X-linked sideroblastic anaemia in a female fetus: a case report and a literature review

Background X-linked sideroblastic anaemia (XLSA) is commonly due to mutations in the ALAS2 gene and predominantly affects hemizygous males. Heterozygous female carriers of the ALAS2 gene mutation are often asymptomatic or only mildly anaemic. XLSA is usually characterized by microcytic erythrocytes (reduced mean corpuscular volume (MCV)) and hypochromia, along with increased red cell distribution width. However, in females with XLSA the characteristic laboratory findings can be dimorphic and present with macrocytic (elevated MCV) in addition to microcytic red cells. Case presentation We report a case of fetal anaemia, presenting in the early third trimester of pregnancy, in a female fetus. Ultrasound findings at 29 weeks were of cardiomegaly, prominent umbilical veins, a small rim of ascites, and mean cerebral artery peak systolic velocity (PSV) value above 1.5 Multiples of the Median (MoM). She underwent non-invasive prenatal testing that determined the rhesus genotype of the fetus to be rhesus B negative. No red blood cell antibodies were reported. Other investigations to determine the underlying cause of fetal anaemia included microarray comparative genomic hybridization, serology to exclude congenital infection and a peripheral blood film and fetal bilirubin to detect haemolysis. The maternal grandmother had a history of sideroblastic anaemia diagnosed at the age of 17 years. The mother had mild macrocytic anaemia with haemoglobin of 10.4 g/dl and MCV of 104 fl. The fetal anaemia was successfully treated with two in utero transfusions (IUTs), and delivery occurred via caesarean section at 37 weeks of gestation. The red cell gene sequencing in both the mother and fetus were heterozygous for an ALAS2 mutation causing in utero manifestations of XLSA. The haemoglobin on discharge to the local hospital at five days of age was 19.1 g/dl. Subsequently, the infant became anaemic, requiring regular 3–4 monthly blood transfusions and demonstrating overall normal development. Her anaemia was unresponsive to pyridoxine. Conclusions This is one of four cases reporting multiple female members presenting with discordant clinical features of XLSA from being entirely asymptomatic to hydropic in utero. Our report is novel in that there are no previous cases in the literature of anaemia in a female fetus heterozygous for ALAS2 mutation.

Acquired Hyperzincaemia Due to Zinc-Laden Denture Adhesives Leading to Hypocupraemia as a Cause of Neutropenia

Introduction: Copper deficiency or hypocupraemia is a rare cause of anaemia and neutropenia. Case description: We hereby present the case of a 34-year-old female with gastric bypass surgery who presented with neutropenic fever, abdominal pain and diarrhoea, later found to have extended-spectrum beta-lactamase resistant Escherichia coli urinary tract infection and small bowel bacterial overgrowth syndrome, with her anaemia and neutropenia being caused by copper deficiency due to hyperzincaemia induced by using zinc denture adhesive cream. Discussion: Various causes of copper deficiency have been recognized including, but not limited to, malnutrition, gastrectomy, gastric bypass surgery, protein-losing enteropathies (coeliac disease, tropical sprue), Wilson disease and Menkes syndrome. Copper deficiency caused by zinc overuse is not very prevalent. The haematologic abnormalities associated with copper deficiency are neutropenia, sideroblastic anaemia and/or pancytopenia. Conclusion: Because of its low prevalence and nonspecific haematologic and clinical manifestations, the diagnosis of zinc-induced copper deficiency (ZICD) can be missed.

Novel frameshift variant (c.409dupG) in SLC25A38 is a common cause of congenital sideroblastic anaemia in the Indian subcontinent

AimsCongenital sideroblastic anaemias (CSAs) are a group of rare disorders with the presence of ring sideroblasts in the bone marrow. Pathogenic variants are inherited in an autosomal recessive/X-linked fashion. The study was aimed at characterising the spectrum of mutations in SLC25A38 and ALAS2 genes in sideroblastic anaemia patients, exploring the genotype-phenotype correlation and identifying the haplotype associated with any recurrent mutation.Patients and methodsTwenty probable CSA patients were retrospectively analysed for genetic variants in ALAS2 and SLC25A38 genes by direct bidirectional sequencing. Real-time PCR was used to quantify gene expression in a case with promoter region variant in ALAS2. Three single nucleotide polymorphisms were used to establish the haplotype associated with a recurrent variant in the SLC25A38 gene.ResultsSix patients had causative variants in ALAS2 (30%) and 11 had variants in SLC25A38 (55%). The ALAS2 mutated cases presented at a significantly later age than the SLC25A38 cases. A frameshift variant in SLC25A38 (c.409dupG) was identified in six unrelated patients and was a common variant in our population exhibiting ‘founder effect’.ConclusionThis is the largest series of sideroblastic anaemia cases with molecular characterisation from the Indian subcontinent.

Anaemias resulting from defective maturation of red cells

Defective maturation of red cells leads to premature destruction of nucleated red cell precursors before they leave the haematopoietic bone marrow, which results in expansion of the marrow, haemolytic jaundice, peripheral signs of increased erythroid turnover on blood films, and (in long-standing disorders) iron overload due to enhanced absorption. Causes of ineffective erythropoiesis include (1) inhibition of erythroid DNA synthesis (e.g. megaloblastic anaemias (vitamin B12 or folate deficiency), drugs blocking DNA synthesis); (2) clonal disorders of erythropoiesis (e.g. refractory anaemia, acquired idiopathic sideroblastic anaemia, acute erythroleukaemia); (3) genetic disorders of erythropoiesis (e.g. thalassaemia syndromes, hereditary sideroblastic anaemia, congenital dyserythropoietic anaemia); and (4) other causes (e.g. alcohol). Sideroblastic anaemias—these result from defects in haem biosynthesis, with most cases being acquired as a clonal disorder of erythropoiesis, with varying degrees of myelodysplasia. Other causes are (1) hereditary (e.g. inherited deficiency of the erythroid-specific 5-aminolaevulinic acid synthase 2 gene on the X-chromosome causes congenital sideroblastic anaemia); (2) acquired (e.g. due to drugs or toxins such as ethanol, isoniazid, or lead; following chemotherapy or irradiation; or of unknown cause (idiopathic)). Diagnosis, treatment, and prognosis—diagnosis is achieved by finding ring sideroblasts (erythroblasts containing five or more iron-positive granules arranged in a perinuclear location around one-third or more of the nucleus) on bone marrow aspirate stained with Prussian blue iron reagent. Aside from supportive care with blood transfusion and iron chelation, a trial of pyridoxine is generally indicated (25% of hereditary cases—but few acquired cases—show some response). Acquired idiopathic sideroblastic anaemia has a median survival of 42 to 76 months, with 3 to 12% progressing to acute leukaemia.

Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors

ObjectivesTo characterise the clinical features, immune manifestations and molecular mechanisms in a recently described autoinflammatory disease caused by mutations in TRNT1, a tRNA processing enzyme, and to explore the use of cytokine inhibitors in suppressing the inflammatory phenotype.MethodsWe studied nine patients with biallelic mutations in TRNT1 and the syndrome of congenital sideroblastic anaemia with immunodeficiency, fevers and developmental delay (SIFD). Genetic studies included whole exome sequencing (WES) and candidate gene screening. Patients’ primary cells were used for deep RNA and tRNA sequencing, cytokine profiling, immunophenotyping, immunoblotting and electron microscopy (EM).ResultsWe identified eight mutations in these nine patients, three of which have not been previously associated with SIFD. Three patients died in early childhood. Inflammatory cytokines, mainly interleukin (IL)-6, interferon gamma (IFN-γ) and IFN-induced cytokines were elevated in the serum, whereas tumour necrosis factor (TNF) and IL-1β were present in tissue biopsies of patients with active inflammatory disease. Deep tRNA sequencing of patients’ fibroblasts showed significant deficiency of mature cytosolic tRNAs. EM of bone marrow and skin biopsy samples revealed striking abnormalities across all cell types and a mix of necrotic and normal-appearing cells. By immunoprecipitation, we found evidence for dysregulation in protein clearance pathways. In 4/4 patients, treatment with a TNF inhibitor suppressed inflammation, reduced the need for blood transfusions and improved growth.ConclusionsMutations of TRNT1 lead to a severe and often fatal syndrome, linking protein homeostasis and autoinflammation. Molecular diagnosis in early life will be crucial for initiating anti-TNF therapy, which might prevent some of the severe disease consequences.