Nationwide survey of late-onset hemolysis in very low birthweight infants.

BACKGROUND: In Japan, some cases of late-onset acute hemolysis in very low birthweight (VLBW) infants have been reported. These cases had common features but the cause of hemolysis was unknown. The incidence and prognosis of this disease are also unknown. However, there are only few reports of such hemolytic episodes in countries other than Japan. Thus, this study aimed to examine the incidence and clinical course of late-onset acute hemolysis and to establish it as a new disease concept. METHODS: A nationwide prospective survey was conducted from 2011 to 2015 as a rare disease surveillance project of the Japan Society for Neonatal Health and Development. RESULTS: Twenty-four cases were confirmed. The median (range) gestational age, birthweight, and onset of hemolytic episodes were 26 weeks and 2 days (23 weeks and 4 days-31 weeks and 2 days), 898 g (627-1,416 g), and 19 days after birth (9-33 days), respectively. Phototherapy, blood transfusion, and exchange transfusion were required in 22 (96%), 24 (100%), and 7 (29%) cases, respectively. During the observation period, no recurrence of the hemolytic episode occurred. All patients survived; however, one case developed kernicterus and suffered severe neurological sequelae. CONCLUSIONS: In this study, at least 1 out of 1,259 VLBW infants developed hemolysis at 9-33 days after birth in Japan. Owing to the risk of kernicterus, this disease should be recognized as among the important pathological conditions of VLBW infants, suggesting the need to manage jaundice and anemia until 5 weeks after birth.

Atypical erythroblastosis in a patient with Diamond-Blackfan anemia who developed del(20q) myelodysplasia.

Diamond-Blackfan anemia (DBA) is a congenital red cell aplasia arising from ribosomal protein (RP) defects. Affected patients present with neonatal anemia, occasional dysmorphism, and cancer predisposition. An anemic newborn was diagnosed with DBA due to RPL5 mutation (c.473_474del, p.K158SfsX26). Refractory anemia required regular transfusions and iron chelation therapy. Pancytopenia occurred at age 16 years. Bone-marrow studies showed myelodysplasia, erythroblastosis, and clonal evolution of del(20)(q11.2q13.3). Severe anemia required transfusions. Del(20q), including the L3MBTL1 gene, is reported to be relevant to the hematological phenotype of Shwachman-Diamond syndrome. A combined defect of RPL5 and L3MBTL1 may contribute to the aberrant erythropoiesis in the present case.

An Elevation of Serum Ferritin Level Might Increase Clinical Risk for the Persistence of Patent Ductus Arteriosus, Sepsis and Bronchopulmonary Dysplasia in Erythropoietin-Treated Very-Low-Birth-Weight Infants.

BACKGROUND: The substantial risk of iron overload is not routinely monitored in most of the neonatal intensive care units (NICUs) in Japan; however, blood transfusion is an essential strategy for successfully treating preterm low-birth-weight infants. OBJECTIVE: The aim of this study was to investigate the iron status and clinical features of infants with a birth weight of <1,500 g, i.e. very-low-birth-weight infants (VLBWIs). METHODS: This prospective observational study enrolled 176 (82.6%) patients from a total of 213 VLBWIs admitted to our NICU from 2009 to 2014. Clinical information was collected including maternal records and infant morbidity and treatment. Management strategies including enteral iron supplementation, erythropoietin administration and blood transfusion were allowed according to the consensus in Japan. The hematological status was surveyed from birth to 12 postnatal weeks of age. The iron status was determined according to serum iron, unbound iron-binding capacity and serum ferritin. The definition of hyperferritinemia was set as a value of ≥500 ng/ml. RESULTS: Twenty-four (13.6%) infants displayed hyperferritinemia. A multiple logistic analysis selected 3 associated factors of hyperferritinemia: surgical ligation for patent ductus arteriosus, sepsis and moderate or severe states of bronchopulmonary dysplasia. We also verified that the value of ferritin was significantly correlated with those of aspartate transaminase, creatine kinase and C-reactive protein according to a multilinear regression analysis. After excluding the ferritin data of these outliers, we did not observe any factors associated with hyperferritinemia. CONCLUSIONS: Hyperferritinemia might be associated with oxygen radical diseases and susceptibility to infection.

Female agammaglobulinemia due to the Bruton tyrosine kinase deficiency caused by extremely skewed X-chromosome inactivation.

We analyzed the cause of agammaglobulinemia in a girl whose father had been diagnosed as having X-linked agammaglobulinemia (XLA). Flow cytometric analysis revealed the lack of peripheral B cells with the block of B-cell differentiation in the stages between pro-B cells and pre-B cells in the bone marrow, and the defect of the Bruton tyrosine kinase (BTK) expression on monocytes. We found a BTK gene mutation in the first single base pair of intron 11 in her father and heterozygous mutation in the patient at the site. Sequence analysis of abnormally smaller-sized polymerase chain reaction (PCR) products of cDNA confirmed splicing abnormalities due to the mutation. Maternally derived X chromosome was exclusively inactivated in peripheral blood and oral mucosal cells. This is the first report of female XLA caused by heterozygous BTK gene abnormality and extreme nonrandom inactivation of X chromosome on which normal BTK gene is located.