH after insulin tolerance test (ITT) higher than 5 μg/liter were recruited from a cohort of 42 patients with childhood-onset GHD and ectopic posterior pituitary at magnetic resonance imaging. GH secretion after ITT and GHRH plus arginine, IGF-I concentration, and body mass index, waist circumference, blood pressure, total cholesterol, and fibrinogen were evaluated at baseline and at 2-yr follow-up. Results: At mean age of 19.2 ± 0.7 yr, the mean peak GH response decreased significantly after ITT (P = 0.00001) and GHRH plus arginine (P = 0.0001). GH peak values after ITT and GHRH plus arginine were less than 5 and 9 μg/liter in 10 and eight patients, respectively. Additional pituitary defects were documented in eight patients. Significant changes were found in the values of IGF-I sd score (P = 0.0026), waist circumference (P = 0.00001), serum total cholesterol (P = 0.00001), and serum fibrinogen (P = 0.0004). Conclusions: The results of this study underline the importance of further reassessment of pituitary function in young adults with GHD of childhood-onset and poststimulation GH responses suggestive of partial GHD.

Background: In past decades, our understanding of the vasopressin-mediated renal concentration mechanism has improved considerably due to the discovery of new endocrine-related neurotransmitters and the elucidation of the roles of crucial molecular players in this process. The identification of disease-causing genes in hereditary disorders of water balance has been extremely helpful in identifying these pivotal molecules. Acquired diseases, however, are the most frequent causes of impaired water homeostasis. Diagnosis: The clinical and biochemical diagnosis of hormonal deficit is confirmed by standard laboratory tests, but recent advances in imaging techniques have shed new light on the pathophysiology of many of these diseases. Management: Magnetic resonance imaging (MRI) permits identification of the posterior pituitary in vivo and can clearly delineate the shape, size and enhancement pattern of the pituitary stalk, as well as its functional integrity. Thickening of the pituitary stalk is a common finding on MRI scans in several pituitary stalk pathologies, but it is not specific to any single pathological subtype. However, biopsy of an enlarged pituitary stalk should be reserved for selected patients with hypothalamic-pituitary mass or with progressive thickening of the pituitary stalk.

Context: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported.Objectives: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD.Design and Setting: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit.Patients and Methods: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 μg/liter after an insulin tolerance test or peak GH levels less than 5 μg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal.Results: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis.Conclusions: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.

The accurate analysis of the hypothalamic-pituitary area is essential in the diagnosis of endocrine-related diseases. High-quality magnetic resonance imaging represents the examination modality of choice in the evaluation of hypothalamic-pituitary morphology. Indeed, the advent of molecular biology and neuroimaging techniques has led to significant progress in the understanding of the pathogenesis of disorders affecting the pituitary gland, specifically by demonstrating a clear phenotype-genotype relationship. Animal studies, along with the correlation of a particular genetic profile to certain endocrine and magnetic resonance imaging phenotypes in humans, have yielded great insights into pituitary development. Today, there is convincing evidence to support the hypothesis that marked magnetic resonance imaging differences in pituitary morphology indicate a variety of disorders that affect anterior pituitary gland organogenesis and function with a variety of diverse prognoses.

Central diabetes insipidus (CDI) has been linked to vascular central nervous system damage, although the pathophysiology of the mechanism has never been perfectly understood. Indeed, the vascular system of human pituitary gland has rarely been the subject of rigorous investigation except at postmortem. Recently, studies of pituitary gland blood supply have been carried out by means of a time evaluation of pituitary gland enhancement with noninvasive dynamic magnetic resonance (MR) imaging after contrast medium injection. In the present study, we decided to investigate the status of posterior pituitary blood supply by evaluating vascular pituitary patterns in a group of 19 patients with idiopathic CDI in whom previous standard MR imaging had failed to identify causal specific lesions. The control group was composed of 55 subjects with a median age of 12 yr (range, 4.2–17 yr) who had idiopathic isolated GH deficiency and normal pituitary morphology and 15 young adults (18–25 yr) who had normal pituitary gland and no endocrine dysfunction. Nineteen patients (12 females and seven males), ranging in age at the time of diagnosis of CDI from 0.5–14.9 yr (median, 5 yr), were examined with dynamic MR imaging between 1990 and 1997 at a median age of 14.1 yr (range, 5.0–26.3 yr). CDI was diagnosed according to clinical findings of polyuria and polydipsia, water deprivation test, and desmopressin acetate therapeutic trial. All of the patients had permanent CDI and were being treated with satisfactory results with desmopressin, two to three times daily, either intranasally or orally. The previous MR imaging findings of the 19 CDI patients had shown the absence of posterior pituitary hyperintensity, normal pituitary stalk, and normal anterior pituitary size. Enhancement of the straight sinus, representing a temporal reference point and occurring in normal subjects simultaneously to that of the posterior pituitary gland, was observed in all subjects after iv gadopentetate dimeglumine administration, with no substantial differences between patients and controls. However, the enhancement of the posterior pituitary lobe occurred simultaneously with the enhancement of the straight sinus in all of the controls but in only 14 of the 19 patients with CDI. In the remaining five patients, the enhancement of the straight sinus was not associated with the expected contrast enhancement of the posterior pituitary gland, suggesting abnormal blood supply to the posterior pituitary lobe. This is in keeping with vascular impairment of the inferior hypophyseal artery system and suggests that abnormal blood supply to the posterior pituitary gland is associated with what, until now, has been considered idiopathic CDI.

Central diabetes insipidus (CDI) is considered idiopathic in 20% to 50% of affected subjects.The purpose of this study was to determine whether a systematic diagnostic workup could achieve better etiologic diagnosis in children and adolescents presenting with polyuria and polydipsia.This is a prospective study conducted at a tertiary referral center. Patients underwent clinical and endocrine evaluations every 6 months and neuroimaging every 6 months for 2 years and yearly for 3 years. Endocrine function and neuroimaging were also reassessed after adult height achievement.A total of 85 consecutive patients with CDI were enrolled at a median age of 7.5 years; those with idiopathic CDI were stratified based on pituitary stalk thickness.To establish the etiology of CDI, we determined the time lag between its onset and the specific diagnosis, the long-term impact on pituitary function, and the overall long-term outcomes.Of the subjects, 24 (28.2%) received an etiologic diagnosis at presentation and 11 (13%) within 2.5 years (n = 7 germinomas and n = 4 Langerhans cell histiocytosis), 7 (8.2%) were lost to follow-up, and 43 (50.6%) were considered to have idiopathic disease and were followed until the median age of 17.3 years. Neuroimaging identified 40 of 43 patients with self-limited inflammatory/autoimmune pituitary stalk thickness within the first 6 months, the severity of which was significantly correlated to pituitary dysfunction. The probability of10-year-survival without an anterior pituitary defect was related to the severity of pituitary stalk thickness, and 53% showed permanent anterior pituitary defects. Three patients developed Langerhans cell histiocytosis and 1 developed Hodgkin lymphoma after a median of 9 and 13 years, respectively.A diagnostic etiology was achieved in 96% of patients with CDI. Risk stratification based on the degree of pituitary stalk thickness is of prognostic value for long-term outcomes including permanent pituitary dysfunction. New guidance is provided for the management of these patients.

Magnetic resonance imaging (MRI) allows a detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. The identification of posterior pituitary hyperintensity, now considered a marker of neurohypophyseal functional integrity, has been the most striking advance for the diagnosis and understanding of anterior and posterior pituitary diseases. The advent of MRI has in fact led to a significant improvement in the understanding of the pathogenesis of disorders that affect the hypothalamo-pituitary area. Today, there is convincing evidence to support the hypothesis that marked MRI differences in pituitary morphology indicate a diverse range of disorders which affect the organogenesis and function of the anterior pituitary gland with different prognoses. Furthermore, the association of extrapituitary malformations accurately defined by MRI has supported a better definition of several conditions linked to pituitary hormone deficiencies and midline defects. MRI is a very informative procedure that should be used to support a diagnosis of hypopituitarism. It is useful in clinical management, because it helps endocrinologists determine which patients to target for further molecular studies and genetic counselling, which ones to screen for additional hormone deficits, and which ones may need growth hormone replacement into adult life.

Objective Plasma total Adiponectin (tAN) is a novel biomarker with interesting potentialities in pediatrics. Age-related intervals are needed for the correct interpretation of results. In this study, we calculated the reference values for tAN using a large number of results derived from pediatric patients. Design and methods tAN was determined by ELISA in more than 4000 samples and the results collected in the Laboratory Information System were used for the calculation of reference intervals. Results tAN reference values for the different age intervals were obtained and age related tAN reference intervals were calculated. Some differences were observed in males and females. In obese children, no correlation between age and tAN could be observed. On the contrary, significant relations were observed in the total group of patients and in healthy control subjects. For this reason, the parameters of the equations to calculate tAN reference values using age as a continuous variable were defined. Conclusion The use of continuous tAN reference intervals, calculated on age, should be considered a useful laboratory tool, at least in the pediatric population, for those biomarkers whose reference values have been shown to change from birth to the late adolescence.

SummaryObjective It is still not known whether fat mass excess could exert a positive effect on bone. The aim of our study was to evaluate bone strength and quality in a group of overweight and obese children and adolescents by assessing bone geometry at metacarpal bones and ultrasound at phalangeal level. Design and patients This is a cross sectional observational study performed in 123 subjects, aged 11·2 ± 2·9 years. Measurements Digitalized X-rays were evaluated at the level of the 2nd metacarpal bone for the determination of the outer (D) and inner (d) diameter, cortical area (CA), medullary endocortical area (EA), metacarpal index (MI) and bone strength (Bending Breaking Resistance Index; BBRI). A total of 98 subjects underwent amplitude dependent speed of sound (Ad-SOS) and bone transmission time (BTT) assessment by phalangeal ultrasonography. Results SDs for each measured parameter were as follows: Males: D = −0·71 ± 0·95, d = −0·29 ± 0·86, CA = −0·69 ± 0·69, EA = −0·32 ± 0·79, Ad-SOS = −1·14 ± 0·91, BTT = −1·17 ± 1·11 and BBRI (417 ± 151 vs 495 ± 174 mm3) were all significantly lower than in controls (P

Magnetic resonance imaging (MRI) allows a detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. The identification of posterior pituitary hyperintensity, now considered a marker of neurohypophyseal functional integrity, has been the most striking advance for the diagnosis and understanding of anterior and posterior pituitary diseases. The advent of MRI has in fact led to a significant improvement in the understanding of the pathogenesis of disorders that affect the hypothalamo-pituitary area. Today, there is convincing evidence to support the hypothesis that marked MRI differences in pituitary morphology indicate a diverse range of disorders which affect the organogenesis and function of the anterior pituitary gland with different prognoses. Furthermore, the association of extrapituitary malformations accurately defined by MRI has supported a better definition of several conditions linked to pituitary hormone deficiencies and midline defects. MRI is a very informative procedure that should be used to support a diagnosis of hypopituitarism. It is useful in clinical management, because it helps endocrinologists determine which patients to target for further molecular studies and genetic counselling, which ones to screen for additional hormone deficits, and which ones may need growth hormone replacement into adult life.

The 19q13 microdeletion syndrome is a recently identified disorder of which very few cases have been reported so far. Growth deficiency, microcephaly, ectodermal anomalies and intellectual disability are the major features reported in all the described cases. The critical region has been estimated to span 750 Kb. We report an Italian patient carrying a de novo 1.37 Mb deletion in chromosome 19q13, who presented all the cardinal features of the syndrome, and multiple pituitary hormone deficiency. Our findings might contribute to further refine the critical region to 460 Kb and restrict the list of candidate genes.

Magnetic resonance imaging (MRI) is the radiological examination method of choice for evaluating hypothalamo-pituitary-related endocrine disease and is considered essential in the assessment of patients with suspected hypothalamo-pituitary pathology. Physicians involved in the care of such patients have, in MRI, a valuable tool that can aid them in determining the pathogenesis of their patients' underlying pituitary conditions. Indeed, the use of MRI has led to an enormous increase in our knowledge of pituitary morphology, improving, in particular, the differential diagnosis of hypopituitarism. Specifically, MRI allows detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. MRI recognition of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding in the diagnosis and understanding of certain forms of 'idiopathic' and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient's endocrine profile. Indeed, several trends have emerged and have been confirmed: (i) a normal MRI or anterior pituitary hypoplasia generally indicates isolated growth hormone deficiency that is mostly transient and resolves upon adult height achievement; (ii) patients with multiple pituitary hormone deficiencies (MPHD) seldom show a normal pituitary gland; and (iii) the classic triad of ectopic posterior pituitary, pituitary stalk hypoplasia/agenesis and anterior pituitary hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have also been reported in patients with hypopituitarism carrying mutations in several genes encoding transcription factors. Establishing endocrine and MRI phenotypes is extremely useful for the selection and management of patients with hypopituitarism, both in terms of possible genetic counselling and in the early diagnosis of evolving anterior pituitary hormone deficiencies. Going forward, neuroimaging techniques are expected to progressively expand and improve our knowledge and understanding of pituitary diseases.

To obtain longitudinal data on growth/puberty in a large-scale, multi-national prospective cohort of juvenile systemic lupus erythematosus (SLE).Data from 331/557 (59.4%) patients ≤18 years old with juvenile SLE in active phase, with anthropometric data available at four follow-up visits, were studied.There was a significant reduction in parent-adjusted height z score with time in females and males (p0.0001), with a significant gender difference (p0.0001) and with male height being most affected. Median body mass index z score peaked at 6 months and was still significantly above baseline after 26 months (p0.01), with no gender difference. Standardised height reduction was inversely related to age at onset. Females with onset age12 years had a median parent-adjusted height z score of -0.87 with no catch-up growth. At the end of the study, growth failure was seen in 14.7% of the females and 24.5% of the males. Height deflection (less than -0.25/year) was found in 20.7% of the females and 45.5% of the males. Delayed pubertal onset was seen in 15.3% and 24% of the females and males, respectively, and delayed/absent menarche was seen in 21.9%, while 36.1% of the females and 44% of the males had some degree of delayed pubertal development. Growth failure baseline determinants were previous growth failure (OR: 56.6), age at first visit ≤13.4 years (OR: 4.2) and cumulative steroid dose426 mg/kg (OR: 3.6).The children at risk of having a negative effect on height and pubertal development are prepubertal and peripubertal children treated with400 mg/kg cumulative dose of corticosteroids.

Central diabetes insipidus (CDI) is the end result of a number of conditions that affect the hypothalamic-neurohypophyseal system. The known causes include germinoma/craniopharyngioma, Langerhans cell histiocytosis (LCH), local inflammatory, autoimmune or vascular diseases, trauma resulting from surgery or an accident, sarcoidosis, metastases and midline cerebral and cranial malformations. In rare cases, the underlying cause can be genetic defects in vasopressin synthesis that are inherited as autosomal dominant, autosomal recessive or X-linked recessive traits. The diagnosis of the underlying condition is challenging and raises several concerns for patients and parents as it requires long-term follow-up. Proper etiological diagnosis can be achieved via a series of steps that start with clinical observations and then progress to more sophisticated tools. Specifically, MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a clear marker of neurohypophyseal functional integrity, together with the careful analysis of pituitary stalk shape and size, have provided the most striking findings contributing to the diagnosis and understanding of some forms of ‘idiopathic’ CDI. MRI STIR (short-inversion-time inversion recovery sequencing) is a promising technology for the early identification of LCH-dependent CDI.

ObjectiveControversies exist about posterior pituitary (PP) function in subjects with ectopic PP (EPP) and with cerebral midline defects and/or their co-occurrence. We investigate water and electrolyte disturbances in patients at risk for PP dysfunction.DesignThe study was conducted in a single Pediatric Endocrinology Research Unit.MethodsForty-two subjects with childhood-onset GH deficiency were subdivided into five groups: normal magnetic resonance imaging (n=8, group 1); EPP (n=15, group 2); septo-optic dysplasia (SOD) with normal PP (n=4, group 3); EPP and SOD without (n=7, group 4), and with additional midline brain abnormalities (n=8, group 5). At a mean age of 16.0±1.1 years, they underwent a 120 min i.v. infusion with hypertonic 5% saline and evaluation of plasma osmolality (Posm), arginine vasopressin (AVP), thirst score (in groups 1 and 2), and urinary osmolality were performed.ResultsMean Posm and AVP significantly increased from baseline scores (284.7±4.9 mosm/kg and 0.6±0.2 pmol/l) to 120 min after saline infusion (300.5±8.0 mosm/kg and 10.3±3.3 pmol/l, PPConclusionsPatients with midline brain abnormalities and EPP have defective osmoregulated AVP. Patients with EPP and congenital hypopituitarism have normal PP function.

ObjectivePremature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP.Patients and methodsA total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects.ResultsBaseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations.ConclusionIn children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation.

Until the advent of magnetic resonance imaging (MRI), only small advances were made in the field of pituitary imaging. MRI, however, led to an enormous increase in our detailed knowledge of pituitary morphology, thus improving the differential diagnosis of hypopituitarism. Indeed, MRI represents the examination method of choice for evaluating hypothalamic-pituitary-related endocrine diseases thanks to its ability to provide strongly contrasted high-resolution multiplanar and spatial images. Specifically, MRI allows for a detailed and precise anatomical study of the pituitary gland by differentiating between the anterior and posterior pituitary lobes. The MRI identification of pituitary hyperintensity in the posterior part of the sella, now considered a marker of neurohypophyseal functional integrity, has been the most striking finding for the diagnosis and understanding of some forms of “idiopathic” and permanent growth hormone deficiency (GHD). Published data show a number of correlations between pituitary abnormalities as observed on MRI and a patient’s endocrine profile. Indeed, several trends have emerged and have been confirmed: (1) normal MRI or anterior pituitary hypoplasia generally indicates isolated GHD which is transient and not confirmed after adult height achievement; (2) patients with MPHD seldom show a normal pituitary gland; (3) the classic triad of ectopic posterior pituitary gland, pituitary stalk hypoplasia/agenesis, and anterior pituitary gland hypoplasia is more frequently reported in MPHD patients and is generally associated with permanent GHD. Pituitary abnormalities have been reported in patients with GHD carrying mutations in several genes encoding transcription factors such as POU1F1, PROP1, HESX1, LHX3, LHX4, GLI2, PITX1, PITX2, SOX3, SOX2, and OTX2. Establishing endocrine and MRI phenotypes is extremely helpful in the selection and management of patients with hypopituitarism, both in terms of possible genetic counseling, as well as that of early diagnosis of evolving anterior pituitary hormone deficiencies.

The accuracy of the glucagon test in the diagnosis of central adrenal insufficiency in young children has not yet been definitively established.The aim of this study was to investigate the diagnostic accuracy of the glucagon test as an alternative to the insulin tolerance test (ITT) in children with GH deficiency under 6 yr of age.This was a prospective study conducted in two Pediatric Endocrinology Centers.Forty-eight children (median age, 4.2 yr) with GH deficiency confirmed by a peak GH to ITT and arginine less than 10 microg/liter were enrolled: 24 with normal hypothalamic-pituitary anatomy, seven with isolated anterior pituitary hypoplasia, and 17 with structural hypothalamic-pituitary abnormalities at magnetic resonance imaging. Twelve subjects had central adrenal insufficiency defined by a peak cortisol response of less than 20 microg/dl to ITT. All children underwent a glucagon stimulation test with blood sampling for cortisol and glucose (time 0 to 180 min) after the im administration of 30 microg/kg of glucagon.The mean peak cortisol after glucagon was not significantly different from that obtained after ITT in the whole cohort (25.9 vs. 26.0 microg/dl; P = 0.908), and it was significantly reduced in patients with structural hypothalamic-pituitary abnormalities (P0.001). Receiver operating characteristic curve analysis showed that the best diagnostic accuracy was obtained with a peak cortisol cutoff to glucagon of 14.6 microg/dl (sensitivity, 66.67%; specificity, 100%; area under the curve = 0.91; 95% confidence interval, 0.82-0.99). Using this cutoff, 91.67% of the patients were correctly classified.This study shows that glucagon is an accurate and safe diagnostic test for adrenal function in young children who are at risk for adrenal insufficiency.

Context: Considerable evidence indicates that osteoblasts and adipocytes share a common progenitor cell in the bone marrow that is capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation. Objective: The purpose of this study was to examine the relation between bone acquisition and changes in marrow adiposity. Design: This was a longitudinal study. Outcome Measures and Subjects: Computed tomography measurements of femoral cortical bone area (CBA), cross-sectional area (CSA), and marrow density, and dual-energy x-ray absorptiometry (DXA) measurements of total body fat and lean mass (LM) were obtained in 39 healthy females (15–20 yr of age) at baseline and 18–24 months later. Results: Marrow adiposity was inversely related to CBA at baseline and follow-up (r = 0.39 and 0.33; P = 0.015 and 0.039, respectively) but was not associated to CSA (r = 0.19 and 0.17; P = 0.24 and 0.32, respectively). The association between marrow fat and CBA persisted, even after controlling for body mass and DXA values of LM and femoral CSA. Gains in CBA during the course of the study were related to decreases in marrow fat (r = 0.41; P = 0.009), a relation that persisted, even after accounting for changes in bone size. Marrow fat was not associated to anthropometric measures or DXA values of body fat and LM (all r's between −0.15 and 0.19; P > 0.05). Conclusions: Bone acquisition in the appendicular skeleton of healthy young females is inversely related to changes in marrow adiposity. These results provide support for the growing body of evidence indicating an inversely coupled relationship between osteogenesis and adipogenesis in the skeleton.

The 2007 Consensus Statement suggested a peak GH cutoff to insulin tolerance test (ITT) of less than 6 microg/liter in the diagnosis of permanent GH deficiency (GHD) in young adults with childhood-onset GHD (COGHD), although further validation was recommended.The aim of the study was to evaluate the accuracy of ITT, mean 12-h spontaneous nocturnal GH (SNGH), and IGF-I in the definition of permanent GHD.The study was conducted in two Pediatric Endocrinology Centers.ITT, 12-h SNGH, and IGF-I were evaluated as single or combined tests in 79 subjects with COGHD (median age, 18.0 yr). The cohort consisted of 48 subjects with isolated GHD or one additional pituitary defect and normal MRI or anterior pituitary hypoplasia (group LLGHD, low likelihood GHD), and 31 subjects with structural hypothalamic-pituitary abnormalities or multiple pituitary hormone deficiencies (group HLGHD, high likelihood GHD).Receiver operating characteristic analysis showed the best diagnostic accuracy for peak GH cutoffs to ITT of 5.62 microg/liter or less [sensitivity, 77.4%; specificity, 93.8%; area under the curve (AUC) = 0.92], mean 12-h SNGH of 1.20 microg/liter or less (sensitivity, 90.3%; specificity, 89.6%; AUC = 0.93), and IGF-I of -2.83 sd score or less (sensitivity, 80.7%; specificity, 95.7%; AUC = 0.93). Seven patients in group HLGHD showed a peak GH to ITT above 5.62 microg/liter, but a median IGF-I that was significantly lower than that of group LLGHD (-3.30 vs. -0.73 sd score; P = 0.0001). Peak GH to ITT of 3.6 microg/liter or less and arginine of 3.1 microg/liter or less at childhood diagnosis can predict a future permanent GHD condition.The adopted peak GH to ITT below 5.62 microg/liter is an accurate diagnostic cutoff point for HLGHD in young adults with COGHD. In addition, IGF-I is a reliable marker providing information about the severity of GHD. Careful follow-up is required for subjects with discordant ITT and IGF-I results.

While the molecular mechanisms of anterior pituitary development are now better understood than in the past, both in animals and in humans, little is known about the mechanisms regulating posterior pituitary development. The posterior pituitary gland is formed by the evagination of neural tissue from the floor of the third ventricle. It consists of the distal axons of the hypothalamic magnocellular neurones that shape the neurohypophysis. After its downward migration, it is encapsulated together with the ascending ectodermal cells of Rathke's pouch which form the anterior pituitary. By the end of the first trimester, this development is completed and vasopressin and oxytocin can be detected in neurohypophyseal tissue. Abnormal posterior pituitary migration such as the ectopic posterior pituitary lobe appearing at the level of median eminence or along the pituitary stalk have been reported in idiopathic GH deficiency or in subjects with HESX1, LHX4 and SOX3 gene mutations. Another intriguing feature of abnormal posterior pituitary development involves genetic forms of posterior pituitary neurodegeneration that have been reported in autosomal-dominant central diabetes insipidus and Wolfram disease. Defining the phenotype of the posterior pituitary gland can have significant clinical implications for management and counseling, as well as providing considerable insight into normal and abnormal mechanisms of posterior pituitary development in humans.

While the molecular mechanisms of anterior pituitary development are now better understood than in the past, both in animals and in humans, little is known about the mechanisms regulating posterior pi

Background: Studies in the elderly suggest a reciprocal relation between increased marrow adiposity and bone loss, supporting basic research data indicating that osteoblasts and adipocytes share a common progenitor cell. However, whether this relation represents a preferential differentiation of stromal cells from osteoblasts to adipocytes or whether a passive accumulation of fat as bone is lost and marrow space increases with aging is unknown. To address this question and avoid the confounding effect of bone loss, we examined teenagers and young adults. Methods: Using computed tomography, we obtained measurements of bone density and cross-sectional area of the lumbar vertebral bodies and cortical bone area, cross-sectional area, marrow canal area, and fat density in the marrow of the femurs in 255 sexually mature subjects (126 females, 129 males; 15–24.9 yr of age). Additionally, values for total body fat were obtained with dual-energy x-ray absorptiometry. Results: Regardless of gender, reciprocal relations were found between fat density and measures of vertebral bone density and femoral cortical bone area (r = 0.19–0.39; all P values ≤ .03). In contrast, there was no relation between marrow canal area and cortical bone area in the femurs, neither between fat density and the cross-sectional dimensions of the bones. We also found no relation between anthropometric or dual-energy x-ray absorptiometry fat values and measures for marrow fat density. Conclusions: Our results indicate an inverse relation between bone marrow adiposity and the amount of bone in the axial and appendicular skeleton and support the notion of a common progenitor cell capable of mutually exclusive differentiation into the cell lineages responsible for bone and fat formation.

Bone marrow transplantation (BMT) recipients are at risk of bone mass impairment and skeletal morbidity. We investigated bone status with quantitative ultrasound (QUS) technique in children and adolescents with hematological diseases before and after BMT.Phalangeal QUS measures for amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) were obtained in 144 hematological patients (81M, 63F; 11.6+/-5.2 years); forty two were evaluated before BMT and 102 after allogeneic or autologous BMT. Bone parameters were expressed as Z-scores based on age-sex-matched normal controls.Mean BTT Z-score was reduced in subjects after BMT compared to patients before BMT (M, -0.35+/-1.04 vs. 0.70+/-1.11, P0.001; F, -0.60+/-1.23 vs. 0.23+/-1.17, P0.05). Females and males with hormone deficiencies showed reduced BTT Z-scores when compared with subjects without hormone defects (M, -0.52+/-1.0 vs. 0.05+/-1.17, P0.05; F, -0.50+/-1.27 vs. -0.19+/-1.26; P=0.06). AD-SoS and BTT Z-scores were reduced in 15 subjects with fractures and/or avascular osteonecrosis compared to patients without bone events (-1.52+/-1.7 vs. -0.41+/-1.32 and -0.85+/-1.19 vs. -0.10+/-1.18; both Ps0.05). Bone event cumulative incidence was 4 times greater in subjects who suffered from chronic GVHD.Assessment of phalangeal QUS in young BMT survivors points towards impairment of bone status and endocrine dysfunction and chronic GVHD as risk factors of adverse bone events.