Inquiry of the Metabolic Traits in Relationship with Daily Magnesium Intake: Focus on Type 2 Diabetic Population.

Magnesium (Mg), an essential nutrient with a wide area of physiological roles, stands as a cofactor in over 600 enzymatic reactions involved in the synthesis of proteins and nucleic acids, DNA repair, neuromuscular functions, neuronal transmission, cardiac rhythm regulation, and the modulation of metabolic pathways, as well as acting as a natural blocker for the calcium channels. Our objective was to highlight the most recent clinical data with respect to daily Mg intake (DMI) and metabolic traits, particularly type 2 diabetes mellitus (DM). This was a PubMed-based review of the English-language medical papers across different key terms of search; the time frame was from January 2019 until April 2024. We included (clinically relevant) original studies and excluded cases reports, series, reviews, editorials, opinion, experimental studies, and non-human data as well as studies that did not specifically assessed DMI and only provided assays of serum Mg, studies on patients diagnosed with type 1 or secondary DM. A total of 30 studies were included and we organized the key findings into several sections as follows. Studies investigating DMI in relationship with the adherence to local recommendations in diabetic subjects (n = 2, one transversal and another retrospective cohort; N = 2823) found that most of them had lower DMI. Deficient DMI was correlated with the risk of developing/having DM across five studies (n = 5, one prospective and four of cross-sectional design; N = 47,166). An inverse correlation between DMI and DM prevalence was identified, but these data are presented amid a rather heterogeneous spectrum. Four novel studies (N = 7279) analysed the relationship between DMI and DM control according to various methods (HbA1c, fasting and postprandial glycaemia, and insulin); the association may be linear in diabetic subjects only at certain levels of DMI; additionally, the multifactorial influence on HBA1c should take into consideration this dietary determinant, as well, but there are no homogenous results. Three studies concerning DMI and diabetic complications (one cross-sectional, one prospective, and another case-control study) in terms of retinopathy (n = 1, N = 3794) and nephropathy (n = 2, N = 4805) suggested a lower DMI was associated with a higher risk of such complications. Additionally, two other studies (one prospective and one retrospective cohort) focused on mortality (N = 6744), which, taking only certain mortality indicators into consideration, might be decreased in the subgroups with a higher DMI. Seven studies (N = 30,610) analysed the perspective of DMI in the general population with the endpoint of different features amid glucose profile, particularly, insulin resistance. Concerning HOMA-IR, there were three confirmatory studies and one non-confirmatory, while fasting plasma glucose was highlighted as inversely correlated with a DMI (n = 1). The highest level of evidence regarding Mg supplementation effects on glucose metabolism stands on seven randomised controlled trials (N = 350). However, the sample size was reduced (from 14 to 86 individuals per study, either diabetic or pre-diabetic) and outcomes were rather discordant. These clinical aspects are essential from a multidisciplinary perspective and further trials are mandatory to address the current areas of discordant results.

Turning Points in Cross-Disciplinary Perspective of Primary Hyperparathyroidism and Pancreas Involvements: Hypercalcemia-Induced Pancreatitis, MEN1 Gene-Related Tumors, and Insulin Resistance.

We aimed to provide an in-depth analysis with respect to three turning points in pancreas involvement in primary hyperparathyroidism (PHP): hypercalcemia-induced pancreatitis (HCa-P), MEN1 (multiple endocrine neoplasia)-related neuroendocrine tumors (NETs), and insulin resistance (IR). This was a comprehensive review conducted via a PubMed search between January 2020 and January 2024. HCa-P (n = 9 studies, N = 1375) involved as a starting point parathyroid NETs (n = 7) or pancreatitis (n = 2, N = 167). Case report-focused analysis (N = 27) showed five cases of pregnancy PHP-HCa-P and three reports of parathyroid carcinoma (female/male ratio of 2/1, ages of 34 in women, men of 56). MEN1-NET studies (n = 7) included MEN1-related insulinomas (n = 2) or MEN1-associated PHP (n = 2) or analyses of genetic profile (n = 3), for a total of 877 MEN1 subjects. In MEN1 insulinomas (N = 77), the rate of associated PHP was 78%. Recurrence after parathyroidectomy (N = 585 with PHP) was higher after less-than-subtotal versus subtotal parathyroidectomy (68% versus 45%, p < 0.001); re-do surgery was 26% depending on surgery for pancreatic NETs (found in 82% of PHP patients). MEN1 pathogenic variants in exon 10 represented an independent risk factor for PHP recurrence. A single pediatric study in MEN1 (N = 80) revealed the following: a PHP rate of 80% and pancreatic NET rate of 35% and 35 underlying germline MEN1 pathogenic variants (and 3/35 of them were newly detected). The co-occurrence of genetic anomalies included the following: CDC73 gene variant, glucokinase regulatory protein gene pathogenic variant (c.151C>T, p.Arg51*), and CAH-X syndrome. IR/metabolic feature-focused analysis identified (n = 10, N = 1010) a heterogeneous spectrum: approximately one-third of adults might have had prediabetes, almost half displayed some level of IR as reflected by HOMA-IR > 2.6, and serum calcium was positively correlated with HOMA-IR. Vitamin D deficiency was associated with a higher rate of metabolic syndrome (n = 1). Normocalcemic and mildly symptomatic hyperparathyroidism (n = 6, N = 193) was associated with a higher fasting glucose and some improvement after parathyroidectomy. This multilayer pancreas/parathyroid analysis highlighted a complex panel of connections from pathogenic factors, including biochemical, molecular, genetic, and metabolic factors, to a clinical multidisciplinary panel.

Insights into Hyperparathyroidism-Jaw Tumour Syndrome: From Endocrine Acumen to the Spectrum of CDC73 Gene and Parafibromin-Deficient Tumours.

A total of 1 out of 10 patients with primary hyperparathyroidism (PHP) presents an underlying genetic form, such as multiple endocrine neoplasia types 1, 2A, etc., as well as hyperparathyroidism-jaw tumour syndrome (HJT). We aimed to summarise the recent data, thus raising more awareness regarding HJT, from the clinical perspective of PHP in association with the challenges and pitfalls of CDC73 genetic testing and parafibromin staining. This narrative review included a sample-focused analysis from the past decade according to a PubMed search. We identified 17 original human studies (≥4 patients per article). The mean age at disease onset was between 20.8 and 39.5 years, while the largest study found that 71% of patients had HJT recognised before the age of 30. Males and females seemed to be equally affected, in contrast with sporadic PHP. PHP represented the central manifestation of HJT, occurring as the first manifestation in up to 85% of HJT cases. A biochemistry panel found a mean serum calcium level above the level of 12 mg/dL in PHP. PTH was elevated in HJT as well, with average values of at least 236.6 pg/mL. The most frequent pathological type in PHP was a parathyroid adenoma, but the incidence of a parathyroid carcinoma was much higher than in non-HJT cases (15% of all parathyroid tumours), with the diagnosis being established between the age of 15 and 37.5. In some families up to 85% of carriers suffered from a parathyroid carcinoma thus indicating that certain CDC73 pathogenic variants may harbour a higher risk. An important issue in HJT was represented by the parafibromin profile in the parathyroid tumours since in HJT both parathyroid adenomas and carcinomas might display a deficient immunoreactivity. Another frequent manifestation in HJT was ossifying fibromas of the jaw (affecting 5.4% to 50% of patients; the largest study found a prevalence of 15.4%). HJT was associated with a wide variety of kidney lesion (mostly: kidney cysts, with a prevalence of up to 75%, and renal tumours involved in 19% of patients). The risk of uterine lesions seemed increased in HJT, especially with concern to leiomyomas, adenofibromas, and adenomyosis. The underlying pathogenic mechanisms and the involvement of CDC73 pathogenic variants and parafibromin expression are yet to be explored. Currently, the heterogeneous expression of parafibromin status and, the wide spectrum of CDC73 mutations including the variety of clinical presentations in HJT, make it difficult to predict the phenotype based on the genotype. The central role of HJT-PHP is, however, the main clinical element, while the elevated risk of parathyroid carcinoma requires a special awareness.

Trabecular Bone Score (TBS) in Individuals with Type 2 Diabetes Mellitus: An Updated Review.

Bone fragility is a complication of type 2 diabetes mellitus (T2DM) that has been identified in recent decades. Trabecular bone score (TBS) appears to be more accurate than bone mineral density (BMD) in diabetic bone disease, particularly in menopausal women with T2DM, to independently capture the fracture risk. Our purpose was to provide the most recent overview on TBS-associated clinical data in T2DM. The core of this narrative review is based on original studies (PubMed-indexed journals, full-length, English articles). The sample-based analysis (n = 11, N = 4653) confirmed the use of TBS in T2DM particularly in females (females/males ratio of 1.9), with ages varying between 35 and 91 (mean 65.34) years. With concern to the study design, apart from the transversal studies, two others were prospective, while another two were case-control. These early-post-pandemic data included studies of various sample sizes, such as: males and females (N of 245, 361, 511, and 2294), only women (N of 80, 96, 104, 243, 493, and 887), and only men (N = 169). Overall, this 21-month study on published data confirmed the prior profile of BMD-TBS in T2DM, while the issue of whether checking the fracture risk is mandatory in adults with uncontrolled T2DM remains to be proven or whether, on the other hand, a reduced TBS might function as a surrogate marker of complicated/uncontrolled T2DM. The interventional approach with bisphosphonates for treating T2DM-associated osteoporosis remains a standard one (n = 2). One control study on 4 mg zoledronic acid showed after 1 year a statistically significant increase of lumbar BMD in both diabetic and non-diabetic groups (+3.6%, p = 0.01 and +6.2%, p = 0.01, respectively). Further studies will pinpoint additive benefits on glucose status of anti-osteoporotic drugs or will confirm if certain glucose-lowering regimes are supplementarily beneficial for fracture risk reduction. The novelty of this literature research: these insights showed once again that the patients with T2DM often have a lower TBS than those without diabetes or with normal glucose levels. Therefore, the decline in TBS may reflect an early stage of bone health impairment in T2DM. The novelty of the TBS as a handy, non-invasive method that proved to be an index of bone microarchitecture confirms its practicality as an easily applicable tool for assessing bone fragility in T2DM.

Cross-Disciplinary Approach of Adrenal Tumors: Insights into Primary Aldosteronism-Related Mineral Metabolism Status and Osteoporotic Fracture Risk.

Our objective was to overview the novel aspects in the field of adrenal gland neoplasms, namely, the management of bone status with respect to primary aldosteronism (PA). In the current narrative review, a PubMed study was conducted from inception until June 2023. The inclusion criteria were: human (clinically relevant) studies of any study design (at least 10 patients per study); English papers; and the following combination of key words within the title and/or abstract: "aldosterone" AND "bone", "skeleton", "osteoporosis", "fracture", "calcium", "parathyroid", "DXA", "osteocalcin", "P1NP", "alkaline phosphatase", "bone marker", "trabecular bone score", or "FRAX". The exclusion criteria were in vitro or animal studies, reviews, and case reports/series. We screened 1027 articles and finally included 23 studies (13 of case-control type, 3 cross-sectional, 5 prospective, 1 observational cohort, and 1 retrospective study). The assessments provided in these studies were as follows: nine studies addressed Dual-Energy X-ray Absorptiometry (DXA), another study pointed out a bone microarchitecture evaluation underlying trabecular bone score (TBS), and seven studies investigated the bone turnover markers (BTMs) profile. Moreover, 14 studies followed the subjects after adrenalectomy versus medical treatment, and 21 studies addressed secondary hyperparathyroidism in PA patients. According to our study on published data during a period of almost 40 years (n = 23, N = 3965 subjects aged between 38 and 64, with a mean age 56.75, and a female-to-male ratio of 1.05), a higher PTH in PA versus controls (healthy persons or subjects with essential hypertension) is expected, secondary hyperparathyroidism being associated in almost half of the adults diagnosed with PA. Additionally, mineral metabolism anomalies in PA may include lower serum calcium and higher urinary calcium output, all these three parameters being reversible under specific therapy for PA, regardless medical or surgical. The PA subgroup with high PTH seems at higher cardiovascular risk, while unilateral rather than bilateral disease was prone to this PTH anomaly. Moreover, bone mineral density (BMD) according to central DXA might show a higher fracture risk only in certain adults, TBS being a promising alternative (with a still unknown perspective of diabetes' influence on DXA-TBS results in PA). However, an overall increased fracture prevalence in PA is described in most studies, especially with respect to the vertebral site, the fracture risk that seems correctable upon aldosterone excess remission. These data recommend PA as a cause of secondary osteoporosis, a treatable one via PA intervention. There is still an area of debate the way to address BMTs profile in PA, the case's selection toward specific bone evaluation in every day practice, and further on, the understanding of the potential genetic influence at the level of bone and mineral complications in PA patients.

Landscape of Adrenal Tumours in Patients with Congenital Adrenal Hyperplasia.

Our aim is to update the topic of adrenal tumours (ATs) in congenital adrenal hyperplasia (CAH) based on a multidisciplinary, clinical perspective via an endocrine approach. This narrative review is based on a PubMed search of full-length, English articles between January 2014 and July 2023. We included 52 original papers: 9 studies, 8 case series, and 35 single case reports. Firstly, we introduce a case-based analysis of 59 CAH-ATs cases with four types of enzymatic defects (CYP21A2, CYP17A1, CYP17B1, and HSD3B2). Secondarily, we analysed prevalence studies; their sample size varied from 53 to 26,000 individuals. AT prevalence among CAH was of 13.3-20%. CAH prevalence among individuals with previous imaging diagnosis of AT was of 0.3-3.6%. Overall, this 10-year, sample-based analysis represents one of the most complex studies in the area of CAH-ATs so far. These masses should be taken into consideration. They may reach impressive sizes of up to 30-40 cm, with compressive effects. Adrenalectomy was chosen based on an individual multidisciplinary decision. Many tumours are detected in subjects with a poor disease control, or they represent the first step toward CAH identification. We noted a left lateralization with a less clear pathogenic explanation. The most frequent tumour remains myelolipoma. The risk of adrenocortical carcinoma should not be overlooked. Noting the increasing prevalence of adrenal incidentalomas, CAH testing might be indicated to identify non-classical forms of CAH.

Pediatric Neuroendocrine Neoplasia of the Parathyroid Glands: Delving into Primary Hyperparathyroidism.

Our objective was to overview the most recent data on primary hyperparathyroidism (PHP) in children and teenagers from a multidisciplinary perspective. Methods: narrative review based on full-length, English-language papers (from PubMed, between January 2020 and July 2023). Results: 48 papers (14 studies of ≥10 subjects/study, and 34 case reports/series of <10 patients/study). Study-sample-based analysis: except for one case-control study, all of the studies were retrospective, representing both multicenter (n = 5) and single-center (n = 7) studies, and cohort sizes varied from small (N = 10 to 19), to medium-sized (N = 23 to 36) and large (N = 63 to 83); in total, the reviewed studies covered 493 individuals with PHP. Case reports/series (n = 34, N = 41): the mean ages studied varied from 10.2 to 14 years in case reports, and the mean age was 17 years in case series. No clear female predominance was identified, unlike that observed in the adult population. Concerning the assessments, there were four major types of endpoints: imaging data collection, such as ultrasound, 99mTc Sestamibi, or dual-phase computed tomography (CT); gene testing/familial syndrome identification; preoperative findings; and exposure to surgical outcome/preoperative drugs, like cinacalcet, over a 2.2-year median (plus two case reports of denosumab used as an off-label calcium-lowering agent). Single-gland cases (representing 85% of sporadic cases and 19% of genetic PHP cases) showed 100% sensitivity for neck ultrasounds, with 98% concordance with 99mTc Sestamibi, as well as a 91% sensitivity for dual-phase CT, with 25% of the lesions being ectopic parathyroids (mostly mediastinal intra-thymic). Case reports included another 9/41 patients with ectopic parathyroid adenomas, 3/41 with parathyroid carcinomas, and 8/41 subjects with brown tumors. Genetic PHP (which has a prevalence of 5-26.9%) mostly involved MEN1, followed by CDC73, CASR, RET, and CDKN1B, as well as one case of VHL. Symptomatic PHP: 70-100% of all cases. Asymptomatic PHP: 60% of genetic PHP cases. Renal involvement: 10.5% of a cohort with genetic PHP, 71% of sporadic PHP cases; 50% (in a cohort with a mean age of 16.7), 29% (in a cohort with a mean age of 15.2); 0% (in infancy) to 50-62% (in teenagers). Bone anomalies: 83% of the children in one study and 62% of those in two other studies. Gastrointestinal issues: 40% of one cohort, but the data are heterogeneous. Cure rate through parathyroidectomy: 97-98%. Recurrent PHP: 2% of sporadic PHP cases and 38% of familial PHP cases. Hungry bone syndrome: maximum rate of 34-40%. Case reports identified another 7/41 subjects with the same post-parathyroidectomy condition; a potential connection with ectopic presentation or brown tumors is suggested, but there are limited data. Minimally invasive thoracoscopic approaches for ectopic tumors seemed safe. The current level of statistical evidence on pediatric PHP qualifies our study- and case-sample-based analysis (n = 48, N = 534) as one of the largest of its kind. Awareness of PHP is the key factor to benefit our young patients.

Paget's Disease of the Bone and Lynch Syndrome: An Exceptional Finding.

Our objective is to present an exceptional case of a patient diagnosed with Paget's disease of the bone (PDB) while being confirmed with Lynch syndrome (LS). A 44-year-old woman was admitted for progressive pain in the left forearm 2 years ago, and was partially relieved since admission by non-steroidal anti-inflammatory drugs. Suggestive imaging findings and increased blood bone turnover markers helped the diagnosis of PDB. She was offered zoledronate 5 mg. She had two more episodes of relapse, and a decision of new medication was taken within the following years (a second dose of zoledronate, as well as denosumab 60 mg). Her family history showed PDB (mother) and colorectal cancer (father). Whole exome sequencing was performed according to the manufacturer's standard procedure (Ion AmpliSeq™ Exome RDY S5 Kit). A heterozygous pathogenic variant in the SQSTM1 gene (c.1175C>T, p.Pro392Leu) was confirmed, consistent with the diagnosis of PDB. Additionally, a heterozygous pathogenic variant of MSH2 gene (c.2634+1G>T) was associated with LS. The patient's first-degree relatives (her brother, one of her two sisters, and her only daughter) underwent specific genetic screening and found negative results, except for her daughter, who tested positive for both pathogenic variants while being clinically asymptomatic. The phenotype influence of either mutation is still an open issue. To our current knowledge, no similar case has been published before. Both genetic defects that led to the two conditions appeared highly transmissible in the patient's family. The patient might have an increased risk of osteosarcoma and chondrosarcoma, both due to PDB and LS, and a review of the literature was introduced in this particular matter. The phenotypic expression of the daughter remains uncertain and is yet to be a lifelong follow-up as the second patient harbouring this unique combination of gene anomalies.

Challenges of Pituitary Apoplexy in Pregnancy.

Our purpose is to provide new insights concerning the challenges of pituitary apoplexy in pregnancy (PAP) and the postpartum period (PAPP). This is a narrative review of the English literature using a PubMed search. The inclusion criteria were clinically relevant original studies (January 2012-December 2022). Overall, we included 35 original studies: 7 observational studies (selected cases on PA) and 28 case reports, including 4 case series (N = 49; PAP/PAPP = 43/6). The characteristics of PAP patients (N = 43) are as follows: maternal age between 21 and 41 (mean of 27.76) years; 21/43 subjects with a presentation during the third trimester (only one case during first trimester); average weak of gestation of 26.38; most females were prim gravidae; 19 (out of 30 patients with available data on delivery) underwent a cesarean section. Headache remains the main clinical feature and is potentially associated with a heterogeneous panel (including visual anomalies, nausea, vomiting, cranial nerve palsies, diabetes insipidus, photophobia, and neck stiffness). Pre-pregnancy medication included dopamine agonists (15/43) and terguride (1/43) in addition to subsequent insulin therapy for gestational diabetes (N = 2) and type 1 diabetes mellitus (N = 1). Overall, 29/43 females received the conservative approach, and 22/43 women had trans-sphenoidal surgery (TSS) (and 10/22 had the initial approach). Furthermore, 18/43 patients had a pituitary adenoma undiagnosed before pregnancy. Most PA-associated tumors were prolactinomas (N = 26/43), with the majority of them (N = 16/26) being larger than 1 cm. A maternal-fetal deadly outcome is reported in a single case. The characteristics of PAPP patients (N = 6) are as follows: mean age at diagnosis of 33 years; 3/6 subjects had PA during their second pregnancy; the timing of PA varied between 5 min and 12 days after delivery; headache was the main clinical element; 5/6 had no underlying pituitary adenoma; 5/6 patients were managed conservatively and 1/6 underwent TSS; pituitary function recovered (N = 3) or led to persistent hypopituitarism (N = 3). In conclusion, PAP represents a rare, life-threatening condition. Headache is the most frequent presentation, and its prompt distinction from other conditions associated with headache, such as preeclampsia and meningitis, is essential. The index of suspicion should be high, especially in patients with additional risk factors such as pre-gestation treatment with dopamine agonists, diabetes mellitus, anticoagulation therapy, or large pituitary tumors. The management is conservative in most cases, and it mainly includes corticosteroid substitution and dopamine agonists. The most frequent surgical indication is neuro-ophthalmological deterioration, although the actual risk of pituitary surgery during pregnancy remains unknown. PAPP is exceptionally reported. To our knowledge, this sample-case series study is the largest of its kind that is meant to increase the awareness to the benefit of the maternal-fetal outcomes from multidisciplinary insights.

Pituitary Apoplexy in Patients with Pituitary Neuroendocrine Tumors (PitNET).

Various complications of pituitary neuroendocrine tumors (PitNET) are reported, and an intratumor hemorrhage or infarct underlying pituitary apoplexy (PA) represents an uncommon, yet potentially life-threatening, feature, and thus early recognition and prompt intervention are important. Our purpose is to overview PA from clinical presentation to management and outcome. This is a narrative review of the English-language, PubMed-based original articles from 2012 to 2022 concerning PA, with the exception of pregnancy- and COVID-19-associated PA, and non-spontaneous PA (prior specific therapy for PitNET). We identified 194 original papers including 1452 patients with PA (926 males, 525 females, and one transgender male; a male-to-female ratio of 1.76; mean age at PA diagnostic of 50.52 years, the youngest being 9, the oldest being 85). Clinical presentation included severe headache in the majority of cases (but some exceptions are registered, as well); neuro-ophthalmic panel with nausea and vomiting, meningism, and cerebral ischemia; respectively, decreased visual acuity to complete blindness in two cases; visual field defects: hemianopia, cranial nerve palsies manifesting as diplopia in the majority, followed by ptosis and ophthalmoplegia (most frequent cranial nerve affected was the oculomotor nerve, and, rarely, abducens and trochlear); proptosis (N = 2 cases). Risk factors are high blood pressure followed by diabetes mellitus as the main elements. Qualitative analysis also pointed out infections, trauma, hematologic conditions (thrombocytopenia, polycythemia), Takotsubo cardiomyopathy, and T3 thyrotoxicosis. Iatrogenic elements may be classified into three main categories: medication, diagnostic tests and techniques, and surgical procedures. The first group is dominated by anticoagulant and antiplatelet drugs; additionally, at a low level of statistical evidence, we mention androgen deprivation therapy for prostate cancer, chemotherapy, thyroxine therapy, oral contraceptives, and phosphodiesterase 5 inhibitors. The second category includes a dexamethasone suppression test, clomiphene use, combined endocrine stimulation tests, and a regadenoson myocardial perfusion scan. The third category involves major surgery, laparoscopic surgery, coronary artery bypass surgery, mitral valvuloplasty, endonasal surgery, and lumbar fusion surgery in a prone position. PA in PitNETs still represents a challenging condition requiring a multidisciplinary team from first presentation to short- and long-term management. Controversies involve the specific panel of risk factors and adequate protocols with concern to neurosurgical decisions and their timing versus conservative approach. The present decade-based analysis, to our knowledge the largest so far on published cases, confirms a lack of unanimous approach and criteria of intervention, a large panel of circumstantial events, and potential triggers with different levels of statistical significance, in addition to a heterogeneous clinical picture (if any, as seen in subacute PA) and a spectrum of evolution that varies from spontaneous remission and control of PitNET-associated hormonal excess to exitus. Awareness is mandatory. A total of 25 cohorts have been published so far with more than 10 PA cases/studies, whereas the largest cohorts enrolled around 100 patients. Further studies are necessary.

Approach of Multiple Endocrine Neoplasia Type 1 (MEN1) Syndrome-Related Skin Tumors.

Non-endocrine findings in patients with MEN1 (multiple endocrine neoplasia) syndrome also include skin lesions, especially tumor-type lesions. This is a narrative review of the English-language medical literature including original studies concerning MEN1 and dermatological issues (apart from dermatologic features of each endocrine tumor/neuroendocrine neoplasia), identified through a PubMed-based search (based on clinical relevance, with no timeline restriction or concern regarding the level of statistical significance). We identified 27 original studies involving clinical presentation of patients with MEN1 and cutaneous tumors; eight other original studies that also included the genetic background; and four additional original studies were included. The largest cohorts were from studies in Italy (N = 145 individuals), Spain (N = 90), the United States (N = 48 and N = 32), and Japan (N = 28). The age of patients varied from 18 to 76 years, with the majority of individuals in their forties. The most common cutaneous tumors are angiofibromas (AF), collagenomas (CG), and lipomas (L). Other lesions are atypical nevi, basocellular carcinoma, squamous cell carcinoma, acrochordons, papillomatosis confluens et reticularis, gingival papules, and cutaneous T-cell lymphoma of the eyelid. Non-tumor aspects are confetti-like hypopigmentation, café-au-lait macules, and gingival papules. MEN1 gene, respective menin involvement has also been found in melanomas, but the association with MEN1 remains debatable. Typically, cutaneous tumors (AF, CG, and L) are benign and are surgically treated only for cosmetic reasons. Some of them are reported as first presentation. Even though skin lesions are not pathognomonic, recognizing them plays an important role in early identification of MEN1 patients. Whether a subgroup of MEN1 subjects is prone to developing these types of cutaneous lesions and how they influence MEN1 evolution is still an open issue.

Approach of Heterogeneous Spectrum Involving 3beta-Hydroxysteroid Dehydrogenase 2 Deficiency.

We aim to review data on 3beta-hydroxysteroid dehydrogenase type II (3ßHSD2) deficiency. We identified 30 studies within the last decade on PubMed: 1 longitudinal study (N = 14), 2 cross-sectional studies, 1 retrospective study (N = 16), and 26 case reports (total: 98 individuals). Regarding geographic area: Algeria (N = 14), Turkey (N = 31), China (2 case reports), Morocco (2 sisters), Anatolia (6 cases), and Italy (N = 1). Patients' age varied from first days of life to puberty; the oldest was of 34 y. Majority forms displayed were salt-wasting (SW); some associated disorders of sexual development (DSD) were attendant also-mostly 46,XY males and mild virilisation in some 46,XX females. SW pushed forward an early diagnosis due to severity of SW crisis. The clinical spectrum goes to: premature puberty (80%); 9 with testicular adrenal rest tumours (TARTs); one female with ovarian adrenal rest tumours (OARTs), and some cases with adrenal hyperplasia; cardio-metabolic complications, including iatrogenic Cushing' syndrome. More incidental (unusual) associations include: 1 subject with Barter syndrome, 1 Addison's disease, 2 subjects of Klinefelter syndrome (47,XXY/46,XX, respective 47,XXY). Neonatal screening for 21OHD was the scenario of detection in some cases; 17OHP might be elevated due to peripheral production (pitfall for misdiagnosis of 21OHD). An ACTH stimulation test was used in 2 studies. Liquid chromatography tandem-mass spectrometry unequivocally sustains the diagnostic by expressing high baseline 17OH-pregnenolone to cortisol ratio as well as 11-oxyandrogen levels. HSD3B2 gene sequencing was provided in 26 articles; around 20 mutations were described as "novel pathogenic mutation" (frameshift, missense or nonsense); many subjects had a consanguineous background. The current COVID-19 pandemic showed that CAH-associated chronic adrenal insufficiency is at higher risk. Non-adherence to hormonal replacement contributed to TARTs growth, thus making them surgery candidates. To our knowledge, this is the largest study on published cases strictly concerning 3ßHSD2 deficiency according to our methodology. Adequate case management underlines the recent shift from evidence-based medicine to individualized (patient-oriented) medicine, this approach being particularly applicable in this exceptional and challenging disorder.

Network analytics for drug repurposing in COVID-19.

To better understand the potential of drug repurposing in COVID-19, we analyzed control strategies over essential host factors for SARS-CoV-2 infection. We constructed comprehensive directed protein-protein interaction (PPI) networks integrating the top-ranked host factors, the drug target proteins and directed PPI data. We analyzed the networks to identify drug targets and combinations thereof that offer efficient control over the host factors. We validated our findings against clinical studies data and bioinformatics studies. Our method offers a new insight into the molecular details of the disease and into potentially new therapy targets for it. Our approach for drug repurposing is significant beyond COVID-19 and may be applied also to other diseases.