X-linked acrogigantism (X-LAG) is a rare disease that represents a severe form of pituitary gigantism characterized by early-onset growth hormone (GH), insulin-like growth factor 1 (IGF1) and prolactin excess. X-LAG is associated with duplications involving the gene GPR101 on chromosome Xq26.3. Clinically, X-LAG manifests in infancy, with a median age at onset of 18 months, presenting as rapid linear growth, acral enlargement, and large pituitary macroadenomas. While predominantly a sporadic disease affecting females through constitutional duplications, somatic mosaicism is found in sporadic male cases. Three familial cases of X-LAG have been described. Management is difficult due to the young age of affected patients and the relative resistance of GH excess to somatostatin analogs. Multimodal therapy, including neurosurgery and medical therapy such as pegvisomant, is often required to achieve hormonal control and limit final adult height.Unlike other genetic forms of pituitary tumorigenesis that are due to sequence-based mutations, X-LAG is caused by structural changes in 3D genome architecture. Specifically, microduplications on chromosome Xq26.3 disrupt a topologically associating domain (TAD) containing GPR101. This process facilitates the formation of a "neoTAD," where the GPR101 promoter is driven by ectopic enhancers, primarily an intronic enhancer located within the VGLL1 gene, leading to massive pituitary upregulation of this constitutively active receptor and GH excess. X-LAG is an example of how novel disease mechanisms can explain the molecular dysregulation behind rare and difficult to manage endocrine pathologies.

Del Castillo, Trabucco and De la Balze syndrome was described in five patients in Buenos Aires in 1947. Secondary sexual characteristics and urological examination were normal, except for small testicle volume ("the size of an olive"). Treatment with hCG was ineffective. On testicular biopsy, only Sertoli cells and seminiferous tubules were detected, with no spermatozoa or spermatogonia. For this reason, it is currently known as testicular germ cell aplasia or Sertoli cell-only syndrome (SCOS). SCOS is the most severe histological phenotype of male infertility, associated with non-obstructive azoospermia and low testicular volume. This review provides a comprehensive synthesis of the historical background, clinical presentation, hormonal and histological features, genetic underpinnings and emerging therapeutic perspectives in SCOS.

Primary hyperparathyroidism (PHPT), considered a rare disease almost a century ago, has shown a notable increase in incidence over the past five decades, driven largely by improved diagnostic screening and greater clinical awareness. Following the same trend, the incidence of parathyroid carcinoma (PC), a very rare but aggressive malignancy accounting for approximately 1% of PHPT cases, appears to be rising. This increase parallels the overall rise in PHPT detection, suggesting that enhanced surveillance contributes to identifying more PC cases. PC is mostly characterized by severe hypercalcaemia, due to tumoral parathyroid hormone (PTH) over-secretion and a high rate of local recurrence and metastasis, making early diagnosis and surgical treatment crucial. Recent advances in genetics and epigenetics have profoundly expanded our understanding of PC pathogenesis. Germline and somatic mutations in the tumour suppressor gene CDC73 (encoding parafibromin) are implicated in up to 75% of familial and sporadic PC cases. Additional recurrent mutations in genes such as MEN1 and PRUNE2, alterations in cell cycle regulators such as CCND1 and EZH2, and disruptions in signalling pathways including PI3K/AKT/mTOR have been identified. Epigenetic modifications, including microRNA expression changes and promoter hypermethylation, also play a significant role in tumour development and progression. This mini review synthesizes epidemiological trends demonstrating an increasing incidence of PC following the rise of PHPT and highlights pivotal genetic and epigenetic findings contributing to tumourigenesis. Integrating new molecular insights with advances in clinical surveillance offers promise for improved diagnosis, prognostic stratification, and the development of future targeted therapies for parathyroid carcinoma.

Structural variants (SVs) that disrupt topologically associating domains can cause disease by rewiring enhancer-promoter interactions. Duplications involving GPR101 are known to cause X-linked acrogigantism (X-LAG) through ectopic GPR101 expression, but not all of these duplications are pathogenic. This presents a diagnostic challenge, especially in the prenatal setting. We evaluated POSTRE, a tool that predicts the regulatory impact of SVs, to distinguish pathogenic from benign GPR101 duplications. We analyzed seven non-pathogenic duplications and 27 known X-LAG-associated duplications. To enable predictions in an X-LAG-relevant tissue, enhancer maps built using H3K27ac ChIP-seq, ATAC-seq, and RNA-seq data derived from human anterior pituitary samples (NIH research protocol 97-CH-0076, Clinicaltrials.gov Identifier NCT00001595, submitted on 11 March 1999) were integrated into POSTRE. POSTRE correctly classified all 34 duplications as benign or pathogenic. In addition, one X-LAG case with mild clinical features (i.e. severe growth hormone hypersecretion without pituitary tumorigenesis) was found to include only 2/5 VGLL1 enhancers, whereas all typical X-LAG cases had ≥4 enhancers duplicated. This suggests that partial enhancer hijacking at VGLL1 could explain the different clinical features in this individual. These findings support the utility of POSTRE to support diagnostic pipelines when interpreting SVs affecting chromatin architecture in pituitary disease and highlight its potential to reduce uncertainty in genetic counseling without requiring chromatin conformation capture assays.

PurposeMultiple 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.MethodsClinical, genetic, pathological, radiological and hormonal investigations to identify and characterize disease status related to germline MAX gene sequence status.ResultsWe 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.ConclusionWe 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.

Background and Clinical Significance: Ectopic ACTH secretion is a rare, potentially life-threatening cause of Cushing’s syndrome that can be overlooked when small neuroendocrine tumors evade standard imaging. Case Presentation: A 34-year-old woman presented with rapidly progressing clinical signs/symptoms of Cushing’s syndrome and demonstrated marked hypercortisolism (cortisol 2428 nmol/L; ACTH 163 ng/mL; urinary free cortisol 815 μg/24 h; K+ 2.4 mmol/L). Small hypermetabolic nodules were noted in her right lung on 18F-FDG PET/CT but were initially deemed to be infectious; DOTANOC PET-CT and inferior petrosal sinus sampling were non-diagnostic. After medically induced inhibition of cortisol, repeat PET/CT showed a persistent 13 mm lung nodule. Biopsy confirmed a well-differentiated pulmonary carcinoid (Ki-67 3%), and lobectomy achieved biochemical remission. Conclusions: Diagnostic delay stemmed from human factors despite early suggestive imaging. Ectopic ACTH secretion should remain high on the differential diagnosis in rapidly evolving, severe ACTH-dependent Cushing’s disease; early, decisive diagnosis and coordinated care overseen by endocrinologists—preferably in expert centers—can shorten exposure to deleteriously high cortisol levels and improve outcomes.

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. 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

Background Olfactory neuroblastoma (ONB) is a rare malignant neuroectodermal tumour that usually arises in the nasal cavity, typically presenting with unilateral nasal obstruction and epistaxis. In rare instances, ONB can manifest as a paraneoplastic syndrome of inappropriate antidiuretic hormone (SIADH) secretion, leading to hyponatraemia. Case presentation We describe a 42-year-old woman with a 4-year history of cyclical, symptomatic hyponatraemia characterised by intermittent episodes of dizziness, severe headaches and marked fatigue, initially without overt nasal or otolaryngological symptoms. Investigations confirmed SIADH, yet repeated imaging (including thoracic CT and FDG PET-CT) failed to identify a source. Eventually, a 68Ga-DOTANOC PET-CT revealed an isolated lesion in the left ethmoid region. Surgical resection via an endoscopic approach confirmed the diagnosis of a Hyams grade 1 ONB. Following complete tumour removal, the patient’s hyponatraemia resolved. Literature review ONB accounts for <3% of nasal tumours and can present with non-specific symptoms, delaying diagnosis. Most patients have a typical combination of nasal obstruction and epistaxis, but paraneoplastic SIADH is reported in about 2% of cases. Complete surgical excision is the cornerstone of therapy, often accompanied by radiotherapy or chemotherapy for higher-grade lesions. Recent advances suggest that somatostatin receptor imaging and targeted radionuclide therapy might benefit select patients, particularly those with unresectable or recurrent disease. Conclusion This case highlights the importance of considering ONB in patients with unexplained SIADH, especially when initial investigations are inconclusive. It also underscores the utility of 68Ga-DOTANOC PET-CT in detecting occult neuroendocrine tumours, and reinforces the value of prompt surgical intervention for definitive treatment.

Introduction: Pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) are common intracranial tumors, clinically affecting 1:1000 individuals and most cases remain genetically unexplained. Emerging research has highlighted the major contribution of germline pathogenic variants to tumorigenesis across many tissue types in young subjects . We investigated whether young-onset (<30 years old) pituitary macroadenomas that were negative for known genetic causes harbor pathogenic or likely pathogenic (P/LP) variants in cancer-risk genes. Methods: We retrospectively analyzed 48 subjects (29 males; 96% GH- or PRL-secreting) with sporadic pituitary macroadenomas that were negative for known germline variants (AIP, MEN1, CDKN1B) or duplications (GPR101). Whole-exome sequencing (WES) was performed on germline DNA. Bioinformatics analysis including variant calling (for small variants and CNVs), annotation and variant prioritization were performed, using secondary analysis pipelines for WES data and AION predictor platform for tertiary analysis. Variants in established cancer-risk genes were prioritized. Results: P/LP germline variants in cancer-risk genes were identified in 14.6% of subjects on ClinVar/ACMG criteria. This rose to 31.3% of subject with deleterious variants when additional in silico and AION predictor criteria were used. Genes included: BAP1, BRCA1, BUB1, ELAC2, FLCN, MCPH1, MSR1, MUTYH, PDE11A, POLE, POLG, PMS2, RAD51C, RECQL4, SDHA, SDHD, SEC23B, TMEM127, WRN . Conclusions: Our findings expand the spectrum of genes potentially associated with young-onset pituitary macroadenomas. The identification of a high rate of deleterious germline variants in cancer-risk genes in pituitary adenomas/PitNETs echoes similar findings in young patients across a wide range of tumors. These results may have relevance for genetic counseling and potentially could expand targeted management strategies in young patients with large pituitary tumors. ### Competing Interest Statement The authors have nothing to disclose that would impact the presentation or interpretation of the study. ### Funding Statement The study was funded by the Fonds dInvestissement Pour la Recherche (FIRS) grants of the Centre Hospitalier Universitaire Liège ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The Ethics Committee of the Centre Hospitalier Universitaire Liège, University of Liège gave ethical approval for this work I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present study are available upon reasonable request to the authors

In 1849, Thomas Addison discovered alterations in the adrenal glands at autopsy of three patients who had died with idiopathic anemia. Struck by Addison's work, Charles-Edouard Brown-Séquard demonstrated in 1851 that bilateral adrenalectomy in dogs was fatal. It was not until 1950 that the discovery of the hormones of the adrenal cortex, their structure and their biological effects allowed Kendall, Reichstein and Hench to win the Nobel Prize in Physiology or Medicine. Nowadays, autoimmune adrenalitis accounts for almost 80 % of cases diagnosed with Addison's disease. The causes of this serious condition, which doubles the mortality rate of affected patients compared to the general population, have been expanded by genetic and iatrogenic causes. The latter are increasingly associated with immunological cancer therapies. It is essential to educate the patients with Addison's disease to improve the management of their condition and to remain responsive to the many triggers such as stress, infections or surgery. The management of Addison's disease is of interest not only to endocrinologists but also to general medical practitioners and critical care specialists. Recent studies aim to improve the understanding of the physiological and therapeutic effects of hydrocortisone, mineralocorticoids and adrenal androgens.

Introduction Le gène KAL-1 (ANOS1) encode l’anosmine, protéine clé dans la migration des neurones à GNRH et des nerfs olfactifs vers l’hypothalamus. KAL-1 est localisé sur le bras court d’un chromosome X (en Xp22.3) et ses mutations sont responsables d’un syndrome de Kallmann. Cas clinique Patient de 15 ans qui consulte pour retard pubertaire. Il mesure 1m76 et pèse 69kg. À noter des syncinésies des mains. Il a des antécédents d’ectopie testiculaire bilatérale opérée, micro pénis néonatal et anosmie. LH : <0,1UI/mL, FSH : 0,3UI/mL, testostérone 5,7nmol/L (8–30), le reste du bilan hypophysaire est normal. Testicule gauche de 0,6mL et droit de 0,8mL par échographie. Pas d’agénésie ni de malformations rénales. L’IRM hypophysaire démontre une selle turcique partiellement vide et une agénésie des bulbes olfactifs.Un panel génétique de 80 gènes d’hypogonadisme identifie le variant à l’état hémizygote c.827_856+49delinsGTA au niveau du gène KAL1. Cette délétion/insertion in frame emporte 11 résidus au niveau de la protéine anosmine (Ala276 à Asp286) et entraîne, à leur place, l’insertion d’une glycine et d’une asparagine. Il s’agit d’une mutation non décrite encore, avec un effet pathogène sur l’anosmine, d’après les modèles in silico. Cette mutation étant absente chez la mère du patient, elle est donc survenue de novo chez le patient, argument supplémentaire en faveur d’un lien de causalité. Conclusions Le syndrome de Kallmann est un syndrome complexe et neurodéveloppemental, intéressant différentes spécialités, dont l’endocrinologie. Nous décrivons une nouvelle mutation de KAL-1 responsable de ce syndrome.

X-linked acrogigantism (X-LAG; MIM: 300942) is a severe form of pituitary gigantism caused by chromosome Xq26.3 duplications involving GPR101. X-LAG-associated duplications disrupt the integrity of the topologically associating domain (TAD) containing GPR101 and lead to the formation of a neo-TAD that drives pituitary GPR101 misexpression and gigantism. As X-LAG is fully penetrant and heritable, duplications involving GPR101 identified on prenatal screening studies, like amniocentesis, can pose an interpretation challenge for medical geneticists and raise important concerns for patients and families. Therefore, providing robust information on the functional genomic impact of such duplications has important research and clinical value with respect to gene regulation and triplosensitivity traits. We employed 4C/HiC-seq as a clinical tool to determine the functional impact of incidentally discovered GPR101 duplications on TAD integrity in three families. After defining duplications and breakpoints around GPR101 by clinical-grade and high-density aCGH, we constructed 4C/HiC chromatin contact maps for our study population and compared them with normal and active (X-LAG) controls. We showed that duplications involving GPR101 that preserved the centromeric invariant TAD boundary did not generate a pathogenic neo-TAD and that ectopic enhancers were not adopted. This allowed us to discount presumptive/suspected X-LAG diagnoses and GPR101 misexpression, obviating the need for intensive clinical follow-up. This study highlights the importance of TAD boundaries and chromatin interactions in determining the functional impact of copy number variants and provides proof-of-concept for using 4C/HiC-seq as a clinical tool to acquire crucial information for genetic counseling and to support clinical decision-making in cases of suspected TADopathies.

X-linked acrogigantism (X-LAG) is a rare form of pituitary gigantism that is associated with growth hormone (GH) and prolactin-secreting pituitary adenomas/pituitary neuroendocrine tumors (PitNETs) that develop in infancy. It is caused by a duplication on chromosome Xq26.3 that leads to the misexpression of the gene GPR101, a constitutively active stimulator of pituitary GH and prolactin secretion. GPR101 normally exists within its own topologically associating domain (TAD) and is insulated from surrounding regulatory elements. X-LAG is a TADopathy in which the duplication disrupts a conserved TAD border, leading to a neo-TAD in which ectopic enhancers drive GPR101 over-expression, thus causing gigantism. Here we trace the full diagnostic and therapeutic pathway of a female patient with X-LAG from 4C-seq studies demonstrating the neo-TAD through medical and surgical interventions and detailed tumor histopathology. The complex nature of treating young children with X-LAG is illustrated, including the achievement of hormonal control using a combination of neurosurgery and adult doses of first-generation somatostatin analogs.