Effects of medicinal plants and natural compounds in models of prostate cancer related to sex steroids: A systematic review.

Prostate cancer remains a health problem for men. Targeting androgen (AR) and estrogen (ER) receptors improves the outcomes of the disease, and many medicinal plants exert their effects by modulating these pathways. Therefore, a systematic review was conducted to identify medicinal plants and their natural compounds that may modulate the AR and/or ER pathways in cell and animal models. A search was conducted across EMBASE, LILACS, PubMed, Scopus, and Web of Science, with grey literature from Google SCHOLAR and ProQuest. Two authors independently selected eligible studies based on their titles and abstracts, and a third author resolved conflicts. Then, data from the full text of eligible studies were extracted and synthesized. In total, 75 studies were included. Results showed the effects of several different medicinal plants and natural compounds in reduction of AR and/or ER transcription and translation and AR secondary effects: cell growth reduction, induction of apoptosis, and cell cycle arrest. In animal models, tumor size reduction, increase in apoptosis, and downregulation of AR expression in tumors were also observed. No single phytochemical group concentrating molecules with anti-AR and/or ER activity was identified. Nevertheless, several phytochemical compounds showed potential for future clinical studies in the management of the disease.

Successful pregnancy after ovulation induction with human chorionic gonadotropin in a woman with selective luteinising hormone deficiency.

Selective LH deficiency has been described in several men, but only in two women who presented normal pubertal development but secondary amenorrhoea due to anovulation. Despite its rarity, this condition represents a valuable model for studying the processes regulated by FSH or LH during late folliculogenesis and ovulation in humans. A woman previously diagnosed with selective LH deficiency due to a homozygous germline splice site mutation in LHB (IVS2 + 1G→C mutation) was submitted to an individualised ovarian induction protocol, first with recombinant LH and then with highly purified urinary hCG. Ovarian follicle growth and ovulation were achieved, and a healthy baby was born after an uneventful term pregnancy. The treatment described herein demonstrates that the clinical actions of exogenous LH or hCG in inducing late-stage follicular development in women with deficient LH production or performance might be interchangeable or inevitable, once FSH-dependent early follicular growth is assured.

Decaffeinated coffee improves insulin sensitivity in healthy men.

Epidemiological studies have found coffee consumption is associated with a lower risk for type 2 diabetes mellitus, but the underlying mechanisms remain unclear. Thus, the aim of this randomised, cross-over single-blind study was to investigate the effects of regular coffee, regular coffee with sugar and decaffeinated coffee consumption on glucose metabolism and incretin hormones. Seventeen healthy men participated in five trials each, during which they consumed coffee (decaffeinated, regular (containing caffeine) or regular with sugar) or water (with or without sugar). After 1 h of each intervention, they received an oral glucose tolerance test with one intravenous dose of [1-13C]glucose. The Oral Dose Intravenous Label Experiment was applied and glucose and insulin levels were interpreted using a stable isotope two-compartment minimal model. A mixed-model procedure (PROC MIXED), with subject as random effect and time as repeated measure, was used to compare the effects of the beverages on glucose metabolism and incretin parameters (glucose-dependent insulinotropic peptide (GIP)) and glucagon-like peptide-1 (GLP-1)). Insulin sensitivity was higher with decaffeinated coffee than with water (P<0·05). Regular coffee with sugar did not significantly affect glucose, insulin, C-peptide and incretin hormones, compared with water with sugar. Glucose, insulin, C-peptide, GLP-1 and GIP levels were not statistically different after regular and decaffeinated coffee compared with water. Our findings demonstrated that the consumption of decaffeinated coffee improves insulin sensitivity without changing incretin hormones levels. There was no short-term adverse effect on glucose homoeostasis, after an oral glucose challenge, attributable to the consumption of regular coffee with sugar.

Effects of metformin on endometrial cancer: Systematic review and meta-analysis.

BACKGROUND: Endometrial cancer is one of the most common gynecological cancers, which is frequently preceded by atypical endometrial hyperplasia, a premalignant lesion. Metformin, an antidiabetic drug, has emerged as a new adjunctive strategy for different cancer types, including endometrial cancer. This systematic review and meta-analysis aimed to evaluate the effects of metformin in atypical endometrial hyperplasia and endometrial cancer patients. METHODS: The search was conducted on January 2017 and the articles were collected in Cochrane, LILACS, PubMed, Scopus and Web of Science. A grey literature search was undertaken using Google SCHOLAR, ProQuest and Open Grey. Nineteen studies were included, which contained information about the following outcomes: reversal of atypical endometrial hyperplasia, cellular proliferation biomarkers expression and overall survival in metformin-users compared to non-users. RESULTS: Metformin was associated with reversion of atypical endometrial hyperplasia to a normal endometrial, and with decreased cell proliferation biomarkers staining, from 51.94% (CI=36.23% to 67.46%) to 34.47% (CI=18.55% to 52.43%). However, there is a high heterogeneity among studies. Metformin-users endometrial cancer patients had a higher overall survival compared to non-metformin users and non-diabetic patients (HR=0.82; CI: 0.70-0.95; p=0.09, I2=40%). CONCLUSION: Regardless the high heterogeneity of the analyzed studies, the present review suggests that adjunct metformin treatment may assist in the reversal of atypical endometrial hyperplasia to normal endometrial histology, in the reduction of cell proliferation biomarkers implicated in tumor progression, and in the improvement of overall survival in endometrial cancer. Further work on prospective controlled trials designed to address the effects of adjunct metformin on clinical outcomes is necessary for definite conclusions.

Radiation induced a supra-additive cytotoxic effect in head and neck carcinoma cell lines when combined with plant extracts from Brazilian Cerrado biome.

OBJECTIVES: Antineoplastic effects of molecules derived from plants have recently gained increasing attention as an additive to traditional therapies. The aim of this study was to evaluate the cytotoxic activity of plant extracts from the Brazilian Cerrado biome associated with radiotherapy in head and neck carcinoma cells (HNSCC). MATERIALS AND METHODS: Fifteen extracts derived from five Cerrado plants were tested in HNSCC cell lines (SCC-25, SCC-9, FaDu) and keratinocyte cells (HaCat). Cell cytotoxicity of extracts and association extract/radiation (2Gy/min) was assessed by MTT assay. Cisplatin (50 µg/mL) was used as a positive control. Extracts with the major cytotoxic activity were selected and their IC50 concentrations were defined. Apoptosis was assessed using flow cytometric analysis. RESULTS: Ten isolated extracts resulted in moderate cytotoxicity (>20 and ≤ 50 % of viable cells), while three extracts induced severe cytotoxic effects (≤ 20 % of viable cells). Plant extracts treatment improved radiotherapy cytotoxicity in all cell lines. Although plant extracts are not as potent as cisplatin plus radiation, in FaDu cells, seven extracts associated with irradiation showed cytotoxic activity similar or better than the association of cisplatin and radiation. Hexanic extract of Erythroxylum daphinites could induce apoptosis in oral cancer cells; however, necrosis was the prevalent kind of death in FaDu cells treated with hexanic extract of Erythroxylum suberosum. CONCLUSIONS: Pre-treatment of HNSCC cells with the extract derived from Cerrado plants followed by irradiation induced a supra-additive cytotoxic effect. CLINICAL RELEVANCE: This study highlights the potential biological relevance of the Cerrado biome when associated with traditional therapy for cancer.

Developing a clinical-pathological framework of long COVID-related fatigue applied to public safety workers.

In the wake of the COVID-19 pandemic, millions worldwide are still struggling with persistent or recurring symptoms known as long COVID. Fatigue is one of the most prevalent symptoms associated with long COVID, and for many it can be debilitating. Understanding the potential pathological processes that link fatigue to long COVID is critical to better guide treatment. Challenges with diagnosis and treatment are reviewed, recognizing that post-COVID fatigue does not always present with corroborating clinical evidence, a situation that is frustrating for both patients and healthcare providers. Firefighters are a group of public safety workers who are particularly impacted by long COVID-related fatigue. Firefighters must be able to engage in strenuous physical activity and deal with demanding psychological situations, both of which may be difficult for those suffering from fatigue. Disruption in public safety worker health can potentially impact community welfare. This review creates a framework to explain the clinical-pathological features of fatigue resulting from long COVID, addresses diagnosis and treatment challenges, and explores the unique impact fatigue may pose for public safety workers and their organizations.

Association of Endogenous Testosterone with Physical Fitness Measures during Firefighter Occupational Health Evaluations.

Firefighting is a physically demanding profession associated with unacceptably high on-duty cardiovascular mortality. Low endogenous total testosterone (TT) is an emerging cardiometabolic (CM) risk factor in men, but limited data exists on its interactions with physical fitness (PF). Data from occupational health and fitness assessments of 301 male career firefighters (FFs) were analyzed. TT was categorized as low (<264 ng/dL), borderline (264-399 ng/dL), and reference (400-916 ng/dL). PF tests included cardiorespiratory fitness (submaximal treadmill), body fat percentage (BF%), push-ups, plank, and handgrip strength assessments. In the crude analyses, FFs in the low TT group had worse muscular and cardiorespiratory fitness measures compared to the referent group. However, after adjusting for age and BF%, none of the PF differences remained statistically significant. Similarly, the odds of less-fit FFs (PF performance below median values) having low TT were higher compared to the fitter ones only before adjusting for age and BF%. Therefore, in the final adjusted model, there was no significant association between TT and PF. Our data suggest that age and body fat confound the association between PF and TT. Low TT and poor PF are important components of FFs' CM risk profile, and there is potential benefit to considering TT screening as part of a comprehensive occupational health program that manages performing medical evaluations and provides education and preventative programming.

Mouse Testicular Mkrn3 Expression Is Primarily Interstitial, Increases Peripubertally, and Is Responsive to LH/hCG.

Studies in humans and mice support a role for Makorin RING finger protein 3 (MKRN3) as an inhibitor of gonadotropin-releasing hormone (GnRH) secretion prepubertally, and its loss of function is the most common genetic cause of central precocious puberty in humans. Studies have shown that the gonads can synthesize neuropeptides and express MKRN3/Mkrn3 mRNA. Therefore, we aimed to investigate the spatiotemporal expression pattern of Mkrn3 in gonads during sexual development, and its potential regulation in the functional testicular compartments by gonadotropins. Mkrn3 mRNA was detected in testes and ovaries of wild-type mice at all ages evaluated, with a sexually dimorphic expression pattern between male and female gonads. Mkrn3 expression was highest peripubertally in the testes, whereas it was lower peripubertally than prepubertally in the ovaries. Mkrn3 is expressed primarily in the interstitial compartment of the testes but was also detected at low levels in the seminiferous tubules. In vitro studies demonstrated that Mkrn3 mRNA levels increased in human chorionic gonadotropin (hCG)-treated Leydig cell primary cultures. Acute administration of a GnRH agonist in adult mice increased Mkrn3 expression in testes, whereas inhibition of the hypothalamic-pituitary-gonadal axis by chronic administration of GnRH agonist had the opposite effect. Finally, we found that hCG increased Mkrn3 mRNA levels in a dose-dependent manner. Taken together, our developmental expression analyses, in vitro and in vivo studies show that Mkrn3 is expressed in the testes, predominantly in the interstitial compartment, and that Mkrn3 expression increases after puberty and is responsive to luteinizing hormone/hCG stimulation.

OSR1 disruption contributes to uterine factor infertility via impaired Müllerian duct development and endometrial receptivity.

Three sisters, born from consanguineous parents, manifested a unique Müllerian anomaly characterized by uterine hypoplasia with thin estrogen-unresponsive endometrium and primary amenorrhea, but with spontaneous tubal pregnancies. Through whole-exome sequencing followed by comprehensive genetic analysis, a missense variant was identified in the OSR1 gene. We therefore investigated OSR1/OSR1 expression in postpubertal human uteri, and the prenatal and postnatal expression pattern of Osr1/Osr1 in murine developing Müllerian ducts (MDs) and endometrium, respectively. We then investigated whether Osr1 deletion would affect MD development, using WT and genetically engineered mice. Human uterine OSR1/OSR1 expression was found primarily in the endometrium. Mouse Osr1 was expressed prenatally in MDs and Wolffian ducts (WDs), from rostral to caudal segments, in E13.5 embryos. MDs and WDs were absent on the left side and MDs were rostrally truncated on the right side of E13.5 Osr1-/- embryos. Postnatally, Osr1 was expressed in mouse uteri throughout their lifespan, peaking at postnatal days 14 and 28. Osr1 protein was present primarily in uterine luminal and glandular epithelial cells and in the epithelial cells of mouse oviducts. Through this translational approach, we demonstrated that OSR1 in humans and mice is important for MD development and endometrial receptivity and may be implicated in uterine factor infertility.

Insulinoma diagnosed in the postpartum: clinical and immunohistochemical features.

Insulinomas are rare pancreatic ß-cell tumors with an estimated incidence of 1:250.000 persons/year. We present a novel case of insulinoma manifesting immediately after childbirth. Eight days after delivery, a 21-year-old, previously healthy woman presented paresthesia in hands, upper and lower limbs muscle weakness with difficult walking, which worsened during breastfeeding sessions. Laboratory tests showed blood glucose levels between 37 and 55 mg/dL with inappropriately normal insulin levels (7.78 µUI/mL; normal range: 5-29). An abdominal computed tomography showed a nodular lesion measuring 2 cm at the head of the pancreas. Tumor enucleation resulted in complete resolution of hypoglycemia. Histopathological and immunohistochemical analysis were consistent with an insulinoma. About 27 cases of insulinoma associated with pregnancy have been reported to date, mostly diagnosed before the 16th week. The beginning of symptoms soon after delivery is less common. Understanding the interactions between pancreatic ß-cell function and all the physiological metabolic and hormonal adaptations associated with gestation is essential for the adequate management of hypoglycemic disorders in pregnant women.

Antiproliferative effects of metformin in cellular models of pheochromocytoma.

Pheochromocytomas (PCCs) are rare neuroendocrine tumors derived from adrenal medulla chromaffin cells. Malignancy and recurrence are rare but demand effective treatment. Metformin exerts antiproliferative effects in several cancer cell lines. We thus evaluated the effects of metformin on cell viability and proliferation, cellular respiration and AMPK-AKT-mTOR-HIFA proliferation pathway on a rat PCC cell line (PC12-Adh). We then addressed metformin's effects on the AMPK-AKT-mTOR-HIFA pathway on two human primary cultures: one from a VHL-mutant PCC and other from a sporadic PCC. Metformin (20 mM) inhibited PC12-Adh cell proliferation, and decreased oxygen consumption, ATP production and proton leak, in addition to loss of mitochondrial membrane potential. Further, metformin induced AMPK phosphorylation and impaired AMPK-PI3k-AKT-mTOR pathway activation. The mTOR pathway was also inhibited in human VHL-related PCC cells, however, in an AMPK-independent manner. Metformin-induced decrease of HIF1A levels was likely mediated by proteasomal degradation. Altogether our results suggest that metformin impairs PCC cellular proliferation.

Low testosterone and cardiometabolic risks in a real-world study of US male firefighters.

Low serum total testosterone (TT) is associated with increased cardiovascular risk and metabolic derangements, with fatty liver (FL) emerging as an additional cardiometabolic threat. We investigated the associations between TT and cardiometabolic (CM) health in 298 US male firefighters. Cross-sectional data from occupational health examination were analyzed. TT was categorized as low (< 264 ng/dL), borderline (264-399 ng/dL), and reference (400-916 ng/dL). Conventional CM risk factors were compared among TT categories, and between firefighters with and without FL. 81% of firefighters were obese/overweight; almost 40% had FL. In the low-TT group, only 3.1% had normal BMI, while 78.1% had FL. The low-TT group had a worse CM profile, independently of age and BMI, and a fourfold higher adjusted odds of having FL. FL was associated with lower TT, regardless of age, BMI and HbA1c. Having a FL, HbA1c ≥ 5.7% or triglycerides ≥ 150 mg/dL increased the odds for low-TT by 4.1, 2.7 and 6.6 times, respectively. These real-world data reveal strong associations between low-TT and CM risk factors and support a call for action towards screening for low-TT and FL, regardless of age, BMI or dysmetabolic conditions in firefighters. Recognizing cardiometabolic risks in firefighters provides an opportunity to lessen cardiovascular diseases burden.

Luteinizing hormone beta mutation and hypogonadism in men and women.

Selective luteinizing hormone deficiency due to mutations in the luteinizing hormone beta-subunit gene (LHB) is a rare cause of hypogonadism. We describe the clinical features of a consanguineous family in which three siblings, two men and one woman, had hypogonadism related to isolated luteinizing hormone deficiency. These subjects have a newly discovered homozygous mutation of a 5' splice site in LHB: IVS2+1G-->C. This mutation disrupts the splicing of messenger RNA (mRNA), generating a gross abnormality in the processing of the luteinizing hormone beta-subunit mRNA, which abrogates the secretion of luteinizing hormone. We also determined that the female phenotype of this LHB mutation is characterized by normal pubertal development, secondary amenorrhea, and infertility.

Borderline-low testosterone levels are associated with lower left ventricular wall thickness in firefighters: An exploratory analysis.

BACKGROUND: Low endogenous testosterone has been associated with increased cardiovascular risk in men. OBJECTIVES: To determine the prevalence of low serum testosterone level (TT) in a cohort of male US career firefighters and to examine its relation with left ventricular wall thickness (LVWT). MATERIALS AND METHODS: We conducted a cross-sectional study among 341 career firefighters, (age: 37.5 ± 10.3 years; BMI: 28.9 ± 4.5 kg/m2 ), who underwent an occupational medical screening examination. TT quartiles were determined, and LVWT distribution among them was plotted. Then, TT values were categorized as low (<264 ng/dL), borderline (264-399 ng/dL), reference range (400-916 ng/dL), and high (>916 ng/dL). To further investigate the association of mildly decreased TT on LVWT, we divided the borderline group into borderline-low (264-319 ng/dL) and borderline-high (320-399 ng/dL) ranges. LVWT values were classified as low LVWT when <0.6 cm. A multivariate model was used to compare LVWT, age, BMI, systolic blood pressure (SBP), and HbA1c among groups by TT values. RESULTS: The prevalence of low TT was 10.6% and of borderline was 26.4%, while 58.7% had levels in the reference range. The low-TT group was older and had higher BMI and SBP as compared to the reference group (P < .01). LVWT values were different among groups (P = .04) and significantly lower in firefighters with borderline-low TT as compared to the reference group (P < .05). This finding also occurred within obese firefighters (P = .03). The borderline-low group had a higher adjusted risk for a low LVWT as compared to the reference group [OR: 4.11 (95% CI: 1.79-9.43)]. DISCUSSION: Our findings highlight the possible relationship between a mild reduction in testosterone levels (borderline) and lower LVWT. CONCLUSIONS: A high prevalence of subnormal TT levels (low and borderline: 37%) was observed in this relatively homogeneous cohort of career firefighters. Mildly decreased TT levels and lower LVWT might represent a preclinical condition and a window of opportunity for cardiovascular preventive interventions in firefighters.

Inactivating mutations of luteinizing hormone beta-subunit or luteinizing hormone receptor cause oligo-amenorrhea and infertility in women.

Women harbouring inactivating mutations in luteinizing hormone (LH) beta subunit (LHB) or LH receptor (LHCGR) genes have similar clinical manifestations characterized by female external genitalia, spontaneous breast and pubic hair development at puberty, and normal or late menarche followed by oligo-amenorrhea and infertility. Oestradiol and progesterone levels are normal for the early to midfollicular phase, but do not reach ovulatory or luteal phase levels, confirming lack of ovulation. Notably, serum LH levels are low in patients with LHB mutations and high in those with LHCGR mutations, whereas follicle-stimulating hormone levels are normal or only slightly increased. Pelvic ultrasound has demonstrated a small or normal uterus and normal or enlarged ovaries with cysts. Women with LHB mutations may be treated with hCG (human chorionic gonadotropin) or LH, whereas those with mutations in LHCGR are resistant. Lhb and Lhcgr knockout female mice are close phenocopies of the respective human mutations, and confirm that early follicular development, low levels of oestrogen production and theca cell development are independent of LH action, which is necessary for ovulation. Although inactivating mutations in LHB and LHCGR are rare in comparison to other genetic and non-genetic causes of hypogonadism, they should be considered in the differential diagnosis of oligo-amenorrhea and infertility.

MKRN3 Mutations in Central Precocious Puberty: A Systematic Review and Meta-Analysis.

MKRN3 mutations represent the most common genetic cause of central precocious puberty (CPP) but associations between genotype and clinical features have not been extensively explored. This systematic review and meta-analysis investigated genotype-phenotype associations and prevalence of MKRN3 mutations in CPP. The search was conducted in seven electronic databases (Cochrane, EMBASE, LILACS, LIVIVO, PubMed, Scopus, and Web of Science) for articles published until 4 September 2018. Studies evaluating MKRN3 mutations in patients with CPP were considered eligible. A total of 22 studies, studying 880 subjects with CPP, fulfilled the inclusion criteria. Eighty-nine subjects (76 girls) were identified as harboring MKRN3 mutations. Girls, compared with boys, exhibited earlier age at pubertal onset (median, 6.0 years; range, 3.0 to 7.0 vs 8.5 years; range, 5.9 to 9.0; P < 0.001), and higher basal FSH levels (median, 4.3 IU/L; range, 0.7 to 13.94 IU/L vs 2.45 IU/L; range, 0.8 to 13.70 IU/L; P = 0.003), and bone age advancement (ΔBA; median, 2.3 years; range, -0.9 to 5.2 vs 1.2 years; range, 0.0 to 2.3; P = 0.01). Additional dysmorphisms were uncommon. A total of 14 studies evaluating 857 patients were included for quantitative analysis, with a pooled overall mutation prevalence of 9.0% (95% CI, 0.04 to 0.15). Subgroup analysis showed that prevalence estimates were higher in males, familial cases, and in non-Asian countries. In conclusion, MKRN3 mutations are associated with nonsyndromic CPP and manifest in a sex-dimorphic manner, with girls being affected earlier. They represent a common cause of CPP in western countries, especially in boys and familial cases.

What determines mortality in malignant pheochromocytoma? - Report of a case with eighteen-year survival and review of the literature.

Pheochromocytoma (PCC) is a tumor derived from adrenomedullary chromaffin cells. Prognosis of malignant PCC is generally poor due to local recurrence or metastasis. We aim to report a case of malignant PCC with 18-year survival and discuss which factors may be related to mortality and long-term survival in malignant pheochromocytoma. The patient, a 45-year-old man, reported sustained arterial hypertension with paroxysmal episodes of tachycardia, associated with head and neck burning sensation, and hand and foot tremors. Diagnosis of PCC was established biochemically and a tumor with infiltration of renal parenchyma was resected. No genetic mutation or copy number variations were identified in SDHB, SDHD, SDHC, MAX and VHL. Over 18 years, tumor progression was managed with 131I-MIBG (iodine-metaiodobenzylguanidine) and 177Lutetium-octreotate therapy. Currently, the patient is asymptomatic and presents sustained stable disease, despite the presence of lung, para-aortic lymph nodes and femoral metastases. Adequate response to treatment with control of tumor progression, absence of significant cardiovascular events and other neoplasms, and lack of mutations in the main predisposing genes reported so far may be factors possibly associated with the prolonged survival in this case. Early diagnosis and life-long follow-up in patients with malignant pheochromocytoma are known to be crucial in improving survival.

Thyroxine-binding globulin deficiency due to a novel SERPINA7 mutation: Clinical characterization, analysis of X-chromosome inactivation pattern and protein structural modeling.

OBJECTIVE: Thyroxine-binding globulin (TBG) is the major human thyroid hormone transport protein, encoded by the SERPINA7 gene (Xq22.2). We aim to investigate the molecular basis of partial TBG deficiency (TBG-PD) in a female, by evaluating the X-chromosome inactivation pattern as well as the mutant protein structural modeling. DESIGN AND METHODS: Sequencing of the coding region of the SERPINA7 gene was performed in a female with a TBG-PD phenotype and her first-degree relatives. The proband presented with low serum levels of total T3 (TT3) and total T4 (TT4), serum TSH level of 5.4 µUI/mL (normal range, 0.35-5.5), and serum TBG level of 5.5 mg/L (normal range, 13.6-27.2). X-chromosome inactivation pattern was evaluated by methylation analysis of the androgen receptor gene (Xq11.2). Structural analysis of the SERPIN family was performed using Pymol and Areaimol, and PFSTATS for conservation analysis and family-wide investigation of equivalent positions in human homologs. Modeller was used for point mutation structural modeling. RESULTS: A novel missense SERPINA7 mutation (p.R35W; c.163C > T) was found in heterozygosity in the proband, and in hemizygosity in her affected siblings. The proband X-chromosome inactivation ratio was 20:80. The substitution of an arginine by a tryptophan is predicted to disrupt the protein surface and main electrostatic interactions. Tryptophans are extremely rare (0.1%) in this position. CONCLUSIONS: We report a new SERPINA7 variant associated with TBG-PD in three siblings. We named this variant TBG-Brasilia. The X-chromosome inactivation pattern may have accounted for the rare phenotypic expression in a female. The hydrophobic nature of the mutant is predicted to create an apolar patch at the surface, which results in protein aggregation and/or misfolding, potentially responsible for thyroid hormone transport defect.

Insights on the phenotypic heterogenity of 11ß-hydroxylase deficiency: clinical and genetic studies in two novel families.

PURPOSE: 11ß-hydroxylase deficiency accounts for 5% of congenital adrenal hyperplasia cases. Diagnosis suspiction is classically based on the association between abnormal virilization, precocious puberty, and hypertension in 46XX or 46XY subjects. We investigated two families with siblings presenting with opposed clinical features, and provided a review of the mechanisms involved in mineralocorticoid-dependent phenotypic heterogeneity. METHODS: The coding region of the CYP11B1 gene of 4 patients was sequenced and familial segregation was confirmed. Clinical characterization and blood steroid profile were performed. RESULTS: Family 1 comprised a female and a male siblings who presented in middle childhood with genital ambiguity (Prader II) and precocious puberty, respectively, associated with hypertension. In the second decade of life, the woman had three full-term pregnancies, and then evolved normotensive with no treatment over a 5-year follow up. On the other hand, her brother had hypertensive end-organ damage at age 24. In family 2, a 2.9 year-old boy presented with precocious puberty and hypertension, whereas his 21 days-old sister had genital ambiguity (Prader III) and salt wasting. A homozygous exon 4 splice site mutation was identified (IVS4ds-1G > A; c.799 G > A) in family 1, while a nonsense mutation in exon 6 (p. Q356X; c.1066 C > T) was found in family 2. CONCLUSION: CYP11B1 mutations were associated with highly variable phenotypes, from mild to severe virilization, and early-onset hypertension or salt wasting. Further analysis of variants in other hypertension-related genes, steroid synthesis and metabolism compensatory pathways, and/or the investigation of chimeric CYP11B genes are needed to clarify the phenotypic heterogeneity in 11ß-hydroxylase deficiency.