Case report: A family of atypical hemolytic uremic syndrome involving a CFH::CFHR1 fusion gene and CFHR3-1-4-2 gene duplication

Mutations in the complement factor H (CFH) gene are associated with complement dysregulation and the development of atypical hemolytic uremic syndrome (aHUS). Several fusion genes that result from genomic structural variation in the CFH and complement factor H-related (CFHR) gene regions have been identified in aHUS. However, one allele has both CFHR gene duplication and CFH::CFHR1 fusion gene have not been reported. An 8-month-old girl (proband) presented with aHUS and was treated with ravulizumab. Her paternal grandfather developed aHUS previously and her paternal great grandmother presented with anti-neutrophil cytoplasmic antibody-associated vasculitis and thrombotic microangiopathy (TMA). However, the proband’s parents have no history of TMA. A genetic analysis revealed the presence of CFH::CFHR1 fusion gene and a CFHR3-1-4-2 gene duplication in the patient, her father, and her paternal grandfather. Although several fusion genes resulting from structural variations of the CFH–CFHR genes region have been identified, this is the first report of the combination of a CFH::CFHR1 fusion gene with CFHR gene duplication. Because the CFH–CFHR region is highly homologous, we hypothesized that CFHR gene duplication occurred. These findings indicate a novel pathogenic genomic structural variation associated with the development of aHUS

MicroRNA Profile Predicts Recurrence after Resection in Patients with Hepatocellular Carcinoma within the Milan Criteria

Objective: Hepatocellular carcinoma (HCC) is difficult to manage due to the high frequency of post-surgical recurrence. Early detection of the HCC recurrence after liver resection is important in making further therapeutic options, such as salvage liver transplantation. In this study, we utilized microRNA expression profiling to assess the risk of HCC recurrence after liver resection. Methods: We examined microRNA expression profiling in paired tumor and non-tumor liver tissues from 73 HCC patients who satisfied the Milan Criteria. We constructed prediction models of recurrence-free survival using the Cox proportional hazard model and principal component analysis. The prediction efficiency was assessed by the leave-one-out crossvalidation method, and the time-averaged area under the ROC curve (ta-AUROC). Results: The univariate Cox analysis identified 13 and 56 recurrence-related microRNAs in the tumor and non-tumor tissues, such as miR-96. The number of recurrence-related microRNAs was significantly larger in the non-tumor-derived microRNAs (N-miRs) than in the tumor-derived microRNAs (T-miRs, P, 0.0001). The best ta-AUROC using the whole dataset, T-miRs, NmiRs, and clinicopathological dataset were 0.8281, 0.7530, 0.7152, and 0.6835, respectively. The recurrence-free survival curve of the low-risk group stratified by the best model was significantly better than that of the high-risk group (Log-rank: P = 0.00029). The T-miRs tend to predict early recurrence better than late recurrence, whereas N-miRs tend to predict late recurrence better (P, 0.0001). This finding supports the concept of early recurrence by the dissemination of primary tumor cells and multicentric late recurrence by the ‘field effect’. Conclusion: microRNA profiling can predict HCC recurrence in Milan criteria cases

A-Kinase-Anchoring Protein 95 Functions as a Potential Carrier for the Nuclear Translocation of Active Caspase 3 through an Enzyme-Substrate-Like Association

Caspase-mediated proteolysis is a critical and central element of the apoptotic process, and caspase 3, one of the effector caspases, is proposed to play essential roles in the nuclear morphological changes of apoptotic cells. Although many substrates for caspase 3 localize in the nucleus and caspase 3 translocates from the cytoplasm to the nuclei after activation in apoptotic cells, the molecular mechanisms of nuclear translocation of active caspase 3 have been unclear. Recently, we suggested that a substrate-like protein(s) served as a carrier to transport caspase 3 from the cytoplasm into the nucleus. In the present study, we identified A-kinase-anchoring protein 95 (AKAP95) as a caspase 3-binding protein. Small interfering RNA-mediated depletion of AKAP95 reduced apoptotic nuclear morphological changes, suggesting that AKAP95 is involved in the process of apoptotic nuclear morphological changes. The association of AKAP95 with active caspase 3 was analogous to an enzyme-substrate interaction. Furthermore, overexpression of AKAP95 with nuclear localization sequence mutations inhibited nuclear morphological changes in apoptotic cells. These results indicate that AKAP95 is a potential carrier protein for active caspase 3 from the cytoplasm into the nuclei in apoptotic cells

Acute Lymphoblastic Leukemia Presenting as Fanconi Syndrome

Acute lymphoblastic leukemia (ALL) presenting as Fanconi syndrome (FS) is extremely rare. Here, we report a case of ALL presenting as bilateral nephromegaly following FS. A 2-year-old girl was unexpectedly diagnosed with bilateral nephromegaly. After 2 weeks, she developed general fatigue, thirst, and polyuria. Laboratory examinations revealed renal tubular acidosis, hypokalemia, hypophosphatemia, and aminoaciduria, and FS was diagnosed. Replacement of bicarbonate and potassium did not improve her condition. Two weeks after the onset of FS, leukemic cells appeared on a peripheral blood smear, and the patient was diagnosed with precursor B-cell ALL presenting as nephromegaly and FS. Chemotherapy brought about a prompt resolution of acidosis and electrolyte abnormalities, without renal dysfunction. The patient remains well 4 years after the onset of the disease. Although extremely rare, FS should be recognized as one of the emerging renal complications of ALL

Neonatal Acute Megakaryoblastic Leukemia Presenting with Leukemia Cutis and Multiple Intracranial Lesions Successfully Treated with Unrelated Cord Blood Transplantation

Neonatal acute megakaryoblastic leukemia (AMKL) without Down syndrome (DS) is an extremely rare disorder. We report of a one-day-old male infant without DS who developed AMKL with leukemia cutis and right facial nerve palsy. Magnetic resonance imaging of the patient’s brain revealed multiple intracranial tumors. A biopsy specimen of the skin lesion was suggestive of AMKL, but the bone marrow leukemic cells were less than 5% of the marrow nucleated cells. The skin and intracranial lesions had spontaneously regressed within one and a half months, but the patient’s anemia and thrombocytopenia gradually worsened and the leukemic cells in the bone marrow gradually increased to more than 20% of the nucleated cells. In addition, multiple intracranial lesions reappeared at 72 days of life. We diagnosed the patient with AMKL, and chemotherapy followed by unrelated cord blood transplantation after a reduced-intensity conditioning regimen resulted in sustained complete remission. At present, the patient is well, and he has demonstrated normal development for five years