Andrea Secco

Idiopathic central diabetes insipidus in children and young adults is commonly associated with vasopressin‐cell antibodies and markers of autoimmunity

Objectives  Autoimmune targeting of hypothalamic‐neurohypophyseal structures in children and young adults with posterior pituitary and anterior pituitary dysfunction, as well as pituitary stalk involvement, are not yet completely understood.

Reassessment of the Growth Hormone Status in Young Adults with Childhood-Onset Growth Hormone Deficiency: Reappraisal of Insulin Tolerance Testing

CONTEXT 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. OBJECTIVE 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. DESIGN AND SETTING The study was conducted in two Pediatric Endocrinology Centers. PATIENTS AND METHODS 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). RESULTS 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. CONCLUSIONS 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.

The Glucagon Test in the Diagnosis of Growth Hormone Deficiency in Children With Short Stature Younger than 6 Years

CONTEXT Few studies have addressed the diagnostic role of the glucagon test in children with suspected GH deficiency (GHD). OBJECTIVE 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. DESIGN AND SETTING This study was conducted in two pediatric endocrinology centers. PATIENTS AND METHODS 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. RESULTS Median GH peak response to glucagon (13.5 microg/liter) was significantly higher than that observed after ITT and arginine (P < 0.0001). 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, P < 0.0001). CONCLUSIONS 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.

The Accuracy of the Glucagon Test Compared to the Insulin Tolerance Test in the Diagnosis of Adrenal Insufficiency in Young Children with Growth Hormone Deficiency

CONTEXT The accuracy of the glucagon test in the diagnosis of central adrenal insufficiency in young children has not yet been definitively established. OBJECTIVE 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. DESIGN AND SETTING This was a prospective study conducted in two Pediatric Endocrinology Centers. PATIENTS AND METHODS 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. RESULTS 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 (P < 0.001). 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. CONCLUSIONS 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.

Quantitative ultrasound detects bone impairment after bone marrow transplantation in children and adolescents affected by hematological diseases

PURPOSE 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. METHODS 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. RESULTS 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, P<0.001; F, -0.60+/-1.23 vs. 0.23+/-1.17, P<0.05). 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, P<0.05; 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 Ps<0.05). Bone event cumulative incidence was 4 times greater in subjects who suffered from chronic GVHD. CONCLUSIONS 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.

Structural Abnormalities in Congenital Growth Hormone Deficiency

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.