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Acute myeloid leukemia with germline NPM1 mutation in twin sisters: First case report
*Corresponding author: Nikhil Nagpal, Senior Resident (Acad.), Department of Medical Oncology Hematology, All India Institute of Medical Sciences, Rishikesh, Uttarakhand, India. nikhilnagpal2011@gmail.com
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Received: ,
Accepted: ,
How to cite this article: Nagpal N, Karthik SR, Rathaur V, Nath U. Acute myeloid leukemia with germline NPM1 mutation in twin sisters: First case report. J Hematol Allied Sci. 2025;5:201-3. doi: 10.25259/JHAS_24_2025
Abstract
Mutations in the Nucleophosmin 1 (NPM1) gene define a well-established subtype of acute myeloid leukemia (AML) with distinct clinical and molecular characteristics. While somatic NPM1 mutations are frequent, germline involvement remains exceedingly rare and largely unreported in the context of AML. This report details the case of genetically identical twin sisters who were both diagnosed with AML harboring NPM1 mutations. Twin A presented at age 4 with fever and weakness, while Twin B presented 3 years later at age 7 with fever and gastrointestinal bleeding. Both had high leukocyte counts, thrombocytopenia, and >95% marrow blast involvement on aspirate smears. Flow cytometry confirmed myeloid lineage blasts, and multiplex PCR identified NPM1 mutations in both siblings. Conventional cytogenetics showed normal female karyotype (46,XX). Both had pulmonary infiltrates suggestive of fungal infection at baseline. Twin B had additional complications including central nervous system involvement and cardiac vegetations. Both were treated with the berlin frankfurt munster (BFM) 2004 protocol. Twin A remains in remission after 3.5 years of follow-up. Twin B is currently on maintenance with negative measurable residual disease by flow cytometry. This is the first reported case of germline NPM1-mutated AML in twin sisters, suggesting a potential inherited predisposition. It emphasizes the importance of molecular diagnostics and consideration of germline mutations in familial pediatric AML.
Keywords
BFM 2004
Familial leukemia
Germline mutation
India
NPM1 mutation
Pediatric acute myeloid leukemia
Twin sisters
INTRODUCTION
The NPM1 gene encodes nucleophosmin, a multifunctional nucleolar phosphoprotein involved in ribosome biogenesis, genomic stability, and centrosome duplication. [1,2] Mutations in NPM1 – particularly in exon 12 – lead to mislocalization of the protein into the cytoplasm of leukemic blasts, a hallmark of this acute myeloid leukemia (AML) subtype.[3] This mutation is most commonly found in AML with normal karyotype and has been linked to favorable outcomes, especially in the absence of co-occurring FMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations.[1,4]
The WHO classification incorporated NPM1-mutated AML as a unique entity in 2017 based on its distinct clinical and biological features.[5,6] While somatic NPM1 mutations are extensively studied, germline mutations are rarely reported and have primarily been described in relation to ribosomopathies such as dyskeratosis congenital.[6,7] We present the first documented instance of twin sisters with NPM1-mutated AML, strongly indicating a germline origin.
CASE REPORT
Twin A
A 4-year-old female presented with persistent fever and general malaise. Laboratory findings revealed a hemoglobin level of 8.7 g/dL, a white blood cell (WBC) count of 85 × 109/L, and platelets at 41 × 109/L. Peripheral smear showed 63% blasts. Bone marrow aspirate demonstrated 95% blasts with characteristic nuclear cup-like invaginations and open chromatin. Flow cytometry revealed positivity for cluster of differentiation (CD33), CD38, dim CD117, and cytoplasmic myeloperoxidase (MPO), with negativity for CD13, CD34, and human leukocyte antigen-DR isotype (HLA-DR).
Cytogenetics revealed a normal 46, XX female karyotype. Multiplex PCR detected an NPM1 mutation. High resolution computed tomography (HRCT) chest revealed left lower lobe nodular opacities patchy ground glass opacities, likely of fungal origin. She was initiated on the BFM 2004 protocol for pediatric AML and achieved complete morphologic remission post-induction. She remains disease-free 3.5 years after completing therapy.
Twin B
Three years later, the older twin (7–years-old) presented with fever and hematochezia. Her hemoglobin was 7.7 g/dL, WBC was 71 × 109/L, and platelets were 1.93 × 109/L. Bone marrow examination showed hypercellularity with 95% blasts. Flow cytometry demonstrated CD33 (bright), CD13 (moderate), cytoplasmic MPO (bright), CD45 (dim-moderate), CD38, and CD14 expression.
Like her sibling, she tested positive for an NPM1 mutation and had a normal 46 XX karyotype, consolidation and ground glass opacities karyotype. HRCT chest revealed left lower lobe consolidation suggestive of fungal infection. Echocardiography detected vegetations on the tricuspid valve, while brain imaging and cerebrospinal fluid cytology confirmed central nervous system (CNS) III disease. She was treated with BFM 2004 protocol, including intrathecal therapy, and achieved measurable residual disease-negative remission. She is currently on maintenance chemotherapy.
DISCUSSION
The presence of NPM1 mutations in both monozygotic twins, in the absence of identifiable somatic mutations or environmental exposures, strongly suggests a germline mutation.[6-9] While somatic NPM1 mutations are a known hallmark of AML with favorable prognosis,[1] the possibility of inherited predisposition through germline alterations has only been recently proposed in molecular studies.[6] Notably, both patients presented with features consistent with pediatric AML, including hyperleukocytosis and marrow blast infiltration. Additional complications included fungal pneumonia in both patients and CNS as well as cardiac involvement in Twin B. Despite these challenges, both responded well to treatment, reinforcing the prognostic implications of NPM1 mutations.[7]
Previous studies have linked germline NPM1 mutations to ribosomal dysregulation and rare inherited syndromes.[6] However, this is the first clinical report to suggest direct leukemic transformation due to germline NPM1 mutation in siblings. It highlights the importance of considering familial molecular testing in pediatric AML, particularly when there is sibling involvement or early-onset disease.[10]
CONCLUSION
We report the first known instance of germline NPM1-mutated AML in monozygotic twin sisters, suggesting a heritable susceptibility to leukemogenesis through this mutation. Both children showed excellent therapeutic response to standard AML therapy. This case highlights the clinical importance of genetic evaluation in pediatric AML and underscores the role of germline predisposition in familial cases.
Acknowledgments:
We thank the Departments of Pediatric Oncology and Hematopathology at our institution for their involvement in clinical management and diagnostic evaluation. We are grateful to the family for their cooperation and consent in the publication of this report.
Ethical approval:
The Institutional Review Board approval is not required.
Declaration of patient consent:
The authors certify that they have obtained all appropriate patient consent.
Conflicts of interest:
There are no conflicts of interest.
Use of artificial intelligence (AI)-assisted technology for manuscript preparation:
The authors confirm that there was no use of artificial intelligence (AI)-assisted technology for assisting in the writing or editing of the manuscript and no images were manipulated using AI.
Financial support and sponsorship: Nil.
References
- NPM1-mutated acute myeloid leukemia: From bench to bedside. Blood. 2020;136:1707-21.
- [CrossRef] [PubMed] [Google Scholar]
- Nucleophosmin in its interaction with ligands. Int J Mol Sci. 2020;21:4885.
- [CrossRef] [PubMed] [Google Scholar]
- Cytoplasmic nucleophosmin in acute myelogenous leukemia with a normal karyotype. N Engl J Med. 2005;352:254-66.
- [CrossRef] [PubMed] [Google Scholar]
- Acute myeloid leukemia with mutated nucleophosmin (NPM1): Is it a distinct entity? Blood. 2011;117:1109-20.
- [CrossRef] [PubMed] [Google Scholar]
- WHO Classification of tumours of haematopoietic and lymphoid tissues Lyon: IARC; 2017. p. :130-49.
- [Google Scholar]
- Germline NPM1 mutations lead to altered rRNA 2'-o-methylation and cause dyskeratosis congenita. Nat Genet. 2019;51:1518-29.
- [CrossRef] [PubMed] [Google Scholar]
- Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017;129:424-47.
- [CrossRef] [PubMed] [Google Scholar]
- Mutations in AML: Prognostic and therapeutic implications. Hematol Oncol Clin North Am. 2019;34:17-28.
- [Google Scholar]
- Genetic predisposition to hematologic malignancies: Management and surveillance. Blood. 2017;130:424-32.
- [CrossRef] [PubMed] [Google Scholar]