TY  - JOUR
AB  - BACKGROUND: Human adverse childhood experiences (ACEs) are associated with various types of mental and physical pathological outcomes in adulthood. Among them, they may present the enlargement of the pituitary gland and have been suggested to be a risk factor for the development of Cushing syndrome. Previously, we showed on outbred CD-1 male mice that chronic pain induced during the weaning time by pharmacological experimental design procedures caused endocrine and metabolic alterations in adulthood, suggestive of human mild hypercortisolism. Specifically, we observed an increase in pituitary glands weight and in adrenocorticotropic hormone (ACTH) expression, associated with the lack of the negative feedback mechanisms exerted by corticosterone that controls proopiomelanocortin- derived ACTH secretion. METHODS: Here, to better understand the phenotype of mice subjected to early-life pain (ELP), their pituitary glands were examined. Mice tissues and plasma hormones measurements were conducted by ELISA assays. Analysis of brain and pituitary gland was performed using anatomic and diffusion-weighted magnetic resonance imaging. Hematoxylin and eosin-stained sections of pituitary glands were also examined. RESULTS: Mice subjected to ELP showed an increase in total body weight, in pituitary ACTH expression and in plasmatic corticosterone levels. Imaging of the pituitary glands revealed a significant increment of their volume without apparent pathological alterations. CONCLUSION: The findings of this study may support the role of ELP as a risk factor for ACTH-dependent hypercortisolism in adulthood associated with an enlarged pituitary gland.
AU  - Dipol, T.*
AU  - Fortuna, A.*
AU  - Morsilli, O.*
AU  - Zecca, V.*
AU  - Singh, T.*
AU  - Palombelli, G.*
AU  - Mattei, F.*
AU  - Favero, V.*
AU  - Candelise, N.*
AU  - Maroccia, Z.*
AU  - Loizzo, A.*
AU  - Rimondini, R.*
AU  - Campana, G.*
AU  - Pellegata, N.S.
AU  - Loizzo, S.*
AU  - Canese, R.*
AU  - Chiodini, I.*
C1  - 74926
C2  - 57747
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Mild chronic post-natal pain induces endocrine and metabolic alterations associated to enlargement in pituitary glands size in adult CD-1 male mice.
JO  - Endocrine
PB  - Springer
PY  - 2025
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - PURPOSE: Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome of endocrine and non-endocrine tumors caused by germline pathogenic variants or genomic rearrangements of the MAX gene. Although MAX variants are predominantly associated with pheochromocytoma-paraganglioma (PPGL) risk, there are a growing number of associated tumors in other organs, including pituitary adenomas. We characterized the clinical presentation of various tumors in an extensive new kindred with a novel germline pathogenic variant of MAX. METHODS: Clinical, genetic, pathological, radiological and hormonal investigations to identify and characterize disease status related to germline MAX gene sequence status. RESULTS: We identified a novel germline pathological variant in exon 4 of the MAX gene, c.228delG, which was predicted to lead to a truncated protein (p.Asn78Thrfs*92). The propositus had developed pituitary gigantism due to a mixed growth hormone-prolactin secreting pituitary macroadenoma, which was controlled after two surgeries, medical therapy and radiotherapy. He subsequently developed bilateral and recurrent pheochromocytomas and following his death, an extra-adrenal myelolipoma was identified that was negative on MAX immunohistochemistry. An extensive history of pheochromocytomas or uncontrolled hypertension was present in the kindred and multiple affected and unaffected carriers of the c.228delG MAX pathogenic variant were characterized. CONCLUSION: We report the first case of pituitary gigantism in association with a pathogenic variant in the MAX gene, and characterize myeloplipoma as a new disease-association in MEN5. Increased awareness of MEN5 as a clinical entity and comprehensive screening of MAX pathogenic variant carriers can help to identify rare disease associations beyond PPGL.
AU  - Haider, A.*
AU  - Sundar, J.*
AU  - Beckers, A.*
AU  - Mohr, H.
AU  - Kasajima, A.*
AU  - Pellegata, N.S.
AU  - Petrossians, P.*
AU  - Daly, A.F.*
C1  - 73370
C2  - 57019
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Expanding the phenotype of multiple endocrine neoplasia type 5 (MEN5): Pituitary gigantism, myelolipoma and familial pheochromocytoma due to a germline pathogenic MAX variant.
JO  - Endocrine
PB  - Springer
PY  - 2025
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - Background: Endocrine disorders are heterogeneous and include a significant number of rare monogenic diseases. Methods: We performed exome sequencing (ES) in 106 children recruited from a single center within the TRANSLATE‑NAMSE project. They were categorized into subgroups: proportionate short stature (PSS), disproportionate short stature (DSS), hypopituitarism (H), differences in sexual development (DSD), syndromic diseases (SD) and others. Results: The overall diagnostic yield was 34.9% (n = 37/106), including 5 patients with variants in candidate genes, which have contributed to collaborations to identify gene-disease associations. The diagnostic yield varied significantly between subgroups: PSS: 16.6% (1/6); DSS: 18.8% (3/16); H: 17.1% (6/35); DSD: 37.5% (3/8); SD: 66.6% (22/33); others: 25% (2/8). Confirmed diagnoses included 75% ultrarare diseases. Three patients harbored more than one disease-causing variant, resulting in dual diagnoses. Conclusions: ES is an effective tool for genetic diagnosis in pediatric patients with complex endocrine diseases. An accurate phenotypic description, including comprehensive endocrine diagnostics, as well as the evaluation of variants in multidisciplinary case conferences involving geneticists, are necessary for personalized diagnostic care. Here, we illustrate the broad spectrum of genetic endocrinopathies that have led to the initiation of specific treatment, surveillance, and family counseling. Graphical Abstract: [Figure not available: see fulltext.].
AU  - Gippert, S.*
AU  - Wagner, M.
AU  - Brunet, T.*
AU  - Berruti, R.*
AU  - Brugger, M.*
AU  - Schwaibold, E.M.C.*
AU  - Haack, T.B.*
AU  - Hoffmann, G.F.*
AU  - Bettendorf, M.*
AU  - Choukair, D.*
C1  - 68807
C2  - 53719
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Exome sequencing (ES) of a pediatric cohort with chronic endocrine diseases: A single-center study (within the framework of the TRANSLATE-NAMSE project).
JO  - Endocrine
PB  - Springer
PY  - 2023
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - Adrenocortical carcinoma (ACC) is a rare, heterogenous and highly malignant disease. Management of ACC is dependent on disease stage with complete surgical resection as the only potentially curative option. However, advanced, un-resectable, metastatic stages and also recurrences often require systemic treatments, which are unfortunately nowadays still unsatisfactory. The scarcity of preclinical models reflecting patient heterogeneities and furthermore drug-resistant phenotypes, has hampered the progress and development of new therapies in recent years. In this review, we provide an overview on the classical models and substantial progress which has been made over the last years in context of this aggressive disease.
AU  - Sigala, S.*
AU  - Rossini, E.*
AU  - Abate, A.*
AU  - Tamburello, M.*
AU  - Bornstein, S.R.
AU  - Hantel, C.
C1  - 65589
C2  - 52389
SP  - 432-437
TI  - An update on adrenocortical cell lines of human origin.
JO  - Endocrine
VL  - 77
IS  - 3
PY  - 2022
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - PURPOSE: Pheochromocytomas and Paragangliomas (PPGL) result in chronic catecholamine excess and serious health complications. A recent study obtained a metabolic signature in plasma from PPGL patients; however, its targeted nature may have generated an incomplete picture and a broader approach could provide additional insights. We aimed to characterize the plasma metabolome of PPGL patients before and after surgery, using an untargeted approach, and to broaden the scope of the investigated metabolic impact of these tumors. DESIGN: A cohort of 36 PPGL patients was investigated. Blood plasma samples were collected before and after surgical tumor removal, in association with clinical and tumor characteristics. METHODS: Plasma samples were analyzed using untargeted nuclear magnetic resonance (NMR) spectroscopy metabolomics. The data were evaluated using a combination of uni- and multi-variate statistical methods. RESULTS: Before surgery, patients with a nonadrenergic tumor could be distinguished from those with an adrenergic tumor based on their metabolic profiles. Tyrosine levels were significantly higher in patients with high compared to those with low BMI. Comparing subgroups of pre-operative samples with their post-operative counterparts, we found a metabolic signature that included ketone bodies, glucose, organic acids, methanol, dimethyl sulfone and amino acids. Three signals with unclear identities were found to be affected. CONCLUSIONS: Our study suggests that the pathways of glucose and ketone body homeostasis are affected in PPGL patients. BMI-related metabolite levels were also found to be altered, potentially linking muscle atrophy to PPGL. At baseline, patient metabolomes could be discriminated based on their catecholamine phenotype.
AU  - Bliziotis, N.G.*
AU  - Kluijtmans, L.A.J.*
AU  - Soto, S.*
AU  - Tinnevelt, G.H.*
AU  - Langton, K.*
AU  - Robledo, M.*
AU  - Pamporaki, C.*
AU  - Engelke, U.F.H.*
AU  - Erlic, Z.*
AU  - Engel, J.*
AU  - Deutschbein, T.*
AU  - Nölting, S.*
AU  - Prejbisz, A.*
AU  - Richter, S.*
AU  - Prehn, C.
AU  - Adamski, J.
AU  - Januszewicz, A.*
AU  - Reincke, M.*
AU  - Fassnacht, M.*
AU  - Eisenhofer, G.*
AU  - Beuschlein, F.*
AU  - Kroiss, M.*
AU  - Wevers, R.A.*
AU  - Jansen, J.J.*
AU  - Deinum, J.*
AU  - Timmers, H.J.L.M.*
AU  - Adamski, J.*
C1  - 63041
C2  - 51227
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Pre- versus post-operative untargeted plasma nuclear magnetic resonance spectroscopy metabolomics of pheochromocytoma and paraganglioma.
JO  - Endocrine
PB  - Springer
PY  - 2021
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - Selenoprotein P (SELENOP) has been previously related to various metabolic traits with partially conflicting results. The identification of SELENOP-associated metabolites, using an untargeted metabolomics approach, may provide novel biological insights relevant to disentangle the role of SELENOP in human health.In this cross-sectional study, 572 serum metabolites were identified by comparing the obtained LC-MS/MS spectra with spectra stored in Metabolon's spectra library. Serum SELENOP levels were measured in 832 men and women using an ELISA kit.Circulating SELENOP levels were associated with 24 out of 572 metabolites after accounting for the number of independent dimensions in the metabolomics data, including inverse associations with alanine, glutamate, leucine, isoleucine and valine, an unknown compound X-12063, urate and the peptides gamma-glutamyl-leucine, and N-acetylcarnosine. Positive associations were observed between SELENOP and several lipid compounds. Of the identified metabolites, each standard deviation increase in the branched-chain amino acids (isoleucine, leucine, valine), alanine and gamma-glutamyl-leucine was related to higher odds of having T2DM [OR (95% CI): 1.96 (1.41-2.73); 1.62 (1.15-2.28); 1.94 (1.45-2.60), 1.57 (1.17-2.11), and 1.52 (1.13-2.05), respectively].Higher serum SELENOP levels were associated with an overall healthy metabolomics profile, which may provide further insights into potential mechanisms of SELENOP-associated metabolic disorders.
AU  - di Giuseppe, R.*
AU  - Koch, M.*
AU  - Nöthlings, U.*
AU  - Kastenmüller, G.
AU  - Artati, A.
AU  - Adamski, J.
AU  - Jacobs, G.*
AU  - Lieb, W.*
C1  - 54770
C2  - 45814
CY  - 233 Spring St, New York, Ny 10013 Usa
SP  - 486-495
TI  - Metabolomics signature associated with circulating serum selenoprotein P levels.
JO  - Endocrine
VL  - 64
IS  - 3
PB  - Springer
PY  - 2019
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - MEN1 is the main gene responsible for tumorigenesis of syndromic and sporadic primary hyperparathyroidism (PHPT). Germline mutations of the CDKN1B/p27(Kip) gene have been associated with multiple endocrine tumors in rats and humans. To evaluate the involvement of the CDKN1B gene and its relationship with MEN1 in sporadic PHPT, we carried out sequencing and loss of heterozygosity analyses of the CDKN1B gene in 147 sporadic parathyroid adenomas. p27 immunohistochemistry and genetic screening of the MEN1 gene were performed in 50 cases. Three germline CDKN1B variants (c.-80C>T, c.-29_-26delAGAG, c.397C>A) were identified in 3/147 patients. Reduction of CDKN1B gene transcription rate was demonstrated in vitro for the novel c.-80C>T and the c.-29_-26delAGAG variants. Loss of p27 expression was detected in the tumor carrying the c.-29_-26delAGAG variant. Two tumors carrying the CDKN1B variants also harbored a MEN1 mutation. Fifty-four percent of 50 CDKN1B mutation-negative tumors had a reduction of p27 nuclear staining. Somatic MEN1 mutations, identified in 15/50 samples, significantly segregated in tumors negative for nuclear and cytoplasmic p27 staining. The germline nature of the CDKN1B mutations suggests that they might predispose to PHPT. The lack of somatic CDKN1B mutations in our samples points to a rare involvement in parathyroid adenomas, despite the frequent loss of nuclear p27 expression. MEN1 biallelic inactivation seems to be directly related to down-regulation of p27 expression through the inhibition of CDKN1B gene transcription.
AU  - Borsari, S.*
AU  - Pardi, E.*
AU  - Pellegata, N.S.
AU  - Lee, M.S.
AU  - Saponaro, F.*
AU  - Torregrossa, L.*
AU  - Basolo, F.*
AU  - Paltrinieri, E.*
AU  - Zatelli, M.C.*
AU  - Materazzi, G.*
AU  - Miccoli, P.*
AU  - Marcocci, C.*
AU  - Cetani, F.*
C1  - 48244
C2  - 41013
CY  - New York
SP  - 386-397
TI  - Loss of p27 expression is associated with MEN1 gene mutations in sporadic parathyroid adenomas.
JO  - Endocrine
VL  - 55
IS  - 2
PB  - Springer
PY  - 2017
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - Exercise as a key prevention strategy for diabetes and obesity is commonly accepted and recommended throughout the world. Unfortunately, not all individuals profit to the same extent, some exhibit exercise resistance. This phenomenon of non-response to exercise is found for several endpoints, including glucose tolerance and insulin sensitivity. Since these non-responders are of notable quantity, there is the need to understand the underlying mechanisms and to identify predictors of response. This displays the basis to develop personalized training intervention regimes. In this review, we summarize the current knowledge on response variability, with focus on human studies and improvement of glucose homeostasis as outcome.
AU  - Böhm, A.
AU  - Weigert, C.
AU  - Staiger, H.
AU  - Häring, H.-U.
C1  - 47860
C2  - 39604
CY  - New York
SP  - 390-401
TI  - Exercise and diabetes: Relevance and causes for response variability.
JO  - Endocrine
VL  - 51
IS  - 3
PB  - Springer
PY  - 2016
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - X-linked acro-gigantism (X-LAG) syndrome is a newly described disease caused by microduplications on chromosome Xq26.3 leading to copy number gain of GPR101. We describe the clinical progress of a sporadic male X-LAG syndrome patient with an Xq26.3 microduplication, highlighting the aggressive natural history of pituitary tumor growth in the absence of treatment. The patient first presented elsewhere aged 5 years 8 months with a history of excessive growth for >2 years. His height was 163 cm, his weight was 36 kg, and he had markedly elevated GH and IGF-1. MRI showed a non-invasive sellar mass measuring 32.5 × 23.9 × 29.1 mm. Treatment was declined and the family was lost to follow-up. At the age of 10 years and 7 months, he presented again with headaches, seizures, and visual disturbance. His height had increased to 197 cm. MRI showed an invasive mass measuring 56.2 × 58.1 × 45.0 mm, with compression of optic chiasma, bilateral cavernous sinus invasion, and hydrocephalus. His thyrotrope, corticotrope, and gonadotrope axes were deficient. Surgery, somatostatin analogs, and cabergoline did not control vertical growth and pegvisomant was added, although vertical growth continues (currently 207 cm at 11 years 7 months of age). X-LAG syndrome is a new genomic disorder in which early-onset pituitary tumorigenesis can lead to marked overgrowth and gigantism. This case illustrates the aggressive nature of tumor evolution and the challenging clinical management in X-LAG syndrome.
AU  - Naves, L.A.*
AU  - Daly, A.F.*
AU  - Dias, L.A.*
AU  - Yuan, B.*
AU  - Zakir, J.C.*
AU  - Barra, G.B.*
AU  - Palmeira, L.*
AU  - Villa, C.*
AU  - Trivellin, G.*
AU  - Júnior, A.J.*
AU  - Neto, F.F.*
AU  - Liu, P.P.*
AU  - Pellegata, N.S.
AU  - Stratakis, C.A.*
AU  - Lupski, J.R.*
AU  - Beckers, A.*
C1  - 47428
C2  - 40582
CY  - New York
SP  - 236-244
TI  - Aggressive tumor growth and clinical evolution in a patient with X-linked acro-gigantism syndrome.
JO  - Endocrine
VL  - 51
IS  - 2
PB  - Springer
PY  - 2015
SN  - 1355-008X
ER  - 

TY  - JOUR
AB  - Genetic alterations frequently are involved in the development of a pituitary adenoma in young age. We here characterize the functional role of a deletion in CDKN1B 5'-UTR region (c.-29_-26delAGAG) identified in an acromegalic patient that developed a growth hormone in pituitary adenoma during childhood. Our results show that the identified novel heterozygous deletion in the CDKN1B 5'-UTR region associates with a reduction in CDKN1B mRNA levels, a predicted altered secondary mRNA structure, and a reduced CDKN1B 5'-UTR transcriptional activity in vitro. The patient displayed loss of heterozygosity in the same CDKN1B 5'-UTR region at tissue level and the 5'UTR region containing the deleted sequence encompasses a GRE. These findings indicate that the identification of functional alterations of newly discovered genetic derangements need to be fully characterized and always correlated with the clinical manifestations.
AU  - Sambugaro, S.*
AU  - di Ruvo, M.*
AU  - Ambrosio, M.R.*
AU  - Pellegata, N.S.
AU  - Bellio, M.*
AU  - Guerra, A.*
AU  - Buratto, M.*
AU  - Foschini, M.P.*
AU  - Tagliati, F.*
AU  - degli Uberti, E.C.*
AU  - Zatelli, M.C.*
C1  - 43347
C2  - 36343
CY  - Totowa
SP  - 58-64
TI  - Early onset acromegaly associated with a novel deletion in CDKN1B 5'UTR region.
JO  - Endocrine
VL  - 49
IS  - 1
PB  - Humana Press Inc
PY  - 2015
SN  - 1355-008X
ER  -