Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.

Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.

What is the context?Inherited thrombocytopenias (ITs) are rare conditions characterized by low platelet counts. Inherited thrombocytopenia 2 (THC2) is caused by ANKRD26 gene changes leading to increased ANKRD26 expression as the main reason for subsequent thrombocytopenia. THC2 results in a mild-to-moderate decrease in platelet count and increases blood cancer risk. We focused on understanding two ANKRD26 variants in a family with a history of thrombocytopenia.What is new?We conducted functional analysis to understand the effect of variants on platelet function and gene expression. We identified three thrombocytopenic family members as carriers of ANKRD26 variant c.-118C>T. This variant is linked to increased expression of the ANKRD26 gene and confirmed as the likely cause of THC2. Another variant, c.-140C>G, was present in four healthy family members. Although it was considered causal for THC2 in the past, our study suggests that the c.-140C>G variant does not elevate ANKRD26 expression and does not cause thrombocytopenia.What is the impact?Understanding the genetic and functional implications of ANKRD26 gene variants is crucial for THC2 diagnosis and management. Our study emphasizes the necessity of conducting functional analyses to precisely evaluate the clinical significance of variants linked to inherited blood disorders. Carriers of the c.-118C>T variant should undergo vigilant monitoring for THC2 and potential cancer development. Conversely, the c.-140C>G variant does not pose a risk of THC2 or heightened cancer susceptibility.

Pancytopenia, panhypopituitarism and liver cirrhosis: analysis of a difficult clinical case.

Panhypopituitarism following craniopharyngioma resection has systemic impact with potential influence on physio-logical hematopoiesis. There is a growing body of evidence of liver fibrosis/cirrhosis risk development due to altered metabolism and lipid accumulation. The authors present a case report of a woman with a history of craniopharyngioma resection followed by aggravating pancytopenia with suspected indolent lymphoproliferative disorder and possible acquired bone marrow aplasia syndrome due to paroxysmal nocturnal hemoglobinuria. A complex hemostasis disorder with deficiency of multiple coagulation factors (FXII, FXI, FX, FIX, FVII, FX, FV, FXIII, antitrombin, protein C, protein S) was accidentally detected. Despite normal sonographic liver imaging, all possible causes of chronic liver disease were systematically excluded (viral hepatitis, hemochromatosis, Wilson´s disease, α-1-antitrypsin deficiency); anti-LKM-1 and anti-ENA antibodies were detected. Finally, the magnetic resonance imaging confirmed image of liver cirrhosis - with signs of portal hypertension.

[Is it necessary to revaccinate against hepatitis B virus when the titer of anti-HBs drops below 10 IU/L?]

Viral hepatitis B still represents a major epidemiological issue worldwide. After recombinant vaccine administration, a titer of anti-HBs antibodies ≥ 10 IU/L has long been considered to be seroprotective. Persons without this antibody level after complete vaccination are referred to as non-responders. A progressive decline in anti-HBs levels over years is also commonly seen in responders. Recently, there has been increasing evidence that the titer of anti-HBs ≥ 10 IU/L does not provide 100 % protection against infection and clinically manifest illness. Additionally, an important role of cellular immune memory has been demonstrated - without any correlation with anti-HBs titer. Based on current knowledge, there is no need for regular anti-HBs titer testing or booster vaccination in immunocompetent individuals with anti-HBs ≤ 10 IU/L. At present, regular serological testing and, if need be, revaccination to maintain anti-HBs ≥ 10 IU/L are recommended in immunocompromised persons and after liver transplantation.

Successful treatment of steroid-refractory hepatitic variant of liver graft-vs-host disease with pulse cyclophosphamide.

OBJECTIVE: Corticosteroid-resistant graft-vs-host disease (GVHD) is difficult to manage and is associated with high morbidity and mortality. No standard treatment exists. We have previously seen good results with pulse cyclophosphamide (Cy) in the treatment of liver GVHD in contrast to gastrointestinal GVHD, and here we report results of pulse Cy protocol in the treatment of steroid-refractory hepatitic variant of liver GVHD, with no association to the gut. MATERIALS AND METHODS: Cy was infused at a dose of 1,000 mg/m(2). Twenty-nine cyclophosphamide administrations were given to 21 patients. Median time of GVHD onset and Cy administration after transplantation, or donor lymphocyte infusion, were 58 and 69 days, respectively. RESULTS: Eleven patients (52%) achieved complete remission and 6 patients (29%) achieved partial remission. Four patients (19%) did not respond, however, their condition stabilized and, upon additional therapy, three achieved partial remission and one complete remission. Overall survival of all 21 patients is 86%, with median and maximal follow-up of 33 and 81 months, respectively. Toxicity was mild and easily manageable without influencing chimerism or disease status. CONCLUSIONS: Pulse Cy seems to be an effective treatment for steroid-refractory hepatitic variant of liver GVHD with a good toxicity profile, which may favor its use instead of drugs with more pronounced immunosuppressive effects.