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To study the utility of T2-weighted MRI sequences in the identification of the inferior intercavernous sinus (IICS), a potential source of bleeding during transsphenoidal surgery of pituitary adenomas.Pituitary sagittal T1W and coronal T2W MRI sequences were analyzed in 237 consecutive patients, after the exclusion of postoperative MRIs and those revealing an empty sella or a pituitary macroadenoma. Sphenoid sinus pneumatization was defined as incomplete (group 1) if it did not reach the nadir of the sella turcica, as complete (group 2) if it extended beyond the nadir of the sella or asymmetric (group 3), when only one side of the sinus was completely pneumatized.In Group 2 (70% of the patients), the IICS was rarely visualized on coronal T2W MRI (6/167 patients-3.6%), whereas in Group 1 it was identified in nearly all patients (55/57 patients - 96.5%, p 0.001). In Group 3, the IICS was only visible above the non-pneumatized part of the sphenoid sinus.The IICS can be identified on coronal T2W images in patients with an incompletely pneumatized sphenoid sinus, but very rarely in patients with a totally pneumatized sinus. This information can help to increase awareness among pituitary surgeons of the need to potentially manage IICS bleeding during transsphenoidal surgery in patients with an incompletely pneumatized sphenoid sinus.

Infertility 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 (

Background The prevalence of thyroid cancer is increasing steadily in most countries, partly due to better, earlier diagnosis. However, there is little data for developing countries, where the technical platform is often very limited, especially in Africa. Objectives To assess the frequency of thyroid cancer in the Democratic Republic of the Congo (DRC) and to analyze the epidemiological, clinical, and ultrasound risk factors. Material and methods This is a multicenter cross-sectional study of 594 patients operated on for a thyroid mass from 2005 to 2019, in 35 centers in the DRC and for whom histopathological analyses were performed. Results The frequency of thyroid cancers in our cohort was 20%, mostly in patients over the age of 40 (62% of patients). These cancers were mainly diagnosed at the clinical stage, due to the presence of palpable masses. Papillary cancer was the most common (67.2% of patients), followed by follicular cancer (28% of cases). We found a high prevalence of anaplastic cancer (7.6%). These frequencies are probably the consequence of the fact that histopathological analyses are not systematically performed in the DRC, but mostly on tissues that the thyroid surgeons suspect to be malignant. Age ≥60 years, the presence of adenopathies upon palpation or on ultrasound, the solid nature and hypoechogenicity of nodules, the presence of macronodules and calcifications were the factors independently associated with the diagnosis of cancer in the study population. Conclusions In this first study performed in the DRC, we have found that thyroid cancer is common. It is mainly detected at clinical stages, with patients over the age of 40 years and women being the most affected. The histopathology distribution differs from that in developed countries, with a lower prevalence of papillary cancer and a higher prevalence of the anaplastic type. In developing countries, it appears necessary to introduce the use of more precise diagnostic tools for thyroid cancer and also, to reinforce the improvement of known, controllable risk factors such as iodine deficiency.

Context Ectopic acromegaly is a consequence of rare neuroendocrine tumors (NETs) that secrete GHRH. This abnormal GHRH secretion drives GH and IGF-1 excess, with a clinical presentation similar to classical pituitary acromegaly. Identifying the underlying cause for the GH hypersecretion in the setting of ectopic GHRH excess is, however, essential for proper management both of acromegaly and the NET. Owing to the rarity of NETs, the imaging characteristics of the pituitary in ectopic acromegaly have not been analyzed in depth in a large series. Objective Characterize pituitary magnetic resonance imaging (MRI) features at baseline and after NET treatment in patients with ectopic acromegaly. Design Multicenter, international, retrospective. Setting Tertiary referral pituitary centers. Patients Thirty ectopic acromegaly patients having GHRH hypersecretion. Intervention None. Main outcome measure MRI characteristics of pituitary gland, particularly T2-weighted signal. Results In 30 patients with ectopic GHRH-induced acromegaly, we found that most patients had hyperplastic pituitaries. Hyperplasia was usually moderate but was occasionally subtle, with only small volume increases compared with normal ranges for age and sex. T2-weighted signal was hypointense in most patients, especially in those with hyperplastic pituitaries. After treatment of the NET, pituitary size diminished and T2-weighted signal tended to normalize. Conclusions This comprehensive study of pituitary MRI characteristics in ectopic acromegaly underlines the utility of performing T2-weighted sequences in the MRI evaluation of patients with acromegaly as an additional tool that can help to establish the correct diagnosis.

Premature ovarian insufficiency (POI), a condition affecting up to 1% of women by the age of 40 years, is characterized by an extremely low chance of spontaneous pregnancy. Currently, fertility restoration options are virtually nonexistent for this population. To become pregnant, the only solution is egg donation. Interestingly, animal studies have provided encouraging results in terms of fertility restoration, and consequently, research has begun into the most promising approaches for women suffering from POI. The PubMed database was searched for studies in which techniques aiming at restoring fertility in women with spontaneous POI were tested. Although robust studies are lacking, the literature suggests a positive effect of certain techniques on fertility restoration in women with POI. The most promising approaches seem to be intraovarian injection of autologous platelet-rich plasma or of mesenchymal stem cells. In addition to these, in vitro and mechanical activation of dormant follicles and etiology-driven therapies have also been studied with mixed results. No safety concerns were raised in these studies. The absence of robust studies does not allow us to draw meaningful conclusions on the efficacy or superiority of any single technique at this stage, and so research in this area should continue using robust study designs, i.e., multicenter randomized controlled trials including sufficient subjects to achieve statistical power.

Magnetic resonance imaging (MRI) is currently considered as a major keystone of the diagnosis of diseases of the hypothalamic-hypophyseal region. The relatively small size of the pituitary gland, its deep location at the skull base, and the numerous physiological variants impede the precise assessment of the anatomical structure of the pituitary gland. Advanced MRI technology, particularly 3T MR, is able to depict tiny lesions such as corticotropic picoadenomas with greater reliability, but also helps in the differential diagnosis of larger tumours, their extension, and their relationship with the surrounding structures. This chapter describes and illustrates the role of MRI in the diagnosis of the main different lesions of the sellar region, which are likely to interest endocrinologists such as pituitary adenomas, Rathke cleft cysts, hypophysitis, and a few neoplastic and non-neoplastic entities.

Testosterone production by the fetal testis depends on a functional relationship between hCG and the LH/chorionic gonadotropin 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 46,XY 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 46,XY DSD illustrates how 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.

Gigantism 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.

AIP mutations are rare in sporadic acromegaly but they are seen at a higher frequency among certain specific populations of pituitary adenoma patients (pituitary gigantism cases, familial isolated pituitary adenoma (FIPA) kindreds, and patients with macroadenomas who are diagnosed ≤30 years). AIP mutations are most prevalent in patients with pituitary gigantism (29% of this group were found to have mutations in AIP gene). These data support targeted genetic screening for AIP mutations/deletions in these groups of pituitary adenoma patients. Earlier diagnosis of AIP-related acromegaly-gigantism cases enables timely clinical evaluation and treatment, thereby improving outcomes in terms of excessive linear growth and acromegaly comorbidities.

T2-weighted MRI signal intensity of GH-secreting pituitary adenomas is gaining recognition as a marker of disease characteristics and may be a predictor of response to treatment of acromegaly. Adenomas that are T2-hypointense are more common, are smaller and are less likely to invade the cavernous sinus compared to the T2-iso and hyperintense tumors. T2-hypointense tumors are also accompanied by higher IGF1 values at baseline. When presurgical somatostatin receptor ligand (SRL) therapy is administered, T2-hypointense adenomas have better hormonal responses and have greater tumor shrinkage. Adjuvant SRL therapy of patients with T2-hypointense tumors that are uncured by surgery is also associated with a better hormonal response. We review the studies that have dealt with the T2-weighted signal intensity of GH-secreting pituitary tumors and elaborate on the details and nuances of this promising avenue of research.

Glycoprotein hormones are complex hormonally active macromolecules. Luteinizing hormone (LH) is essential for the postnatal development and maturation of the male gonad. Inactivating Luteinizing hormone beta (LHB) gene mutations are exceptionally rare and lead to hypogonadism that is particularly severe in males. We describe a family with selective LH deficiency and hypogonadism in two brothers. DNA sequencing of LHB was performed and the effects of genetic variants on hormone function and secretion were characterized by mutagenesis studies, confocal microscopy and functional assays. A 20-year-old male from a consanguineous family had pubertal delay, hypogonadism and undetectable LH. A homozygous c.118_120del (p.Lys40del) mutation was identified in the patient and his brother, who subsequently had the same phenotype. Treatment with hCG led to pubertal development, increased circulating testosterone and spermatogenesis. Experiments in HeLa cells revealed that the mutant LH is retained intracellularly and showed diffuse cytoplasmic distribution. The mutated LHB heterodimerizes with the common alpha-subunit and can activate its receptor. Deletion of flanking glutamic acid residues at positions 39 and 41 impair LH to a similar extent as deletion of Lys40. This region is functionally important across all heterodimeric glycoprotein hormones, because deletion of the corresponding residues in hCG, follicle-stimulating hormone and thyroid-stimulating hormone beta-subunits also led to intracellular hormone retention. This novel LHB mutation results in hypogonadism due to intracellular sequestration of the hormone and reveals a discrete region in the protein that is crucial for normal secretion of all human glycoprotein hormones.

Familial pituitary adenomas account for approximately 5–8% of all pituitary adenomas. Besides the adenomas occurring as part of syndromic entities that group several endocrine or nonendocrine disorders (multiple endocrine neoplasia type 1 or 4, Carney complex and McCune–Albright syndrome), 2–3% of familial pituitary adenomas fit into the familial isolated pituitary adenomas (FIPA) syndrome, an autosomal dominant condition with incomplete penetrance. About 20% of FIPA cases are due to mutations in the AIP gene and have distinct clinical characteristics. Recent findings have isolated a new non-AIP FIPA syndrome called X-linked acrogigantism, resulting from a microduplication that always includes the GPR101 gene. These new advances in the field of pituitary disease are opening up a new challenging domain to both clinicians and researchers. This review will focus on these recent findings and their contribution to the diagnosis and the management of familial pituitary adenomas.

X-linked acrogigantism (XLAG) is a new, pediatric-onset genetic syndrome, due to Xq26.3 microduplications encompassing the GPR101 gene. XLAG has a remarkably distinct phenotype with disease onset occurring before the age of 5 in all cases described to date, which is significantly younger than in other forms of pituitary gigantism. These patients have mixed GH and prolactin positive adenomas and/or mixed-cell hyperplasia and highly elevated levels of GH/IGF-1 and prolactin. Given their particularly young age of onset, the significant GH hypersecretion can lead to a phenotype of severe gigantism with very advanced age-specific height Z-scores. If not adequately treated in childhood, this condition results in extreme final adult height. XLAG has a clinical course that is highly similar to some of the tallest people with gigantism in history.

Objective Both antitumor and antisecretory efficacies of dopamine agonists (DA) make them the first-line treatment of macroprolactinomas. However, there is no guideline for MRI follow-up once prolactin is controlled. The aim of our study was to determine whether a regular MRI follow-up was necessary in patients with long-term normal prolactin levels under DA. Patients and methods We conducted a retrospective multicenter study (Marseille, Paris La Pitie Salpetriere and Nancy, France; Liege, Belgium) including patients with macroprolactinomas (largest diameter: >10 mm and baseline prolactin level: >100 ng/mL) treated by dopamine agonists, and regularly followed (pituitary MRI and prolactin levels) during at least 48 months once normal prolactin level was obtained. Results In total, 115 patients were included (63 men and 52 women; mean age at diagnosis: 36.3 years). Mean baseline prolactin level was 2224 ± 6839 ng/mL. No significant increase of tumor volume was observed during the follow-up. Of the 21 patients (18%) who presented asymptomatic hemorrhagic changes of the macroprolactinoma on MRI, 2 had a tumor increase (2 and 7 mm in the largest size). Both were treated by cabergoline (1 mg/week) with normal prolactin levels obtained for 6 and 24 months. For both patients, no further growth was observed on MRI during follow-up at the same dose of cabergoline. Conclusion No significant increase of tumor size was observed in our patients with controlled prolactin levels on DA. MRI follow-up thus appears unnecessary in patients with biologically controlled macroprolactinomas.

Adipsic diabetes insipidus is a rare complication of intracranial tumors in which impaired antidiuretic hormone secretion is associated with the loss of thirst sensation. Here, we present the case of a patient with bifocal intracranial germinoma, diagnosed due to symptoms mainly caused by adipsic diabetes insipidus. This is, to our knowledge, the first case of adipsic diabetes insipidus revealing an intracranial germinoma reported in the literature. We describe the diagnostic procedures and the three-year follow-up of this patient. Management of intracranial germ-cell tumors is made complex by the wide range of histological features. Although germinomas have a generally better prognosis than most nongerminomatous tumors, they can have severe or even life-threatening presentations. Adipsic diabetes insipidus is one such severe presentation and its rarity can make it difficult to recognize and manage. Awareness of this potential entity is therefore important for clinical practice.

Breast cancer is rare in male patients. Certain predisposing factors, be they genetic (e.g., BRCA2 gene mutations) or hormonal (imbalance between estrogen and androgen levels), have been implicated in male breast cancer pathophysiology. Male-to-female (MtF) transsexualism is a condition that generally involves cross-sex hormone therapy. Anti-androgens and estrogens are used to mimic the female hormonal environment and induce the cross-sex secondary characteristics. In certain situations, the change in the hormonal milieu can be disadvantageous and favor the development of hormone-dependent pathologies, such as cancer. We report a case of a MtF transgender patient who developed breast cancer after 7 years of cross-sex hormonal therapy. The patient was found to be BRCA2 positive, and suffered recurrent disease. The patient was unaware of being a member of an established BRCA2 mutation-positive kindred. This represents the first case of a BRCA2 mutation predisposing to breast cancer in a MtF transgender patient.

Somatic mosaicism has been implicated as a causative mechanism in a number of genetic and genomic disorders. X-linked acrogigantism (XLAG) syndrome is a recently characterized genomic form of pediatric gigantism due to aggressive pituitary tumors that is caused by submicroscopic chromosome Xq26.3 duplications that includeGPR101. We studied XLAG syndrome patients (n= 18) to determine if somatic mosaicism contributed to the genomic pathophysiology. Eighteen subjects with XLAG syndrome caused by Xq26.3 duplications were identified using high-definition array comparative genomic hybridization (HD-aCGH). We noted that males with XLAG had a decreased log2ratio (LR) compared with expected values, suggesting potential mosaicism, whereas females showed no such decrease. Compared with familial male XLAG cases, sporadic males had more marked evidence for mosaicism, with levels of Xq26.3 duplication between 16.1 and 53.8%. These characteristics were replicated using a novel, personalized breakpoint junction-specific quantification droplet digital polymerase chain reaction (ddPCR) technique. Using a separate ddPCR technique, we studied the feasibility of identifying XLAG syndrome cases in a distinct patient population of 64 unrelated subjects with acromegaly/gigantism, and identified one female gigantism patient who had had increased copy number variation (CNV) threshold forGPR101that was subsequently diagnosed as having XLAG syndrome on HD-aCGH. Employing a combination of HD-aCGH and novel ddPCR approaches, we have demonstrated, for the first time, that XLAG syndrome can be caused by variable degrees of somatic mosaicism for duplications at chromosome Xq26.3. Somatic mosaicism was shown to occur in sporadic males but not in females with XLAG syndrome, although the clinical characteristics of the disease were similarly severe in both sexes.

GH-secreting pituitary adenomas can be hypo-, iso- or hyper-intense on T2-weighted MRI sequences. We conducted the current multicenter study in a large population of patients with acromegaly to analyze the relationship between T2-weighted signal intensity on diagnostic MRI and hormonal and tumoral responses to somatostatin analogs (SSA) as primary monotherapy. Acromegaly patients receiving primary SSA for at least 3 months were included in the study. Hormonal, clinical and general MRI assessments were performed and assessed centrally. We included 120 patients with acromegaly. At diagnosis, 84, 17 and 19 tumors were T2-hypo-, iso- and hyper-intense, respectively. SSA treatment duration, cumulative and mean monthly doses were similar in the three groups. Patients with T2-hypo-intense adenomas had median SSA-induced decreases in GH and IGF-1 of 88% and 59% respectively, which were significantly greater than the decreases observed in the T2-iso- and hyper-intense groups (P P P r = 0.22), IGF-1 (P r = 0.14) and adenoma volume (P r = 0.33). The T2-weighted signal intensity of GH-secreting adenomas at diagnosis correlates with hormone reduction and tumor shrinkage in response to primary SSA treatment in acromegaly. This study supports its use as a generally available predictive tool at diagnosis that could help to guide subsequent treatment choices in acromegaly.

Pituitary incidentalomas are a by-product of modern imaging technology. The term ‘incidentaloma’ is neither a distinct diagnosis nor a pathological entity. Rather, it is a collective designation for different entities that are discovered fortuitously, requiring a working diagnosis based on the input of the radiologist, endocrinologist and often a neurosurgeon. In addition to pathological conditions affecting the pituitary gland, a thorough knowledge of the radiological characteristics of normal variants and technical artifacts is required to arrive at an accurate differential diagnosis. After careful radiological and hormonal evaluation, the vast majority of pituitary incidentalomas turn out to be non-functioning pituitary microadenomas and Rathke’s cleft cysts (RCCs). Based on the low growth potential of non-functioning pituitary microadenomas and RCCs, periodic MRI surveillance is currently considered the optimal management strategy. Stricter follow-up is required for macroadenomas, as increases in size occur more frequently.

Parathyroid carcinoma is a malignant neoplasm affecting 0.5 to 5.0% of all patients suffering from primary hyperparathyroidism. This cancer continues to cause challenges for diagnosis and treatment because of its rarity, overlapping features with benign parathyroid disease, and lack of distinct characteristics. The third/second generation PTH assay ratio provides valuable information to distinguish between benign parathyroid disease and parathyroid carcinoma. An abnormal ratio (>1) could indicate a high suspicion regarding carcinoma and metastatic disease. Early en bloc surgical resection of the primary tumour with clear margins remains the best curative treatment. Although prolonged survival is possible with recurrent or metastatic disease, cure is rarely achievable. The efficacy of classical adjuvant therapies, such as radiotherapy and chemotherapy, in management of persistent, recurrent, or metastatic disease has been disappointing. In metastatic disease the goal of therapeutic support is to control the PTH-driven hypercalcemia that represents the primary cause of mortality. Calcimimetics, which are allosteric modulators of the calcium sensing receptor, have a sustained effect in lowering serum calcium levels. Bone anti-resorptive therapy, like intravenous bisphosphonates (pamidronate and zolendronate), or more recently denosumab (fully human monoclonal antibody with high affinity to bind RANK ligand) might be temporarily useful. In a small number of cases treated with anti-PTH immunotherapy, inducing anti-PTH antibodies, promising results have been seen with clinical improvements and decrease of calcemia. In one case metastasis shrinkage has been observed.

Responses of GH-secreting adenomas to multimodal management of acromegaly vary widely between patients. Understanding the behavioral patterns of GH-secreting adenomas by identifying factors predictive of their evolution is a research priority. The aim of this study was to clarify the relationship between the T2-weighted adenoma signal on diagnostic magnetic resonance imaging (MRI) in acromegaly and clinical and biological features at diagnosis. An international, multicenter, retrospective analysis was performed using a large population of 297 acromegalic patients recently diagnosed with available diagnostic MRI evaluations. The study was conducted at ten endocrine tertiary referral centers. Clinical and biochemical characteristics, and MRI signal findings were evaluated. T2-hypointense adenomas represented 52.9% of the series, were smaller than their T2-hyperintense and isointense counterparts (PP=0.0001), invaded the cavernous sinus less frequently (P=0.0002), and rarely caused optic chiasm compression (PP=0.067) and presented higher IGF1 values (P=0.01). Although in total, adenomas had a predominantly inferior extension in 45.8% of cases, in men this was more frequent (PP=0.0067). Most adenomas (45.1%) measured between 11 and 20 mm in maximal diameter and bigger adenomas were diagnosed at younger ages (P=0.0001). The T2-weighted signal differentiates GH-secreting adenomas into subgroups with particular behaviors. This raises the question of whether the T2-weighted signal could represent a factor in the classification of acromegalic patients in future studies.

ObjectiveThe LH/chorionic gonadotrophin receptor (LHCGR) is a G protein-coupled receptor (GPCR) that plays a central role in male sexual differentiation, regulation of ovarian follicular maturation, ovulation and maintenance of corpus luteum and pregnancy, as well as maintenance of testicular testosterone production. Mutations in theLHCGRgene are very rare. The aim of this work was to study the clinical and molecular characteristics of a rare familialLHCGRmutation.MethodsFive affected members of a family, including a phenotypically female, but genotypically male (46,XY), patient with Leydig cell hypoplasia type 1 and four genotypically female siblings with reproductive abnormalities, were studied genetically. Cell trafficking studies as well as signalling studies of mutated receptor were performed.ResultsThe five affected patients were all homozygous for a novel mutation in theLHCGRgene, a deletion of guanine in position 1850 (1850delG). This resulted in a frameshift affecting most of the C-terminal intracellular domain.In vitrostudies demonstrated that the 1850delG receptor was completely incapable of transit to the cell membrane, becoming trapped within the endoplasmic reticulum. This could not be rescued by small-molecule agonist treatment or stimulated intracellularly by co-expression of a yoked human chorionic gonadotrophin.ConclusionsThis novelLHCGRmutation leads to complete inactivation of the LHCGR receptor due to trafficking and signalling abnormalities, which improves our understanding of the impact of the affected structural domain on receptor trafficking and function.

Ghrelin is an important neuroendocrine peptide having as main purpose the stimulation of growth hormone (GH) secretion. It is also an important regulator of the long-term energy balance and short-term nutritional intake. Ghrelin has several other biological actions, among which the capacity to regulate gastrointestinal motility, to modulate the reproductive and stress axes as well as the glucose metabolism, and other well-defined actions within the cardiovascular and renal physiology. Due to its numerous effects, ghrelin is considered on one hand a potential target in the treatment of obesity and on the other, a therapeutic option in other dysfunctions and illnesses.

Introduction Les kystes de la poche de Rathke (KPR) sont les lesions sellaires les plus frequemment decouvertes de maniere fortuite. Pourtant, des formes symptomatiques existent, manifestees par des cephalees, troubles visuels et dysfonctionnement hypophysaire. Observation Notre patient, âge de 45 ans, s’est presente aux urgences avec des cephalees frontales d’apparition brutale. Un KPR venait d’etre diagnostique lors de l’exploration pour un diabete insipide installe recemment. Le bilan endocrinologique a confirme le diabete insipide et a mis aussi en evidence des deficits sur les axes thyreo-, somato- et gonadotropes. L’IRM retrouve la lesion sellaire et suprasellaire de 13 mm diametre cranio-caudale avec prise de contraste peripherique et atteinte meningee. Une prise en charge chirurgicale est decidee, mais l’IRM hypophysaire de controle montre l’effondrement de la lesion sur son axe cranio-caudal. Concomitamment, le bilan hormonal thyroidien se normalise. Une attitude attentiste est preferee. Deux semaines plus tard, le patient revient aux urgences pour installation brutale des cephalees holocrâniennes, pulsatiles, accompagnees par des nausees et vomissements et une asthenie importante. Le bilan biologique revele une aggravation des deficits antehypophysaires avec insuffisance thyreo- et corticotrope. L’IRM montre la re-augmentation de la lesion hypophysaire. La sanction chirurgicale est retenue. Discussion Nous rapportons un cas de KPR avec importants retentissements cliniques et biologiques. A notre connaissance, une evolution aussi fluctuante sur une periode de temps si courte n’a jamais ete aussi bien documentee. Ce genre de lesions necessite une intervention chirurgicale avec la resection la plus complete de la paroi kystique afin d’assurer les meilleures chances de guerison.

Introduction L’hypogonadisme hypogonadotrope idiopathique (HHI) est caracterise par un manque de developpement pubertaire du a une anomalie congenitale de secretion ou d’action du GnRH (Gonadotropin Releasing Hormone). Elle peut s’associer a une hypo- ou anosmie (syndrome de Kallmann) ou une olfaction normale (HHI normosmique). Observation Un patient de 25 ans nous a ete adresse pour l’exploration d’un retard pubertaire. L’examen clinique trouve un habitus eunuchoid, un micropenis, des testicules sous-developpes, absence de pilosite androgeno-dependante, absence d’autres anomalies squelettiques ou de la ligne mediane. Il n’y avait pas d’antecedents familiaux de retard pubertaire, infertilite ou anosmie. Biologiquement, un hypogonadisme hypogonadotrope est diagnostique sans autre anomalie hormonale hypophysaire. Le caryotype est 46,XY. Le volume testiculaire en echographie est prepubertaire (2,5 mL). Il n’y a pas de trouble olfactif, ni d’anomalie hypophysaire ou renale en imagerie. Le traitement par hCG (gonadotrophine chorionique humaine) a ete debute avec une evolution clinique favorable : virilisation et debut de la spermatogenese apres 7 mois de traitement. La recherche genetique a trouve la mutation heterozygote intronique perte de fonction c.1663 + 1G > A du gene FGFR1. Elle modifie le splicing de l’exon 13 et, a notre connaissance, n’a jamais ete decrite precedemment. Discussion Nous rapportons un cas de HHI cause par une nouvelle mutation FGFR1 d’apparition de novo avec une tres bonne reponse au traitement par hCG. Les mutations dans ce gene peuvent resulter en une grande variabilite phenotypique et quelques cas d’HHI reversibles ont ete rapportes. Des recherches supplementaires sont necessaires afin de mieux connaitre les mecanismes expliquant la variabilite d’expression et la reversibilite.

Introduction Le traitement de 1re ligne des macroprolactinome est le plus souvent medicamenteux. Une fois la prolactine normalisee sous agonistes dopaminergiques, il n’existe pas de recommandation sur la necessite d’un suivi IRM. L’objectif de notre etude etait d’evaluer si les patients porteurs de macroprolactinome dont la prolactine etait normalisee medicalement pouvaient presenter une augmentation de volume tumoral au cours du suivi. Patients et methodes Etude retrospective multicentrique incluant des patients porteurs de macroprolactinome (taille superieure a 10 mm et prolactine superieure a 100 ng/mL au diagnostic) traites exclusivement par agoniste dopaminergique et pour lesquels un suivi d’au moins 48 mois sous traitement etait disponible. Resultats Cent quatorze patients (64 hommes et 50 femmes, âge moyen de 36,3 ans) ont ete inclus. La prolactine initiale moyenne etait de 1380 ng/mL (100–18 000 ng/mL). Deux patients (prolactine initiale, 275 et 665 ng/mL) ont presente une augmentation de volume tumoral Conclusion L’augmentation de volume tumoral est rare chez les patients controles sur le plan secretoire par agonistes dopaminergiques. Une surveillance IRM ne semble donc pas justifiee si la prolactinemie est surveillee au long cours apres normalisation.

Introduction Le syndrome de Cushing reste un des diagnostics les plus difficiles en endocrinologie. Son evaluation repose sur des mesures repetees de cortisol. La maladie de Cushing est causee, dans la majorite des cas, par un micro-adenome hypophysaire. Cependant, l’evaluation par IRM ne permet pas toujours de le deceler. Cas clinique Notre patiente âgee de 19 ans souffre de prise de poids et de resistance a l’insuline. Notre premiere evaluation biologique retrouve une legere majoration des CLUs (81,9 microg/24 h - normal Conclusion L’IRM hypophysaire permet aujourd’hui d’eviter le recours au catheterisme des sinus petreux dans un grand nombre de cas. Toutefois, certaines maladies de Cushing restent un defi diagnostique, tant sur le plan biologique que sur le plan radiologique et anatomopathologique.

Introduction Prolactinoma is a frequent cause of hypogonadisme. Dopamine agonist treatment is usually safe and efficient to restore fertility. During pregnancy, prolactinoma behavior depends on its initial size and its management can be challenging. In consequence, follow-up should be intensified in pregnant women. Observation We report here the case of a 28-year-old women, treated for symptomatic macroprolactinoma (adenoma size: 11mm (figure)-PRL: 429 mg/L). Cabergoline treatment (0,5 mg/week) allows a rapid clinical and radiological response (size: 5mm-PRL: 2,1 mg/L), leading to regular menses. Cabergoline treatment was stopped on July 2015 because of a pregnancy. After 4 months, she reports galactorrhea. At that time, PRL levels raised up to 827 mg/L and MRI revealed a tumor growth (size: 18 mm). Low dose cabergoline treatment (dose: 0,25 mg/week) was then reintroduced but did not control PRL levels (1226 mg/L). Treatment was then intensified (dose: 0,5 mg/week) and led to a better control of PRL levels (247 mg/L) and tumor size (11 mm). Conclusion Estrogen levels can influence lactotroph cells replication and prolactinoma size. Tumor growth of prolactinoma during pregnancy depends on their size (4,8% in treated macroprolactinomas, − 2,7% in treated microprolactinomas, − 22,9% in untreated marcoprolactinomas). On the other hand, dopamine agonists are usually discontinued during pregnancy, although evidences about cabergoline and bromocriptine safety are growing. As PRL levels rise physiologically during pregnancy, management of prolactinoma in this situation can be challenging. In our case, a rapid elevation of PRL levels suggests a tumor growth. We therefore recommend a monthly evaluation in macroprolactinoma, even if initial response to dopamine agonist was positive.

Introduction L’hypercalcemie hypocalciurique familiale (HHF) represente une maladie benigne, generalement asymptomatique, ne necessitant pas de traitement. Nous rapportons un cas de HHF avec pancreatites aigues recurrentes. Observation Un patient de 17 ans a ete hospitalise dans notre centre pour la prise en charge d’un episode recurrent de pancreatite aigue. Les explorations biologiques et d’imagerie n’ont pas trouve de facteur declenchant pour la pancreatite aigue sauf une importante hypercalcemie a 3,28 mmol/L (N :2,15–2,60), associee a l’augmentation de la parathormone-33 ng/L (N :4–26), de la 1,25(OH)2 vitamine D-133 pg/mL (N :23–109) et a une calciurie indosable. L’anamnese familiale a revele la notion d’hypercalcemie chez 5 membres de la famille maternelle. Le diagnostic de HHF a ete donc retenu. Le sequencage du gene calcium-sensing receptor (CaSR) a mis en evidence la mutation heterozygote R185Q. Devant l’absence de pathologie pancreatique chez les apparentes atteints d’HHF, la recherche des mutations des genes de predisposition aux pancreatites idiopathiques a ete menee. La mutation heterozygote N34S du gene SPINK1 est trouvee. Pour controler l’hypercalcemie, facteur precipitant des pancreatites, un traitement par cinacalcet a ete debute avec baisse de la calcemie a 2,95 mmol/L et sans recurrences pancreatiques. Discussion Nous presentons le cas d’une forme severe de HHF due a une mutation heterozygote avec effet dominant negatif du CaSR. Cette mutation engendre un degre d’hypercalcemie des plus severes rapportees dans la litterature, ce qui participe a l’apparition des pancreatites aigues recurrentes. Malgre le fait que l’HHF ne requiert pas normalement de traitement, dans ce cas, l’administration de cinacalcet a ete benefique.

Introduction Dix pour cent des hyperparathyroidies primaires sont des formes familiales, dont 10 % sont des hyperparathyroidies primaires isolees (familial isolated hyperparathyroidism [FIHP]). Observation Le patient, âge de 55 ans, nous a ete adresse pour la prise en charge d’une hyperparathyroidie recidivante apres parathyroidectomie (resection de 2 parathyroides) realisee 12 ans auparavant. L’aspect anatomopathologique correspondait a une hyperplasie. L’anamnese familiale releve une hyperparathyroidie connue chez la mere du patient et aussi chez 2 de ses 3 freres. Le geste de parathyroidectomie est etendu, en gardant uniquement une partie d’une des 2 parathyroides restantes, toutes les 2 hyperplasiques. En postoperatoire, le bilan phosphocalcique revient dans les normes. La recherche genetique montre une mutation heterozygote missense Ser253Leu du gene MEN1. Cette mutation a deja ete mentionnee dans un registre suedois, dans une famille d’apparente FIHP. Elle semble coder pour une menine moins stable que le wild-type, mais moins rapidement degradee par rapport aux mutations associees avec un phenotype de neoplasie endocrine multiple de type 1. Discussion Nous rapportons un nouveau cas familial de FIHP avec 4 membres atteints sur 2 generations. L’absence d’autre maladie dans le cadre d’une neoplasie endocrine multiple de type 1 et l’âge avance d’installation de l’hyperparathyroidie plaident pour le caractere isole de l’atteinte parathyroidienne. Malgre le fait qu’une correlation nette genotype-phenotype n’existe pas pour les mutations MEN1, il parait quand meme que certaines d’entre elles predisposent vers le phenotype plus leger de FIHP. Des recherches supplementaires doivent etre menees pour expliquer ces differences.

Introduction La synthese de PRL et de GH a ete documentee dans le tissu lymphoide normal. Une hyperprolactinemie paraneoplasique est rapportee chez quelques rares patients avec une leucemie (See et al. BMJ Case Rep 2013). Un seul cas d’acromegalie dependante d’un lymphome non-Hodgkin a ete publiee (Beuschlein et al. NEJM 2000) Observation Une femme africaine de 31 ans consulte pour fievre et malaises, neuf mois post-partum : le bilan biologique et la biopsie de moelle confirment une leucemie myeloblastique aigue. Malgre l’arret de l’allaitement, elle presente une galactorrhee et une amenorrhee persistante. Avant la premiere cure de chimio, la prolactine est de 6389 mUI/L. Un test au TRH documente ensuite une hyperprolactinemie a 3639 mUI/L (100–500) stimulable a 10 973 mUI/L. L’IGF1 est elevee a 429 μg/L (73–224). Un test HGPO 75 g demontre une GH basale a 0,64 μg/L avec un nadir de 0,11 μg/L. Au cours de 3 mois de seances de chimiotherapie, on observe une normalisation des parametres hematologiques. Parallelement, on observe une diminution progressive de la prolactine (3639–3617–396 mUI/L), de la GH (6,4–1,4–0,28) et de l’IGF1 (429–303–286). Une IRM hypohysaire n’objective pas de lesion hypothalamo-hypophysaire. Un scanner thoraco-abdominal et cerebral sont sans particularites. Discussion La normalisation progressive de prolactine et d’IGF1 au cours de la chimiotherapie et l’absence de lesion hypophysaire associee, rendent plausible une secretion paraneoplasique. Etant donne que l’echantillon de moelle etait insuffisant cette hypothese n’a pas pu etre documentee.

Objectif Le but de cette etude est de comparer la reponse des adenomes hypophysaires a GH au traitement en premiere ligne par analogues de la somatostatine(SSA) en fonction de l’intensite du signal IRM des adenomes en sequence T2. Materiel et methodes Au total, 95 patients acromegales traites par SSA pour une periode entre 3–12 mois ont ete inclus dans cette etude multicentrique de maniere retro- et prospective. Le volume tumoral, l’intensite du signal T2 sur l’IRM de diagnostic, aussi bien que des donnees biologiques (valeurs de GH et IGF1) avant et apres traitement par SSA ont ete retenus. Resultats Au diagnostic, il y avait 70 % d’adenomes T2-hypointenses, 14 % hyperintenses et 16 % isointenses. Les adenomes T2-hypointenses ont presente une diminution volumique mediane sous traitement de 32,8 %, ceux T2-hyperintenses de 22,4 % et ceux isointenses de 12,7 % (p = 0,0009). Concernant la reponse biologique aux SSA, la diminution mediane du taux d’IGF1 sous traitement a ete plus importante pour les adenomes T2-hypointenses (59 %) versus T2-hyperintenses (33 %) et T2-isointenses (30 %)(p = 0,001). Discussion Les premiers resultats de notre etude soutiennent le role du signal T2 des adenomes a GH comme facteur predictif de la reponse biologique et tumorale au traitement par SSA, avec une reponse plus importante des adenomes T2-hypointenses. Une analyse de ces donnees sur une serie encore plus nombreuse serait interessante, ainsi que la correlation entre le signal T2 et l’aspect histologique de ces adenomes.

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.Les inhibiteurs des checkpoints immunitaires ont considérablement changé la prise en charge des cancers. Ces thérapeutiques sont actuellement représentées par les anticorps monoclonaux anti-CTLA-4 (cytotoxic T-lymphocyte antigen 4), anti-PD-1 (programmed cell death protein-1) et anti-PD-L1 (un de ses ligands). En bloquant ces récepteurs ou ligands, les anticorps contrecarrent le freinage immunitaire instauré par la cellule cancéreuse sur le lymphocyte T et favorisent, alors, la réactivation du lymphocyte et son activité anti-tumorale. Ces checkpoints sont essentiels dans le maintien de la tolérance immune aux auto-antigènes. En les ciblant, des effets secondaires de type auto-immun peuvent apparaître. S’ils privilégient principalement le système cutané et digestif, les glandes endocrines n’en sont néanmoins pas oubliées. Dans cet article, nous suggérons des algorithmes de surveillance et de prise en charge de ces manifestations indésirables endocriniennes. Le diagnostic précoce de celles-ci et leur traitement adéquat permettraient de réduire leur impact négatif sur la prise en charge de la maladie cancéreuse.