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Perinatal-lethal nonimmune fetal hydrops attributed to MECOM-associated bone marrow failure
Camille A Dash1, Jill A Madden2,3, Christy Cummings1
1Division of Newborn Medicine, Department of Pediatrics, Boston Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Abstract:
Pathogenic variants in MECOM, a gene critical to the self-renewal and proliferation of hematopoietic stem cells, are known to cause a rare bone marrow failure syndrome associated with amegakaryocytic thrombocytopenia and bilateral radioulnar synostosis known as RUSAT2. However, the spectrum of disease seen with causal variants in MECOM is broad, ranging from mildly affected adults to fetal loss. We report two cases of infants born preterm who presented at birth with symptoms of bone marrow failure including severe anemia, hydrops, and petechial hemorrhages; radioulnar synostosis was not observed in either patient, and, unfortunately, neither infant survived. In both cases, genomic sequencing revealed de novo variants in MECOM considered to be responsible for their severe presentations. These cases add to the growing body of literature that describe MECOM-associated disease, particularly MECOM as a cause of fetal hydrops due to bone marrow failure in utero. Furthermore, they support the use of a broad sequencing approach for perinatal diagnosis, as MECOM is absent from available targeted gene panels for hydrops, and highlight the importance of postmortem genomic investigation.
Insights
Pathogenic variants in the MECOM gene can cause severe fetal bone marrow failure, leading to hydrops and early death. These findings emphasize the need for broad genomic sequencing in diagnosing such critical perinatal conditions.
Area of Science:
- Genetics
- Hematology
- Developmental Biology
Background:
- Pathogenic variants in the MECOM gene are associated with RUSAT2, a rare bone marrow failure syndrome.
- The clinical spectrum of MECOM-related disorders ranges from mild adult phenotypes to fetal loss.
Purpose of the Study:
- To describe two cases of severe, lethal, fetal bone marrow failure due to de novo MECOM variants.
- To highlight MECOM as a cause of fetal hydrops and underscore the importance of comprehensive genomic testing in perinatal diagnostics.
Main Methods:
- Case report of two preterm infants presenting with symptoms of severe bone marrow failure.
- Whole-exome or genome sequencing to identify causative genetic variants.
Main Results:
- Both infants presented with severe anemia, hydrops, and petechial hemorrhages at birth.
- Genomic sequencing revealed de novo pathogenic variants in the MECOM gene in both cases.
- Neither infant survived; radioulnar synostosis was notably absent in these cases.
Conclusions:
- MECOM variants can cause severe fetal bone marrow failure, presenting as hydrops fetalis.
- These cases expand the known phenotype of MECOM-associated disorders.
- Broad genomic sequencing is crucial for perinatal diagnosis, especially when targeted panels for hydrops do not identify a cause. Postmortem genomic investigation is also highlighted.
