Several cases of T-cell lymphomas after Metreleptin exposure in patients with AGL have been described and led to a black box warning for the approval of Metreleptin in the United States. Over the past several years, there have been several case reports of AGL patients presenting with T-cell lymphomas who have never received leptin therapy. Given the rarity of the AGL, documentation of cases with T-cell lymphoma in the absence of Metreleptin therapy is quite important to provide the evidence base needed to provide assurance that Metreleptin is not playing a causal role in the development of the T-cell lymphomas. Our current report describes a unique case of a patient who developed adult onset AGL (which is quite rare), and who got diagnosed with the AGL after the remission of her T-cell lymphoma. It is important to underscore that this is distinctive than cases of children developing partial lipodystrophy who have undergone hematopoietic stem cell transplantation during childhood .
Lymphomas, particularly peripheral T-cell lymphomas (PTCL), have been noted in AGL [12, 13]. Brown et al. reported 5 cases of AGL and lymphoma . The coexistence of AGL and lymphoma likely relates to an underlying autoimmune preponderance. Autoimmune diseases can occur commonly in patients with AGL [8, 12, 14, 15], including both organ-specific autoimmunity (e.g. type 1 diabetes, autoimmune hepatitis) and systemic autoimmune diseases (e.g. juvenile dermatomyositis) .
Lymphoma can be considered a systemic feature of AGL instead of an association with lipodystrophy per se given that other forms of lipodystrophy have not been associated with an increased risk of lymphomas . Furthermore, it appears that patients with AGL are at an increased risk of the development of T-cell lymphomas, especially (PTCL), which is a heterogeneous and generally aggressive disorder. It is thought to be related to acquired lipodystrophy, as a subtype of PTCL localizes to the subcutaneous fat, termed subcutaneous panniculitis-like T-cell lymphoma. Panniculitis may be the presenting feature of AGL, as in the patient with AGL and PTCL reported by Yiannias and colleagues . The clinical assessment of the potential role of Metreleptin in contributing to development and/or progression of lymphoma is limited by the lack of long term, controlled studies. Three out of 17 patients with AGL (18%) developed T-cell lymphoma within the NIH cohort , an incidence significantly higher than what is observed in the general population (approximately 2 per 100,000) .
Another interesting case of PTCL subsequently complicated by AGL has been described by Aslam et al. . Misra and Garg proposed three classification types for AGL based on the etiology and pathological mechanisms: type 1 represents AGL associated with panniculitis; type 2 represents AGL with accompanying autoimmune diseases, and type 3 represents idiopathic AGL . Aslam et al. felt that their patient developed AGL and likely represented an overlap of both the type 2 and 3 varieties . The classification of AGL is likely not to be as simple, and there are newer case reports that may change or challenge these earlier classifications.
The time course of the development of AGL was interesting in our case. One possibility is that our patient started to develop AGL while she was going through the diagnosis of her T cell lymphoma as she had panniculitis related T-cell lymphoma. Her treatment with chemotherapy and steroids may have been a contributing factor in her clinical presentation. Steroids might have also masked the features of AGL until the remission of T cell lymphoma and discontinuation of steroids.
In conclusion, there are several clinical lessons from our case. First, development of extensive panniculitis in an adult patient who is losing body fat should raise suspicion of for both T-cell lymphoma and AGL. These patients should be vigilantly monitored for the development of metabolic complications over time. Finally, the association of T-cell lymphoma with known panniculitis within the setting of AGL may be expected and is not likely impacted by Metreleptin therapy.