Acquired Generalized Lipodystrophy Research Articles

Metreleptin (Myalepta)

Reimbursement reviews are comprehensive assessments of the clinical effectiveness and cost-effectiveness, as well as patient and clinician perspectives, of a drug or drug class. The assessments inform non-binding recommendations that help guide the reimbursement decisions of Canada’s federal, provincial, and territorial governments, with the exception of Quebec. This review assesses metreleptin (Myalepta), 3 mg, 5.8 mg, and 11.3 mg, powder for solution, subcutaneous injection. Indication: As an adjunct to diet as a replacement therapy to treat the complications of leptin deficiency in lipodystrophy patients: with confirmed congenital generalized lipodystrophy (Berardinelli-Seip syndrome) or acquired generalized lipodystrophy (Lawrence syndrome) in adults and children 2 years of age and above with confirmed familial partial lipodystrophy (PL) or acquired PL (Barraquer-Simons syndrome), in adults and children 12 years of age and above with persistent significant metabolic disease for whom standard treatments have failed to achieve adequate metabolic control.

Immune Checkpoint Inhibitors-Associated Generalized Lipodystrophy: Reconstructive Challenges of an Emerging and Distinct Form of Lipodystrophy.

Total and permanent loss of facial and nonfacial fat is a rare side effect of immune checkpoint inhibitors (ICIs). Consequently, effective treatment modalities for patients remain undefined. Here, we discuss the surgical treatment of a patient with both ICI-related acquired generalized lipodystrophy (AGL). We additionally performed a comprehensive literature review (Cochrane, Embase, and MEDLINE) to summarize what is known about ICI-related lipodystrophy and available treatments for this rare complication. A 66-year-old female diagnosed with metastatic lung adenocarcinoma started ICI (pembrolizumab) treatment. She developed generalized lipodystrophy 13 months after her first cycle. Her primary concern was the loss of facial fat volume, which significantly aged her appearance. The patient underwent a 2-staged restoration of her facial fat compartments using dermal grafts from the lower abdomen and medial thighs. The patient recovered uneventfully and was satisfied with the aesthetic improvement at 18 months of follow-up. The authors identified 8 case reports with patients with ICI-AGL. The mean age was 53.63 years, and the mean BMI was 36.72kg/m2. The average onset of symptoms was 7.44 months after ICI initiation. None of the studies described any sort of surgical or nonsurgical options to restore the volume of the facial fat compartments. The management of combined facial and nonfacial lipodystrophy remains challenging due to the lack of suitable autologous fat donor sites. In this report, the authors demonstrate that staged volume restoration can be achieved using autologous dermal grafts from the thigh, making it a viable reconstructive option in this subset of patients.

Metreleptin (Myalepta)

We recommend that Myalepta should be reimbursed by public drug plans as an adjunct to diet as a replacement therapy to treat the complications of leptin deficiency in patients with lipodystrophy (LD) if certain conditions are met. Myalepta should be covered to treat patients with confirmed congenital generalized LD (GL) (Berardinelli-Seip syndrome) or acquired GL (Lawrence syndrome) in both adults and children who are at least 2 years old and have at least 1 metabolic abnormality of diabetes, insulin resistance, or high levels of triglycerides (TGs). Myalepta should also be covered to treat patients who have confirmed familial partial LD (PL) or acquired PL in adults and children who are at least 12 years old and have persistent significant metabolic abnormalities, even after trying other treatments for at least 12 months. Myalepta should only be reimbursed if prescribed by an endocrinologist or pediatric endocrinologist with expertise in treating LD and if the cost of Myalepta is reduced. When first prescribed, Myalepta should only be reimbursed for 12 months. Reimbursement may be renewed on a yearly basis for patients who show improvement in their blood sugar and/or triglyceride levels.

Lipodystrophy for the Diabetologist—What to Look For

Genetic or acquired lipodystrophies are characterized by selective loss of body fat along with predisposition towards metabolic complications of insulin resistance, such as diabetes mellitus, hypertriglyceridemia, hepatic steatosis, polycystic ovarian syndrome, and acanthosis nigricans. In this review, we discuss the various subtypes and when to suspect and how to diagnose lipodystrophy. The four major subtypes are autosomal recessive, congenital generalized lipodystrophy (CGL); acquired generalized lipodystrophy (AGL), mostly an autoimmune disorder; autosomal dominant or recessive familial partial lipodystrophy (FPLD); and acquired partial lipodystrophy (APL), an autoimmune disorder. Diagnosis of lipodystrophy is mainly based upon physical examination findings of loss of body fat and can be supported by body composition analysis by skinfold measurements, dual-energy x-ray absorptiometry, and whole-body magnetic resonance imaging. Confirmatory genetic testing is helpful in the proband and at-risk family members with suspected genetic lipodystrophies. The treatment is directed towards the specific comorbidities and metabolic complications, and there is no treatment to reverse body fat loss. Metreleptin should be considered as the first-line therapy for metabolic complications in patients with generalized lipodystrophy and for prevention of comorbidities in children. Metformin and insulin therapy are the best options for treating hyperglycemia and fibrates and/or fish oil for hypertriglyceridemia. Lipodystrophy should be suspected in lean and muscular subjects presenting with diabetes mellitus, hypertriglyceridemia, non-alcoholic fatty liver disease, polycystic ovarian syndrome, or amenorrhea. Diabetologists should be aware of lipodystrophies and consider genetic varieties as an important subtype of monogenic diabetes.

Marked Hypoleptinemia precedes Overt Fat Loss in Immune Checkpoint Inhibitor-induced Acquired Generalized Lipodystrophy

<h3>Lead Author's Financial Disclosures</h3> Nothing to disclose. <h3>Study Funding</h3> None. <h3>Background/Synopsis</h3> The development of immune checkpoint inhibitors (ICIs) targeting cancer cells that evade immune T-cell regulation has revolutionized the treatment of metastatic carcinomas. Unfortunately, secondary endocrinopathies associated with ICI use, including adrenal insufficiency, primary hypothyroidism, autoimmune diabetes, and rarely hypoparathyroidism, are increasing. Lipodystrophy, presumably due to autoimmune destruction of adipocytes, leading to metabolic complications is a less well recognized adverse effect of ICI therapy. <h3>Objective/Purpose</h3> To report the clinical features and evolution of Acquired Generalized Lipodystrophy (AGL) in a patient on ICI therapy. <h3>Methods</h3> Case Report: A 66-year-old woman with metastatic lung adenocarcinoma was started on combination chemo/immunotherapy with programmed cell death-1 (PD-1) inhibitor- pembrolizumab after surgical resection of cerebellar mass and radiation. She had good tumor response but developed primary hypothyroidism and secondary adrenal insufficiency approximately ten months after initiation of ICI. <h3>Results</h3> Approximately 15 months following the treatment, she developed new-onset insulin requiring diabetes mellitus but without autoantibodies associated with type 1 diabetes. At that time, she was also noted to have hypertriglyceridemia (436 mg/dL), and elevated liver enzymes (3-4 X ULN), and a subsequent liver biopsy revealed severe macrovesicular steatosis. Her BMI was 30 kg/m2 and she had mild loss of buccal fat. Skin fold thickness measurements over the trunk and limbs were in the normal range. However, she had an undetectable serum leptin level and whole body fluorodeoxyglucose (FDG)- positron emission tomography (PET) scan, obtained for cancer surveillance, showed mild diffuse FDG activity throughout the subcutaneous tissues. She was advised low fat diet and started on insulin therapy. Over the next three months, she lost about 20 kg weight with generalized loss of subcutaneous fat from face, trunk, and extremities. Pioglitazone was started but discontinued after 4 weeks due to pedal edema and no effect on fat loss. Despite generalized lipodystrophy, she has maintained good glucose control on moderate dose insulin therapy (0.6 â€" 0.8 units/kg) and with normalization of liver enzymes and serum triglycerides. <h3>Conclusions</h3> ICI therapy can be associated with AGL, and the diagnosis must be considered in patients who develop metabolic complications such as diabetes, dyslipidemia, or steatohepatitis. Interestingly, metabolic abnormalities may precede overt fat loss. Hypoleptinemia and diffuse FDG uptake of subcutaneous tissue suggest subclinical panniculitis and adipocyte dysfunction even before clinically evident lipodystrophy.

Characterization and Clinical Association of Autoantibodies Against Perilipin 1 in Patients With Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by massive loss of adipose tissue through the body, causing severe metabolic complications. Autoimmune destruction of adipocytes is strongly suspected based on the frequent association of AGL with autoimmune disorders. In 2018, autoantibodies against perilipin 1 (PLIN1) were identified in three patients with autoimmune-associated AGL. However, the pathogenic mechanism and clinical impact of anti-PLIN1 remain unsolved. The prevalence of anti-PLIN1 autoantibodies in an AGL cohort of 40 patients was 50% (20 of 40). Among positive patients, 10 had the autoimmune variety and 10 had panniculitis-associated AGL. The IgG isotype was predominant, although some IgM antibodies were detected. Epitope-mapping studies did not identify a single, major epitope. Instead, autoantibodies typically bound to several different peptides, among which the central (233-405) domain was detected in all antibody-positive patients, for both IgG and IgM autoantibodies. In-depth epitope mapping indicated that anti-PLIN1 autoantibodies predominantly recognize the αβ-hydrolase domain containing 5 (ABHD5) binding site (383-405). Autoantibodies dose-dependently blocked the binding of PLIN1 to ABHD5 and caused a dislocation of ABHD5 toward the cytosol, leading to an increase in lipolysis and lipase activities. Finally, anti-PLIN1 titers significantly correlated with the amount of fat loss, metabolic control impairment, and severity of liver injury. Our data strongly support that anti-PLIN1 autoantibodies are a diagnostic biomarker and a cause of lipodystrophy in patients with AGL.

Abstract #1185191: Acquired Generalized Lipodystrophy Presenting As Severe Insulin Resistance

Roughly 100-150 cases are reported in the literature of acquired generalized lipodystrophy (AGL). This rare disorder is characterized by leptin deficiency resulting from low adipose mass and metabolic derangements such as hypertriglyceridemia and severe insulin resistance. These metabolic derangements lead to increased risk for pancreatitis, nonalcoholic fatty liver disease, and adverse cardiovascular events. The most common progression of AGL is onset of symptoms in childhood or adolescence with progression of complications into adulthood.

Lawrence Syndrome “acquired generalized lipodystrohy” with type 1 diabetes mellitus in 7 years boy of Bahawalpur

Lipodystrophy syndromes are rare disorders characterized by either generalized or partial lack of adipose tissue. They are congenital or acquired. These syndromes are associated with various metabolic and harmonal disorders leading to severe comorbidities including hypertriglyceridemia, diabetes mellitus, acanthosis nigricans, xanthomas, polycystic ovarian syndrome (POS) and non-alcoholic fatty liver disease. Keywords: Lawrence syndrome, lipodystrophy, diabetes mellitus

Long Term Effects of Leptin on Hepatic Fibrosis in Generalized Lipodystrophy

Lipodystrophy syndromes are caused by deficiency of adipose tissue leading to severe insulin resistance, hypertriglyceridemia, and non-alcoholic fatty liver disease (NAFLD), which may progress to cirrhosis. Advanced fibrosis/cirrhosis was previously thought to be irreversible; however, eradication of hepatitis C or long-term viral suppression of hepatitis B can reverse cirrhosis. Metreleptin treatment in patients with lipodystrophy improves liver transaminases and NAFLD activity score (NAS) after a mean of 2 years, but the latter improvements were due to lower inflammation and steatosis, with no change in fibrosis. The long-term effects of metreleptin in subjects with advanced fibrosis are unknown. We analyzed 24 subjects with advanced fibrosis (NAS stage 3 or 4) prior to metreleptin. Seven had liver biopsies both before and after ≥ 3 years of metreleptin with mean treatment duration 7.8±2.9 years. Five of six subjects with stage 3 fibrosis at baseline had improved fibrosis scores after metreleptin, and 0 of 1 with stage 4 fibrosis improved. 17 patients (8 with stage 3, 9 stage 4) did not have follow up biopsies after ≥3 years. Of these 17, 4 (all stage 4) died from end stage liver disease, and 1 (stage 3) from other causes. There was no clinical indication for repeat biopsy in 6 patients (2 stage 3, 4 stage 4). 6 were lost to follow up. Of the 24 patients with advanced fibrosis, 13 had congenital generalized lipodystrophy (CGL), 7 had acquired generalized lipodystrophy (AGL), 3 had familial partial lipodystrophy (FPL) and 1 had acquired partial lipodystrophy (APL). Of the 5 subjects with improvement in their fibrosis score, 2 had AGL, 2 had CGL, and one had a novel FPL mutation (1). Of the two patients that did not improve, one had FPL and one had CGL. In conclusion, subjects with stage 3 fibrosis due to lipodystrophy may have regression of fibrosis after long-term metreleptin treatment. This improvement may be secondary to near-elimination of the inciting factors (excess nutrient intake leading to ectopic lipid storage in the liver), analogous to clearance of Hepatitis C infection. However, additional data is needed to determine if metreleptin can reverse fibrosis in subjects with stage 4 fibrosis.

SUN-610 Acquired Generalized Lipodystrophy: A Rare Side Effect of PD1-Inhibitor Therapy

Background:Program cell death-1 (PD1) inhibitors, such as nivolumab and pembrolizumab, have shown efficacy as adjuvant treatment for cancers, including melanoma, and their frequency of use is increasing. A potential, but rare, side effect of PD1-inhibitors is acquired generalized lipodystrophy (AGL), an immune-related adverse event characterized by loss of subcutaneous adipose tissue (SAT) and insulin resistance-associated complications. AGL can result in irreversible endocrinopathies, including diabetes. Clinical Case: A 60-year-old overweight female (BMI 29.2), with no related metabolic complications or medical history of autoimmune disorders, was treated with nivolumab (240mg IV q2 weeks) for 1 year for metastatic melanoma on her right arm (staged T4bN2a) that underwent wide local resection. She completed therapy with no complications or lab abnormalities.One-month post-treatment, she noticed rapid weight loss and facial atrophy. Within 3 months, she had a 58% weight loss withsignificant loss of SAT; insulin resistance and diabetes(impaired fasting glucose 201; A1c 9.2%);hepatic steatosis diagnosed by liver biopsy; hypertriglyceridemia (5,309 mg/dL,); and undetectable leptin levels. She also developed prominent forearm muscles and leg veins. GAD antibody was negative. The loss of SAT and rapid weight loss, physical exam findings, onset of diabetes, steatosis and hypertriglyceridemia—all closely following therapy with nivolumab—led to a diagnosis of nivolumab-associated AGL. In addition to treatment for hypertriglyceridemia, the patient was placed on multiple oral and parenteral antihyperglycemic medications, including metformin, SGLT2i, GLP-1, and DPP4, but all were discontinued due to side effects. Ultimately, her A1c increased to 12.4% and she was placed on basal/bolus therapy. Discussion: AGL is associated with an increased risk of lymphoma. Metreleptin, a recombinant analogue of human leptin, is approved for treatment of metabolic complications of AGL. Some instances of lymphoma in AGL have occurred while the patient was receiving metreleptin, but data is inconclusive as to whether development of lymphoma is a side effect of metreleptin.(Brown RJ, Chan JL, Jaffe ES, et al, 2016) We believe treatment with metreleptin would have benefited our patient, but she declined due to potential side effects, including lymphoma. Nine months after nivolomuab therapy, her melanoma is in remission but she still has lipodystrophic characteristics with insulin resistant diabetes. She is being treated with pioglitazone and multiple daily insulin injections but has not achieved euglycemia despite a total daily insulin dose of 2 u/kg. Of note, injecting insulin and use of a continuous glucose monitor have been a challenge given the lack of SAT. Although AGL resulting from PD1-inhibitor therapy is rare, it is a condition for which this patient will need life-long treatment.

SAT-574 Whole Exome Sequencing Identifies Several Variants Associated with Immune Deficiency, Inflammasomopathy and Non-Ischemic Dilated Cardiomyopathy in a Complex Case of Acquired Generalized Lipodystrophy

Background: Acquired generalized lipodystrophy (AGL) is characterized by near-total fat loss that develops after birth. Although the molecular pathogenesis of AGL is unclear, there is a link to autoimmunity and inflammation. Notably, the panniculitis associated variety of AGL may present with subcutaneous inflammatory nodules that ultimately progress to generalized fat loss. Here, we report on a complex patient with AGL in whom whole-exome sequencing (WES) identified several pathogenic variants and variants of uncertain significance (VUS) that encourage us to think about AGL more broadly. Clinical Case: This is a 38-year-old male who was first diagnosed with juvenile rheumatoid arthritis at age 2, after being evaluated for delayed ability to ambulate. At that time, he was also diagnosed with Weber-Christian disease following a skin biopsy due to the suspicion of panniculitis. Over time, he progressively lost body fat throughout the body and developed hypertriglyceridemia, hypertension, and nephropathy leading to the diagnosis of AGL. At age 10, he was diagnosed with type 1 diabetes mellitus, and at age 14, with autoimmune hepatitis. Due to the tightening of his hands, calf pain, and increased CPK levels, a muscle biopsy was performed, suggesting polymyositis. He had been treated with azathioprine and steroids, which were discontinued at age 26, after a liver biopsy that showed grade 2 fibrosis. Further, he was diagnosed with non-ischemic dilated cardiomyopathy (DCM), evolving with atrial fibrillation with a rapid ventricular response and complicated with left atrial appendage thrombus. Of interest, his mother and two maternal aunts had been diagnosed with atrial fibrillation. One of his maternal uncles presented non-ischemic cardiomyopathy and an early sudden cardiac arrest. His mother also had mitochondrial myopathy, and his father had type 2 diabetes mellitus and IgG deficiency. WES identified three different variants: a maternally inherited pathogenic variant in TTN (c.88473_88477delAGCTT; p.W29493X) associated with DCM, a paternally inherited pathogenic variant in TNFRSF13B (c.310T>C; p.C104R) associated with CVID/IgA deficiency, and a maternally inherited variant of uncertain clinical significance in NLRP3 (c.1469G>A; p.R490K). Although the frequency of this variant was relatively high, several variants in the NLRP3 gene have been previously associated with inflammasomopathy. Conclusion: This case highlights challenging presentations of AGL and the complexity of the disease. As we are yet beginning to understand the molecular mechanisms behind the so-called “acquired fat loss” and its relation to inflammatory and complex immune system diseases, further efforts are critical to better recognize different AGL phenotypes and phenotype-genotype correlations. Additional efforts should be placed on WES for AGL patients and functional validation of identified VUSs.

OR33-03 Congenital Leptin Deficiency: Clinical Insights from the First Reported US Cases

Background: Congenital leptin deficiency (CLD) is a rare autosomal recessive form of monogenic obesity caused by loss-of-function mutations in the leptin gene. Targeted therapy is available in the form of recombinant human leptin (metreleptin). Previous case series have reported dramatic weight loss and metabolic improvements with treatment, but metreleptin’s only FDA-approved indication is acquired generalized lipodystrophy (AGL). Metreleptin has a black box warning for risk of T-cell lymphoma, which has been reported in AGL patients, both treated and untreated with metreleptin. Clinical Case: Two sisters ages 18 yrs (sister A; BMI 45.2 kg/m2) and 20 yrs (sister B; 45.0 kg/m2) were referred for evaluation of obesity. They are of Pakistani origin with a family history of consanguinity. Birth weight was normal, but hyperphagia and excessive weight gain developed by age 3 months. They had been seen by endocrinologists, obesity specialists, and a geneticist during childhood but work-up for monogenic obesity was not pursued. They were treated with combination OCPs in adolescence due to primary amenorrhea and hypogonadotropic hypogonadism. Sister A was diagnosed with type 2 diabetes at age 15 years. Sister B had comorbidities of hydrocephalus s/p VP shunt, developmental delay, hyponatremia, autoimmune thyroid disease, growth hormone deficiency, and prediabetes. At the time of their present evaluation, serum leptin levels were obtained and were undetectable in both sisters. After discontinuing OCPs, testing confirmed hypogonadotropic hypogonadism. Both patients were homozygous for the pathogenic variant c398delG in exon 3 of the leptin gene (LEP), which causes a frameshift/premature stop codon. On MR elastography performed for hepatic steatosis, sister B had an incidental finding of axillary lymphadenopathy. Surgical biopsy and staging work-up confirmed diagnosis of nodular lymphocyte predominant Hodgkin lymphoma (a B cell lymphoma), Stage II disease. She was treated with R-ABVD with adjuvant radiation and achieved clinical remission, prior to treatment with metreleptin. The patients were enrolled in an observational treatment protocol, and responses to metreleptin therapy will be reported in future. Conclusion: To our knowledge, these are the first cases of CLD diagnosed in the U. S. In previous reports, CLD and other monogenic obesity disorders were prevalent among children with severe obesity in a consanguineous Pakistani population. Leptin deficiency should be considered in all patients with early onset obesity and hypothalamic amenorrhea. Furthermore, to our knowledge, this is the first report of lymphoma in a patient with CLD, occurring prior to any treatment with metreleptin. The risk for lymphoma associated with metreleptin may relate to preexisting autoimmune disease or immunologic abnormalities related to leptin deficiency rather than medication adverse effect.

Acquired generalized lipodystrophy type 2-lawrence syndrome: a rare case report

Lawrence syndrome (Acquired Generalized Lipodystrophy) is a rare disorder, characterized by various dermatological and systemic manifestations such as lipodystrophy, hypertriglyceridemia, hepatomegaly, acanthosis nigricans and acromegaloid features. Because of its rare occurrence we are reporting a case with similar manifestations in a 10 years old child.

A Case of Acquired Generalized Lipodystrophy Associated with Pembrolizumab in a Patient with Metastatic Malignant Melanoma

To describe an unusual immune-related adverse event (irAE), acquired generalized lipodystrophy (AGL), from checkpoint inhibitor therapy in a patient treated with pembrolizumab. This is a case report of a 67-year-old male with metastatic melanoma who was treated with pembrolizumab. Prior to pembrolizumab, the patient was treated with another immune-checkpoint inhibitor and developed autoimmune hemolytic anemia. After starting pembrolizumab, he developed a scrotal mass consistent with panniculitis and after several subsequent cycles, he developed AGL. Loss of subcutaneous fat, unexplained weight loss in combination with worsening insulin resistance and worsening hypertriglyceridemia after initiation of pembrolizumab were consistent with AGL. Autoimmune disorders and other etiologies were ruled out. Despite this irAE, the patient continued to receive pembrolizumab given stabilization of melanoma with treatment. We report the second case of a patient who developed AGL secondary to pembrolizumab, and the fourth case to report such complication secondary to antiprogrammed cell death receptor-1 inhibitors. As use of checkpoint inhibitors becomes more common to treat several types of cancer, it is vital for clinicians to recognize these rare irreversible complications that are not frequently reported in clinical trials.

Acquired generalized lipodystrophy: a new cause of Anti-PD-1 immune-related diabetes

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

MON-155 A Patient with Acquired Generalized Lipodystrophy (AGL, Lawrence Syndrome) in Association with CTLA-4 Haploinsufficiency

Acquired generalized lipodystrophy (AGL) is a rare disease which develops during early childhood and adolescence, characterized by selective loss of adipose tissue from large regions of the body. Diabetes mellitus with insulin resistance, hepatomegaly, and hypertriglyceridemia develop as a result of the fat loss. In addition to the symptoms associated with fat loss, patients with the autoimmune variety of AGL (Type 2) present with multiple autoimmune diseases. Recently a case of AGL with multiple autoimmune diseases was reported to harbor a mutation in the AIRE gene. Here we report a heterozygous variant (c.4_5insGTTGG, p.Ala2GlyfsTer14) resulting in haploinsufficiency in the immune checkpoint protein CTLA-4, identified in a patient with AGL and accompanying complex autoimmune cluster. The patient was born term with a normal spontaneous vaginal delivery and no complications. At age 6 months, she developed failure to thrive followed by type 1 diabetes and hypertriglyceridemia by ages 2 and 4 years, respectively, and was diagnosed with AGL. Her childhood clinical course was further complicated by poor weight gain despite adequate calorie intake, hepatomegaly with massive splenomegaly and chronic severe diarrhea (onset age 8 years). Her family history is notable for type 1 diabetes in her maternal uncle, type 1 diabetes, recurrent infections, cytopenias, and a mildly hypocellular bone marrow in her maternal cousin, hypothyroidism in her mother and maternal grandfather, and Addison's disease in her maternal grandfather. She presented to Michigan Medicine in acute liver failure and severe jaundice at the age of 14 years. She had mixed inflammatory hepatitis on liver biopsy. With supportive care, her condition improved, but it was noted that she had autoimmune enteropathy and Coombs-positive hemolytic anemia with thrombotic microangiopathy and subsequently developed nephrotic syndrome and progressive kidney insufficiency. Her lipodystrophy related abnormalities included severe insulin resistance (280 units /day with body weight: 41 lbs, hbA1c: 10.7), acanthosis nigricans and severe hypertriglyceridemia (varying between 600 to 6000 mg/dL) and hypertrophic cardiomyopathy. Recombinant metreleptin therapy was utilized during a 9-month hospitalization in 2016, but the patient could not sustain daily injections as an outpatient. Despite aggressive treatment of her kidney disease with specific immune therapies, her kidney disease and her enteropathy progressed. She is currently on hemodialysis, IVIG therapy, and abatacept, vedolizumab, and pentamidine. In conclusion, we report the novel association of CTLA-4 haploinsufficiency and concurrent presence of AGL and providing evidence that AGL can occur within the spectrum of immune dysregulation syndromes, opening the door to investigating these pathways as an etiology for an autoimmune variety of AGL.

Diagnosis of acquired generalized lipodystrophy in a single patient with T-cell lymphoma and no exposure to Metreleptin

BackgroundMetreleptin, a recombinant methionyl -human -leptin, was approved to treat patients with generalized lipodystrophy (GL) in February 2014. However, leptin therapy has been associated with the development of lymphoma. We present a unique case of a patient with prior history of T cell lymphoma in remission, who was diagnosed with Acquired Generalized Lipodystrophy (AGL) during the following year after a clinical remission of her lymphoma without receiving leptin therapy.Case presentationA 33-year-old woman with a diagnosis of stage IV subcutaneous panniculitis like T-cell lymphoma in 2011, underwent chemotherapy. Shortly after completion therapy, she had a relapse and required more chemotherapy with complete response, followed by allogenic stem cell transplant on June 28, 2012. Since that time, she has been on observation with no evidence of disease recurrence. Subsequent to the treatment, she was found to have high triglycerides, loss of fat tissue from her entire body and diagnosis of diabetes. Constellation of these findings led to the diagnosis of AGL in 2013. Her leptin level was low at 3.4 ng/mL (182 pmol/mL). She is currently not receiving any treatment with Metreleptin for her AGL.ConclusionsCausal association between exogenous leptin therapy and T-cell lymphoma still remains unclear. We hereby present a case of a young woman who was diagnosed with AGL after going into remission from T-cell lymphoma and who has never been treated with Metreleptin. Steroid therapy and chemotherapy might have masked the diagnosis of AGL in this patient. We believe that patients can develop these 2 conditions independent of each other.

Autoantibodies Against Perilipin 1 as a Cause of Acquired Generalized Lipodystrophy.

Acquired generalized lipodystrophy (AGL) is a rare condition characterized by an altered distribution of adipose tissue and predisposition to develop hepatic steatosis and fibrosis, diabetes, and hypertriglyceridemia. Diagnosis of AGL is based on the observation of generalized fat loss, autoimmunity and lack of family history of lipodystrophy. The pathogenic mechanism of fat destruction remains unknown but evidences suggest an autoimmune origin. Anti-adipocyte antibodies have been previously reported in patients with AGL, although their involvement in the pathogenesis has been poorly studied and the autoantibody target/s remain/s to be identified. Using a combination of immunochemical and cellular studies, we investigated the presence of anti-adipocyte autoantibodies in patients with AGL, acquired partial lipodystrophy, localized lipoatrophy due to intradermic insulin injections or systemic lupus erythematosus. Moreover, the impact of anti-adipocyte autoantibodies from AGL patients was assessed in cultured mouse preadipocytes. Following this approach, we identified anti-perilipin 1 IgG autoantibodies in the serum of patients with autoimmune variety-AGL, but in no other lipodystrophies tested. These autoantibodies altered the ability of perilipin 1 to regulate lipolysis in cultured preadipocytes causing abnormal, significantly elevated basal lipolysis. Our data provide strong support for the conclusion that perilipin 1 autoantibodies are a cause of generalized lipodystrophy in these patients.

Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis

BackgroundJuvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome.Case presentationA previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation.ConclusionsThis is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted.

Clinical Features and Management of Non-HIV-Related Lipodystrophy in Children: A Systematic Review.

Lipodystrophy syndromes are characterized by generalized or partial absence of adipose tissue. We conducted a systematic review to synthesize data on clinical and metabolic features of lipodystrophy (age at onset, < 18 years). Sources included Medline, Embase, Cochrane Library, Scopus and Non-Indexed Citations from inception through January 2016. Search terms included lipodystrophy, and age 0 to 18 years. Patients with unambiguous diagnosis of lipodystrophy were included. Lipodystrophy secondary to HIV treatment was excluded. We identified 1141 patients from 351 studies. Generalized fat loss involving face, neck, abdomen, thorax, and upper and lower limbs was explicitly reported in 65% to 93% of patients with congenital generalized lipodystrophy (CGL) and acquired generalized lipodystrophy (AGL). In familial partial lipodystrophy (FPL), fat loss occurred from upper and lower limbs, with sparing of face and neck. In acquired partial lipodystrophy (APL), upper limbs were involved while lower limbs were spared. Other features were prominent musculature, acromegaloid, acanthosis nigricans and hepatosplenomegaly. Diabetes mellitus was diagnosed in 48% (n = 222) of patients with CGL (mean age at onset, 5.3 years). Hypertriglyceridemia was observed in CGL, AGL and FPL. Multiple interventions were used, with most patients receiving ≥ 3 interventions and being ≥ 18 years of age at the initiation of interventions. To our knowledge, this is the largest reported pooled database describing lipodystrophy patients with age at onset < 18 years. We have suggested core and supportive clinical features and summarized data on available interventions, outcomes and mortality.