A Well-Curated Cost-Effective Next-Generation Sequencing Panel Identifies a Diverse Landscape of Pathogenic and Novel Germline Variants in a Bone Marrow Failure Cohort in a Resource-Constraint Setting.

The current study is a 4-year experience in diagnosis and screening of inherited and immune bone marrow failure cases using a targeted sequencing panel. A total of 171 cases underwent targeted next-generation sequencing and were categorized as suspected inherited bone marrow failure syndrome (IBMFS) group (106; 62%) and immune/idiopathic aplastic anemia (IAA) group (65; 38%) based on clinical and laboratory criteria. A total of 110 (64%) were pediatric (aged 0 to 12 years) patients and 61 (36%) were adolescent and adult (aged 13 to 47 years) patients. In suspected IBMFS group, 47 (44%), and in IAA group, 8 (12%) revealed a likely germline pathogenic variation. Whole-exome sequencing performed in 15 of 59 suspected IBMFS group cases was negative on targeted panel, and revealed a clinically important variation in 3 (20%) cases. A total of 11 novel variants were identified. The targeted panel helped establish a diagnosis in 44% (27/61) of unclassified bone marrow failure syndrome cases and led to amendment of clinical diagnosis in 5 (4.7%) cases. Overall, diagnostic yield of this well-curated small panel was comparable to Western studies with larger gene panels. Moreover, this was achievable at a much lower cost, making it suitable for resource-constraint settings. In addition, high frequency (>10%) of cryptic pathogenic IBMFS gene variations in IAA cohort suggests routine incorporation of targeted next-generation sequencing screening in these cases.

Acute monocytic leukemia presenting as generalized lymphadenopathy and skin rash in a toddler: highlighting the clinicopathologic mimics.

Acute myeloid leukemia (AML) is the fifth most common malignancy in children. Extramedullary involvement in acute myeloid leukemia is rare and can be seen in soft tissues, central nervous system, skin and lymphoreticular organs. The clinical presentations can often be non-specific and hence, the diagnosis can be very challenging, especially in cases without a prior hematologic diagnosis. We report a case of pediatric acute monocytic leukemia presenting with generalized lymphadenopathy and cutaneous rash. Fine-needle aspiration was performed from the lymph nodes and a cytologic diagnosis of infiltration by a lymphoreticular malignancy was suggested. Peripheral blood, bone marrow and cerebrospinal fluid involvement were noted subsequently. Flow cytometry on the bone marrow aspirate confirmed a diagnosis of acute monocytic leukemia. The index case besides highlighting an uncommon presentation of acute monocytic leukemia in a toddler, also emphasizes the need to consider acute monocytic leukemia as a cytomorphologic differential in such presentations.