Severe course with lethal hepatocellular injury and skeletal muscular dysgenesis in a neonate with infantile liver failure syndrome type 1 caused by novel LARS1 mutations.

Infantile liver failure syndrome type 1 (ILFS1) is a recently recognized autosomal recessive disorder caused by deleterious mutations in the leucyl-tRNA synthetase 1 gene (LARS1). The LARS1 enzyme is responsible for incorporation of the amino acid leucine during protein polypeptide synthesis. Individuals with LARS1 mutations typically show liver failure from infancy to early childhood during periods of illness or other physiological stress. While 25 patients from 15 families with ILFS1 have been reported in the literature, histological reports from autopsy findings are limited. We report here a premature male neonate who presented with severe intrauterine growth retardation, microcytic anemia, and fulminant liver failure, and who was a compound heterozygote for two novel deleterious mutations in LARS1. An autopsy showed fulminant hepatitis-like hepatocellular injury and fibrogenesis in the liver and a lack of uniformity in skeletal muscle, accompanied by the disruption of striated muscle fibers. Striking dysgenesis in skeletal muscle detected in the present case indicates the effect of LARS1 functional deficiency on the musculature. Whole-exome sequencing may be useful for neonates with unexplained early liver failure if extensive genetic and metabolic testing is inconclusive.

Infantile Pyknocytosis in a Premature Dichorionic Diamniotic Twin.

Infantile pyknocytosis is a rare and self-limiting cause of hemolytic anemia in neonates. It can result in severe anemia and hyperbilirubinemia. The pathogenesis is unknown: a genetic origin has been discussed; however, based on the current literature it is not clear which genetic mutations should be considered. We present a case of a premature twin, in whom genetic screening was performed. Genetic mutations in 46 genes associated with hereditary hemolytic anemia and dyserythropoietic anemia were tested. No mutations were found. In infantile pyknocytosis, a genetic defect in these genes is unlikely.

A family affair-Severe fetal and neonatal hemolytic anemia due to novel alpha-spectrin mutations in two siblings.

Hereditary spherocytosis (HS) is the most common cause of inherited, nonimmune hemolytic anemia. When inherited in an autosomal dominant fashion, the anemia is typically mild. However, severe, transfusion-dependent anemia is seen in autosomal recessive HS, which is often associated with deficient or absent red blood cell membrane protein alpha-spectrin. We report a 26-year-old para one who was referred to our center at 28 weeks' gestation due to concerns for fetal anemia. Evaluation revealed elevated peak systolic velocity in the middle cerebral artery by Doppler scan and fetal cardiomegaly. Fetal hematocrit obtained by sampling the umbilical vein was 9% confirming severe fetal anemia. Fetal peripheral smear was consistent with hereditary spherocytosis. Genetic analysis of both parents confirmed heterozygosity for the SPTA1 variants (pathogenic variant c.4180del (p.C1394Afs*25), and a variant of uncertain significance, c.1677G>T (p.G449G)) detected by a hemolytic anemia panel in the patient's first child. It is important to consider genetic causes of anemia in patients presenting with severe nonimmune fetal anemia, including autosomal recessive HS. We present a case of autosomal recessive HS with a novel pathogenic variant in the SPTA1 gene which resulted in significant impact on prenatal management.

A Novel Mutation of Glucose Phosphate Isomerase (GPI) Causing Severe Neonatal Anemia Due to GPI Deficiency.

Glucose-6-phosphate isomerase (GPI) deficiency is very rare, but one of the most common erythroenzymopathies, causing hereditary nonspherocytic hemolytic anemia. This case report describes the clinical features and the molecular etiology of a Dutch patient with GPI deficiency. She is the fifth patient with GPI deficiency identified to date in the Netherlands and was found to be compound heterozygous for the previously reported c.1615G>A p.(Asp539Asn) mutation and a novel c.271A>T p.(Asn91Tyr) variant.

Tubular immaturity causes erythropoietin-deficiency anemia of prematurity in preterm neonates.

Kidneys are physiologically hypoxic due to huge oxygen consumption for tubular reabsorption. The physiological hypoxia makes the kidney an appropriate organ for sensitively detecting oxygen levels and producing erythropoietin (EPO). In preterm neonates, immature kidneys cannot produce sufficient EPO, which results in anemia of prematurity (AOP). The cause of EPO insufficiency in AOP has been unclear, therefore current therapeutic options are transfusion and injection of recombinant human EPO. This report shows that the cause of insufficient EPO production in AOP is elevated renal oxygen levels due to poor oxygen consumption by immature tubules. Neonatal mice with AOP showed low tubular transporter expression and elevated renal oxygen levels compared with those without AOP. Enhancing transporter expression in AOP mice induced renal hypoxia and EPO production. In preterm neonates, red blood cell counts, hemoglobin levels, and hematocrit levels correlated with tubular function, but not with serum creatinine, gestational age, or birth weight. Furthermore, pharmacological upregulation of hypoxia signaling ameliorated AOP in mice. These data suggest that tubular maturation with increased oxygen consumption is required for renal EPO production.

Neomorphic effects of the neonatal anemia (Nan-Eklf) mutation contribute to deficits throughout development.

Transcription factor control of cell-specific downstream targets can be significantly altered when the controlling factor is mutated. We show that the semi-dominant neonatal anemia (Nan) mutation in the EKLF/KLF1 transcription factor leads to ectopic expression of proteins that are not normally expressed in the red blood cell, leading to systemic effects that exacerbate the intrinsic anemia in the adult and alter correct development in the early embryo. Even when expressed as a heterozygote, the Nan-EKLF protein accomplishes this by direct binding and aberrant activation of genes encoding secreted factors that exert a negative effect on erythropoiesis and iron use. Our data form the basis for a novel mechanism of physiological deficiency that is relevant to human dyserythropoietic anemia and likely other disease states.

Anemia in the Neonate: The Differential Diagnosis and Treatment.

Anemia is a common problem in the neonatal period. Presenting symptoms may suggest numerous possible diagnoses ranging from anemia seen as a normal part of development to anemia due to critical pathology. An illustrative case is presented to highlight the appropriate evaluation of the neonate with significant anemia. Several important features of the evaluation of neonatal anemia are highlighted. The constellation of signs and symptoms that occur in conjunction with the anemia are critical for the evaluation. The evaluation should be performed in a step-wise process that starts by eliminating common causes of anemia. Manual review of the peripheral blood smear with a hematologist can be helpful.

KLF1-null neonates display hydrops fetalis and a deranged erythroid transcriptome.

We describe a case of severe neonatal anemia with kernicterus caused by compound heterozygosity for null mutations in KLF1, each inherited from asymptomatic parents. One of the mutations is novel. This is the first described case of a KLF1-null human. The phenotype of severe nonspherocytic hemolytic anemia, jaundice, hepatosplenomegaly, and marked erythroblastosis is more severe than that present in congenital dyserythropoietic anemia type IV as a result of dominant mutations in the second zinc-finger of KLF1. There was a very high level of HbF expression into childhood (>70%), consistent with a key role for KLF1 in human hemoglobin switching. We performed RNA-seq on circulating erythroblasts and found that human KLF1 acts like mouse Klf1 to coordinate expression of many genes required to build a red cell including those encoding globins, cytoskeletal components, AHSP, heme synthesis enzymes, cell-cycle regulators, and blood group antigens. We identify novel KLF1 target genes including KIF23 and KIF11 which are required for proper cytokinesis. We also identify new roles for KLF1 in autophagy, global transcriptional control, and RNA splicing. We suggest loss of KLF1 should be considered in otherwise unexplained cases of severe neonatal NSHA or hydrops fetalis.

εGγAγδß0-thalassemia: a rare but clinically significant cause of hemolytic anemia in infants.

Normal hemoglobin is made of a tetramer of 2 α-globin and 2 ß-globin polypeptide chains. Deletions in the ß-globin gene cluster can range from a few hundred base pairs to loss of the entire cluster resulting in rare, but clinically significant, thalassemias. One such entity is εGγAγδß0-thalassemia, a condition that presents within the first few weeks of life as a Coombs-negative hemolytic anemia and is not identified on routine newborn screening or hemoglobin electrophoresis.

A novel epsilon gamma delta beta thalassemia presenting with pregnancy complications and severe neonatal anemia.

OBJECTIVE: The epsilon gamma delta beta (εγδß)-thalassemias are rare sporadic disorders caused by deletion of the ß-globin gene cluster. The main clinical feature is marked prenatal and neonatal anemia that resolves spontaneously within a few months. Reports originating mainly from Europe have so far identified 30 such deletions The aim of the present work was to describe a novel 1.78-Mb deletion, the longest ever reported, and to detail the clinical features in 12 members of an extended Bedouin family. METHODS: The deletion was identified by globin gene multiplex ligation-dependent probe amplification (MLPA) of the ß-globin cluster and further characterized by comparative genomic hybridization. Past and present clinical and laboratory data of ten symptomatic and two asymptomatic patients were collected. RESULTS: A 1.78-Mb εγδß-deletion, the largest ever described, was identified in all patients. Although other genes were included in the deletion, no other symptoms were observed. Of the ten symptomatic fetuses and neonates, three died of the disease. The remainder required packed cell transfusions during the first months of life. Pregnancy complications included intrauterine growth restriction and oligohydramnios, as well as additional neonatal complications including prematurity and persistent pulmonary hypertension of the neonate. CONCLUSIONS: We suggest that εγδß-thalassemia be added to the list of hemoglobinopathies that can cause neonatal anemia and that MLPA of the ß-globin cluster be used to confirm its diagnosis. Careful surveillance during pregnancy is important to reduce neonatal mortality and morbidity, especially given the dramatic improvement that occurs later.

[Neonatal Pearson syndrome. two case studies]. / Le syndrome de Pearson : à propos de 2 observations à révélation néonatale.

Among the etiologies of anemia in the newborn, those related to mitochondrial cytopathies are rare. Pearson syndrome is mostly diagnosed during infancy and characterized by refractory sideroblastic anemia with vacuolization of marrow progenitor cells and exocrine pancreatic dysfunction. We describe two diagnosed cases of Pearson syndrome in the early neonatal period caused by severe macrocytic aregenerative anemia. Bone marrow aspiration revealed sideroblastic anemia and vacuolization of erythroblastic precursors. The diagnosis was confirmed by genetic analysis revealing a deletion in the mitochondrial DNA. These two newborns received monthly transfusions. Five other newborns suffering from Pearson syndrome with various clinical symptoms were found in literature. Pearson syndrome, rarely diagnosed in newborns, should be suspected in the presence of macrocytic aregenerative anemia and requires a bone marrow aspirate followed by a genetic analysis from a blood sample.

Neonatal anemia associated with Southeast Asian ovalocytosis.

The purposes of this study were to evaluate the reliability of the previously described diagnostic criteria for Southeast Asian ovalocytosis (SAO) in adults in the diagnosis of SAO in newborns and to describe the role of SAO in newborn infants presenting with pallor and jaundice. The inclusion criteria in this retrospective descriptive study were that the patient be a newborn with pallor or jaundice and with ovalocytes in the peripheral blood smear (PBS). The exclusion criteria were newborn status with other causes of neonatal hemolysis or anemia. Controls were age-matched newborn infants who did not have SAO or other causes of neonatal anemia or hemolysis. Hematological data were assessed with a hematology analyzer. DNA analysis for SAO band 3 was done by polymerase chain reaction. Among 107 newborn infants with SAO, 30 infants were excluded from the study. The exclusions were premature infants, an infant with congenital syphilis, low-birth-weight infants, infants with ABO blood group incompatibility, infants with 3-thalassemia, infants with hemoglobin E heterozygote or homozygotes, glucose-6-phosphate dehydrogenase-deficient infants, and infants with fetomaternal hemorrhage. The DNA analysis for SAO band 3 was done in 56 newborns, and 54 had positive results for SAO band 3 gene deletion. Approximately one half of the 54 newborn infants with SAO had hyperbilirubinemia, and 3 had severe hyperbilirubinemia. The mean hemoglobin concentration, packed cell volume, and red blood cell (RBC) count in the infants with SAO in the first week of life were significantly lower than those in control infants. The mean absolute number of reticulocytes, mean corpuscular hemoglobin, and red cell volume distribution width in infants with SAO band 3 in the first week of life were significantly higher than those in control infants. The neonatal diagnosis of SAO can be made by examination of RBC morphology in the PBS with the presence of stomatocytes, theta cells, and > or = 25% ovalocytes. SAO plays a role in anemia and hyperbilirubinemia in newborn infants.

Hb Dartmouth [alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG)]: a novel alpha2-globin gene mutation associated with severe neonatal anemia when inherited in trans with Southeast Asian alpha-thalassemia-1.

We report a novel mutation at alpha66(E15)Leu-->Pro (alpha2) (CTG-->CCG), that we have named Hb Dartmouth for the medical center at which the patients were cared for, in monozygotic twins who also inherited the Southeast Asian alpha-thalassemia-1 deletion. The mother, of Khmer ancestry, is heterozygous for alpha-thalassemia-1. The father, who is of Scottish-Irish ancestry, is a silent carrier of the codon 66 mutation. The twins had severe neonatal anemia requiring transfusion.

Erythropoietin production by macrophages from preterm infants: implications regarding the cause of the anemia of prematurity.

In the human fetus, liver macrophages appear to be the primary source of erythropoietin (Epo). Epo production shifts from the liver to peritubular cells in the kidney sometime during the 3rd trimester. Some preterm infants experience a hyporegenerative anemia that appears to be caused by inadequate Epo production. It is not clear whether this anemia is due to deficient Epo production by liver macrophages or renal peritubular cells. To assess this situation, we measured Epo mRNA and protein in macrophages obtained from cord blood of preterm and term infants and from peripheral blood of adults. Macrophages from preterm infants generated Epo mRNA and protein as effectively as those from term infants and adults. It appears that the anemia of prematurity is not due to defective Epo production by macrophages.