Severe Neonatal Anemia with Multi-Organ Failure, Extreme Placentomegaly, and Placental Megaloblastic Erythroblastosis as Features in Identifying Congenital Dyserythropoietic Anemia Type 1: A Case Report Open Access

Congenital dyserythropoietic anemia (CDA) is a group of rare, heterogeneous inherited erythroid disorders characterized by ineffective erythropoiesis. They are classified into various types and variants according to their clinical, bone marrow morphology and molecular features [1].

CDA-1 is an autosomal recessive condition, with an incidence of approximately 1 per 100,000 births per year [2]. In 90% of CDA-1 cases, a mutation is found in the CDAN1 or C15orf41 genes [1, 3]. These genes encode a protein playing a crucial role in DNA repair and/or in chromatin reassembly after DNA replication. CDA-1 is usually diagnosed in childhood, adolescence or adulthood [4]. Neonatal presentations are rare and clinical signs include moderate to severe neonatal anemia which is generally macrocytic with relative reticulocytopenia, intrauterine growth restriction, early cholestatic jaundice, transient thrombocytopenia, liver dysfunction, persistent pulmonary arterial hypertension, early iron overload and signs of extramedullary hematopoiesis such as hepatosplenomegaly. Patients may also have skeletal abnormalities involving the extremities as well as thoracic deformities [1‒5, 6].

Neonatal clinical presentation of CDA-1 is rare and nonspecific, making diagnosis particularly challenging. Only a few cases of newborns are reported in the literature [7, 8]. We present here the case of a newborn with severe CDA-1, diagnosed in the context of severe anemia and multi-organ failure. This case is unique in that it reveals an association with placentomegaly and an identifiable erythroblastosis with dysplastic and megaloblastic features within the fetal placental circulation.

A full-term male newborn was delivered via emergency cesarean section due to reduced fetal movements and a restricted cardiotocogram, following an uneventful pregnancy from a healthy mother. He presented poor neonatal adaptation (APGAR 5/3/5) and signs of hypotensive shock. Intubation, massive fluid resuscitation with crystalloids and packed red blood cell transfusion, as well as norepinephrine support were required in the delivery room. An initial arterial blood gas analysis at 1 h of life showed severe anemia with a hemoglobin level of 40 g/L prior blood transfusion, and severe metabolic, lactic and respiratory acidosis (pH: 7.1; pCO₂: 53 mm Hg; bicarbonates: 16 mmol/L; base excess: −12 mmol/L; lactates: 12 mmol/L).

Clinical examination revealed growth restriction with a birth weight of 2,380 g (P3) and microcephaly (31 cm; <P3), significant pallor, hepato-splenomegaly and “blueberry muffin” rash. Antenatal ultrasounds were unremarkable.

The patient developed multi-organ failure, including persistent pulmonary arterial hypertension, right ventricular heart failure, and hypotensive shock; cholestasis and hepatitis with severe hyperferritinemia; disseminated intravascular coagulation; severe thrombocytopenia (nadir: 23 G/L); acute renal failure; and hypoglycemia associated with transient hyperinsulinism. Due to severe agenerative normocytic anemia and disseminated intravascular coagulation, the patient required multiple transfusions in the first days of life (red blood cells 70 mL/kg; platelets 70 mL/kg; plasma 43 mL/kg).

Persistent pulmonary hypertension with right ventricular dysfunction and hypotensive shock required inhaled nitrite oxide, noradrenaline, milrinone, hydrocortisone and high-frequency oscillation ventilation. He was extubated on day of life 7.

Cholestasis and hepatic cytolysis were present from day of life 1 and progressively worsened during the first week of life (peak alanine transaminase 132UI/L; peak direct bilirubin 262 μmol/L; peak gamma glutoaryltransferase 419 UI/L). Severe hyperferritinemia of 8,878 μg/L was identified at 1 week of life. Thrombocytopenia resolved by the second week of life.

Macroscopic examination of the placenta revealed placentomegaly (weight of 1,103 g, > P95 for 37 weeks of gestation). Histology demonstrated severe fetal erythroblastosis, without evidence of parvovirus B19 viral inclusions on routine and immunohistochemical stainings. Giemsa staining revealed macro- and megaloblastic maturation of the numerous CD71-positive proerythroblasts with dysplastic irregular nuclear contours. Few images suspicious for nuclear chromatin bridges were difficult to confirm on placental sections as erythroid precursors were tightly packed within the villous capillaries. There were no CD34-positive blasts (shown in Fig. 1, 2a, b).

Differential diagnosis included hemolytic anemia, feto-maternal transfusion, congenital infection, hemorrhagic or neoplastic cause, inherited bone marrow failures and metabolic disease. Whole exome sequencing, with targeted analysis of a congenital dyserythropoietic anemia gene panel identified the pathogenic variants c.2140C>T (p.Arg714Trp) and c.2173C>T (p.Arg725Trp) in heterozygosity in the CDAN1 gene. Familial segregation analysis, performed by Sanger sequencing on DNA extracted from leukocytes, confirmed that each parent carried one of the aforementioned variants.

The patient was discharged at 1 month of life. Red blood cells transfusions were required every 5 weeks until 6 months of life. Ferritin gradually decreased, reaching a value of 1,161 μg/L at 12 months, and no iron chelation was necessary. Liver tests and cholestasis had normalized at 4 months of life. Neurodevelopment was normal at 12 months of life.

Diagnosis of CDA-1 is based on clinical, bone marrow morphological and molecular features. Bone marrow biopsy in neonates is complex and nonspecific and was not performed in our case. Genetic testing by WES (non-phenotype-targeted analysis) confirmed the diagnosis, highlighting the role of such assays in situations where conventional investigations are not feasible or are limited.

In this case, placental analysis reveals marked placentomegaly with placental megaloblastic and dysplastic erythroblastosis. In the absence of viral inclusion of Parvovirus B19, the observation of megaloblastic erythroblastosis may indicate disorders of folate or vitamin B12 metabolism. However, when the megaloblastic component is particularly prominent, the differential diagnosis should be broadened to include rare congenital disorder such as CDA-1. Therefore, in cases of unexplained placental erythroblastosis with prominent megaloblastic features, associated with suggestive clinical features, clinicians and pathologists should maintain a high index of suspicion for CDA-1.

The treatment of CDA-1 is mainly supportive and focuses on the standard of care for anemia and iron overload. Some patients respond to interferon-alpha [9]. In our case, despite a very severe neonatal phenotype, early diagnosis led to a favorable outcome.

Ethical approval is not required for this study in accordance with local or national guidelines. Written informed consent was obtained from the patient’s parents for publication of this case report and any accompanying images.

The authors have no conflict of interest to declare.

No funding was granted for this work.

O.R. wrote the initial draft and revised and approved the final draft with support from L.B. and C.G. L.B. and J.-F.T. contributed to the neonatal case management. C.G. and S.S. were responsible for the placental analysis and J.-M.G. was involved in the genetic testing. All authors reviewed the manuscript and approved the final manuscript.

All data generated or analyzed during this study are not publicly available. Further inquiries can be directed to the corresponding author. We declare that this case report adheres to the CARE guidelines for the writing and presentation of clinical case reports (CARE checklist available in online suppl. material; for all online suppl. material, see https://doi.org/10.1159/000546794).