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Heterozygous POLE or POLD1 germline pathogenic variants (PVs) cause polymerase proofreading associated polyposis (PPAP), a constitutional polymerase proofreading deficiency that typically presents with colorectal adenomas and carcinomas in adulthood. Constitutional mismatch‐repair deficiency (CMMRD), caused by germline bi‐allelic PVs affecting one of four MMR genes, results in a high propensity for the hematological, brain, intestinal tract, and other malignancies in childhood. Nonmalignant clinical features, such as skin pigmentation alterations, are found in nearly all CMMRD patients and are important diagnostic markers. Here, we excluded CMMRD in three cancer patients with highly suspect clinical phenotypes but identified in each a constitutional heterozygous POLE PV. These, and two additional POLE PVs identified in published CMMRD‐like patients, have not previously been reported as germline PVs despite all being well‐known somatic mutations in hyper‐mutated tumors. Together, these five cases show that specific POLE PVs may have a stronger “mutator” effect than known PPAP‐associated POLE PVs and may cause a CMMRD‐like phenotype distinct from PPAP. The common underlying mechanism, that is, a constitutional replication error repair defect, and a similar tumor spectrum provide a good rationale for monitoring these patients with a severe constitutional polymerase proofreading deficiency according to protocols proposed for CMMRD.

Cancer predisposition syndromes (CPS) are underdiagnosed in the pediatric population, though the diagnosis of a CPS has important implications for the child and their family. CPS are often diagnosed by geneticists or oncologists with expertise in CPS following a malignancy. This requires a member of the care team, most commonly, the treating oncologist to suspect a CPS and refer the patient for CPS assessment. An online survey was distributed to members of the Children's Oncology Group to elucidate current referral practices and barriers to referral for patients suspected to have a CPS. Of the 183 respondents, 86.1% was pediatric oncologists and most (68.5%) used formal guidelines to aid in assessment. Most respondents indicated they would rarely refer patients with tumors highly associated with CPS for genetic assessment. Participants were more likely to refer patients with malignancy and additional features of a CPS than for a specific type of cancer, despite the use of guidelines. Parent knowledge of family history was considered the most challenging barrier to obtaining a family history, though a thorough pedigree was not consistently elicited. Providers indicated the most significant barrier to referral for CPS assessment was priority given the patient's immediate care needs. Identification of these barriers provides direction to focus efforts to increase referrals. Provider education about CPS, clear referral guidelines, and implementation of or increased collaboration with a genetic counselor in the pediatric oncology clinic may encourage CPS assessment and enable oncologists to focus on the patient's immediate care needs.

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Genomic medicine and the use of genetic information in pediatric oncology has provided insight on the molecular underpinnings of childhood cancers and has demonstrated that cancer predisposition syndromes (CPS) are underdiagnosed. Diagnosis of a CPS has important implications for the patient and their family. In childhood, CPS are often diagnosed by geneticists or oncologists with expertise in CPS following a malignancy, however, this requires a member of the care team, most commonly, the treating oncologist to suspect a CPS and refer them for assessment. We sought to understand current referral practices of pediatric oncology healthcare providers and barriers to referral for evaluation of a CPS. An online survey was sent to members of the Children's Oncology Group. Of the 189 respondents, 80.4% were pediatric hematologists/oncologists and most (69%) used formal guidelines to aid in referral assessment.Guideline use was associated with a higher proportion (>5%) of patients with a CPS in the respondent's practice. Participants were more likely to refer patients with malignancy and additional features of a CPS than for a specific type of cancer, despite the use of guidelines. Most respondents indicated they would rarely refer patients with tumors highly associated with CPS.Patient/parent knowledge of family history was considered the most challenging barrier to obtaining a family history, though a thorough three-generation pedigree was not consistently attempted. Overall, participants indicated the most significant barrier to referral was priority given the patient's more immediate care needs. Other barriers to genetics referral identified elsewhere

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Pediatric B-cell acute lymphoblastic leukemia (B-ALL) is associated with various specific cytogenetic and molecular markers that have significant influence on treatment and prognosis. A subset of children has a much higher risk of developing B-ALL due to constitutional genetic alterations such as trisomy 21 (Down's syndrome). In these patients, B-ALL is often associated with specific genomic profiles leading to leukemic transformation. In rare cases, constitutional structural chromosomal abnormalities involving chromosome 21, such as the der(15;21) Robertsonian translocation and a ring 21 chromosome, have been associated with intrachromosomal amplification of chromosome 21 (iAMP21) B-ALL. Here, we report the development of B-ALL in a child with Down's syndrome who carries a constitutional isodicentric chromosome 21 [idic(21)], described previously by Putra et al., 2017. This idic(21) appeared to be unstable during mitosis, leading to somatic rearrangements consistent with iAMP21 amplification, resulting in the development of leukemia. In this case, a single constitutional structural chromosome 21 rearrangement resulted in a B-ALL with Down syndrome-associated genomic lesions as well as genomic lesions not common to the Down syndrome subtype of B-ALL. Our findings highlight the need for counseling of individuals with constitutional structural chromosome 21 rearrangements regarding their risks of developing a B-ALL.