Hemoglobin (Hb) Bart9s hydrops fetalis syndrome (BHFS) resulting from α⁰-thalassemia is considered a universally fatal disorder. However, over the last 3 decades, improvements in intrauterine interventions and perinatal intensive care have resulted in increasing numbers of BHFS survivors. We have initiated an international registry containing information on 69 patients, of which 31 are previously unpublished. In this perspective, we analyze the available clinical information to document the natural history of BHFS. In the future, once we have accrued sufficient cases, we aim to build on this study and provide information to allow counseling of at-risk couples. To date, 39 patients have survived beyond the age of 5 years, 18 of whom are now older than 10 years. Based on the available cases, we find evidence to suggest that intrauterine therapy provides benefits during the perinatal and neonatal period; however, it may not provide additional benefits to long-term growth and neurodevelopmental outcomes. Growth retardation is a major adverse long-term outcome among BHFS patients with ∼40% being severely affected in terms of weight and ∼50% in terms of height. There is also an increased risk of neurodevelopmental delay as we find 20% (11/55) of BHFS survivors suffer from a serious delay of ≥6 months. Most patients in the registry require lifelong transfusion and often have associated congenital abnormalities and comorbidities. This perspective is a first step in gathering information to allow provision of informed counseling on the predicted outcomes of affected babies.

Summary: Congenital dyserythropoietic anaemia type I (CDA‐I) is one of a heterogeneous group of inherited anaemias characterised by ineffective erythropoiesis. CDA‐I is caused by bi‐allelic mutations in either CDAN1 or C15orf41 and, to date, 56 causative mutations have been documented. The diagnostic pathway is reviewed and the utility of genetic testing in reducing the time taken to reach an accurate molecular diagnosis and avoiding bone marrow aspiration, where possible, is described. The management of CDA‐I patients is discussed, highlighting both general and specific measures which impact on disease progression. The use of interferon alpha and careful management of iron overload are reviewed and suggest the most favourable outcomes are achieved when CDA‐I patients are managed with a holistic and multidisciplinary approach. Finally, the current understanding of the molecular and cellular pathogenesis of CDA‐I is presented, highlighting critical questions likely to lead to improved therapy for this disease.

The α- and β-globin loci harbor developmentally expressed genes, which are silenced throughout post-natal life. Reactivation of these genes may offer therapeutic approaches for the hemoglobinopathies, the most common single gene disorders. Here, we address mechanisms regulating the embryonically expressed α-like globin, termed ζ-globin. We show that in embryonic erythroid cells, the ζ-gene lies within a ~65 kb sub-TAD (topologically associating domain) of open, acetylated chromatin and interacts with the α-globin super-enhancer. By contrast, in adult erythroid cells, the ζ-gene is packaged within a small (~10 kb) sub-domain of hypoacetylated, facultative heterochromatin within the acetylated sub-TAD and that it no longer interacts with its enhancers. The ζ-gene can be partially re-activated by acetylation and inhibition of histone de-acetylases. In addition to suggesting therapies for severe α-thalassemia, these findings illustrate the general principles by which reactivation of developmental genes may rescue abnormalities arising from mutations in their adult paralogues.

Hemoglobin Bart’s hydrops fetalis syndrome (BHFS) represents the most severe form of α-thalassemia, arising from deletion of the duplicated α-globin genes from both alleles. The absence of α-globin leads to the formation of nonfunctional hemoglobin (Hb) Bart’s (γ4) or HbH (β4) resulting in severe anemia, tissue hypoxia, and, in some cases, variable congenital or neurocognitive abnormalities. BHFS is the most common cause of hydrops fetalis in Southeast Asia; however, owing to global migration, the burden of this condition is increasing worldwide. With the availability of intensive perinatal care and intrauterine transfusions, an increasing number of patients survive with this condition. The current approach to long-term management of survivors involves regular blood transfusions and iron chelation, a task made challenging by the need for intensified transfusions to suppress the production of nonfunctional HbH–containing erythrocytes. Although our knowledge of outcomes of this condition is evolving, it seems, in comparison to individuals with transfusion-dependent β-thalassemia, those with BHFS may face an elevated risk of complications arising from chronic anemia and hypoxia, ongoing hemolysis, iron overload, and from their respective treatments. Although stem cell transplantation remains a viable option for a select few, it is not without potential side effects. Looking ahead, potential advancements in the form of genetic engineering and innovative therapeutic approaches, such as the reactivation of embryonic α-like globin gene expression, hold promise for furthering the treatment of this condition. Prevention remains a crucial aspect of care, particularly in areas with high prevalence or limited resources.

Rheumatology key message. Clinical variability in Majeed syndrome, favourable response to IL-1 blockade and recommendations for genetic screening.

Background: Congenital dyserythropoietic anaemia type I (CDA-I) is a hereditary anaemia caused by biallelic mutations in the widely expressed genes CDAN1 and C15orf41. Little is understood about either protein and it is unclear in which cellular pathways they participate. Methods: Genetic analysis of a cohort of patients with CDA-I identifies novel pathogenic variants in both known causative genes. We analyse the mutation distribution and the predicted structural positioning of amino acids affected in Codanin-1, the protein encoded by CDAN1. Using western blotting, immunoprecipitation and immunofluorescence, we determine the effect of particular mutations on both proteins and interrogate protein interaction, stability and subcellular localisation. Results: We identify six novel CDAN1 mutations and one novel mutation in C15orf41 and uncover evidence of further genetic heterogeneity in CDA-I. Additionally, population genetics suggests that CDA-I is more common than currently predicted. Mutations are enriched in six clusters in Codanin-1 and tend to affect buried residues. Many missense and in-frame mutations do not destabilise the entire protein. Rather C15orf41 relies on Codanin-1 for stability and both proteins, which are enriched in the nucleolus, interact to form an obligate complex in cells. Conclusion: Stability and interaction data suggest that C15orf41 may be the key determinant of CDA-I and offer insight into the mechanism underlying this disease. Both proteins share a common pathway likely to be present in a wide variety of cell types; however, nucleolar enrichment may provide a clue as to the erythroid specific nature of CDA-I. The surprisingly high predicted incidence of CDA-I suggests that better ascertainment would lead to improved patient care.