The Phenotypic Variability Associated with Hepatocyte Nuclear Factor 1B Genetic Defects Poses Challenges in Both Diagnosis and Therapy.

The evolving landscape of clinical genetics is becoming increasingly relevant in the field of nephrology. HNF1B-associated renal disease presents with a diverse array of renal and extrarenal manifestations, prominently featuring cystic kidney disease and diabetes mellitus. For the genetic analyses, whole exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) were performed. Bioinformatics analysis was performed with Ingenuity Clinical Insights software (Qiagen). The patient's electronic record was utilized after receiving informed consent. In this report, we present seven cases of HNF1B-associated kidney disease, each featuring distinct genetic abnormalities and displaying diverse extrarenal manifestations. Over 12 years, the mean decline in eGFR averaged -2.22 ± 0.7 mL/min/1.73 m2. Diabetes mellitus was present in five patients, kidney dysplastic lesions in six patients, pancreatic dysplasia, hypomagnesemia and abnormal liver function tests in three patients each. This case series emphasizes the phenotypic variability and the fast decline in kidney function associated with HNF-1B-related disease. Additionally, it underscores that complex clinical presentations may have a retrospectively straightforward explanation through the use of diverse genetic analytical tools.

Pituitary Tumorigenesis-Implications for Management.

Pituitary neuroendocrine tumors (PitNETs), the third most common intracranial tumor, are mostly benign. However, some of them may display a more aggressive behavior, invading into the surrounding structures. While they may rarely metastasize, they may resist different treatment modalities. Several major advances in molecular biology in the past few years led to the discovery of the possible mechanisms involved in pituitary tumorigenesis with a possible therapeutic implication. The mutations in the different proteins involved in the Gsa/protein kinase A/c AMP signaling pathway are well-known and are responsible for many PitNETS, such as somatotropinomas and, in the context of syndromes, as the McCune-Albright syndrome, Carney complex, familiar isolated pituitary adenoma (FIPA), and X-linked acrogigantism (XLAG). The other pathways involved are the MAPK/ERK, PI3K/Akt, Wnt, and the most recently studied HIPPO pathways. Moreover, the mutations in several other tumor suppressor genes, such as menin and CDKN1B, are responsible for the MEN1 and MEN4 syndromes and succinate dehydrogenase (SDHx) in the context of the 3PAs syndrome. Furthermore, the pituitary stem cells and miRNAs hold an essential role in pituitary tumorigenesis and may represent new molecular targets for their diagnosis and treatment. This review aims to summarize the different cell signaling pathways and genes involved in pituitary tumorigenesis in an attempt to clarify their implications for diagnosis and management.

The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors.

Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3-1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5-75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb +/- mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.

Gigantism and acromegaly due to Xq26 microduplications and GPR101 mutation.

BACKGROUND: Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS: We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS: We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein-coupled receptor, was overexpressed in patients' pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone-producing cells. CONCLUSIONS: We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.).

Functional characterization of two novel germline mutations of the KCNJ5 gene in hypertensive patients without primary aldosteronism but with ACTH-dependent aldosterone hypersecretion.

BACKGROUND: Germline mutations of the KCNJ5 gene encoding Kir3·4, a member of the inwardly rectifying K+ channel, have been identified in 'normal' adrenal glands, patients with familial hyperaldosteronism (FH) type III, aldosterone-producing adenomas (APAs) and sporadic cases of primary aldosteronism (PA). OBJECTIVE: To present two novel KCNJ5 gene mutations in hypertensive patients without PA, but with Adrenocorticotropic hormone (ACTH)-dependent aldosterone hypersecretion. DESIGN AND PATIENTS: Two hypertensive patients without PA, who exhibited enhanced ACTH-dependent response of aldosterone secretion, underwent genetic testing for the presence of the CYP11B1/CYP11B2 chimeric gene and KCNJ5 gene mutations. Genomic DNA was isolated from peripheral white blood cells, and the exons of the entire coding regions of the above genes were amplified and sequenced. Electrophysiological studies were performed to determine the effect of identified mutation(s) on the membrane reversal potentials. Structural biology studies were also carried out. RESULTS: Two novel germline heterozygous KCNJ5 mutations, p.V259M and p.Y348N, were detected in the two subjects. Electrophysiological studies showed that the Y348N mutation resulted in significantly less negative reversal potentials, suggesting loss of ion selectivity, while the V259M mutation did not affect the Kir3.4 current. In the mutated structural biology model, the N348 mutant resulted in significant loss of the ability for hydrogen bonding, while the M259 mutant was capable of establishing weaker interactions. The CYP11B1/CYP11B2 chimeric gene was not detected. CONCLUSIONS: These findings expand on the clinical spectrum of phenotypes associated with KCNJ5 mutations and implicate these mutations in the pathogenesis of hypertension associated with increased aldosterone response to ACTH stimulation.

Puberty suppression in adolescents with gender dysphoria: an emerging issue with multiple implications.

Controversy exists over puberty suppression (PS) in adolescents with gender dysphoria (GD). PS is preferentially achieved with GnRH analogues. By preventing the development of secondary sex characteristics, PS may improve psychological functioning, well-being, quality of life, emotional and behavioral (especially internalizing) problems and depressive symptoms, thus decreasing suicidality. PS can also extend the diagnostic period and give transgender adolescents time to explore their gender identity. GnRHa may also decrease the need for feminization/masculinization surgery. However, 2-year treatment with GnRHa may result in bone mass accrual retardation (decrease in BMD/BMAD z-scores), growth velocity deceleration (decrease in height SDS), increase in fat mass, temporary pause in oocyte/sperm maturation. The most common side effects of GnRHa are hot flashes, mood fluctuations, fatigue and headache. They are usually mild and rarely lead to GnRHa discontinuation. Based on current scientific evidence, PS could be recommended to adolescents who meet the diagnostic criteria of gender incongruence (by DSM-5 and/or ICD-11) and have long-lasting intense GD, which aggravates with puberty onset. Before initiating PS, possible mental issues should be addressed and informed consent (by the adolescent/caregiver) should be given, after counseling on probable reproductive effects of GnRHa. GnRHa can only be started after the adolescent has entered Tanner stage 2. Nevertheless, published studies are inadequate in number, small in size, uncontrolled and relatively short-term, so that it is difficult to draw safe conclusions on efficacy and safety of GnRHa. Large long-term randomized controlled trials are needed to expand knowledge on this controversial issue and elucidate the benefit and risks of PS.

Molecular developments in parasellar tumors and potential therapeutic implications.

The parasellar region is the anatomical area around the sella turcica that represents a crucial crossroad for important adjacent structures. Several distinct tumors can primarily originate from this area, the most common being meningiomas, gliomas, embryonal cell tumors, germ cell tumors and craniopharyngiomas. In addition, a number of systemic and inflammatory disorders can also affect the parasellar region most commonly involving the pituitary. These lesions have different pathology characteristics and malignant potential according to the new WHO CNS5 2021 classification. Signs and symptoms may be non-specific and are mostly related to a mass effect on the surrounding anatomical structures and/or impairment of endocrine function whereas the vast majority lack a secretory component. The mutational signature analysis based on advances in molecular techniques, has recently enabled the identification of specific gene mutations or signalling pathway aberrations. These developments may serve as a powerful mean to delineate the pathophysiology of these lesions and serve as a diagnostic, prognostic and therapeutic tool, particularly for high-risk populations. Treatment options include surgery alone or in combination with radiotherapy, chemotherapy and disease-specific medical therapy in order to prevent recurrence or further tumor growth along with replacement of coexistent pituitary hormonal deficiencies. In this comprehensive review, we present current state-of-the-art developments in the histopathology and molecular biology of these lesions that may be utilized by a dedicated multidisciplinary team of relevant specialties for the diagnosis, monitoring and treatment of the parasellar lesions that often represent a diagnostic and therapeutic challenge.

When rare diseases crisscross within the same patient: von Hippel-Lindau and type 1 gastric neuroendocrine tumor.

Von-Hippel-Lindau (VHL) is a genetic multisystem disorder characterized by visceral cysts and benign and malignant tumors in various organs. Herein, we present the case of a 23-year-old woman with VHL presenting with multiple gastric neuroendocrine neoplasms (gNENs) type 1 in the context of chronic autoimmune gastritis (CAG). Although gNENs are not acknowledged as a typical entity in VHL patients, in the present case, gNENs were composed of neoplastic cells with clear cytoplasm usually seen in tumors related to VHL disease. We additionally performed a literature review on the presence of neuroendocrine clear cell tumors and report on further cases of clear cell NENs. The present case illustrates that clear-cell transformation in gNENs may be due to the dual genetic background of the patient; the real oncogenic stimulus may be more closely related to CAG than to VHL disease accompanied by an interplay between neoplastic and autoimmune processes. Therefore, close monitoring of patients with clear cell NENs appears to be important before excluding VHL disease, even in the context of phenotypically unrelated diseases.

Secondary diabetes mellitus in pheochromocytomas and paragangliomas.

Secondary diabetes mellitus (DM) in secretory pheochromocytomas and paragangliomas (PPGLs) is encountered in up to 50% of cases, with its presentation ranging from mild, insulin resistant forms to profound insulin deficiency states, such as diabetic ketoacidosis and hyperglycemic hyperosmolar state. PPGLs represent hypermetabolic states, in which adrenaline and noradrenaline induce insulin resistance in target tissues characterized by aerobic glycolysis, excessive lipolysis, altered adipokine expression, subclinical inflammation, as well as enhanced gluconeogenesis and glucogenolysis. These effects are mediated both directly, upon adrenergic receptor stimulation, and indirectly, via increased glucagon secretion. Impaired insulin secretion is the principal pathogenetic mechanism of secondary DM in this setting; yet, this is relevant for tumors with adrenergic phenotype, arising from direct inhibitory actions in beta pancreatic cells and incretin effect impairment. In contrast, insulin secretion might be enhanced in tumors with noradrenergic phenotype. This dimorphic effect might correspond to two distinct glycemic phenotypes, with predominant insulin resistance and insulin deficiency respectively. Secondary DM improves substantially post-surgery, with up to 80% remission rate. The fact that surgical treatment of PPGLs restores insulin sensitivity and secretion at greater extent compared to alpha and beta blockade, implies the existence of further, non-adrenergic mechanisms, possibly involving other hormonal co-secretion by these tumors. DM management in PPGLs is scarcely studied. The efficacy and safety of newer anti-diabetic medications, such as glucagon-like peptide 1 receptor agonists and sodium glucose cotransporter 2 inhibitors (SGLT2is), as well as potential disease-modifying roles of metformin and SGLT2is warrant further investigation in future studies.

Primary adrenal insufficiency due to bilateral adrenal hemorrhage-adrenal infarction in a patient with systemic lupus erythematosus and antiphospholipid syndrome: case presentation and review of the literature.

Primary adrenal insufficiency (PAI) is a rare disease which represents the end stage of a destructive process involving the adrenal cortex. Occasionally it may be caused by bilateral adrenal hemorrhagic infarction in patients with antiphospholipid syndrome (APS). We herein report the challenging case of a 30-year-old female patient with systemic lupus erythematosus (SLE) and secondary APS who was admitted to the emergency department (ED) due to fever, lethargy, and syncopal episodes. Hyponatremia, hyperkalemia, hyperpigmentation, shock, altered mental status, and clinical response to glucocorticoid administration were features highly suggestive of an acute adrenal crisis. The patient's clinical status required admission to the intensive care unit (ICU), where steroid replacement, anticoagulation, and supportive therapy were provided, with a good outcome. Imaging demonstrated bilateral adrenal enlargement attributed to recent adrenal hemorrhage. This case highlights the fact that bilateral adrenal vein thrombosis and subsequent hemorrhage can be part of the thromboembolic complications seen in both primary and secondary APS and which, if misdiagnosed, may lead to a life-threatening adrenal crisis. High clinical suspicion is required for its prompt diagnosis and management. A literature search of past clinical cases with adrenal insufficiency (AI) in the setting of APS and SLE was conducted using major electronic databases. Our aim was to retrieve information about the pathophysiology, diagnosis, and management of similar conditions.

Secondary diabetes mellitus in acromegaly.

Secondary diabetes mellitus (DM) is a common complication of acromegaly, encountered in up to 55% of cases. Vice versa, the prevalence of acromegaly is markedly higher in cohorts of patients with type 2 DM (T2DM). The presence of secondary DM depends primarily on acromegaly status and is associated with increased cardiovascular morbidity, malignancy rate and overall mortality. The principal pathophysiologic mechanism is increased insulin resistance due to excessive lipolysis and altered fat distribution, reflected at the presence of intermuscular fat and attenuated, dysfunctional adipose tissue. Insulin resistance is ascribed to the direct, diabetogenic effects of growth hormone (GH), which prevail over the insulin-sensitizing effects of insulin-like growth factor 1 (IGF-1), probably due to higher glucometabolic potency of GH, IGF-1 resistance, or both. Inversely, GH and IGF-1 act synergistically in increasing insulin secretion. Hyperinsulinemia in portal vein leads to enhanced responsiveness of liver GH receptors and IGF-1 production, pointing towards a mutually amplifying loop between GH-IGF-1 axis and insulin. Secondary DM occurs upon beta cell exhaustion, principally due to gluco-lipo-toxicity. Somatostatin analogues inhibit insulin secretion; especially pasireotide (PASI) impairs glycaemic profile in up to 75% of cases, establishing a separate pathophysiologic entity, PASI-induced DM. In contrast, pegvisomant and dopamine agonizts improve insulin sensitivity. In turn, metformin, pioglitazone and sodium-glucose transporters 2 inhibitors might be disease-modifying by counteracting hyperinsulinemia or acting pleiotropically. Large, prospective cohort studies are needed to validate the above notions and define optimal DM management in acromegaly.

Thyroglobulin as a Rapid and Cost-Effective Biomarker for Diagnosis of Thyroid Carcinoma Brain Metastasis: A Case Report of a Patient with Metastatic Hurthle Cell Thyroid Carcinoma.

BACKGROUND Brain metastasis of papillary thyroid cancer (PTC) is rare. Treatment of these patients is challenging due to the lack of specific guidelines. Early diagnosis is accompanied by immediate treatment and less morbidity. Total resection of brain lesions may be unattainable when they include infiltration of eloquent areas. This report is of an 81-year-old man who had undergone total thyroidectomy for goiter in the past and presented with metastatic papillary thyroid carcinoma (PTC) to the neck after a gap of 16 years. After two years, the patient developed a solitary cystic brain PTC metastasis associated with raised thyroglobulin (Tg) inside the cystic lesion aspirated during brain surgery. CASE REPORT An 81-year-old male patient was admitted for a space-occupying brain lesion in the right frontal lobe. The patient's history included metastatic disease of PTC to the neck with cervical lymph node metastasis and local recurrence after surgery and radioactive iodine-131 treatment. The patient underwent craniotomy and removal of the lesion. The aspirated fluid was sent for cytological examination and measurement of Tg levels, which were interestingly high. Pathology of the brain lesion revealed infiltration of brain parenchyma from a metastatic lesion characterized by eosinophilic cells with irregular contours forming grooves, resulting in cytoplasmic pseudo-inclusions, an oncotic variant of PTC. CONCLUSIONS This report has shown that residual tissue may be present following total thyroidectomy and may be the origin of PTC with metastasis to the brain. The patient in this study suffered from a brain lesion that could be excised. However, aspiration of cystic compartments could provide a rapid diagnosis in patients with non-removable brain lesions.

Myxoma of the ear lobe in a 23-month-old girl with Carney complex.

Myxomas of the ear are extremely uncommon, especially in young children. A 23-month-old girl born to a family with known Carney complex, a condition that predisposes to multiple myxomas, presented with a large, cauliflower-like mass located on the back of her right ear. Histopathologically, the lesion was composed of scattered spindle-shaped or stellate cells with abundant associated mucin and a very sparse inflammatory infiltrate containing lymphocytes and neutrophils. The patient was a carrier of a protein kinase A regulatory subunit 1A (PRKAR1A) mutation; PRKAR1A mutations cause Carney complex in most patients with this rare disorder. This is the earliest presentation of an ear lobe myxoma reported in the literature.

Lack of mutations in the gene coding for the hGR (NR3C1) in a pediatric patient with ACTH-secreting pituitary adenoma, absence of stigmata of Cushing's syndrome and unusual histologic features.

BACKGROUND: Rare cases of human glucocorticoid receptor (hGRalpha) (NR3C1) gene mutations have been described in the gemline or somatic state in Cushing's disease (CD). AIM: We describe a pediatric patient with CD with clinical evidence of partial glucocorticoid resistance (GR) due to the relative absence of stigmata of Cushing's syndrome (CS). CASE DESCRIPTION: A 14-year-old boy with slow growth and hypertension, but no other signs of CS was admitted for CD evaluation. Urinary free cortisol levels (UFC) were consistently 2-3-fold the upper normal range. Pituitary magnetic resonance imaging (MRI) revealed a 3x4 mm hypoenhancing lesion in the right side of the pituitary gland anteriorly (microadenoma). A graded dexamethasone suppression test indicated that the patient had partial GR. Histology confirmed an adrenocorticotrophin (ACTH)-producing pituitary adenoma. We hypothesized that a NR3C1 mutation was present. Sequencing of the entire coding region of the gene produced normal results in both peripheral and tumor DNA. CONCLUSION: We present the case of a pediatric patient with an ACTH-producing tumor but little evidence of CS. No mutations in the coding sequence of NR3C1 were detected. We conclude that low level somatic mosaicism for NR3C1 mutations or a mutation in another molecule participating in hGRalpha-signaling may account for this case.

Recurrent left atrial myxomas in Carney complex: a genetic cause of multiple strokes that can be prevented.

BACKGROUND: Intracardiac myxomas in Carney complex are significant causes of cardiovascular morbidity and mortality through embolic stroke and heart failure. The genetic, clinical, and laboratory characteristics of Carney complex-related strokes from atrial myxomas have not been described. The regulatory subunit (R1A) of the protein kinase gene (PRKAR1A) is mutated in >60% of patients with Carney complex. METHODS: We studied patients with strokes and cardiac myxomas that were hospitalized in our institution and elsewhere; a total of 7 patients with 16 recurrent atrial myxomas and >14 episodes of strokes were identified. RESULTS: Neurologic deficits were reported; in 1 patient, an aneurysm developed at the site of a previous stroke. All patients were females, were also diagnosed with Cushing syndrome, and all had additional tumors or other Carney complex manifestations. Other than gender, although there was a trend for patients being overweight and hypertensive, no other risk factors were identified. A total of 5 patients (71%) had a PRKAR1A mutation; all mutations (c418_419delCA, c.340delG/p.Val113fsX15, c.353_365del13/p.Ile118fsX6, c.491_492delTG/p.Val164fsX4, and c.177+1G>A) were located in exons 3 to 5 and introns 2 to 3, and all led to a non-sense PRKAR1A mRNA. CONCLUSIONS: Female patients with Carney complex appear to be at a high risk for recurrent atrial myxomas that lead to multiple strokes. Early identification of a female patient with Carney complex is of paramount importance for the early diagnosis of atrial myxomas and the prevention of strokes.

Comparison of Hospital Consultation and Summer Camp Lifestyle Intervention Programs for Sustained Body Weight Loss in Overweight/Obese Greek Children.

Two lifestyle intervention programs of a health initiative named "Evrostia" were conducted at (a) an outpatient obesity clinic of a children's hospital and (b) summer camp (SC), respectively. Thirty overweight/obese children were randomly selected to participate in each intervention arm to assess the efficacy of the SC intervention and its possible superiority over usual hospital consultation (HC) practice. There was a statistically significant decrease in body weight (BW), and body mass index (BMI) in both programs. A higher duration of reduced BW was observed in the SC compared to HC intervention. Regarding the nutritional behavior, there was a significant increase in the consumption of breakfast, fruit and vegetables, and a reduction in the consumption of beverages and sweets in the SC group. A significant increase in the hours of weekly physical activity was also observed in children of the SC program. The comparison between the two lifestyle intervention programs showed that the SC program improved nutritional behaviors and physical activity and promoted longer preservation of BW loss than that of the HC program. Thus, the holistic and experiential approach of the SC program was more successful in the treatment of overweight and obesity in children than a conventional HC program.

SDHB immunohistochemistry: a useful tool in the diagnosis of Carney-Stratakis and Carney triad gastrointestinal stromal tumors.

Mutations in the tumor suppressor genes SDHB, SDHC, and SDHD (or collectively SDHx) cause the inherited paraganglioma syndromes, characterized by pheochromocytomas and paragangliomas. However, other tumors have been associated with SDHx mutations, such as gastrointestinal stromal tumors (GISTs) specifically in the context of Carney-Stratakis syndrome. Previously, we have shown that SDHB immunohistochemistry is a reliable technique for the identification of pheochromocytomas and paragangliomas caused by SDHx mutations. We hypothesized that GISTs in patients with SDHx mutations would be negative immunohistochemically for SDHB as well. Four GISTs from patients with Carney-Stratakis syndrome and six from patients with Carney triad were investigated by SDHB immunohistochemistry. Five GISTs with KIT or PDGFRA gene mutations were used as controls. In addition, SDHB immunohistochemistry was performed on 42 apparently sporadic GISTs. In cases in which the SDHB immunohistochemistry was negative, mutational analysis of SDHB, SDHC, and SDHD was performed. All GISTs from patients with Carney-Stratakis syndrome and Carney triad were negative for SDHB immunohistochemically. In one patient with Carney-Stratakis syndrome, a germline SDHB mutation was found (p.Ser92Thr). The five GISTs with a KIT or PDGFRA gene mutation were all immunohistochemically positive for SDHB. Of the 42 sporadic tumors, one GIST was SDHB-negative. Mutational analysis of this tumor did not reveal an SDHx mutation. All SDHB-negative GISTs were located in the stomach, had an epithelioid morphology, and had no KIT or PDGFRA mutations. We show that Carney-Stratakis syndrome- and Carney-triad-associated GISTs are negative by immunohistochemistry for SDHB in contrast to KIT- or PDGFRA-mutated GISTs and a majority of sporadic GISTs. We suggest that GISTs of epithelioid cell morphology are tested for SDHB immunohistochemically. In case of negative SDHB staining in GISTs, Carney-Stratakis syndrome or Carney triad should be considered and appropriate clinical surveillance should be instituted.

Medical Therapy for Craniopharyngiomas.

Craniopharyngiomas are rare benign neoplasms presenting in two different types, adamantinomatous (ACP) or papillary (PCP), which are molecularly and clinically distinct. Traditional treatment includes surgical resection and radiotherapy, which are accompanied by a number of debilitating complications because of the tumours' proximity to important brain structures. Recent advances in the understanding of molecular pathogenesis of craniopharyngiomas have opened horizons to medical therapeutic options. ACPs are mainly characterized by mutations of ß-catenin, which activate Wingless/Int (Wnt), and alter the mitogen extracellular kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway, as well as inflammatory, cellular senescence, programmed cell death and sonic hedgehog (SHH) pathways. PCPs are mainly characterized by Ras/Raf/MEK/ERK pathway activation secondary to BRAF-V600E mutations. MEK inhibitors, such as binimetinib, or anti-inflammatory mediators, such as tocilizumab or interferon, have been administered to patients with ACP and the efficacy is mostly favourable. On the other hand, BRAF inhibitors, such as dabrafenib or vemurafenib, either alone or in combination with the MEK inhibitors trametinib and cobimetinib, have been administered to patients with PCP resulting in favourable responses. A number of ongoing trials will shed light on schemes, doses, combined treatments and safety issues of the new molecular-targeted treatments, changing the management of patients with craniopharyngiomas by launching the era of personalized medicine in these rare neoplasms. We conducted a systematic review to identify case series or case reports with patients currently treated with systemic medical therapy.

Diabetes insipidus secondary to sellar/parasellar lesions.

Diabetes insipidus (DI) is a well-recognised transient or permanent complication following transsphenoidal surgery for pituitary adenomas or other sellar/parasellar lesions. However, data regarding the prevalence of pre-operative DI in sellar/parasellar lesions other than pituitary adenomas are scarce. We systematically reviewed the existing data for defining the prevalence of DI before any treatment in adult patients with sellar/parasellar lesions, excluding pituitary adenomas and metastatic lesions. In total, 646 patients with sellar/parasellar lesions presenting with DI at diagnosis were identified. The most common pathologies of sellar/parasellar lesions presenting with DI at diagnosis were lymphocytic hypophysitis (26.5%), craniopharyngiomas (23.4%), Langerhans's cell histiocytosis (18.9%) and Rathke's cleft cyst (12.7%), accounting for the vast majority (more than 80%) of these lesions. Overall, DI at diagnosis was found in 23.4% of all patients with sellar/parasellar lesions, albeit with a wide range from 10.6% to 76.7%, depending on the nature of the pathology. The highest prevalence of DI was found in less commonly encountered lesions namely germ-cell tumours (76.7%), abscesses (55.4%) and neurosarcoidosis (54.5%), each accounting for less than 3% of all sellar/parasellar lesions. Most DI cases (68.8%) were associated with anterior pituitary hormonal deficiencies, in contrast to pituitary adenomas that rarely present with DI. The enlargement and enhancement of the pituitary stalk were the most common findings on magnetic resonance imaging besides the loss of the high signal of the posterior pituitary on T1-weighted images. Resolution of DI spontaneously or following systemic and surgical management occurred in 22.4% of cases. Post-operative DI, not evident before surgery, was found in 27.8% of non-adenomatous sellar/parasellar lesions, and was transient in 11.6% of them. Besides distinctive imaging features and symptoms, early recognition of DI in such lesions is important because it directs the diagnosis towards a non-adenomatous sellar/parasellar tumour and the early initiation of appropriate treatment.