TY  - JOUR
AB  - BACKGROUND: Multiple endocrine neoplasia type 5 (MEN5) is an emerging syndrome caused by germline pathogenic variants involving the MYC Associated Factor X (MAX) gene. Affected individuals typically have pheochromocytomas, often bilateral, at a relatively early age. In MAX pheochromocytoma cohorts, pituitary adenomas are rarely reported. The role of MAX as a tumor suppressor gene in the pituitary gland has not been directly proven to date. METHODS: The propositus came from a pheochromocytoma kindred with a germline pathogenic MAX variant c.97 C>T (p.R33*). In his late thirties he developed asynchronous bilateral pheochromocytomas and underwent bilateral adrenalectomy. At age 46, he developed hyperprolactinemia (45.1 μg/L; 3x ULN) and increased IGF-1 (460 ng/mL; 1.9x ULN). Total testosterone was low (1.5 ng/mL) as was LH (1.2 IU/L). Pituitary MRI showed a microadenoma (6 mm), which was resected and his prolactin, IGF-1, and testosterone levels normalized. A Pituitary adenoma was confirmed on pathology, which showed positivity for prolactin only and a Ki67 of 2%. RESULTS: MAX immunohistochemical staining was lost in the pituitary adenoma cells. Tumoral DNA analysis (120X read depth) showed that at the MAX locus the pathogenic variant c.97 C>T constituted > 90% of the sequencing reads supporting tumoral loss of heterozygosity (LOH). CONCLUSIONS: Loss of MAX staining and the identification of tumor LOH at the MAX locus confirms pituitary adenomas as a component tumor in the emerging MEN5 syndrome due to germline pathogenic MAX variants.
AU  - Delemer, B.*
AU  - Florea, S.M.*
AU  - Decoudier, B.*
AU  - Boulagnon-Rombi, C.*
AU  - Karna, B.
AU  - Pellegata, N.S.
AU  - Buffet, A.*
AU  - Beckers, A.*
AU  - Petrossians, P.*
AU  - Daly, A.F.*
C1  - 76001
C2  - 58338
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
TI  - Loss of heterozygosity and absence of MAX immunostaining in a prolactinoma associated with multiple endocrine neoplasia type 5 (MEN5).
JO  - Pituitary
VL  - 28
IS  - 6
PB  - Springer
PY  - 2025
SN  - 1386-341X
ER  - 

TY  - JOUR
AB  - PURPOSE: Growth hormone (GH) is a central regulator of β-cell proliferation, insulin secretion and sensitivity. Aim of this study was to investigate the effect of GH insensitivity on pancreatic β-cell histomorphology and consequences for metabolism in vivo. METHODS: Pancreata from pigs with growth hormone receptor deficiency (GHR-KO, n = 12) were analyzed by unbiased quantitative stereology in comparison to wild-type controls (WT, n = 12) at 3 and 7-8.5 months of age. In vivo secretion capacity for insulin and glucose tolerance were assessed by intravenous glucose tolerance tests (ivGTTs) in GHR-KO (n = 3) and WT (n = 3) pigs of the respective age groups. RESULTS: Unbiased quantitative stereological analyses revealed a significant reduction in total β-cell volume (83% and 73% reduction in young and adult GHR-KO vs. age-matched WT pigs; p < 0.0001) and volume density of β-cells in the pancreas of GHR-KO pigs (42% and 39% reduction in young and adult GHR-KO pigs; p = 0.0018). GHR-KO pigs displayed a significant, age-dependent increase in the proportion of isolated β-cells in the pancreas (28% in young and 97% in adult GHR-KO vs. age-matched WT pigs; p = 0.0009). Despite reduced insulin secretion in ivGTTs, GHR-KO pigs maintained normal glucose tolerance. CONCLUSION: GH insensitivity in GHR-KO pigs leads to decreased β-cell volume and volume proportion of β-cells in the pancreas, causing a reduced insulin secretion capacity. The increased proportion of isolated β-cells in the pancreas of GHR-KO pigs highlights the dependency on GH stimulation for proper β-cell maturation. Preserved glucose tolerance accomplished with decreased insulin secretion indicates enhanced sensitivity for insulin in GH insensitivity.
AU  - Laane, L.*
AU  - Renner, S.*
AU  - Kemter, E.*
AU  - Stirm, M.*
AU  - Rathkolb, B.
AU  - Blutke, A.*
AU  - Bidlingmaier, M.*
AU  - Hrabě de Angelis, M.
AU  - Wolf, E.*
AU  - Hinrichs, A.*
C1  - 71050
C2  - 55832
CY  - One New York Plaza, Suite 4600, New York, Ny, United States
SP  - 567-576
TI  - Decreased β-cell volume and insulin secretion but preserved glucose tolerance in a growth hormone insensitive pig model.
JO  - Pituitary
VL  - 27
PB  - Springer
PY  - 2024
SN  - 1386-341X
ER  -