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.

Progesterone Hypersensitivity in Assisted Reproductive Technologies: Implications for Safety and Efficacy.

The global rise in the age of childbirth, influenced by changing sociodemographic patterns, has had a notable impact on fertility rates. Simultaneously, assisted reproductive techniques (ARTs) have become increasingly prevalent due to advancements in reproductive medicine. The paper explores the intersection between the surge in ARTs and the rising number of iatrogenic autoimmune progesterone dermatitis (APD). Autoimmune progesterone dermatitis, commonly known as progesterone hypersensitivity, manifests itself as a mucocutaneous hypersensitivity syndrome. It is characterized by a wide range of dermatological symptoms, with urticaria and maculopapular rashes being the most prominent signs. Concurrently, systemic symptoms, such as fever, angioedema, and, in severe instances, anaphylaxis, may ensue. This dermatologic condition poses a significant challenge to women of childbearing age. This intricate syndrome frequently manifests itself in conjunction with menstruation or pregnancy as a reaction to physiological fluctuations in endogenous progesterone. However, given that exposure to exogenous progesterone is an integral component of various modern therapies, secondary APD has also been described. Our findings unveil a heightened likelihood of developing secondary progesterone hypersensitivity in ART patients that is attributed to the administration of exogenous progesterone through intramuscular, intravaginal, and oral routes. The study also explores available therapeutic interventions for facilitating viable pregnancies in individuals grappling with autoimmune progesterone dermatitis within the context of ARTs. This comprehensive analysis contributes valuable insights into the intricate relationship between reproductive technologies, dermatological challenges, and successful pregnancy outcomes.

Vulvar Lichen Sclerosus: Navigating Sex Hormone Dynamics and Pioneering Personalized Treatment Paradigm.

Vulvar lichen sclerosus (VLS) is a frequently overlooked inflammatory disorder affecting the skin and mucous membranes of the vulva. With a propensity for atrophy, severe scarring, functional impairment, and malignant evolution, VLS is a disease that recurs frequently; early diagnosis, rapid treatment, and ongoing patient follow-up are essential. Potent topical corticosteroids (TCSs) are now widely recognized as the most effective treatment for achieving remission in VLS, but considering the potential complications of long-term treatment with potent TCSs, understanding the evolution of VLS during puberty becomes particularly crucial in determining the necessity for aggressive or more conservative therapeutic interventions. Emerging treatments, including PRP (platelet-rich plasma), stem cell therapy, and energy-based lasers like fractional CO2 and Nd-YAG, are being investigated to identify more effective VLS treatments than ultrapotent topical corticosteroids. However, more research is needed to assess the efficacy and safety of these new medicines. Topical clobetasol 0.05% ointment daily for 4-12 weeks is the gold standard for treating VLS. This article is a narrative review of the English-language medical literature from 2017 to November 2023, following three main sections concerning VLS: studies of the evolution amid pubertal hormonal changes; studies of the outcomes of personalized conventional therapies; and studies addressing the spectrum of innovative modalities for VLS.

Cutaneous Manifestations in Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED): A Comprehensive Review.

Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), or polyglandular autoimmune syndrome type 1 (PAS-1/APS-1), is a rare autosomal recessive disorder linked to mutations in the autoimmune regulator (AIRE) gene. This review provides a detailed analysis of cutaneous manifestations in APECED, focusing on chronic mucocutaneous candidiasis (CMC), alopecia areata (AA), and vitiligo. The classic triad of hypoparathyroidism, adrenal insufficiency, and CMC serves as a diagnostic cornerstone. However, the varied clinical spectrum of APECED, particularly its cutaneous presentations, poses a diagnostic challenge. CMC, often an early sign, varies in prevalence across populations, including Finnish (100%), Irish (100%), Saudi Arabian (80%), Italian (60-74.7%), North American (51-86%), and Croatian (57.1%) populations. Similarly, AA prevalence varies in different populations. Vitiligo also exhibits variable prevalence across regions. The review synthesizes the current knowledge arising from a narrative analysis of 14 significant human studies published in English up to October 2023. Moreover, this paper underscores the importance of early detection and monitoring, emphasizing cutaneous manifestations as key diagnostic indicators. Ongoing research and clinical vigilance are crucial for unraveling the complexities of this rare autoimmune syndrome and enhancing patient care.

Thyroid Disorders in Systemic Sclerosis: A Comprehensive Review.

Systemic sclerosis, also referred to as scleroderma, is a chronic autoimmune disease that affects both internal organs and the skin. Systemic sclerosis predominantly affects female patients and can coexist with other disorders, including those affecting the thyroid gland. Common symptoms such as fatigue and weight changes can be attributed to either systemic sclerosis or thyroid disease. In this comprehensive review, an extensive analysis is conducted using research from 2002 to 2022, sourced from PubMed. The main focus of this exploration is to understand the intricate relationship between thyroid disorders and systemic sclerosis. We obtained these results by analyzing a number of 32285 patients included in 21 original studies. The existing evidence suggests that there is a higher incidence of elevated TSH levels and hypothyroidism in patients with systemic sclerosis, particularly in females, compared to the general population. This remains true even when comparing patients from iodine-deficient regions. Additionally, there is an increased occurrence of hyperthyroidism in the context of systemic sclerosis, which negatively impacts the prognosis of these patients. Furthermore, thyroid antibodies, predominantly anti-thyroid peroxidase (anti-TPO) antibodies, and autoimmune disorders are more commonly observed in individuals with systemic sclerosis. Although thyroid nodules are not specifically linked to the disease, when considering thyroid volume, it is observed that the thyroid gland in systemic sclerosis patients has a decreased volume, possibly due to fibrosis. Conversely, other studies have revealed that patients without autoimmune thyroid diseases (AITDs) are more likely to have a history of digital ulcers, pulmonary fibrosis detected by computed tomography scan, and a requirement for immunosuppressive medication. The majority of the studies did not establish a connection between thyroid disease in these patients and the occurrence of the limited or diffuse forms of systemic sclerosis, as well as the presence of digital ulcers, calcinosis, pulmonary arterial hypertension, scleroderma renal crisis, Raynaud phenomenon, and various other clinical manifestations.

Corrigendum: Laparoscopic myomectomy - The importance of surgical techniques.

[This corrects the article DOI: 10.3389/fmed.2023.1158264.].

Infantile Hemangioma: A Cross-Sectional Observational Study.

(1) Background: With an incidence of 4-10%, infantile hemangiomas (IH) are the most encountered benign tumors in infancy. Low birth weight (LBW), prematurity, female sex, multiple gestations, and family history of IH are some of the statistically proven risk factors for developing IH. The aim of our study was to evaluate the prevalence of IH in our clinic and its connection to maternal and perinatal factors. (2) Methods: We conducted a cross-sectional study, over three years (2020-2022), at the Clinical Hospital of Obstetrics and Gynecology, "Prof. Dr. P. Sârbu", in Bucharest, Romania. (3) Results: During this period, 12,206 newborns were born and we identified 14 infants with infantile hemangioma. In our study, the prevalence of infantile hemangioma was 0.11%. The prevalence of IH in pregnancies obtained through in vitro fertilization was 1%, in twin pregnancies it was 2.27%, and in those with placenta previa, it was 4.16%. (4) Conclusions: Our findings provide a solid image of the prevalence of IH in our country and underline that the development of IH is strongly connected to maternal and perinatal variables, such as: preterm newborns, in vitro fertilization, high blood pressure, anemia, hypothyroidism, placenta previa, and twin pregnancy.

The Follicular Dendritic Cells and HPV 18 Interrelation in Head and Neck Squamous Cell Carcinomas of the Larynx.

Background and Objectives: Even if they are cells of controversial origin (mesenchymal, perivascular, or fibroblastic), follicular dendritic cells (FDC) are present in all organs. The aim of this study was to establish the FDC expression pattern and its interrelation with HPV 18 expression in laryngeal squamous cell carcinoma (LSCC). Materials and Methods: Fifty-six cases of LSCC were evaluated by simple and double immunostaining. The following score was used: 0 (negative or few positive cells), 1 (10-30% of positive cells), 2 (30-50% of cells), and 3 (over 50% of cells). Results: The expression of CD 21-positive cells with dendritic morphology (CDM) was noticed in the intratumoral area of conventional (well and poorly differentiated types and HPV 18 positive cases with a value of 2 for the score) and papillary types (HPV-18 negative cases with a score of 1). The highest value of 2 for the score of CDM in HPV-18 positive cases was found in the peritumoral area of well- and poorly-differentiated conventional LSCCs. A significant correlation was found between scores of CDM from the intratumoral area and those of the peritumoral area (p = 0.001), between CDM and non-dendritic morphology cells (NDM) of the intratumoral area (p = 0.001), and between HPV-18 status and peritumoral NDM cells (p = 0.044). Conclusions: The FDC and NDM cell score values of intratumoral and peritumoral areas may represent important parameters of LSCCs. This may contribute to a better stratification of laryngeal carcinoma cases and the individualized selection of clinical treatment protocols.

Conundrum for Psoriasis and Thyroid Involvement.

Strategies concerning thyroid anomalies in patients confirmed with psoriasis, either on clinical level or molecular levels, and their genetic findings remain an open issue. Identification of the exact subgroup of individuals that are candidates to endocrine assessments is also controversial. Our purpose in this work was to overview clinical and pathogenic data concerning psoriasis and thyroid comorbidities from a dual perspective (dermatologic and endocrine). This was a narrative review of English literature between January 2016 and January 2023. We included clinically relevant, original articles with different levels of statistical evidence published on PubMed. We followed four clusters of conditions: thyroid dysfunction, autoimmunity, thyroid cancer, and subacute thyroiditis. A new piece of information in this field was the fact that psoriasis and autoimmune thyroid diseases (ATD) have been shown to be related to the immune-based side effects of modern anticancer drugs-namely, immune checkpoint inhibitors (ICP). Overall, we identified 16 confirmatory studies, but with heterogeneous data. Psoriatic arthritis had a higher risk of positive antithyroperoxidase antibodies (TPOAb) (25%) compared to cutaneous psoriasis or control. There was an increased risk of thyroid dysfunction versus control, and hypothyroidism was the most frequent type of dysfunction (subclinical rather than clinical), among thyroid anomalies correlated with >2-year disease duration, peripheral > axial and polyarticular involvement. With a few exceptions, there was a female predominance. Hormonal imbalance included, most frequently, low thyroxine (T4) and/or triiodothyronine (T3) with normal thyroid stimulating hormone (TSH), followed by high TSH (only one study had higher total T3). The highest ratio of thyroid involvement concerning dermatologic subtypes was 59% for erythrodermic psoriasis. Most studies found no correlation between thyroid anomalies and psoriasis severity. Statistically significant odds ratios were as follows: hypothyroidism: 1.34-1.38; hyperthyroidism: 1.17-1.32 (fewer studies than hypo); ATD: 1.42-2.05; Hashimoto's thyroiditis (HT): 1.47-2.09; Graves' disease: 1.26-1.38 (fewer studies than HT). A total of 8 studies had inconsistent or no correlations, while the lowest rate of thyroid involvement was 8% (uncontrolled studies). Other data included 3 studies on patients with ATD looking for psoriasis, as well as 1 study on psoriasis and thyroid cancer. ICP was shown to potentially exacerbate prior ATD and psoriasis or to induce them both de novo (5 studies). At the case report level, data showed subacute thyroiditis due to biological medication (ustekinumab, adalimumab, infliximab). Thyroid involvement in patients with psoriasis thus remained puzzling. We observed significant data that confirmed a higher risk of identifying positive antibodies and/or thyroid dysfunction, especially hypothyroidism, in these subjects. Awareness will be necessary to improve overall outcomes. The exact profile of individuals diagnosed with psoriasis who should be screened by the endocrinology team is still a matter of debate, in terms of dermatological subtype, disease duration, activity, and other synchronous (especially autoimmune) conditions.

Study of the Thyroid Profile of Patients with Alopecia.

Thyroid hormones are required for the physiological growth and maintenance of hair follicles. We aim to study the thyroid profile of patients with alopecia. This is a narrative review. PubMed literature was searched from 2013 to 2022. We followed different types of alopecia: alopecia areata (AA), androgenic alopecia in males and females, telogen effluvium (TE), frontal fibrosing alopecia (FFA), lichen planopilaris, and alopecia neoplastica (AN). AA shares a common autoimmune background with autoimmune thyroid diseases, either sporadic or belonging to autoimmune polyglandular syndromes. Some data suggested that AA is more severe if thyroid anomalies are confirmed, including subclinical dysfunction or positive antithyroid antibodies with normal hormone values. However, routine thyroid screening for patients with AA, if the patients are asymptomatic from a thyroid point of view and they have negative personal and family history of autoimmunity, remains controversial. TE, apart from the autoimmune type, associates thyroid anomalies of a hormonal assay (between 5.7% and 17%). FFA, mostly a postmenopausal entity (however, not exclusive), associates a higher prevalence of thyroid conditions (up to 50%) than the general population. However, these might have an age-dependent pattern, thus the association may be incidental since there are a limited number of studies. Overall, alopecia remains a very challenging condition for patients and physicians; a multidisciplinary team is required to improve the outcome and quality of life. The common autoimmune background is suggestive of some types of alopecia and thyroid disorders, yet, the underlying mechanisms are still a matter of debate. AA, TE, FFA, LPP, and, potentially, female pattern hair loss have been found to be connected with thyroid entities, thus a state of awareness from a dual perspective, of trichology and endocrinology, is helpful.

An Approach to Traumatic Brain Injury-Related Hypopituitarism: Overcoming the Pediatric Challenges.

Traumatic brain injury (TBI)-related hypopituitarism is a rare polymorphic complication of brain injury, with very little data, particularly concerning children and teenagers. This is a comprehensive review of the literature regarding this pathology, starting from a new pediatric case. The research was conducted on PubMed and included publications from the last 22 years. We identified nine original studies on the pediatric population (two case reports and seven studies; only four of these seven were prospective studies). TBI-related hypopituitarism is associated with isolated hormonal deficits ranging from 22.5% to 86% and multiple hormonal deficiencies from 5.9% to 50% in the studied pediatric population. Growth hormone (GH) deficiency is most often found, including the form with late occurrence after TBI; it was described as persistent in half of the studies. Thyroid-stimulating hormone (TSH) deficiency is identified as a distant complication following TBI; in all three studies, we identified this complication was found to be permanent. Adrenocorticotropic hormone (ACTH) deficiency did not relate to a certain type of brain trauma, and it was transient in reported cases. Hyperprolactinemia was the most frequent hormonal finding, also occurring late after injury. Central diabetes insipidus was encountered early post-TBI, typically with a transient pattern and did not relate to a particular type of injury. TBI-related hypopituitarism, although rare in children, should be taken into consideration even after a long time since the trauma. A multidisciplinary approach is needed if the patient is to safely overcome any acute condition.

Crossroads between Skin and Endocrine Glands: The Interplay of Lichen Planus with Thyroid Anomalies.

In this narrative review, we aimed to overview the interplay between lichen planus (LP) and thyroid conditions (TCs) from a dual perspective (dermatologic and endocrine), since a current gap in understanding LP-TC connections is found so far and the topic is still a matter of debate. We searched PubMed from Inception to October 2023 by using the key terms "lichen planus" and "thyroid", (alternatively, "endocrine" or "hormone"). We included original clinical studies in humans according to three sections: LP and TC in terms of dysfunction, autoimmunity, and neoplasia. Six studies confirmed an association between the thyroid dysfunction (exclusively hypothyroidism) and LP/OL (oral LP); of note, only one study addressed cutaneous LP. The sample size of LP/OLP groups varied from 12-14 to 1500 individuals. Hypothyroidism prevalence in OLP was of 30-50%. A higher rate of levothyroxine replacement was identified among OLP patients, at 10% versus 2.5% in controls. The highest OR (odd ratio) of treated hypothyroidism amid OLP was of 2.99 (p < 0.005). Hypothyroidism was confirmed to be associated with a milder OLP phenotype in two studies. A single cohort revealed a similar prevalence of hypothyroidism in LP versus non-LP. Non-confirmatory studies (only on OLP, not cutaneous LP) included five cohorts: a similar prevalence of hypothyroidism among OLP versus controls, and a single cohort showed that the subjects with OLP actually had a lower prevalence of hypothyroidism versus controls (1% versus 4%). Positive autoimmunity in LP/OLP was confirmed in eight studies; the size of the cohorts varied, for instance, with 619 persons with LP and with 76, 92, 105, 108, 192, 247, and 585 patients (a total of 1405) with OLP, respectively; notably, the largest control group was of 10,441 individuals. Four clusters of approaches with respect to the autoimmunity in LP/OLP were found: an analysis of HT/ATD (Hashimoto's thyroiditis/autoimmune thyroid diseases) prevalence; considerations over the specific antibody levels; sex-related features since females are more prone to autoimmunity; and associations (if any) with the clinical aspects of LP/OLP. HT prevalence in OLP versus controls was statistically significantly higher, as follows: 19% versus 5%; 12% versus 6%; and 20% versus 9.8%. A single study addressing LP found a 12% rate of ATDs. One study did not confirm a correlation between OLP-associated clinical elements (and OLP severity) and antibody values against the thyroid, and another showed that positive TPOAb (anti-thyroperoxidase antibodies) was more often found in erosive than non-erosive OLP (68% versus 33%). Just the reverse, one cohort found that OLP subjects had a statistically significantly lower rate of positive TPOAb versus controls (9% versus 15%). Five case-control studies addressed the issue of levothyroxine replacement for prior hypothyroidism in patients that were diagnosed with OLP (no study on LP was identified); three of them confirmed a higher rate of this treatment in OLP (at 8.9%, 9.7%, and 10.6%) versus controls. In conclusion, with regard to LP/OLP-TC, we note several main aspects as practical points for multidisciplinary practitioners: OLP rather than LP requires thyroid awareness; when it comes to the type of thyroid dysfunction, mostly, hypothyroidism should be expected; female patients are more prone to be associated with ATDs; a potential higher ratio of OLP subjects taking levothyroxine was found, thus a good collaboration with an endocrinology team is mandatory; and so far, OLP individuals have not been confirmed to be associated with a higher risk of thyroid nodules/cancer.

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.

Adapting surgical 'bundles' to prevent surgical site infections in obstetrics and gynecology (Review).

Surgical site infections (SSIs) are a complication in any surgical field and they are responsible for 38% of surgery-related patient deaths. Identifying appropriate prophylaxis and solutions to combat SSIs is of global interest. Several studies and reports on SSI raise awareness of this costly complication, both in terms of physical and mental suffering, and as a monetary burden. Knowing the risk factors and implementing strategies to reduce SSI risk represent an adequate approach to reduce SSI incidence. General risk factors of SSI are applicable in the obstetrics and gynecology field, alongside its specific characteristics, including immunological changes occurring during pregnancy, as well as disturbances of vaginal microbiota. The risk of SSI is determined by patient factors but also by preoperative, intraoperative and postoperative care. 'Bundle' prevention strategies have been smartly adopted and their efficiency has been demonstrated in colorectal surgery, cesarean deliveries and gynecological oncology surgeries. 'Bundle' measures may vary among studies, but they remain important prevention methods, which contribute to decreasing SSIs, which is a favorable outcome, and thus, are increasingly used as a routine practice. Therefore, healthcare personnel should aim for the early identification of risk factors to minimize the risk of SSI. All evidence-based methods for preventing and treating SSIs in all surgical fields should be considered to be integral components in order for the best care to be provided to patients.

An Overview of Cytomegalovirus Infection in Pregnancy.

The objective of this review was to bring to attention cytomegalovirus (CMV) infection during pregnancy, taking into consideration all relevant aspects, such as maternal diagnosis, fetal infection and prevention, prenatal diagnosis, and postnatal prognosis. A literature review was performed regarding adult and congenital infection. General information regarding this viral infection and potential related medical conditions was provided, considering the issues of maternal infection during pregnancy, transmission to the fetus, and associated congenital infection management. Prenatal diagnosis includes maternal serum testing and the confirmation of the infection in amniotic fluid or fetal blood. Additionally, prenatal diagnosis requires imaging techniques, ultrasound, and complementary magnetic resonance to assess cortical and extracortical anomalies. Imaging findings can predict both fetal involvement and the postnatal prognosis of the newborn, but they are difficult to assess, even for highly trained physicians. In regard to fetal sequelae, the early diagnosis of a potential fetal infection is crucial, and methods to decrease fetal involvement should be considered. Postnatal evaluation is also important, because many newborns may be asymptomatic and clinical anomalies can be diagnosed when sequelae are permanent.

Acanthosis Nigricans: Pointer of Endocrine Entities.

Acanthosis nigricans (AN) has been reported in relation to insulin resistance (IR). We aim to review AN through an endocrine and metabolic perspective focusing on IR in association with metabolic complications such as obesity, diabetes mellitus (DM), and metabolic syndrome (MS) with/without polycystic ovary syndrome (PCOS). We revised English papers on PubMed covering publications from the last 5 years. The current prevalence of AN varies from 4.5 to 74% (or even 100%, depending on the studied population), with equal distribution among females and males. Despite higher incidence with an age-dependent pattern, an alarming escalation of cases has been noted for obesity and MS in younger populations. Most frequent IR-associated sites are the neck, axilla, and knuckles, but unusual locations such as the face have also been reported. Quantitative scales such as Burke have been used to describe the severity of the dermatosis, particularly in correlation with IR elements. Dermoscopic examination are required, for instance, in cases with sulcus cutis, hyperpigmented spots, crista cutis, and papillary projections. A skin biopsy may be necessary, but it is not the rule. Both IR that clinically manifests with or without obesity/MS correlates with AN; most studies are cross-sectional, with only a few longitudinal. The approach varied from screening during school periodic checkups/protocols/programs to subgroups of individuals who were already known to be at high cardio-metabolic risk. AN was associated with type2DM, as well as type 1DM. Females with PCOS may already display metabolic complications in 60-80% of cases, with AN belonging to the associated skin spectrum. AN management depends on underlying conditions, and specific dermatological therapy is not generally required, unless the patient achieves metabolic control, has severe skin lesions, or desires cosmetic improvement. In IR cases, lifestyle interventions can help, including weight control up to bariatric surgery. In addition, metformin is a key player in the field of oral medication against DM type 2, a drug whose indication is extended to PCOS and even to AN itself, outside the specific panel of glucose anomalies. In terms of cosmetic intervention, limited data have been published on melatonin, urea cream, topical retinoids, vitamin D analogs, or alexandrite laser. In conclusion, awareness of IR and its associated clinical features is essential to provide prompt recognition of underlying conditions. AN represents a useful non-invasive surrogate marker of this spectrum in both children and adults. The pivotal role of this dermatosis could massively improve endocrine and metabolic assessments.

New Entity-Thalassemic Endocrine Disease: Major Beta-Thalassemia and Endocrine Involvement.

Beta-thalassemia (BTH), a recessively inherited haemoglobin (Hb) disorder, causes iron overload (IO), extra-medullary haematopoiesis and bone marrow expansion with major clinical impact. The main objective of this review is to address endocrine components (including aspects of reproductive health as fertility potential and pregnancy outcome) in major beta-thalassemia patients, a complex panel known as thalassemic endocrine disease (TED). We included English, full-text articles based on PubMed research (January 2017-June 2022). TED includes hypogonadism (hypoGn), anomalies of GH/IGF1 axes with growth retardation, hypothyroidism (hypoT), hypoparathyroidism (hypoPT), glucose profile anomalies, adrenal insufficiency, reduced bone mineral density (BMD), and deterioration of microarchitecture with increased fracture risk (FR). The prevalence of each ED varies with population, criteria of definition, etc. At least one out of every three to four children below the age of 12 y have one ED. ED correlates with ferritin and poor compliance to therapy, but not all studies agree. Up to 86% of the adult population is affected by an ED. Age is a positive linear predictor for ED. Low IGF1 is found in 95% of the population with GH deficiency (GHD), but also in 93.6% of persons without GHD. HypoT is mostly pituitary-related; it is not clinically manifested in the majority of cases, hence the importance of TSH/FT4 screening. HypoT is found at any age, with the prevalence varying between 8.3% and 30%. Non-compliance to chelation increases the risk of hypoT, yet not all studies confirmed the correlation with chelation history (reversible hypoT under chelation is reported). The pitfalls of TSH interpretation due to hypophyseal IO should be taken into consideration. HypoPT prevalence varies from 6.66% (below the age of 12) to a maximum of 40% (depending on the study). Serum ferritin might act as a stimulator of FGF23. Associated hypocalcaemia transitions from asymptomatic to severe manifestations. HypoPT is mostly found in association with growth retardation and hypoGn. TED-associated adrenal dysfunction is typically mild; an index of suspicion should be considered due to potential life-threatening complications. Periodic check-up by ACTH stimulation test is advised. Adrenal insufficiency/hypocortisolism status is the rarest ED (but some reported a prevalence of up to one third of patients). Significantly, many studies did not routinely perform a dynamic test. Atypical EM sites might be found in adrenals, mimicking an incidentaloma. Between 7.5-10% of children with major BTH have DM; screening starts by the age of 10, and ferritin correlated with glycaemia. Larger studies found DM in up to 34%of cases. Many studies do not take into consideration IGF, IGT, or do not routinely include OGTT. Glucose anomalies are time dependent. Emerging new markers represent promising alternatives, such as insulin secretion-sensitivity index-2. The pitfalls of glucose profile interpretation include the levels of HbA1c and the particular risk of gestational DM. Thalassemia bone disease (TBD) is related to hypoGn-related osteoporosis, renal function anomalies, DM, GHD, malnutrition, chronic hypoxia-induced calcium malabsorption, and transplant-associated protocols. Low BMD was identified in both paediatric and adult population; the prevalence of osteoporosis/TBD in major BTH patients varies; the highest rate is 40-72% depending on age, studied parameters, DXA evaluation and corrections, and screening thoracic-lumbar spine X-ray. Lower TBS and abnormal dynamics of bone turnover markers are reported. The largest cohorts on transfusion-dependent BTH identified the prevalence of hypoGn to be between 44.5% and 82%. Ferritin positively correlates with pubertal delay, and negatively with pituitary volume. Some authors appreciate hypoGn as the most frequent ED below the age of 15. Long-term untreated hypoGn induces a high cardiovascular risk and increased FR. Hormonal replacement therapy is necessary in addition to specific BTH therapy. Infertility underlines TED-related hormonal elements (primary and secondary hypoGn) and IO-induced gonadal toxicity. Males with BTH are at risk of infertility due to germ cell loss. IO induces an excessive amount of free radicals which impair the quality of sperm, iron being a local catalyser of ROS. Adequate chelation might improve fertility issues. Due to the advances in current therapies, the reproductive health of females with major BTH is improving; a low level of statistical significance reflects the pregnancy status in major BTH (limited data on spontaneous pregnancies and growing evidence of the induction of ovulation/assisted reproductive techniques). Pregnancy outcome also depends on TED approach, including factors such as DM control, adequate replacement of hypoT and hypoPT, and vitamin D supplementation for bone health. Asymptomatic TED elements such as subclinical hypothyroidism or IFG/IGT might become overt during pregnancy. Endocrine glands are particularly sensitive to iron deposits, hence TED includes a complicated puzzle of EDs which massively impacts on the overall picture, including the quality of life in major BTH. The BTH prognostic has registered progress in the last decades due to modern therapy, but the medical and social burden remains elevated. Genetic counselling represents a major step in approaching TH individuals, including as part of the pre-conception assessment. A multidisciplinary surveillance team is mandatory.

New approaches in predicting and diagnosing preeclampsia: Congo Red Dot Paper Test (Review).

Preeclampsia (PE), a complication of pregnancy that is characterized by de novo hypertension and proteinuria, remains a leading cause of morbidity and mortality during pregnancy, influencing 2.5-7% of singleton and 7-21% of twin pregnancies. At present, diagnosis is based on traditional but unreliable and nonspecific clinical markers, and treatment of PE is suboptimal, with minimal effect on maternal and fetal mortality and morbidity. With the hope of developing an affordable and simple procedure for PE prediction for developing countries, a previous study examined the use of Congo red staining of misfolded and damaged proteins in the urine of women with PE. This feature has diagnostic and prognostic potential since it precedes the onset of clinical manifestations and correlates with disease severity. The test is inexpensive, popular within the medical staff, easy to use, and identifies women with PE in only 3 min. Obstetrical providers benefit from the Congo Red Dot Paper Test analysis, since a negative result promotes lesser waiting times in triage, prevents unneeded admissions, and diminishes the health costs associated per case.

Adrenocortical carcinoma: Pediatric aspects (Review).

Adrenocortical carcinoma (adrenal cortex-derived cancer), an orphan malignancy, is a very aggressive disease that affects both adults and children with an annual incidence of 1-2 adult and 0.2-0.38 pediatric cases/million (in the pediatric population it represents 0.2% of all cancers), with a female predominance. A total of 80-90% of cases have hormonal imbalances such as Cushing syndrome, virilization, and puberty anomalies. Precocious puberty (PP) of iso- or hetero-sexual pattern is independent of gonadotropin-releasing hormone (GnRH) (high testosterone/estrogens and low FSH/LH) but post-operative activation of GnRH may be expected (central PP). PP is accompanied by accelerated growth while Cushing syndrome by reduced growth velocity. Pure androgen-secreting tumors have been exceptionally described. A total of 50-80% of children have different genetic/epigenetic anomalies involving tumor protein p53 (most often, almost half of the cases; with a population cluster in Southern Brazilian children), insulin-like growth factor, multiple endocrine neoplasia type 1 (MEN1), PRKAR1A, dysfunctional alternative lengthening of telomeres. Hereditary syndromes associated to adrenocortical carcinoma include Li-Fraumeni, Beckwith-Wiedemann, MEN1, and Lynch. Recently, mutations in epidermal growth factor receptor have been reported in teenagers, suggesting the future use of tyrosine kinase inhibitors. Adrenalectomy is the first line therapy offering the best prognosis if complete tumor removal is achieved; genetic testing is recommended before surgery. Adjuvant therapies are less standardized in children (mitotane is a key adjuvant drug in addition with different regimes of chemotherapy such as etoposide, Adriamycin and cisplatin). A Ki-67 value of at least 15% is a predictor of poor outcome. Weiss score also serves as a prognostic factor, as well as the tumor size at diagnosis. The prognosis of adrenocortical carcinoma is poor with an overall 5-year survival rate of 55%; a Weiss score of at least 6 is associated with a 2-year survival rate of 35%. At present, pediatric adrenocortical carcinoma still represents a severe condition that requires prompt intervention and a multidisciplinary team. Further development of molecular markers is required for an improved understanding of the disease thus improving the protocols of approach and the prognostic.

Aggressive prolactinoma (Review).

Aggressive prolactinoma (APRL) is a subgroup of aggressive pituitary tumors (accounting for 10% of all hypophyseal neoplasia) which are defined by: invasion based on radiological and/or histological features, a higher proliferation profile when compared to typical adenomas and rapidly developing resistance to standard medication/protocols in addition to an increased risk of early recurrence. This is a narrative review focusing on APRL in terms of both presentation and management. Upon admission, the suggestive features may include increased serum prolactin with a large tumor diameter (mainly >4 cm), male sex, early age at diagnosis (<20 years), and genetic predisposition [multiple endocrine neoplasia type 1 (MEN1), aryl hydrocarbon receptor interacting protein (AIP), succinate dehydrogenase (SDHx) gene mutations]. Potential prognostic factors are indicated by assessment of E-cadherin, matrix metalloproteinase (MMP)-9, and vascular endothelial growth factor (VEGF) status. Furthermore, during management, APRL may be associated with dopamine agonist (DA) resistance (described in 10-20% of all prolactinomas), post-hypophysectomy relapse, mitotic count >2, Ki-67 proliferation index ≥3%, the need for radiotherapy, lack of response in terms of controlling prolactin levels and tumor growth despite multimodal therapy. However, none of these as an isolated element serves as a surrogate of APRL diagnosis. A fourth-line therapy is necessary with temozolomide, an oral alkylating chemotherapeutic agent, that may induce tumor reduction and serum prolactin reduction in 75% of cases but only 8% have a normalization of prolactin levels. Controversies surrounding the duration of therapy still exist; also regarding the fifth-line therapy, post-temozolomide intervention. Recent data suggest alternatives such as somatostatin analogues (pasireotide), checkpoint inhibitors (ipilimumab, nivolumab), tyrosine kinase inhibitors (TKIs) (lapatinib), and mTOR inhibitors (everolimus). APRL represents a complex condition that is still challenging, and multimodal therapy is essential.