6Genetic predisposition syndromes: When should they be considered in the work-up of MDS?
Introduction
Ms. A is a 22-year-old female who presented with progressive fatigue and pancytopenia. Complete blood count revealed a white blood cell count of 2.7 · 103/μl, hemoglobin of 9.1 g/dl with an elevated mean corpuscular volume of 115 fl, and a platelet count of 86 · 103/μl, with a low absolute neutrophil count of 490 · 103/μl. Past medical history was notable for frequent bacterial infections, a cervical conization procedure for Human Papilloma Virus (HPV)-associated cervical intraepithelial neoplasia and lymphedema of her left lower extremity as a child. There were no toxic exposures, and she was taking no medications. Family history was unremarkable. On physical examination, Ms. A was a well-appearing young woman of normal stature, with no abnormal physical findings. A bone marrow aspirate and biopsy revealed a hypocellular marrow with erythroid dysplasia and an expansion of myeloblasts, consistent with MDS. Cytogenetic studies revealed monosomy 7. Due to the patient's young age, an inherited BMFS was suspected. Testing for Dyskeratosis Congenita and Fanconi Anemia was negative. Based on her presentation, she was clinically diagnosed with Emberger Syndrome. After GATA2 genetic testing became available, a de novo pathogenic GATA2 gene mutation was confirmed. She and her family received genetic counseling. No other family members were affected. She elected to proceed with fertility preservation, and subsequently underwent a bone marrow transplant. She is currently doing well.
The 2008 World Health Organization (WHO) classification defines myelodysplastic syndromes as a group of clonal hematopoietic stem cell disorders characterized by cytopenias, dysplasia in one or more myeloid cell lines, ineffective hematopoiesis, and increased risk of acute myeloid leukemia (AML) [1]. Historically defined by blast percentage and dysplastic morphology, MDS is now known to be driven by the sequential acquisition of clonal genetic changes through somatic mutations as well as gain or loss of chromosomal regions. Recurrent mutations found in MDS disrupt key regulatory pathways including RNA splicing (SFSB1, SRSF2, U2AF1 and ZRSR2), epigenetic modifier genes (TET2, DNMT3A, IDH1/IDH2, ASXL1, EZH2, and SETBP1), regulators of transcription (RUNX1, BCOR, ETV6), DNA repair (TP53), signaling pathways (NRAS, KRAS, CBL, JAK2, FLT3, NF1), and cohesins (STAG2) [2].
The incidence of MDS increases with age, with 86% of MDS patients diagnosed over the age of 60 years; the median age at diagnosis is 76 years [3]. Based on the 2001 Surveillance, Epidemiology, and End Results (SEER) data, the incidence of MDS in patients younger than 40 is estimated at 0.14 per 100,000, but rises to over 36 per 100,000 in patients 80 years and older [4]. In children, MDS is exceedingly rare, with an annual incidence of 0.8–4 cases per million [5]. Sporadic, or primary MDS, the most common type of MDS diagnosed in the elderly, is thought to be multifactorial and to arise due to the cumulative age-related genetic damage. In contrast, secondary MDS can frequently be traced to cytotoxic exposures, such as alkylating agents and topoisomerase inhibitors, radiation, and certain environmental and occupational toxins such as benzene, agricultural chemicals and solvents [6]. In pediatric patients, MDS is strongly associated with cytotoxic exposures, classic hereditary BMFS, non-syndromic familial MDS/AML predisposition syndromes, or long history of acquired aplastic anemia [5] (Fig. 1). With the increasing knowledge of hereditary BMFS and familial MDS/AML syndromes, there is a growing appreciation of their contribution to the development of MDS in the younger adult patients (Fig. 2). In this review, we will discuss the importance of recognizing an underlying genetic predisposition syndrome in an MDS patient, will review clinical scenarios when genetic predisposition should be considered, and will provide a practical overview of the common hereditary BMFS and familial MDS/AML syndromes that may be encountered in adult patients with MDS.
Section snippets
The critical importance of recognizing an underlying genetic predisposition syndrome in a patient with MDS
In addition to having implications for genetic counseling of a patient and their family, a diagnosis of an underlying genetic predisposition syndrome in a patient with MDS can be of immediate practical importance for selecting MDS therapy, considering hematopoietic stem cell transplantation (HSCT), and for long-term cancer surveillance and prognosis (Table 1). For the patient in the clinical vignette above, having an accurate genetic diagnosis allowed for genetic counseling, was important for
When to consider hereditary bone marrow failure and familial MDS/AML syndromes in the evaluation of MDS?
Although the majority of patients with classic hereditary BMFS are diagnosed in childhood, some patients have no or only subtle extrahematopoietic manifestations and may present in adulthood with MDS. Other common adult presentations include cytopenias, BMF, AML, or solid tumors; not infrequently, the diagnosis is uncovered due to excessive toxicity to chemotherapy or radiation [17], [22], [23], [24], [25], [26], [27], [28], [29]. Because of the potential for life-threatening toxicities with
What genetic predisposition syndromes are associated with MDS?
There is a growing number of genetic predisposition syndromes associated with MDS, including the classic syndromic BMFS as well as the pure familial MDS/AML syndromes; we refer the reader to several recent in-depth reviews of individual syndromes [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41]. Here, we will focus on the practical information pertinent to evaluating an adult patient with MDS (Table 3, Fig. 3). We will first present genetic syndromes that can present de novo in
Summary
In conclusion, hereditary BMFS and familial MDS/AML syndromes are a heterogenous group of genetic disorders which may present with MDS in both pediatric and adult patients. A diagnosis of a genetic predisposition syndrome in a patient with MDS carries important critical implications for decisions on MDS therapy and HSCT, cancer surveillance, and genetic counseling. Because of the risk for life-threatening toxicities with inappropriate therapy, all pediatric and adult MDS patients under the age
Conflict of interest statement
The authors have no conflict of interest.
Acknowledgments
We thank all patients for participating in studies of bone marrow failure at the Children's Hospital of Philadelphia and the Hospital of the University of Pennsylvania. This work is supported by the NIH 5-T32-HL-07439-34 grant to D.B., and the NCI NIH R01 CA105312, NIDDK DK084188 and the Buck Family Chair in Hematology to M.B.
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- 1
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