Hereditary anemias encompass a genetically heterogeneous spectrum of disorders, often involving multi-locus inheritance, which can complicate clinical management and worsen disease severity. This study investigates the impact of the co-inheritance of SEC23B loss-of-function pathogenic variants, which lead to congenital dyserythropoietic anemia type II (CDA II), and PIEZO1 gain-of-function pathogenic variants, associated with dehydrated hereditary stomatocytosis type I (DHS1), on hematological parameters and iron metabolism. Among 583 patients with suspected hereditary anemia, 13 were found to carry both SEC23B and PIEZO1 variants, leading to a dual diagnosis of CDA II and DHS1. Compared to those with isolated CDA II, these patients exhibited a significantly higher absolute reticulocyte count and bone marrow responsiveness index, alongside an increased prevalence of elevated ferritin levels. Functional studies in Hep3B human hepatoma cells confirmed that SEC23B knockdown combined with PIEZO1 gain-of-function led to marked ferritin accumulation and reduced hepcidin expression, driven by altered BMP/SMAD signaling and ERK1/2 MAPK pathway. These findings demonstrate how multi-locus inheritance can modify disease severity, particularly by exacerbating iron overload. Our results underscore the clinical relevance of comprehensive genetic testing for enhanced risk stratification and personalized management of hereditary anemias.

Congenital dyserythropoietic anemia type II (CDA II), initially described as hereditary erythroblastic multinuclearity with a positive acidified serum test (HEMPAS), is a rare genetic disease inherited in an autosomal recessive mode that presents with mild to severe anemia. The occurrence of this entity is quite uncommon and requires extensive work-up for a conclusive diagnosis. Here, we are reporting a case of two-year-old male child who presented with severe anemia, abdominal distension, and delayed milestones. Evaluation of bone marrow aspirate suggested the possibility of CDA which led to molecular work-up by whole exome sequencing with detection of c.1142C>T (p.Thr381lle) variant in SEC23B (NM_006363.6) gene.

Anderson-Fabry disease, a rare X-linked lysosomal disorder, and congenital dyserythropoietic anemia (CDA) Type II, an autosomal recessive condition, both have distinct inheritance patterns. Their co-occurrence is extremely rare, never been reported before. Therefore, screening is crucial for early management, and families should seek genetic counseling for children showing unusual presentations. Anderson-Fabry disease (AFD) is a rare condition, characterized by a lysosomal storage disorder affecting lipid storage. It manifests in two forms: classic (early-onset) and nonclassic (late-onset). Conversely, congenital dyserythropoietic anemia (CDA) is a rare blood disorder caused by ineffective erythropoiesis, which results in the production of abnormal erythroblasts during the maturation of red blood cells, with CDA type II being the most frequent type. Both disorders have well-understood pathophysiologies, yet they are genetically distinct. AFD is inherited in an X-linked manner, whereas CDA type II follows an autosomal recessive pattern of inheritance. Although both AFD and CDA type II have been reported separately in the literature. The co-existence for both AFD and CDA type II has not been reported. We describe a 10-year-old boy, with both which is believed to be the first documented case.

Congenital dyserythropoietic anemias (CDAs) are rare hereditary disorders, of which type II CDA is the most common. Mutations in the SEC23B gene located on chromosome 20 result in this autosomal recessive disorder. In this case report, we present a case of CDA II with unique biopsy findings being detected via genetic testing. A female aged 30 years presented with major complaints of pallor weakness and easy fatiguability since childhood. The patient gave a history of 25 units of blood transfusion, the majority of which were transfused during pregnancy, followed by regular transfusions thereafter. On examination, all her vitals were in the normal range. Pallor, frontal bossing, and malocclusion of teeth were noted. Her laboratory workup showed the following: hemoglobin (Hb): 3.7 g/dl; mean corpuscular volume: 83 fl; mean corpuscular Hb: 29 g/dl; mean corpuscular Hb concentration: 34.9 g/dl; red cell distribution width: 30.4%; reticulocyte count (RC): 6.2%; corrected RC: 1.3%; lactate dehydrogenase: 441 IU/L; direct Coombs test/indirect Coombs test: negative; serum iron: 242 microgram/dl; transferrin saturation: 96.08%; ferritin: 1,880 ng/ml; and normal high-performance liquid chromatography and eosin-5'-maleimide binding test. The peripheral blood film showed normocytic normochromic anemia with anisopoikilocytosis in the form of a few spherocytes. No immature cells were seen. After obtaining the patient's consent, we performed a hereditary hemolytic anemia gene analysis test, which showed homozygous missense variation in exon 12 of the SEC23B gene. The bone marrow examination showed hyperplasia in the erythroid series with dyserythropoiesis, and surprisingly, myelofibrosis grade I-II (WHO 2017) was also observed on biopsy. Patients with CDA type II generally present with variable degrees of anemia along with pallor, icterus, splenomegaly, gallstones, and iron overload. In our case, the diagnosis of CDA type II was made at an adult age. Also, evidence of myelofibrosis was noted in our case, making it worth reporting. The use of a hereditary hemolytic anemia gene analysis panel test came as a rescue for its exact diagnosis. This case report emphasizes the role of molecular genetic testing for early and accurate diagnosis, which, in turn, could help in appropriate treatment planning and proper genetic counseling. The prevalence of CDA type II is still vaguely known; hence, extensive workup of persistent anemias and proper follow-up would be beneficial.