Genetic determinants of type 1 diabetes in individuals with weak evidence of islet autoimmunity at disease onset.

AIMS/HYPOTHESIS: Islet autoantibodies (AAbs) are detected in >90% of individuals with clinically suspected type 1 diabetes at disease onset. A single AAb, sometimes at low titre, is often detected in some individuals, making their diagnosis uncertain. Type 1 diabetes genetic risk scores (GRS) are a useful tool for discriminating polygenic autoimmune type 1 diabetes from other types of diabetes, particularly the monogenic forms, but testing is not routinely performed in the clinic. Here, we used a type 1 diabetes GRS to screen for monogenic diabetes in individuals with weak evidence of autoimmunity, i.e. with a single AAb at disease onset. METHODS: In a pilot study, we genetically screened 142 individuals with suspected type 1 diabetes, 42 of whom were AAb-negative, 27 of whom had a single AAb (single AAb-positive) and 73 of whom had multiple AAbs (multiple AAb-positive) at disease onset. Next-generation sequencing (NGS) was performed in 41 AAb-negative participants, 26 single AAb-positive participants and 60 multiple AAb-positive participants using an analysis pipeline of more than 200 diabetes-associated genes. RESULTS: The type 1 diabetes GRS was significantly lower in AAb-negative individuals than in those with a single and multiple AAbs. Pathogenetic class 4/5 variants in MODY or monogenic diabetes genes were identified in 15/41 (36.6%) AAb-negative individuals, while class 3 variants of unknown significance were identified in 17/41 (41.5%). Residual C-peptide levels at diagnosis were higher in individuals with mutations compared to those without pathogenetic variants. Class 3 variants of unknown significance were found in 11/26 (42.3%) single AAb-positive individuals, and pathogenetic class 4/5 variants were present in 2/26 (7.7%) single AAb-positive individuals. No pathogenetic class 4/5 variants were identified in multiple AAb-positive individuals, but class 3 variants of unknown significance were identified in 19/60 (31.7%) patients. Several patients across the three groups had more than one class 3 variant. CONCLUSIONS/INTERPRETATION: These findings provide insights into the genetic makeup of patients who show weak evidence of autoimmunity at disease onset. Absence of islet AAbs or the presence of a single AAb together with a low type 1 diabetes GRS may be indicative of a monogenic form of diabetes, and use of NGS may improve the accuracy of diagnosis.

Antibody response to multiple antigens of SARS-CoV-2 in patients with diabetes: an observational cohort study.

AIMS/HYPOTHESIS: The aim of the study was to characterise the humoral response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients with diabetes. Demonstrating the ability to mount an appropriate antibody response in the presence of hyperglycaemia is relevant for the comprehension of mechanisms related to the observed worse clinical outcome of coronavirus disease 2019 (COVID-19) pneumonia in patients with diabetes and for the development of any future vaccination campaign to prevent SARS-CoV-2 infection. METHODS: Using a highly specific and sensitive measurement of antibodies by fluid-phase luciferase immunoprecipitation assays, we characterised the IgG, IgM and IgA response against multiple antigens of SARS-CoV-2 in a cohort of 509 patients with documented diagnosis of COVID-19, prospectively followed at our institution. We analysed clinical outcomes and antibody titres according to the presence of hyperglycaemia, i.e., either diagnosed or undiagnosed diabetes, at the time of, or during, hospitalisation. RESULTS: Among patients with confirmed COVID-19, 139 (27.3%) had diabetes: 90 (17.7%) had diabetes diagnosed prior to the hospital admission (comorbid diabetes) while 49 (9.6%) had diabetes diagnosed at the time of admission (newly diagnosed). Diabetes was associated with increased levels of inflammatory biomarkers and hypercoagulopathy, as well as leucocytosis and neutrophilia. Diabetes was independently associated with risk of death (HR 2.32 [95% CI 1.44, 3.75], p = 0.001), even after adjustment for age, sex and other relevant comorbidities. Moreover, a strong association between higher glucose levels and risk of death was documented irrespective of diabetes diagnosis (HR 1.14 × 1.1 mmol/l [95% CI 1.08, 1.21], p < 0.001). The humoral response against SARS-CoV-2 in patients with diabetes was present and superimposable, as for timing and antibody titres, to that of non-diabetic patients, with marginal differences, and was not influenced by glucose levels. Of the measured antibody responses, positivity for IgG against the SARS-CoV-2 spike receptor-binding domain (RBD) was predictive of survival rate, both in the presence or absence of diabetes. CONCLUSIONS/INTERPRETATION: The observed increased severity and mortality risk of COVID-19 pneumonia in patients with hyperglycaemia was not the result of an impaired humoral response against SARS-CoV-2. RBD IgG positivity was associated with a remarkable protective effect, allowing for a cautious optimism about the efficacy of future vaccines against SARs-COV-2 in people with diabetes. Graphical abstract.

Ovarian hyperstimulation syndrome due to follicle-stimulating hormone-secreting pituitary adenomas.

PURPOSE: Gonadotroph adenomas are pituitary adenomas with inefficient and variable secretory characteristics, that is why they are usually considered as a subgroup of nonfunctioning pituitary adenomas (NFPA) and are recognized only at immunohistochemistry. When gonadotroph adenomas secrete active hormones, they may cause spontaneous ovarian hyperstimulation syndrome (OHSS) in premenopausal women. Aim of our study is to describe three women with OHSS diagnosed before the removal of the adenoma and to calculate the prevalence of OHSS in premenopausal women with a clinical diagnosis of NFPA. METHODS: We reviewed clinical records of premenopausal women that underwent neurosurgery for NFPA at our centre between 1993 and 2014. OHSS was diagnosed in patients with high levels of FSH, suppressed LH, hyperestrogenism, abdominal symptoms, polymenorrhea, enlarged ovaries with cysts or previous surgery for ovarian cysts. RESULTS: 171 women were included into the study; 62 (36.6%) had a gonadotroph adenoma diagnosed at immunohistochemistry. Two patients were retrospectively diagnosed as having OHSS due to gonadotroph adenoma and three had OHSS diagnosed before neurosurgery. The prevalence of OHSS was 2.9% in the overall group of patients with NFPA and 8.1% among patients with a gonadotroph adenoma detected at immunohistochemistry. CONCLUSIONS: Frequency of OHSS due to a gonadotroph adenoma is not negligible. Increased awareness of the characteristic clinical and hormonal picture should permit an early detection of this condition in premenopausal women with a pituitary adenoma.

No Evidence of Long-Term Disruption of Glycometabolic Control After SARS-CoV-2 Infection.

PURPOSE: To assess whether dysglycemia diagnosed during severe acute respiratory syndrome coronavirus 2 pneumonia may become a potential public health problem after resolution of the infection. In an adult cohort with suspected coronavirus disease 2019 (COVID-19) pneumonia, we integrated glucose data upon hospital admission with fasting blood glucose (FBG) in the year prior to COVID-19 and during postdischarge follow-up. METHODS: From February 25 to May 15, 2020, 660 adults with suspected COVID-19 pneumonia were admitted to the San Raffaele Hospital (Milan, Italy). Through structured interviews/ medical record reviews, we collected demographics, clinical features, and laboratory tests upon admission and additional data during hospitalization or after discharge and in the previous year. Upon admission, we classified participants according to American Diabetes Association criteria as having (1) preexisting diabetes, (2) newly diagnosed diabetes, (3) hyperglycemia not in the diabetes range, or (4) normoglycemia. FBG prior to admission and during follow-up were classified as normal or impaired fasting glucose and fasting glucose in the diabetes range. RESULTS: In patients with confirmed COVID (n = 589), the proportion with preexisting or newly diagnosed diabetes, hyperglycemia not in the diabetes range and normoglycemia was 19.6%, 6.7%, 43.7%, and 30.0%, respectively. Patients with dysglycemia associated to COVID-19 had increased markers of inflammation and organs' injury and poorer clinical outcome compared to those with normoglycemia. After the infection resolved, the prevalence of dysglycemia reverted to preadmission frequency. CONCLUSIONS: COVID-19-associated dysglycemia is unlikely to become a lasting public health problem. Alarmist claims on the diabetes risk after COVID-19 pneumonia should be interpreted with caution.

Dysglycemia after COVID-19 pneumonia: a six-month cohort study.

AIM: The aim of this study was to understand whether the dysglycemia associated with SARS-CoV-2 infection persists or reverts when the viral infection resolves. METHODS: We analyzed fasting blood glucose (FBG) after hospital discharge in a cohort of 621 adult cases with suspected COVID-19 pneumonia. RESULTS: At admission, 18.8% of the patients in our cohort had pre-existing diabetes, 9.3% fasting glucose in the diabetes range without a prior diagnosis (DFG), 26% impaired fasting glucose (IFG), 44.9% normal fasting glucose (NFG), while 2% had no FBG available. FBG categories were similarly distributed in the 71 patients without confirmed COVID-19 pneumonia. During follow-up (median time 6 month) FBG was available for 321 out of the 453 (70.9%) surviving patients and showed a trend to a marginal increase [from 97 (87-116) to 100 (92-114) mg/dL; p = 0.071]. Transitions between FBG categories were analyzed in subjects without pre-existing diabetes (265 out of 321). We identified three groups: (i) patients who maintained or improved FBG during follow-up [Group A, n = 185; from 100 (86-109) to 94 (88-99) mg/dL; p < 0.001]; (ii) patients who moved from the NFG to IFG category [Group B, n = 66: from 89 (85-96) to 106 (102-113) mg/dl; p < 0.001]; (iii) patients who maintained or reached DFG during follow-up [Group C, n = 14: from 114 (94-138) to 134 (126-143) mg/dl; p = 0.035]. Male sex and ICU admission during the hospitalization were more prevalent in Group C compared to Group A or B. CONCLUSIONS: Six months after the SARS-CoV-2 infection DFG was evident in only few patients who experienced severe COVID-19 pneumonia.

Transcutaneous electrical stimulation therapy and genetic analysis in Dercum's disease: A pilot study.

ABSTRACT: Dercum's disease (DD), or adiposis dolorosa, is a rare condition of unknown etiology characterized by growth of painful subcutaneous adipose tissue. No specific treatment exists. Pain is often invalidating and resistant to analgesic drugs. We tested the efficacy of Frequency Rhythmic Electrical Modulation System (FREMS) therapy on pain relief. Subcutaneous biopsies were performed for genetic analysis.Nine DD patients were enrolled. Five cycles of FREMS at 3-month intervals during 1 year were administered. Visual analogue scale (VAS), Bartel Index Questionnaire and Short Form 36 questionnaire were used to measure pain and general health status at baseline, 6 and 12 months. Dual-energy X-ray absorptiometry (DEXA) quantified fat mass. Next-Generation Sequencing (NGS) was performed on adipose tissue biopsies and peripheral blood sample to search for somatic variants and specific protein pathway mutation.Seven patients were included in the final analysis. FREMS induced a reduction in VAS score (from 92 to 52.5, P = .0597) and a significant improvement in SF-36 domains (Physical functioning, Role limitation due to physical health, Body pain, Vitality, Social functioning, P < .05). No modification in anthropometrics and DEXA values was observed. The analysis of the mitochondrial Displacement loop (D-loop) region confirmed the clonality of all lipomatous lesions. The presence of the mitochondrially encoded tRNA-Lysine (MT-TK) m.8344A>G variant, occasionally identified in patients with multiple symmetric lipomatosis, was excluded in all subjects. On the other hand, we observed variants in genes belonging to signaling pathways involved in cell cycle and proliferation (Phosphoinositide 3-kinase/AKT/mTOR, MAPK/ERK, and Hippo).FREMS can be a useful tool to alleviate pain and improve overall quality of life in patients with DD. Genetic analysis highlighted the molecular heterogeneity of lipomas.

Type 1 Diabetes Patients' Practice, Knowledge and Attitudes towards Influenza Immunization.

Diabetic patients are at higher risk of developing infectious diseases and severe complications, compared to the general population. Almost no data is available in the literature on influenza immunization in people with type 1 diabetes mellitus (T1DM). As part of a broader project on immunization in diabetic patients, we conducted a cross-sectional study to: (i) report on seasonal influenza coverage rates in T1DM patients, (ii) explore knowledge, attitudes, and practices (KAPs) towards seasonal influenza in this population, and (iii) identify factors associated with vaccine uptake, including the role of family doctors and diabetologists. A survey was administered to 251 T1DM patients attending the Diabetes Clinic at San Raffaele Research Hospital in Milan, Italy and individual-level coverage data were retrieved from immunization registries. Self-reported seasonal influenza immunization coverage was 36%, which decreased to 21.7% when considering regional immunization registries, far below coverage target of 75%. More than a third (36.2%) of T1DM patients were classified as pro-vaccine, 30.7% as hesitant, 17.9% as uninformed, and 15.1% as anti-vaccine. Diabetologists resulted to be the most trusted source of information on vaccines' benefits and risks (85.3%) and should be more actively involved in preventive interventions. Our study highlights the importance of developing tailored vaccination campaigns for people with diabetes, including hospital-based programs involving diabetes specialists.

Pre-Existing Diabetes and COVID-Associated Hyperglycaemia in Patients with COVID-19 Pneumonia.

AIM: The aim of the current study was to compare clinical characteristics, laboratory findings, and major outcomes of patients hospitalized for COVID-19 pneumonia with COVID-associated hyperglycaemia or pre-existing diabetes. METHODS: A cohort of 176 adult patients with a diagnosis of pre-existing diabetes (n = 112) or COVID-associated hyperglycaemia (n = 55) was studied. RESULTS: Patients with COVID-associated hyperglycaemia had lower BMI, significantly less comorbidities, and higher levels of inflammatory markers and indicators of multi-organ injury than those with pre-existing diabetes. No differences between pre-existing diabetes and COVID-associated hyperglycaemia were evident for symptoms at admission, the humoral response against SARS-CoV-2, or autoantibodies to glutamic acid decarboxylase or interferon alpha-4. COVID-associated hyperglycaemia was independently associated with the risk of adverse clinical outcome, which was defined as ICU admission or death (HR 2.11, 95% CI 1.34-3.31; p = 0.001), even after adjustment for age, sex, and other selected variables associated with COVID-19 severity. Furthermore, at the same time, we documented a negative association (HR 0.661, 95% CI 0.43-1.02; p = 0.063) between COVID-associated hyperglycaemia to swab negativization. CONCLUSIONS: Recognizing hyperglycaemia as a specific clinical entity associated with COVID-19 pneumonia is relevant for early and appropriate patient management and close monitoring for the progression of disease severity.

Rapamycin Plus Vildagliptin to Recover ß-Cell Function in Long-Standing Type 1 Diabetes: A Double-Blind, Randomized Trial.

AIM: The aim of this study was to investigate whether treatment with rapamycin plus vildagliptin restores ß-cell function in patients with long-standing type 1 diabetes. METHODS: A phase 2, single-center, randomized, double-blind, placebo-controlled study was conducted in long-standing type 1 diabetes patients randomly assigned (1:1:1) to 4 weeks of rapamycin (group 2), 4 weeks of rapamycin plus 12 weeks of vildagliptin (group 3), or double placebo (group 1). The primary outcome was the proportion of participants with a positive response to the Mixed-Meal Tolerance Test (C-peptide at 90 minutes > 0.2 nmol/L) at weeks 4 and 12. Secondary end points included insulin requirement, standard measures of glycemic control, and hormonal and immunological profile. RESULTS: Fifty-five patients were randomly assigned to group 1 (n = 18), group 2 (n = 19), or group 3 (n = 18). No patient in any group showed a positive C-peptide response, and there was no significant difference at 4 and 12 weeks for the primary outcome. At 4 weeks, insulin requirement decreased from 0.54 to 0.48 U/kg/day in group 2 (P = .013), from 0.59 to 0.51 U/kg/day in group 3 (P < .001), whereas it did not change in group 1. At 12 weeks, glycated hemoglobin significantly decreased both in group 2 (from 7.3% [56 mmol/mol] to 7% [53 mmol/mol]; P = .045] and in group 3 (from 7.2% [55.5 mmol/mol] to 6.9% [52 mmol/mol]; P = .001]. Rapamycin treatment was associated with a decrease in insulin antibody titer and changes in hormonal/immunological profile. CONCLUSIONS: Rapamycin reduced insulin requirement, but did not restore ß-cell function in patients with long-standing type 1 diabetes.

Reduced Follicular Regulatory T Cells in Spleen and Pancreatic Lymph Nodes of Patients With Type 1 Diabetes.

In the attempt to understand the origin of autoantibody (AAb) production in patients with and at risk for type 1 diabetes (T1D), multiple studies have analyzed and reported alterations in T follicular helper (Tfh) cells in presymptomatic AAb+ subjects and patients with T1D. Yet, whether the regulatory counterpart of Tfh cells, represented by T follicular regulatory (Tfr) cells, is similarly altered is still unclear. To address this question, we performed analyses in peripheral blood, spleen, and pancreatic lymph nodes (PLN) of organ donor subjects with T1D. Blood analyses were also performed in living AAb- and AAb+ subjects. While negligible differences in the frequency and phenotype of blood Tfr cells were observed among T1D, AAb-, and AAb+ adult subjects, the frequency of Tfr cells was significantly reduced in spleen and PLN of T1D as compared with nondiabetic control subjects. Furthermore, adoptive transfer of Tfr cells delayed disease development in a mouse model of T1D, a finding that could indicate that Tfr cells play an important role in peripheral tolerance and regulation of autoreactive Tfh cells. Together, our findings provide evidence of Tfr cell alterations within disease-relevant tissues in patients with T1D, suggesting a role for Tfr cells in defective humoral tolerance and disease pathogenesis.

Pregnancy after pancreas-kidney transplantation.

A combined kidney and pancreas transplant is a therapeutic option for patients with type 1 diabetes and end-stage renal disease. After successful transplantation, fertility is rapidly restored, allowing women of childbearing age to have spontaneous pregnancies and men to father pregnancies. These pregnancies are at increased risk for maternal and neonatal adverse outcomes due to immunosuppressive therapy, comorbidities, previous type 1 diabetes and previous transplant surgery, although the majority ends with the birth of a live and healthy offspring. Hypertension, miscarriages, diabetes, infections, graft rejections, preterm delivery and low birth weight may complicate pregnancies after pancreas-kidney transplantation. Since not all immunosuppressive drugs can be safely used in pregnancy, it is important to review immunosuppressive treatment before conception. Adequate pre-conception counseling is important to inform women and their partners about potential risks for the pregnancy and the grafts and the advantages of pregnancy planning. These pregnancies should be managed within a multidisciplinary team, comprising a transplant physician, an endocrinologist, a nephrologist, an obstetrician and a neonatologist. Last but not least, it is very important to continue collecting data on the pregnancies in pancreas-kidney transplantation with the aim to improve knowledge and to generate evidence-based guidelines for the care of women after pancreas-kidney transplants who are considering a pregnancy.

Trends in Factors Affecting Pregnancy Outcomes Among Women With Type 1 or Type 2 Diabetes of Childbearing Age (2004-2017).

Aim: To describe trends in modifiable and non-modifiable unfavorable factors affecting pregnancy outcomes, over time (years 2004-2017), in women with diabetes of childbearing age from an English primary care perspective. Methods: We identified women with diabetes aged 16-45 years from the Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) network, an English primary care sentinel database. Repeated annual cross-sectional analyses (2004-2017) assessed the prevalence of unfavorable factors for pregnancy, such as obesity, poor glycaemic control, microalbuminuria, hypertension, use of medications for treating diabetes, and associated comorbidities not recommended for pregnancy. Results: We identified 3,218 women (61.5% with Type 2 diabetes) in 2004 and 6,657 (65.0% with Type 2 diabetes) in 2017. The proportion of women with ideal glycaemic control for conception (HbA1c<6.5%) increased over time, in patients with Type 1 diabetes from 9.0% (7.1%-11.0%) to 19.1% (17.2%-21.1%), and in those with Type 2 diabetes from 27.2% (24.6%-29.9%) to 35.4% (33.6%-37.1%). The proportion of women with Type 2 diabetes prescribed medications different from insulin and metformin rose from 22.3% (20.5%-24.2%) to 27.3% (26.0%-28.6%).In 2017, 14.0% (12.6%-15.4%) of women with Type 1 and 30.7% (29.3%-32.0%) with Type 2 diabetes were prescribed angiotensin-modulating antihypertensives or statins. We captured at least one unfavorable factor for pregnancy in 50.9% (48.8%-52.9%) of women with Type 1 diabetes and 70.7% (69.3%-72.0%) of women with Type 2 diabetes. Only one third of women with Type 1 diabetes (32.2%, 30.3%-34.0%) and a quarter of those with Type 2 diabetes (23.1%, 21.9%-24.4%) were prescribed hormonal contraception. Contraception was prescribed more frequently to women with unfavorable factors for pregnancy compared to those without, however, the difference was significant only for women with Type 1 diabetes. Conclusions: Despite significant improvements in general diabetes care, the majority of women with Type 1 or Type 2 diabetes have unfavorable, although mostly modifiable, factors for the start of pregnancy. Good diabetes care for women of childbearing age should include taking into consideration a possible pregnancy.

Expression of glucose transporters in duodenal mucosa of patients with type 1 diabetes.

AIMS: A higher SGLT1 and GLUT2 gene expression was shown in the intestine of subjects with type 2 diabetes, while no data have been reported in type 1 diabetes (T1D). The purpose of our study was to evaluate the expression of glucose transporters in duodenal mucosa of subjects with T1D, compared to healthy controls (CTRL) and to patients with celiac disease (CD), as gut inflammatory disease control group. MATERIALS AND METHODS: Gene expression of GLUT1, GLUT2, SGLT1 and SGLT2 was quantified on duodenal mucosa biopsies of subjects with T1D (n = 19), CD (n = 16), T1D and CD (n = 6) and CTRL (n = 12), recruited at San Raffaele Hospital (Milan, Italy), between 2009 and 2018. SGLT2 expression was further evaluated by immunohistochemical and immunofluorescence staining. RESULTS: The expression of all four glucose transporters was detected in duodenal mucosa of all groups. A reduced GLUT2, SGLT1 and SGLT2 expression was observed in CD in comparison with T1D and CTRL, as expected; GLUT1 was significantly more expressed in T1D compared to CTRL. SGLT2 expression was quantified at much lower levels than other transporters, with no differences between groups. SGLT2 expression was confirmed by immunohistochemistry in a restricted number of enterocytes lining in the mucosa of intestinal villi, also shown on immunofluorescence. CONCLUSIONS: Our results show that glucose transporters expression in duodenal mucosa of subjects with T1D, except an increased GLUT1, is not different from that observed in healthy controls. The expression of SGLT2 in human duodenal mucosa, although at low intensity, represents a novel finding.

Low-Carb and Ketogenic Diets in Type 1 and Type 2 Diabetes.

Low-carb and ketogenic diets are popular among clinicians and patients, but the appropriateness of reducing carbohydrates intake in obese patients and in patients with diabetes is still debated. Studies in the literature are indeed controversial, possibly because these diets are generally poorly defined; this, together with the intrinsic complexity of dietary interventions, makes it difficult to compare results from different studies. Despite the evidence that reducing carbohydrates intake lowers body weight and, in patients with type 2 diabetes, improves glucose control, few data are available about sustainability, safety and efficacy in the long-term. In this review we explored the possible role of low-carb and ketogenic diets in the pathogenesis and management of type 2 diabetes and obesity. Furthermore, we also reviewed evidence of carbohydrates restriction in both pathogenesis of type 1 diabetes, through gut microbiota modification, and treatment of type 1 diabetes, addressing the legitimate concerns about the use of such diets in patients who are ketosis-prone and often have not completed their growth.

Three Reportedly Unrelated Families With Liddle Syndrome Inherited From a Common Ancestor.

Liddle syndrome is considered a rare Mendelian hypertension. We have previously described 3 reportedly unrelated families, native of an Italian area around the Strait of Messina, carrying the same mutation (ßP617L) of the epithelial sodium channel. The aims of our study were (1) to evaluate whether a close genomic relationship exists between the 3 families through the analysis of mitochondrial DNA and Y chromosome; and (2) to quantify the genomic relatedness between the patients with Liddle syndrome belonging to the 3 families and assess the hypothesis of a mutation shared through identity by descent. HVRI (the hypervariable region I) of the mitochondrial DNA genome and the Y chromosome short tandem repeats profiles were analyzed in individuals of the 3 families. Genotyping 542 585 genome-wide single nucleotide polymorphisms was performed in all the patients with Liddle syndrome of the 3 families and some of their relatives. A panel of 780 healthy Italian adult samples typed for the same set of markers was used as controls. espite different lineages between the 3 families based on the analysis of mitochondrial DNA and Y chromosome, the 3 probands and their 6 affected relatives share the same ≈5 Mbp long haplotype which encompasses the mutant allele. Using an approach based on coalescent theory, we estimate that the 3 families inherited the mutant allele from a common ancestor ≈13 generations ago and that such an ancestor may have left ≈20 carriers alive today. The prevalence of Liddle syndrome in the region of origin of the 3 families may be much higher than that estimated worldwide.

Successful Treatment of Dercum's Disease by Transcutaneous Electrical Stimulation: A Case Report.

Dercum's disease is a rare condition of painful subcutaneous growth of adipose tissue. Etiology is unknown and pain is difficult to control. We report the case of a 57-year-old man with generalized diffuse Dercum's disease, who improved after the treatment with transcutaneous frequency rhythmic electrical modulation system (FREMS). Treatment consisted in 4 cycles of 30 minutes FREMS sessions over a 6-month period. Measures of efficacy included pain assessment (visual analogue scale, VAS), adipose tissue thickness by magnetic resonance imaging, total body composition and regional fat mass by dual-energy X-ray absorptiometry, physical disability (Barthel index), and health status (Short Form-36 questionnaire). After FREMS treatment the patient's clinical conditions significantly improved, with reduction of pain on the VAS scale from 64 to 17 points, improvement of daily life abilities (the Barthel index increased from 12 to 18) and amelioration of health status (higher scores than baseline in all Short Form-36 domains). Furthermore, we documented a 12 mm reduction in subcutaneous adipose tissue thickness at the abdominal wall and a 7040 g decrease in total body fat mass. FREMS therapy proved to be effective and safe in the treatment of this rare and disabling condition.

A Therapeutic Challenge: Liddle's Syndrome Managed with Amiloride during Pregnancy.

Liddle's syndrome (LS) is a rare heritable form of hypertension that often affects young patients. It is caused by gain-of-function mutations of the kidney epithelial sodium channel (ENaC) and it is classically associated with hypokalemia and suppression of renin and aldosterone. LS is characterized by responsiveness to ENaC inhibitors but not to mineralocorticoid receptor inhibitors. Consequently the most effective treatment is amiloride. This drug is not used in pregnancy, as it has not been sufficiently studied during gestation. However for pregnant LS patient amiloride is the most effective drug in decreasing blood pressure. Herein we report the case of a LS patient, who has been followed up by a multidisciplinary teamwork during her first pregnancy. Hypertension worsened after the 25th week of gestation and amiloride was safely administered, firstly in combination with hydrochlorothiazide (the only formulation commercially available in Italy) and, thereafter, as a single drug. Genetic testing was performed in the patient's family in order to support diagnosis and clinical management.