Heterogeneity and high prevalence of bone manifestations, and bone mineral density in congenital generalized lipodystrophy subtypes 1 and 2.

Introduction: Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease caused by mutations in genes responsible for the formation and development of adipocytes. Bone abnormalities are described. However, there is a scarcity of data. Objective: To describe bone characteristics in a large CGL1 and 2 case series. Methods: Cross-sectional study that assessed bone radiological features of CGL patients of a reference hospital in Fortaleza (CE), Brazil. Patients underwent clinical and bone mineral metabolism evaluation, radiographs of the axial and appendicular skeleton and bone mineral density (BMD) assessment by DEXA (dual energy X-ray absorptiometry). Results: Nineteen patients were included, fourteen were CGL1 and 5, CGL2. Median age was 20 years (8-42) and 58% were women. Median BMI and percentage of body fat were, respectively, 21 Kg/m² (16-24), and 10.5% (7.6-15). The median leptin concentration was 1 ng/mL (0.1-3.3). Diabetes mellitus and dyslipidemia were present in 79% and 63% of patients, respectively. Median calcium and phosphate were normal in almost all patients (95%). Median parathyroid hormone and 25-OH-vitamin D were 23 pg/mL (7-75) and 28 ng/mL (18-43). Osteolytic lesions, osteosclerosis and pseudo-osteopoikylosis, were present in 74%, 42% and 32% of patients, respectively. Lytic lesions were found predominantly in the extremities of long bones, bilaterally and symmetrically, spine was spared. Osteosclerosis was present in axial and appendicular skeleton. Pseudo-osteopoikilosis was found symmetrically in epiphyses of femur and humerus, in addition to the pelvis. BMD Z-score greater than +2.5 SD was observed in 13 patients (68.4%). BMD was higher in CGL1 compared to CGL2 in lumbar spine and total body in adults. No associations were found between high BMD and HOMA-IR (p=0.686), DM (p=0.750), osteosclerosis (p=0.127) or pseudo-osteopoikilosis (p=0.342), and, between pain and bone lesions. Fractures were found in 3 patients. Conclusion: Bone manifestations are prevalent, heterogeneous, and silent in CGL1 and CGL2. Osteolytic lesions are the most common, followed by osteosclerosis and pseudo-osteopoikilosis. Bone mass is high in most cases. There was no pain complaint related to bone lesions. Thus, systematic assessment of bone manifestations in CGL is essential. Studies are needed to better understand its pathogenesis and clinical consequences.

Identifying congenital generalized lipodystrophy using deep learning-DEEPLIPO.

Congenital Generalized Lipodystrophy (CGL) is a rare autosomal recessive disease characterized by near complete absence of functional adipose tissue from birth. CGL diagnosis can be based on clinical data including acromegaloid features, acanthosis nigricans, reduction of total body fat, muscular hypertrophy, and protrusion of the umbilical scar. The identification and knowledge of CGL by the health care professionals is crucial once it is associated with severe and precocious cardiometabolic complications and poor outcome. Image processing by deep learning algorithms have been implemented in medicine and the application into routine clinical practice is feasible. Therefore, the aim of this study was to identify congenital generalized lipodystrophy phenotype using deep learning. A deep learning approach model using convolutional neural network was presented as a detailed experiment with evaluation steps undertaken to test the effectiveness. These experiments were based on CGL patient's photography database. The dataset consists of two main categories (training and testing) and three subcategories containing photos of patients with CGL, individuals with malnutrition and eutrophic individuals with athletic build. A total of 337 images of individuals of different ages, children and adults were carefully chosen from internet open access database and photographic records of stored images of medical records of a reference center for inherited lipodystrophies. For validation, the dataset was partitioned into four parts, keeping the same proportion of the three subcategories in each part. The fourfold cross-validation technique was applied, using 75% (3 parts) of the data as training and 25% (1 part) as a test. Following the technique, four tests were performed, changing the parts that were used as training and testing until each part was used exactly once as validation data. As a result, a mean accuracy, sensitivity, and specificity were obtained with values of [90.85 ± 2.20%], [90.63 ± 3.53%] and [91.41 ± 1.10%], respectively. In conclusion, this study presented for the first time a deep learning model able to identify congenital generalized lipodystrophy phenotype with excellent accuracy, sensitivity and specificity, possibly being a strategic tool for detecting this disease.

Evaluation of the anti-diabetic drug sitagliptin as a novel attenuate to SARS-CoV-2 evidence-based in silico: molecular docking and molecular dynamics.

The current outbreak of COVID-19 cases worldwide has been responsible for a significant number of deaths, especially in hospitalized patients suffering from comorbidities, such as obesity, diabetes, hypertension. The disease not only has prompted an interest in the pathophysiology, but also it has propelled a massive race to find new anti-SARS-CoV-2 drugs. In this scenario, known drugs commonly used to treat other diseases have been suggested as alternative or complementary therapeutics. Herein we propose the use of sitagliptin, an inhibitor of dipeptidyl peptidase-4 (DPP4) used to treat type-II diabetes, as an agent to block and inhibit the activity of two proteases, 3CLpro and PLpro, related to the processing of SARS-CoV-2 structural proteins. Inhibition of these proteases may possibly reduce the viral load and infection on the host by hampering the synthesis of new viruses, thus promoting a better outcome. In silico assays consisting in the modeling of the ligand sitagliptin and evaluation of its capacity to interact with 3CLpro and PLpro through the prediction of the ligand bioactivity, molecular docking, overlapping of crystal structures, and molecular dynamic simulations were conducted. The experiments indicate that sitagliptin can interact and bind to both targets. However, this interaction seems to be stronger and more stable to 3CLpro (ΔG = -7.8 kcal mol-1), when compared to PLpro (ΔG = -7.5 kcal mol-1). This study suggests that sitagliptin may be suitable to treat COVID-19 patients, beyond its common use as an anti-diabetic medication. In vivo studies may further support this hypothesis. Supplementary Information: The online version contains supplementary material available at 10.1007/s13205-022-03406-w.

Bone Mineral Density in Congenital Generalized Lipodystrophy: The Role of Bone Marrow Tissue, Adipokines, and Insulin Resistance.

Congenital Generalized Lipodystrophy (CGL) is a rare syndrome characterized by the almost total absence of subcutaneous adipose tissue due to the inability of storing lipid in adipocytes. Patients present generalized lack of subcutaneous fat and normal to low weight. They evolve with severe metabolic disorders, non-alcoholic fatty liver disease, early cardiac abnormalities, and infectious complications. Although low body weight is a known risk factor for osteoporosis, it has been reported that type 1 and 2 CGL have a tendency of high bone mineral density (BMD). In this review, we discuss the role of bone marrow tissue, adipokines, and insulin resistance in the setting of the normal to high BMD of CGL patients. Data bases from Pubmed and LILACS were searched, and 113 articles published until 10 April 2021 were obtained. Of these, 76 were excluded for not covering the review topic. A manual search for additional literature was performed using the bibliographies of the studies located. The elucidation of the mechanisms responsible for the increase in BMD in this unique model of insulin resistance may contribute to the understanding of the interrelationships between bone, muscle, and adipose tissue in a pathophysiological and therapeutic perspective.

Misdiagnosis of Paget's Disease of Bone in a Congenital Generalized Lipodystrophy Patient: Case Report.

Paget's disease of bone (PDB) is a common skeleton disorder in which the diagnosis is suggested by radiological analyses. Congenital generalized lipodystrophy (CGL) is a rare, but a radiologic differential diagnosis of Paget's disease. Patients present total or almost total lack of subcutaneous adipose tissue, leptin deficiency, and precocious ectopic lipid accumulation, which lead to intense insulin resistance, poorly controlled diabetes mellitus, and hypertriglyceridemia. CGL subtypes 1 and 2 present sclerosis and osteolytic lesions that can resemble "pagetic" lesions. The clinical correlation is, therefore, essential. We report a CGL patient with bone lesions in which the radiographic findings led to a misdiagnosis of PDB. This case report brings awareness to CGL, a life-threating condition. Its early recognition is essential to avoid clinical complications and premature death. Therefore, it is important to consider CGL as PDB's differential diagnosis, especially in countries with high prevalence of this rare disease, such as Brazil.

SARS-COV-2 infection outcomes in patients with congenital generalized lipodystrophy.

BACKGROUND: A new strain of human coronavirus (HCoV) spread rapidly around the world. Diabetes and obesity are associated with a worse prognosis in these patients. Congenital Generalized Lipodystrophy (CGL) patients generally have poorly controlled diabetes and require extremely high doses of insulin. There is no documentation in the literature of cases of COVID in CGL patients. Thus, we aimed to evaluate the prevalence of SARS-CoV-2 infection in CGL patients, and the association of their clinical and metabolic characteristics and outcomes. METHODS: This is a cross-sectional study carried out between July and October 2020. Clinical data collected were respiratory or other flu-like symptoms, need of hospitalization in the last three months, CGL comorbidities, and medications in use. Cholesterol, triglycerides, glycohemoglobin A1c levels, anti-SARS-CoV-2 antibodies and nasopharyngeal swab for RT-qPCR were also obtained in all CGL patients. Mann-Whitney U test was used to analyze the characteristics of the participants, verifying the non-adherence of the data to the Gaussian distribution. In investigating the association between categorical variables, we used Pearson's chi-square test and Fisher's exact test. A significance level of 5% was adopted. RESULTS: Twenty-two CGL patients were assessed. Eight subjects (36.4%) had reactive anti-SARS-CoV-2 antibodies. Only one of these, also presented detectable RT-qPCR. Five individuals (62.5%) were women, median age of 13.5 years (1 to 37). Symptoms like fever, malaise, nausea, diarrhea and chest pain were present, and all asymptomatic patients were children. All subjects had inadequate metabolic control, with no difference between groups. Among positive individuals there was no difference between those with AGPAT2 (75%) and BSCL2 gene mutations (25%) (p > 0.05). No patient needed hospitalization or died. CONCLUSIONS: We described a high prevalence of SARS-CoV-2 infection in CGL patients with a good outcome in all of them. These findings suggest that at least young CGL patients infected by SARS-COV-2 are not at higher risk of poor outcome, despite known severe metabolic comorbidities.

Qualidade da dieta e risco cardiometabólico em crianças e adolescentes com excesso de peso / Diet quality and cardiometabolic risk in children and adolescents with excess weight / Calidad de la dieta y el riesgo cardiometabolico de niños y adolescentes con exceso de peso

Objetivo: Avaliar a qualidade da dieta de crianças e adolescentes com excesso de peso e determinar a relação com fatores de risco cardiometabólico. Métodos: Estudo quantitativo, transversal e analítico, realizado entre dezembro de 2016 e agosto de 2018, com crianças e adolescentes. Coletaram-se variáveis comportamentais (prática de atividade física e tempo de tela), antropométricas (peso, altura, índice de massa corporal, circunferência abdominal e do pescoço) e dietéticas (recordatório de 24 horas) e os dados bioquímicos foram consultados nos prontuários. Avaliou-se a resistência à insulina (RI), usando Homeostasis Model Assessment ­ Insulin Resistance (HOMA-IR), e a qualidade da dieta, por meio do Índice de Qualidade da Dieta Revisado (IQD-R). Análises realizadas pelos testes de Spearman e Mann-Whitney U, com nível de significância de 5%. Resultados: A amostra incluiu 100 crianças e adolescentes, sendo 71 (71%) do sexo feminino, média de idade de 9,42 ± 2,89 anos. IQD-R apresentou valor médio de 61,16 (IC 95%: 59,14 ­ 63,19) e nenhum participante apresentou dieta de boa qualidade. Não foram encontradas associações entre o escore do IQD-R e marcadores cardiometabólicos. Observaram-se associações negativas entre os componentes "vegetais totais e leguminosas" e HOMA-IR (r= -0,290), "vegetais verde-escuros, alaranjados e leguminosas" e HOMA-IR (r= -0,333) e "vegetais verde-escuros, alaranjados e leguminosas" com insulina de jejum (r= -0,291). Participantes com mais de três fatores de risco cardiometabólico tiveram pontuação significativamente maior do componente "gordura sólida e açúcar de adição". Conclusão: Nenhum participante investigado apresentou dieta qualitativamente adequada. A baixa ingestão de vegetais e leguminosas foi associada com marcadores de RI. Descritores: Promoção da Saúde, Obesidade Pediátrica; Consumo de Alimentos; Resistência à Insulina; Doenças Cardiovasculares.

Objective: To assess the quality of the diet of children and adolescents with excess weight and determine its relationship with cardiometabolic risk factors. Methods: This quantitative descriptive cross-sectional study was carried out from December 2016 to August 2018 with children and adolescents. Behavioral (regular physical activity, screen time), anthropometric (weight, height, Body Mass Index, abdominal circumference, neck circumferences) and dietary (24-hour recalls) data were collected, and biochemical data were retrieved from medical records. Insulin resistance (IR) was measured using the Homeostasis Model Assessment ­ Insulin Resistance (HOMA-IR) and diet quality was assessed using the Revised Diet Quality Index (Índice de Qualidade da Dieta Revisado ­ IQD-R). Analyses using Spearman's and Mann-Whitney U tests were performed with a significance threshold set at 5%. Results: The sample consisted of 100 children and adolescents, 71 (71%) of whom were girls, and the mean age was 9.42±2.89 years. The mean IQD-R was 61.16 (95%CI: 59.14 ­ 63.19) and none of the participants presented a good quality diet. No associations were found between the IQD-R score and cardiometabolic markers. However, negative associations were observed between "total vegetables and legumes" and HOMA-IR (r=-0.290), "dark green and orange vegetables and legumes" and HOMA-IR (r=-0.333) and "dark green and orange vegetables and legumes" and fasting insulin (r=-0.291). The participants who presented more than three cardiometabolic risk factors had a significantly higher score on the "solid fat and added sugar" component. Conclusion: None of the participants had a qualitatively adequate diet. The low intake of vegetables and legumes was associated with IR markers. Descriptors: Health Promotion, Pediatric Obesity; Food Intake; Insulin Resistance; Cardiovascular Diseases.

Objetivo: Evaluar la calidad de la dieta de niños y adolescentes con exceso de peso y determinar la relación con los factores de riesgo cardiometabolico. Métodos: Estudio cuantitativo, transversal y analítico realizado entre diciembre de 2016 y agosto de 2018 con niños y adolescentes. Se recogieron las variables de conducta (práctica de actividad física y tiempo de pantalla), antropométricas (peso, altura, índice de masa corporal, circunferencia abdominal y del cuello) y dietéticas (recordatorio de 24 horas) y los datos bioquímicos han sido consultados de los historiales clínicos. Se evaluó la resistencia a la insulina (RI) usando el Homeostasis Model Assessment ­ Insulin Resistance (HOMA-IR) y la calidad de la dieta a través del Índice de Calidad de la Dieta Revisado (ICD-R). Los análisis han sido realizados por las pruebas de Spearman y Mann-Whitney U con el nivel de significancia del 5%. Resultados: La muestra ha sido de 100 niños y adolescentes de los cuales 71 (71%) era del sexo femenino con la media de edad de 9,42 ± 2,89 años. El ICD-R presentó el valor medio de 61,16 (IC 95%: 59,14 - 63,19) y ningún participante presentó dieta de buena calidad. No se ha encontrado asociaciones entre la puntuación del ICD-R y los marcadores cardiometabolicos. Se ha observado asociaciones negativas entre los componentes "vegetales totales y leguminosas" y el HOMA-IR (r= -0,290), "vegetales verde-oscuros, anaranjados y leguminosas" y el HOMA-IR (r= -0,333) y "vegetales verde-oscuros, anaranjados y leguminosas" y la insulina de ayuno (r= - 0,291). Los participantes con más de tres factores de riesgo cardiometabolico tuvieron la puntuación significativamente mayor en el componente "grasa sólida y azúcar de adición". Conclusión: Ningún participante investigado presentó la dieta cualitativamente adecuada. La baja ingesta de vegetales y leguminosas se ha asociado con los marcadores de RI Descriptores: Promoción de la Salud, Obesidad Pediátrica; Consumo de Alimentos; Resistencia a la Insulina; Enfermedades Cardiovasculares.

Leu124Serfs*26, a novel AGPAT2 mutation in congenital generalized lipodystrophy with early cardiovascular complications.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by the near-total loss of subcutaneous adipose tissue soon after birth, resulting in ectopic fat deposition and severe metabolic disturbances. Most cases are caused by AGPAT2 or BSCL2 gene mutations. We aimed to report two unrelated CGL patients with a novel frameshift mutation in AGPAT2 (p.Leu124Serfs*26). METHODS: Clinical features and laboratory were obtained by medical interview and medical records review. DNA was extracted, amplified and sequenced. Mutation Taster was used to estimate the potential biological impact of the AGPAT2 mutations on the protein function. RESULTS: Patient 1: a 30-year-old woman with lipodystrophy phenotype at birth and diagnosis of diabetes at age 13 presented with severe hypertriglyceridemia and pancreatitis at age 17, hypertension and albuminuria at age 18, proliferative diabetic retinopathy with visual loss at age 25, and an acute myocardial infarction due to multivessel coronary disease during a hospitalization for forefoot amputation at age 29. At this time, she required hemodialysis due to end-stage renal disease. Patient 2: a 12-year-old girl with lipodystrophy phenotype and hypertriglyceridemia detected in the first year of life and abnormalities in the global longitudinal strain, evaluated by speckle-tracking echocardiography last year. Molecular analysis identified a c.369_372delGCTC (p.Leu124Serfs*26) AGPAT2 mutation in both unrelated patients, a compound heterozygous mutation in Patient 1, and homozygous mutation in Patient 2. CONCLUSION: We describe two unrelated patients with type 1 CGL due to Leu124Serfs*26, a novel AGPAT2 frameshift mutation, presenting as early cardiovascular disease. These findings suggest an association between Leu124Serfs*26 and a more aggressive phenotype.

Early Left Ventricular Systolic Dysfunction Detected by Two-Dimensional Speckle-Tracking Echocardiography in Young Patients with Congenital Generalized Lipodystrophy.

PURPOSE: Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by the absence of functional adipocytes resulting in ectopic lipid storage, metabolic disorders and early cardiovascular disease. Two-dimensional speckle-tracking (2D-STE) allows the detection of early abnormalities in myocardial function. We aimed to evaluate myocardial deformation in a large sample of CGL patients using 2D-STE. PATIENTS AND METHODS: A cross-sectional study of 22 patients with CGL and 22 healthy subjects, matched for sex and age, was conducted from 2013 to 2018. All participants had undergone standard conventional echocardiography (ECHO) and 2D-STE. Determination of blood glucose, lipids, insulin, and leptin were performed in all CGL patients. RESULTS: In the CGL group the mean age was 14.6±10.7 years where 68.2% (n=15) were younger than 18 years old. All the patients had hypoleptinemia, 95.4% (21/22) low HDL-c, 86.4% (19/22) hypertriglyceridemia, 68.2% (15/22) diabetes, 50% (11/22) hepatic steatosis, 41% (9/22) insulin resistance, 41% (9/22) hypercholesterolemia, and 18.2% (4/22) hypertension. ECHO showed that 36.6% (8/22) of CGL patients presented diastolic dysfunction, 31.8% (7/22) left ventricular hypertrophy (LVH), 27.3% (6/22) increased left atrial volume index (LAVI), and 18.2% (4/22) increased left ventricular systolic diameter (LVDS) but normal ejection fraction (EF), whether using 2D-STE, 68.2% (15/22) of CGL patients showed abnormal global longitudinal strain (GLS) (p<0.01), and in almost LV segments. Positive association between abnormal GLS and A1c (r=0.57, p=0.005), glucose (r=0.5, p=0.018) and basal insulin (r= 0.69, p= 0.024), and negative association with leptin (r = -0.51, p = 0.005) were found in these patients. CONCLUSION: The 2D-STE revealed precocious left ventricular systolic dysfunction in a young CGL population with normal systolic function by ECHO. Early exposure to common metabolic abnormalities as insulin resistance, hyperglycemia, and hypoleptinemia must be involved in myocardial damage in these patients.

Lower Insulin-Dose Adjusted A1c (IDAA1c) Is Associated With Less Complications in Individuals With Type 1 Diabetes Treated With Hematopoetic Stem-Cell Transplantation and Conventional Therapy.

Objective: To evaluate the association between insulin-dose adjusted A1C (IDAA1c) and microvascular complications (MC) and hypoglycemia in a representative Brazilian population of Type 1 diabetes mellitus (T1DM) patients. Research Design and Methods: This was a cross-sectional study based on a previous study, "Microvascular Complications in Type 1 Diabetes: a comparative analysis of patients treated with autologous nonmyeloablative hematopoietic stem-cell transplantation (AHST) and conventional medical therapy (CT)". The 168 patients in that study (144 from CT plus 24 from AHST) were re-subdivided into two groups, according to their IDAA1c values (30 patients had IDAA1c ≤ 9; 138 had IDAA1c > 9). Then, the prevalence of MC (diabetic renal disease, neuropathy, and retinopathy), hypoglycemia (blood glucose <60 mg/dL), and severe hypoglycemic (episode of hypoglycemia that required the assistance of another person to treat) events were compared between the groups. The groups were well-matched on these factors: duration of disease, sex, and age at the time of diagnosis of T1DM. Results: After an average of 8 years after diagnosis, only 6.6% (2/30) of the patients from IDAA1c ≤ 9 group developed any MC, whereas 21.0% (29/138) from the IDAA1c > 9 group had at least one complication (p = 0.044). Regarding hypoglycemic events, the proportion of individuals who reported at least 1 episode of hypoglycemia in the last month was 43.3 and 64.7% from the IDAA1c ≤ 9 and IDAA1c > 9 groups, respectively (p = 0.030). Regarding severe hypoglycemia, the proportion of patients presenting at least one episode in the last month and the rate of episode/patient/month were similar between groups (6.7 vs. 13.2%; p = 0.535; and 0.1/patient/month vs. 0.25/patient/month; p = 0.321). Conclusion: In a representative Brazilian population of T1DM patients, those with IDAA1c ≤ 9 presented a lower frequency of MC, as well as fewer episodes of hypoglycemia, in the month prior to the analysis.

Association between cardiovascular autonomic neuropathy and left ventricular hypertrophy in young patients with congenital generalized lipodystrophy.

BACKGROUND: Congenital generalized lipodystrophy (CGL) is a rare disorder characterized by the absence of subcutaneous adipose tissue, severe insulin resistance, diabetes mellitus, and cardiovascular complications, including cardiac autonomic neuropathy (CAN), left ventricular hypertrophy (LVH), and atherosclerosis. The present study aimed to access the association between CAN parameters and cardiovascular abnormalities in CGL patients. METHODS: A cross-sectional study was conducted with 10 CGL patients and 20 healthy controls matched for age, sex, BMI, and pubertal stage. We evaluated clinical, laboratory, and cardiovascular parameters-left ventricular mass index (LVMI), interventricular septum thickness (IVS), systolic and diastolic function determined by two-dimensional transthoracic echocardiography; carotid intimal media thickness (cIMT); and cQT interval. Heart rate variability (HRV) was evaluated by spectral analysis components-high frequency (HF), low frequency (LF), very low frequency (VLF), LF/HF ratio, and total amplitude spectrum (TAS)-and cardiovascular reflexes tests (postural hypotension test, respiratory, orthostatic and Valsalva coefficients). RESULTS: In CGL group, four patients (40%) had LVH and diastolic dysfunction. HF component (parasympathetic control) was lower in LVH patients. CGL patients presented higher values of cIMT and cQT interval than heathy subjects. Inverse association between LVMI and LF (p = 0.011), IVS and LF (p = 0.007), and cIMT and leptin (p < 0.001) were observed, even after adjustments by HOMA-IR, A1c, and blood pressure. In CGL group, there were associations between LMVI and HF component (IC95%: - 1.000; - 00.553), LVMI and TAS (IC95%: - 1.000; - 0.012), and IVS and HF component (IC95%: - 1.000; - 0.371). CONCLUSION: The association between increased LV mass and parameters of HRV provides possible speculations about the involvement of CAN in the pathophysiology of the cardiac complications, including LVH, in patients with CGL.

Aggressive papillary thyroid carcinoma in a child with type 2 congenital generalized lipodystrophy.

Thyroid carcinoma (TC) is rare in children, particularly in those aged < 10 years. Several studies have demonstrated a correlation between neoplasms and hyperinsulinemia and insulin resistance, which are often associated with a higher risk for and/or aggressiveness of the neoplasm. Congenital generalized lipodystrophy (CGL) with autosomal recessive inheritance is a rare disease and is characterized by the lack of adipose tissue, severe insulin resistance, and early metabolic disturbances. Here, we reported a rare case of a type 2 CGL in a girl who presented with a papillary TC (PTC) at the age of 7 years. She had no family history of TC or previous exposure to ionizing radiation. She had a generalized lack of subcutaneous fat, including the palmar and plantar regions, muscle hypertrophy, intense acanthosis nigricans, hepatomegaly, hypertriglyceridemia, severe insulin resistance, and hypoleptinemia. A genetic analysis revealed a mutation in the BSCL2 gene (p.Thr109Asnfs* 5). Ultrasound revealed a hypoechoic solid nodule measuring 1.8 × 1.0 × 1.0 cm, and fine needle aspiration biopsy suggested malignancy. Total thyroidectomy was performed, and a histopathological examination confirmed PTC with vascular invasion and parathyroid lymph node metastasis (pT3N1Mx stage). This is the first report to describe a case of differentiated TC in a child with CGL. Severe insulin resistance that is generally observed in patients with CGL early in life, especially in those with type 2 CGL, may be associated with this uncommon presentation of aggressive PTC during childhood.

Aggressive papillary thyroid carcinoma in a child with type 2 congenital generalized lipodystrophy

SUMMARY Thyroid carcinoma (TC) is rare in children, particularly in those aged < 10 years. Several studies have demonstrated a correlation between neoplasms and hyperinsulinemia and insulin resistance, which are often associated with a higher risk for and/or aggressiveness of the neoplasm. Congenital generalized lipodystrophy (CGL) with autosomal recessive inheritance is a rare disease and is characterized by the lack of adipose tissue, severe insulin resistance, and early metabolic disturbances. Here, we reported a rare case of a type 2 CGL in a girl who presented with a papillary TC (PTC) at the age of 7 years. She had no family history of TC or previous exposure to ionizing radiation. She had a generalized lack of subcutaneous fat, including the palmar and plantar regions, muscle hypertrophy, intense acanthosis nigricans, hepatomegaly, hypertriglyceridemia, severe insulin resistance, and hypoleptinemia. A genetic analysis revealed a mutation in the BSCL2 gene (p.Thr109Asnfs* 5). Ultrasound revealed a hypoechoic solid nodule measuring 1.8 × 1.0 × 1.0 cm, and fine needle aspiration biopsy suggested malignancy. Total thyroidectomy was performed, and a histopathological examination confirmed PTC with vascular invasion and parathyroid lymph node metastasis (pT3N1Mx stage). This is the first report to describe a case of differentiated TC in a child with CGL. Severe insulin resistance that is generally observed in patients with CGL early in life, especially in those with type 2 CGL, may be associated with this uncommon presentation of aggressive PTC during childhood.

Homozygous and Heterozygous Nuclear Lamin A p.R582C Mutation: Different Lipodystrophic Phenotypes in the Same Kindred.

Background: Dunnigan-type familial partial lipodystrophy (FPLD2) is a rare autosomal dominant disease caused by heterozygous mutations in the LMNA gene that results in regional loss of subcutaneous adipose tissue with onset in puberty. However, a generalized lipodystrophy phenotype has also been associated with heterozygous mutations in this gene, demonstrating the noticeable phenotypic heterogeneity of this disease. Methods: We report and describe clinical and metabolic features of four patients from the same family with the p.R582C LMNA mutation, three homozygous and one in the heterozygous state that present with three distinct lipodystrophic phenotypes. Results: Case description: The proband was a 12-year-old girl who developed severe subcutaneous fat atrophy in limbs and abdomen followed by a remarkable dorsocervical fat accumulation in adulthood along with diabetes at age 23. The proband's sister was a phenotypically normal girl who developed hypertriglyceridemia at age 8, progressive features of partial lipodystrophy at age 11, and diabetes at age 22. The proband's mother was first examined at age 32, presenting diabetes and a severe generalized lipodystrophic phenotype; she developed kidney failure at age 41 and died due to diabetic complications. The proband's father was a 50-year-old man with abdominal fat concentration that was initially considered phenotypically normal. Massively parallel sequencing using a platform of genes related to genetic lipodystrophies, followed by Sanger sequencing, revealed the transversion c.1744C>T at exon 11 of the LMNA gene (p.R582C) in the homozygous (mother and daughters) and heterozygous (father) states. Conclusion: We documented three distinct phenotypes of the homozygous and heterozygous p. R582C LMNA mutation in the same kindred, illustrating that FPLD2 linked to mutations in this gene is a disease of great clinical heterogeneity, possibly due to associated environmental or genetic factors.

Proteomic analysis to identify candidate biomarkers associated with type 1 diabetes.

PURPOSE: Type 1 diabetes mellitus (DM1) is one of the most common chronic diseases observed during childhood. The incidence of DM1 is increasing worldwide, and there is currently no way to prevent or delay the onset or to cure the disease. Most diseases, including diabetes, stem from abnormalities in the functioning of proteins, and some studies have reported the expression of protein variation to be involved in the development of DM1. Thus, the aim of this study was to investigate the differential expression of serum proteins in patients with DM1. MATERIALS AND METHODS: Serum of patients with DM1 (n=30) and healthy controls (n=30) was collected. A proteomic approach was used with depletion of albumin and immunoglobulin G chromatography on serum samples followed by data-independent, label-free mass spectrometric analysis. RESULTS: A total of eight serum proteins were identified as being differentially expressed and involved in the immune system, lipid metabolism, and pathways of coagulation. DM1 was associated with the upregulation of six proteins: alpha-2-macroglobulin, apolipoprotein A-II, ß2 glycoprotein I, Ig alpha-2 chain C region, alpha-1-microglobulin, and prothrombin. A total of two proteins were downregulated, including pregnancy zone protein and complement C4. CONCLUSION: To the best of our knowledge, these findings show differential expression of proteins revealing new proteins that may be involved in the development and progression of diabetes.

Early commitment of cardiovascular autonomic modulation in Brazilian patients with congenital generalized lipodystrophy.

BACKGROUND: Metabolic abnormalities in congenital generalized lipodystrophy (CGL) are associated with microvascular complications. However, the evaluation of different types of neuropathy in these patients, including the commitment of cardiovascular autonomic modulation, is scarce. The objective of the present study was to determine the prevalence of cardiovascular autonomic neuropathy (CAN) in patients with CGL compared with individuals with type 1 diabetes and healthy subjects. METHODS: Ten patients with CGL, 20 patients with type 1 diabetes and 20 healthy subjects were included in the study. Controls were paired 1:2 for age, gender, BMI and pubertal stage. Heart rate variability (HRV) was analyzed using cardiovascular autonomic reflex tests, including postural hypotension test, Valsalva (VAL), respiratory (E/I) and orthostatic (30/15) coefficients, and spectral analysis of the HRV, determining very low (VLF), low (LF) and high (HF) frequencies components. The diagnosis of CAN was defined as the presence of at least two altered tests. RESULTS: CAN was detected in 40% of the CGL patients, 5% in type 1 diabetes patients and was absent in healthy individuals (p < 0.05). We observed a significant reduction in the E/I, VLF, LF and HF in CGL cases vs. type 1 diabetes and healthy individuals and lower levels of 30/15 and VAL in CGL vs. healthy individuals. A significant positive correlation was observed between leptin and 30/15 coefficient (r = 0.396; p = 0.036) after adjusting for insulin resistance and triglycerides. Autonomic cardiovascular tests were associated with HbA1c, HOMA-IR, triglycerides and albumin/creatinine ratio in CGL cases. CONCLUSIONS: We observed a high prevalence of CAN in young patients with CGL, suggesting that insulin resistance, hypertriglyceridemia and hypoleptinemia, may have been involved in early CAN development. Additional studies are needed to evaluate the role of leptinemia in the physiopathogenesis of the condition.

Tumores testiculares bilaterais por hiperplasia congênita de restos adrenais / Bilateral testicular tumors caused by congenital adrenal rest hyperplasia

OBJETIVOS: Tumores testiculares são uma rara condição associada à hiperplasia adrenal congênita (HAC) que decorrem da hiperplasia de restos adrenais intratesticulares (HRA), raramente ocorrendo associados a neoplasias malignas. Sua diferenciação histológica com tumores de células de Leydig é muito difícil, podendo levar a orquiectomias desnecessárias. O objetivo deste relato foi apresentar esse dilema diagnóstico em um paciente com HAC e tumores testiculares bilaterais. MÉTODOS: Relatou-se o caso de um paciente masculino, 16 anos, com diagnóstico de HAC desde os 3 anos de idade, que apresentava tumorações testiculares endurecidas, indolores e de crescimento lento, sendo encaminhado para orquiectomia bilateral. RESULTADOS: Foi decidido por tratamento conservador com prednisona, havendo significativa diminuição do volume testicular e normalização dos níveis de andrógenos. CONCLUSÃO: Este caso demonstra a importância de sempre se considerar a hipótese de HRA intratesticulares no diagnóstico diferencial dos tumores testiculares. A investigação e a conduta devem ser conduzidas de maneira cautelosa para se evitar orquiectomias desnecessárias.

OBJECTIVES: Testicular tumors are a rare condition associated with congenital adrenal hyperplasia (CAH), originated from intratesticular adrenal rest tumors, and they are rarely associated with malignant tumors. Their histological differentiation from Leydig-cell tumors is quite difficult, which would lead to inappropriate orchiectomies. Thus the objective of this report was to present this diagnostic dilemma. METHODS: Reported the case of 16-yr-old boy with previous diagnosis of CAH with bilateral testicular enlargement who was recommended to be submitted to a bilateral orchiectomy. RESULTS: Considering this findings, it was decided to treat conventionally with prednisone with significant reduction of testicular volume, and normalization of androgens levels. CONCLUSION: This case shows the importance of intratesticular adrenal rest tumors in the differential diagnosis of testicular tumors. Cautious approach during investigation and treatment are recommended to avoid inappropriate orchiectomies.

[Bilateral testicular tumors caused by congenital adrenal rest hyperplasia]. / Tumores testiculares bilaterais por hiperplasia congênita de restos adrenais.

OBJECTIVES: Testicular tumors are a rare condition associated with congenital adrenal hyperplasia (CAH), originated from intratesticular adrenal rest tumors, and they are rarely associated with malignant tumors. Their histological differentiation from Leydig-cell tumors is quite difficult, which would lead to inappropriate orchiectomies. Thus the objective of this report was to present this diagnostic dilemma. METHODS: Reported the case of 16-yr-old boy with previous diagnosis of CAH with bilateral testicular enlargement who was recommended to be submitted to a bilateral orchiectomy. RESULTS: Considering this findings, it was decided to treat conventionally with prednisone with significant reduction of testicular volume, and normalization of androgens levels. CONCLUSION: This case shows the importance of intratesticular adrenal rest tumors in the differential diagnosis of testicular tumors. Cautious approach during investigation and treatment are recommended to avoid inappropriate orchiectomies.

Avanços diagnósticos e terapêuticos da puberdade precoce em meninas / Advances in the diagnosis and treatment of precocious puberty in girls

A puberdade é considerada precoce em meninas quando aparece antes dos oito anos, incidindo em uma criança para cada 5.000 a 10.000 que têm desenvolvimento normal. Pode ser classificada em central ou periférica. O diagnóstico procura caracterizar a etiologia, evidenciar o estádio da puberdade e definir a melhor terapêutica. No diagnóstico, a dosagem de gonadotrofinas (basais e/ou estimuladas) é o exame de escolha para o início da investigação. No tratamento, há mais de 20 anos são utilizados os análogos de GnRH, principalmente por via intramuscular. As formulações de depósito, aplicadas a cada quatro semanas, são as mais utilizadas. Implantes subcutâneos com análogos de GnRH têm sido considerados promissores. Pacientes com puberdade precoce e reduzida velocidade de crescimento (VC), com o uso dos análogos, têm sido tratadas associando-se o hormônio de crescimento recombinante humano (rhGH), duplicando habitualmente a VC sem acelerar o ritmo de maturação óssea. O uso da metformina em meninas com baixo peso ao nascer e pubarca precoce ou com puberdade iniciada entre oito e nove anos, porém com previsão de menarca precoce e baixa estatura, pode levar à normalização da evolução puberal, ganho de estatura final, além de diminuição do índice de massa corpórea.