Loss of phospholipase PLAAT3 causes a mixed lipodystrophic and neurological syndrome due to impaired PPARγ signaling.

Phospholipase A/acyltransferase 3 (PLAAT3) is a phospholipid-modifying enzyme predominantly expressed in neural and white adipose tissue (WAT). It is a potential drug target for metabolic syndrome, as Plaat3 deficiency in mice protects against diet-induced obesity. We identified seven patients from four unrelated consanguineous families, with homozygous loss-of-function variants in PLAAT3, who presented with a lipodystrophy syndrome with loss of fat varying from partial to generalized and associated with metabolic complications, as well as variable neurological features including demyelinating neuropathy and intellectual disability. Multi-omics analysis of mouse Plaat3-/- and patient-derived WAT showed enrichment of arachidonic acid-containing membrane phospholipids and a strong decrease in the signaling of peroxisome proliferator-activated receptor gamma (PPARγ), the master regulator of adipocyte differentiation. Accordingly, CRISPR-Cas9-mediated PLAAT3 inactivation in human adipose stem cells induced insulin resistance, altered adipocyte differentiation with decreased lipid droplet formation and reduced the expression of adipogenic and mature adipocyte markers, including PPARγ. These findings establish PLAAT3 deficiency as a hereditary lipodystrophy syndrome with neurological manifestations, caused by a PPARγ-dependent defect in WAT differentiation and function.

Misdiagnosis of sebaceous carcinoma.

BACKGROUND: Sebaceous carcinoma is an aggressive malignant tumour. To prevent mutilating surgery and improve patient outcomes, early diagnosis and prompt treatment are necessary. When the tumour invades surrounding tissues, treatment may become complex. METHODS: We present a case report illustrating complex resection and reconstruction of a sebaceous carcinoma after initial misdiagnosis. RESULTS: A 74-year-old man with a sebaceous carcinoma to his right upper eyelid had a delay in treatment due to initial misdiagnosis. Upon the correct diagnosis, computed tomography scan showed tumour invasion of the medial rectus muscle and tumour spread to the right parotid gland. An orbital exenteration, partial parotidectomy and selective cervical lymphadenectomy were performed. Frozen section examination showed false-free margins, as additional paraffin embedded sections showed uncomplete tumour resection. Adjuvant radiotherapy was offered to the patient. The treatment was complicated by radio necrosis, necessitating surgical reconstruction by a paramedian forehead flap. Final reconstruction of the right orbit was accomplished by a personalised epithesis. CONCLUSIONS: Sebaceous carcinoma is a tumour that is often misdiagnosed. The aim of this case report is to emphasize the possible consequences of its misdiagnosis. An overview of characteristic clinical findings is provided to help reduce the number of misdiagnoses.

Anti-MDA5 positive dermatomyositis complicated with rapidly progressive interstitial lung disease - a case report.

CASE PRESENTATION:  We present a case of a 55-year-old Caucasian male with manifestations of dermatomyositis complicated with rapidly progressive interstitial lung disease (RP-ILD). Diagnosis of anti-MDA5 positive dermatomyositis was made. DISCUSSION:  Myositis specific antibodies (MSA) can be used for diagnosis and predicting prognosis in patients with polymyositis and dermatomyositis. Anti-MDA5 positive dermatomyositis should be considered in patients presenting with dermatomyositis and a disease course resembling antisynthetase syndrome in the absence of antisynthetase autoantibodies, especially if a remarkably high ferritin is noted. Anti-MDA5 autoantibodies have been associated with RP-ILD and adverse outcome. In patients with anti-MDA5 autoantibodies, early diagnosis and aggressive immunosuppressive treatment may improve prognosis. CONCLUSION:  This case highlights the importance of determining MSA in patients with dermatomyositis and associated interstitial lung disease, as this has implications for diagnosis, prognosis and therapy.

Dedifferentiated Liposarcoma of the Retroperitoneum With Heterologous Osteosarcomatous Differentiation and a Striking Aneurysmal Bone Cyst-Like Morphology.

A 69-year-old woman with a 10-year medical history of recurrent retroperitoneal dedifferentiated liposarcoma presented with a 3-cm large hemorrhagic and multicystic left-sided retroperitoneal mass. Histopathological examination of the resected specimen showed a heterogeneous, high-grade mesenchymal nonlipogenic tumor with areas of osteoblastic/osteosarcomatous differentiation and aneurysmal bone cyst-like features. Based on the clinical presentation, the morphology, and the supportive immunohistochemical and molecular findings (MDM2 overexpression and amplification of the MDM2 gene, respectively), a diagnosis of a dedifferentiated liposarcoma with heterologous osteosarcomatous differentiation and an aneurysmal bone cyst-like morphology was made. To the best of our knowledge, this is the first description of aneurysmal bone cyst-like morphology in dedifferentiated liposarcoma, further expanding the broad morphological spectrum of dedifferentiated liposarcoma.