脂肪萎縮症

Fibrillin-1 is an extracellular matrix glycoprotein essential for microfibril integrity, mediating cell-matrix interactions, providing structural support to tissues, and serving as a scaffold for elastogenesis. Pathogenic variants in the fibrillin 1 gene (FBN1) give rise to a spectrum of autosomal dominant connective tissue disorders collectively termed type-1 fibrillinopathies, which include Marfan syndrome, geleophysic dysplasia 2, acromicric dysplasia, Weill-Marchesani syndrome 2, marfanoid-progeroid-lipodystrophy syndrome, stiff skin syndrome, MASS syndrome, and isolated ectopia lentis 1. These disorders predominantly manifest cardiovascular, skeletal, and ocular abnormalities. Among these, aortic and valvular lesions are the principal and most life-threatening complications and therefore warrant the greatest clinical attention. Skeletal anomalies are diverse and can even be diametrically opposed across different phenotypes, while ectopia lentis represents the hallmark of ocular conditions. Notably, mutant fibrillin-1 disrupts microfibril structure and/or function, leading to dysregulated transforming growth factor-β (TGF-β) signaling, which is widely recognized as a central mechanism underlying type-1 fibrillinopathies. Although numerous pathogenic FBN1 variants have been identified, the knowledge of genotype-phenotype correlations remains limited in some specific regions. This review synthesizes the current understanding of the FBN1-related molecular mechanisms linking aberrant TGF-β signaling to distinct phenotypic outcomes and discusses how genetically engineered animal models and human induced pluripotent stem cell models advance mechanistic insights and facilitate therapy development. Additionally, clinical manifestations and genetic characteristics across all phenotypes are elaborated to facilitate diagnosis, treatment, and management of these complex disorders.

BACKGROUND: Among People Living With Human immunodeficiency virus (PLWH) chronic liver disease is a major cause of non-HIV-related death. Factors related to HIV and its treatment may amplify the impact of metabolic risk factors and aging, thus leading to a high frequency of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) among this population. This study aimed to evaluate the frequency and associated factors of MASLD and its severity in older PLWH, and secondarily, to assess the frequency of MASLD-related fibrosis. METHODS: This cross-sectional study included older PLWH followed at a referral center in northeastern Brazil. Hepatic steatosis was assessed by abdominal ultrasonography and liver fibrosis by point Shear-Wave Elastography (pSWE). Multivariable Poisson regression was performed to identify factors independently associated with hepatic steatosis and steatosis severity. RESULTS: Ninety-two older PLWH were included. Hepatic steatosis was identified in 53.3% (n = 49) of participants, of whom 29 (53%) had moderate-to-severe steatosis. Significant fibrosis (F2 or greater) was identified in 10.6% of participants with steatosis who underwent elastography. Increased waist circumference, higher body mass index, metabolic syndrome, higher HbA1c and triglyceride levels were associated with hepatic steatosis. In multivariate analysis, increased waist circumference remained the factor most strongly associated with hepatic steatosis (PR = 4.69; 95% CI 1.53-14.38; p = 0.007). Factors associated with moderate-to-severe steatosis included metabolic and social factors, higher Alanine Aminotransferase (ALT) levels, dolutegravir use, absence of darunavir exposure and higher CD4 nadir. After adjustment, lipodystrophy (aPR = 1.63; 95% CI 1.04-2.56; p = 0.033) and higher Alanine Aminotransferase (ALT) levels (aPR = 1.03; 95% CI 1.01-1.04; p = 0.001) remained independently associated with greater steatosis severity. CONCLUSIONS: MASLD was highly prevalent among older PLWH, with a substantial proportion presenting moderate-to-severe steatosis and significant fibrosis. Metabolic and adiposity-related factors were independently associated with hepatic steatosis, while lipodystrophy and higher ALT levels were associated with greater steatosis severity.

OBJECTIVES: This case series describes the clinical presentation and longitudinal course of four adolescents with genetically confirmed AGPAT2-associated congenital generalized lipodystrophy (CGL) followed at a pediatric lipodystrophy center. CASE PRESENTATION: Despite shared phenotypic features - including generalized lipoatrophy, muscular hypertrophy, acromegaloid features, and hyperphagia - metabolic severity varied markedly, even between siblings carrying the same homozygous AGPAT2 variant. All three female patients experienced rapid metabolic deterioration during puberty, developing insulin resistance, diabetes, and severe hypertriglyceridemia, while the male patient remained relatively metabolically stable. Three patients developed progressive albuminuria during adolescence, and two required ACE inhibitor therapy for hypertension, highlighting early renal involvement independent of diabetes. Metreleptin therapy led to substantial metabolic improvement in all treated patients, with normalization of glycemic control, triglyceride levels, and liver enzymes, as well as reduced hyperphagia and, in one case, spontaneous menarche. However, metabolic decompensation occurred during acute illness in one patient, necessitating treatment escalation, indicating that metreleptin does not fully protect against metabolic stress. Notably, pronounced daytime fatigue persisted in three patients despite metabolic stabilization, suggesting an underrecognized, potentially central component of the disease. CONCLUSIONS: These findings underscore the phenotypic variability of AGPAT2-associated CGL, the critical impact of puberty - especially in females - the frequent early onset of nephropathy, and the partial but incomplete response to leptin replacement. Close monitoring during adolescence and individualized management are essential.

BACKGROUND: The co-occurrence of early-onset type 1 diabetes mellitus (T1DM), acquired generalized lipodystrophy (AGL), and severe insulin resistance (SIR) is extremely rare, poses significant therapeutic challenges and no cases associated with pathogenic Cytotoxic T-lymphocyte-associated 4 (CTLA4) variants have been previously documented. CASE DESCRIPTION: We performed genetic testing, flow cytometric immunophenotyping, leptin measurement and a 4.5-year clinical follow-up in a 3-year-3-month-old boy with early-onset T1DM, insulin allergy following initial insulin therapy, progressive lipodystrophy, SIR and mild hepatic dysfunction. We additionally conducted a systematic literature review to summarize CTLA4 variant-related autoimmune endocrine disorders and fat metabolism abnormalities. Pathological biopsy of subcutaneous adipose tissue revealed scattered lymphocytes and histiocytes infiltrating the fat septa and perivascular areas. A heterozygous pathogenic c.151C>T (p.Arg51*) variant in the CTLA4 gene was identified by whole-exome sequencing (WES) analysis. His father and sister carried the same variant with incomplete penetrance. The patient showed markedly reduced CTLA4 expression on regulatory T cells and undetectable serum leptin. Treatment with abatacept normalized liver function but did not improve glycemic control or insulin resistance. During the follow-up, the patient's growth consistently exceeded the 97th percentile for age and gender. CONCLUSIONS: This report established the first association between a pathogenic CTLA4 variant and AGL, which expands the known clinical phenotypic spectrum of CTLA4-related immune dysregulation disorders. CTLA4 genetic testing should be considered in patients presenting with early-onset T1DM and unexplained lipodystrophy to enable early diagnosis and guide personalized management.

CONTEXT: Approximately 20% of patients with chronic pancreatitis achieve insulin independence one year after total pancreatectomy with islet autotransplantation (TPIAT), an outcome associated with younger age and lower pre-transplant HbA1c. The contribution of diabetes-related genetics to TPIAT outcomes is unknown. Genetic risk scores (GRS) are associated with C-peptide levels in type 1 (T1D) and type 2 (T2D) diabetes. OBJECTIVE: To evaluate whether T1D and T2D GRS and partitioned metabolic polygenic scores (PGS) are associated with diabetes before TPIAT and metabolic outcomes one year after transplant. METHODS: We genotyped 318 patients with chronic pancreatitis undergoing TPIAT in the multicenter "Advancing Treatment for Pancreatitis: A Prospective Observational Study of TPIAT" using a global screening array. Regression models assessed associations of T1D- and T2D-GRS and metabolic PGS with diabetes outcomes one year after TPIAT. RESULTS: Participants were 29±17 years old, 61% female, 84% non-Hispanic White, and 13% had diabetes prior to transplant. T2D-GRS was higher among those with pre-TPIAT diabetes (-0.6±0.3 versus -0.8±0.2, p=0.003) and was associated with higher pre-transplant HbA1c (β=0.19 % per 1-SD [95% CI:0.04, 0.33], p = 0.011). Adjusted for genotype-derived ancestry and islet equivalents/kg, the beta-cell PGS was associated with higher insulin dose (β=0.05 units/kg/day per 1-SD, [95%CI:0.01, 0.09], p=0.016) and higher insulin dose adjusted A1c (IDAA1c) (β=0.34[95%CI:0.03, 0.67], p=0.029) 1-year post-transplant. The lipodystrophy PGS was associated with higher IDAA1c (β=0.38 [95%CI:0.06, 0.69], p=0.019) and lower fasting C-peptide (β=-0.09 [95%CI:-0.18, 0], p=0.041) at 1 year. CONCLUSIONS: T2D genetic risk is associated with diabetes prior to TPIAT, and beta cell and lipodystrophy PGS are associated with post-TPIAT diabetes outcomes. Diabetes-related genetics may influence transplantation outcomes and inform metabolic heterogeneity.