Congenital thrombocytopenia associated with a heterozygous variant in the MEIS1 gene encoding a transcription factor essential for megakaryopoiesis.

The transcription factor MEIS1 (myeloid ectotrophic insertion site 1) is crucial for the maintenance of hematopoietic stem cells and for megakaryopoiesis. Germline variants in MEIS1 are associated with restless-leg syndrome, but were not previously shown to cause cytopenias. This is the first report of a patient with congenital thrombocytopenia associated with a sequence variant in MEIS1, presenting with early onset severe thrombocytopenia and mild signs of bone marrow stress. Whole exome sequencing revealed a de novo monoallelic splice site variant in MEIS1, NM_002398.3:exon4:c.432 + 5 G > C, leading to a premature stop codon. We propose that heterozygous mutations in MEIS1 may cause congenital thrombocytopenia.

Targeted next generation sequencing for the diagnosis of patients with rare congenital anemias.

BACKGROUND: Most patients with anemia are diagnosed through clinical phenotype and basic laboratory testing. Nonetheless, in cases of rare congenital anemias, some patients remain undiagnosed despite undergoing an exhaustive workup. Genetic testing is complicated by the large number of genes involved in rare anemias and the similarities in the clinical presentation of the different syndromes. OBJECTIVE: We aimed to enhance the diagnosis of patients with congenital anemias by using targeted next-generation sequencing. METHODS: Genetic diagnosis was performed by gene capture followed by next-generation sequencing of 76 genes known to cause anemia syndromes. RESULTS: Genetic diagnosis was achieved in 13 out of 21 patients (62%). Six patients were diagnosed with pyruvate kinase deficiency, 4 with dehydrated hereditary stomatocytosis, 2 with sideroblastic anemia, and 1 with CDA type IV. Eight novel mutations were found. In 7 patients, the genetic diagnosis differed from the pretest presumed diagnosis. The mean lag time from presentation to diagnosis was over 13 years. CONCLUSIONS: Targeted next-generation sequencing led to an accurate diagnosis in over 60% of patients with rare anemias. These patients do not need further diagnostic workup. Earlier incorporation of this method into the workup of patients with congenital anemia may improve patients' care and enable genetic counseling.

Pearson disease in an infant presenting with severe hypoplastic anemia, normal pancreatic function, and progressive liver failure.

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

Hypocholesterolemia in children and adolescents with beta-thalassemia intermedia.

OBJECTIVES: To conduct a prospective study to evaluate the lipid profile in children and adolescents with beta-thalassemia intermedia and major, and to examine the contribution of different factors to hypocholesterolemia observed in these patients. STUDY DESIGN: Demographic, clinical, and laboratory data were prospectively obtained from patients with beta-thalassemia intermedia (n = 9) and major (n = 47). Lipid profiles were also determined in a control group of healthy children (n = 18). Lipid values of beta-thalassemics and controls were compared and the relationships between lipid levels and different covariates were determined. RESULTS: beta-thalassemia intermedia patients had significantly lower total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C) compared with beta-thalassemia major and controls (P <.001). With regression analysis, serum lipid levels (TC, HDL-C, and triglycerides) correlated with diagnosis (beta-thalassemia major or intermedia) but not with age, sex, hemoglobin, or ferritin. LDL-C was influenced by both diagnosis and ferritin levels. CONCLUSIONS: Children and adolescents with beta-thalassemia intermedia have significantly lower cholesterol levels than patients with beta-thalassemia major. This is related to their disorder and not influenced by age, sex, hemoglobin, or ferritin levels. In these patients, needless investigations for hypolipidemia should be avoided.