Endocrine consequences of immune checkpoint inhibitors

Immune checkpoints inhibitors have fundamentally changed the management of oncologic patients. These treatments consist of monoclonal antibodies directed against CTLA-4 (cytotoxic T-lymphocyte antigen 4), PD-1 (programmed cell death protein-1) and PD-L1 (one of its ligands). By blocking these receptors or ligands, the antibodies reverse the immune tolerance induced by the cancerous cell on the T-lymphocyte and favour lymphocytic reactivation and anti-tumor activity. Immune tolerance to auto-antigens is maintained with the help of these checkpoints. Targeting them can lead to auto-immune side effects. These latter mostly impact the cutaneous and digestive system, but the endocrine glands are not spared. In this article, we provide monitoring and treatment algorithms for these endocrine immune side effects. An early diagnosis followed by the appropriate treatment would reduce their negative impact on the oncologic care

Gigantism: Clinical diagnosis and description

peer reviewedGigantism has always been the subject of interest among the general public due to connotations of otherworldly strength and abilities. Until quite recently, the study of gigantism as an illness has not received concerted scientific attention, probably due to its very rare nature. International collaborative research has now led to significant advances in the understanding of the molecular mechanisms responsible for some forms of excessively tall stature. The clinical presentation of pituitary gigantism will be detailed here with emphasis on the specific aspects that are typical to the different genetic causes underlying the disease

Meningioma under progestin treatment, what attitude to adopt?

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The Role of MCM9 in the Etiology of Sertoli Cell-Only Syndrome and Premature Ovarian Insufficiency

peer reviewedInfertility in couples is a common problem, with both female and male factors contributing to similar extents. Severe, congenital disorders affecting fertility are, however, rare. While folliculogenesis and spermatogenesis are generally orchestrated via different mechanisms, some genetic anomalies can impair both female and male gametogenesis. Minichromosome maintenance complex component 9 (MCM9) is involved in DNA repair and mutations of the MCM9 gene have been previously reported in females with premature ovarian insufficiency (POI). MCM9 is also an emerging cancer risk gene. We performed next-generation and Sanger sequencing of fertility and related genes and hormonal and imaging studies in a kindred whose members had POI and disordered spermatogenesis. We identified a homozygous pathogenic MCM9 variant, c.394C>T (p.Arg132*) in three sisters affected by POI due to ovarian dysgenesis and their brother who had normal pubertal development but suffered from non-obstructive azoospermia. Testicular biopsy revealed Sertoli cell-only testicular histopathology. No evidence of early onset cancer was found in the homozygotic family members, but they were all young (<30 years) at the time of the study. In the male patient the homozygous MCM9 variant led to normal pubertal development and hormonal levels but caused a Sertoli-cell-only syndrome with non-obstructive azoospermia. In the homozygous females studied, the clinical, hormonal, and gonadal phenotypes revealed ovarian dysgenesis consistent with previous reports. Active screening for potential colorectal and other cancer risks in the homozygotic MCM9 subjects has been instigated

Compound heterozygous mutations in the luteinizing hormone receptor signal peptide causing 46,XY disorder of sex development.

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotrophin receptor (LHCGR). Failure of the receptor to correctly respond to its ligand leads to impaired sexual differentiation in males. A phenotypically-female patient with pubertal delay, had a 46,XY karyotype and was diagnosed with 46X,Y disorder of sex development (DSD). Novel compound heterozygous LHCGR mutations were found in the signal peptide: a duplication p.L10_Q17dup of maternal origin, and a deletion (p.K12_L15del) and a p.L16Q missense mutation of paternal origin. cAMP production was very low for both the deletion and duplication mutations and was halved for the missense mutant. The duplication and missense mutations were both expressed intracellularly, but at very low levels at the cell membrane; they were most likely retained in the endoplasmic reticulum. The deletion mutant had a very limited intracellular expression, indicating impaired biosynthesis. There was reduced expression of all three mutants, which was most marked for the deletion mutation. There was also decreased protein expression of all three mutant receptors. In the deletion mutation, the presence of a lower molecular weight band corresponding to LHCGR monomer, probably due to lack of glycosylation, and a lack of bands corresponding to dimers/oligomers suggests absent ER entry. This novel case of 46X,Y DSD illustrates how three different LHCGR signal peptide mutations led to complete receptor inactivation by separate mechanisms. The study underlines the importance of specific regions of signal peptides and expands the spectrum of LHCGR mutations

Multiple Endocrine Neoplasia Type 1 in Clinical Practice

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Nouveautés dans le diagnostic et la prise en charge des complications en lien avec l'acromégalie

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Shrinkage of pituitary adenomas with pasireotide

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Osteoporosis in a 21-year-old man with normal hormonal work-up, but azoospermia? Ask his sisters!

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