A Pathogenic Germline BRCA1 Variant in a Patient With Cellular Congenital Mesoblastic Nephroma: A Case Report.

Benign cystic tumors of the kidney are well-described in infants and young children. Here we report an infant diagnosed with a cellular congenital mesoblastic nephroma (CMN) with a germline pathogenic variant in BRCA1. This finding is novel because BRCA1 is an adult-onset cancer predisposition gene causing breast, ovarian, pancreatic, and prostate cancers. However, increasing studies are indicating the presence of germline BRCA1 in both malignant and benign childhood cancers.

Assessment of Factors Associated With the Evaluation of Children for Leukemia Predisposition Syndromes: A Retrospective Single-center Study.

Five to 10% of children with cancer are thought to have a cancer predisposition syndrome (CPS). Referral guidelines for leukemia predisposition syndromes are limited and vague, requiring the treating provider to determine whether patients should have a genetics evaluation. We evaluated referrals to the pediatric cancer predisposition clinic (CPP), the prevalence of CPS in those who elected to pursue germline genetic testing, and assessed for associations between a patient's medical history and the diagnosis of a CPS. Data were obtained via chart review of children diagnosed with leukemia or myelodysplastic syndrome between November 1, 2017, and November 30, 2021. A total of 22.7% of pediatric leukemia patients were referred for evaluation in the CPP. Of the participants evaluated with germline genetic testing, the prevalence of a CPS was 25%. Our study was able to find a CPS in different malignancies, including acute lymphoblastic leukemia, acute myeloid leukemia, and myelodysplastic syndrome. We did not find associations between a participant with an abnormal CBC before diagnosis or hematology visit and the diagnosis of a CPS. Our study supports that a genetic evaluation should be available to all children with leukemia as medical and family history alone is not predictors of a CPS.

Constitutional Microsatellite Instability, Genotype, and Phenotype Correlations in Constitutional Mismatch Repair Deficiency.

BACKGROUND & AIMS: Constitutional mismatch repair deficiency (CMMRD) is a rare recessive childhood cancer predisposition syndrome caused by germline mismatch repair variants. Constitutional microsatellite instability (cMSI) is a CMMRD diagnostic hallmark and may associate with cancer risk. We quantified cMSI in a large CMMRD patient cohort to explore genotype-phenotype correlations using novel MSI markers selected for instability in blood. METHODS: Three CMMRD, 1 Lynch syndrome, and 2 control blood samples were genome sequenced to >120× depth. A pilot cohort of 8 CMMRD and 38 control blood samples and a blinded cohort of 56 CMMRD, 8 suspected CMMRD, 40 Lynch syndrome, and 43 control blood samples were amplicon sequenced to 5000× depth. Sample cMSI score was calculated using a published method comparing microsatellite reference allele frequencies with 80 controls. RESULTS: Thirty-two mononucleotide repeats were selected from blood genome and pilot amplicon sequencing data. cMSI scoring using these MSI markers achieved 100% sensitivity (95% CI, 93.6%-100.0%) and specificity (95% CI 97.9%-100.0%), was reproducible, and was superior to an established tumor MSI marker panel. Lower cMSI scores were found in patients with CMMRD with MSH6 deficiency and patients with at least 1 mismatch repair missense variant, and patients with biallelic truncating/copy number variants had higher scores. cMSI score did not correlate with age at first tumor. CONCLUSIONS: We present an inexpensive and scalable cMSI assay that enhances CMMRD detection relative to existing methods. cMSI score is associated with mismatch repair genotype but not phenotype, suggesting it is not a useful predictor of cancer risk.

B-cell acute lymphoblastic leukemia with iAMP21 in a patient with Down syndrome due to a constitutional isodicentric chromosome 21.

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.

Cutaneous Ewing Sarcoma Presenting as a Second Primary Malignancy in a Child.

Ewing sarcoma is an EWS-ETS family member-driven malignancy that most commonly arises from bone. Cutaneous Ewing sarcoma is a rare variant which harbors an EWS-ETS family fusion but demonstrates an immunohistochemical staining pattern distinct from classic Ewing tumors. EWSR1 fluorescence in situ hybridization testing interpretation can be challenging in the setting of cutaneous Ewing sarcoma, making an integrated histologic and sequencing approach key for an accurate diagnosis. Here, we report a pediatric patient with a history of neuroblastoma treated with surgery only that developed a cutaneous nodule and was diagnosed with cutaneous Ewing sarcoma as a second primary cancer.

Evaluation of barriers to referral for cancer predisposition syndromes in pediatric oncology patients in the United States.

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.

Constitutional POLE variants causing a phenotype reminiscent of constitutional mismatch repair deficiency.

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.

Familial Cerebral Cavernous Malformation Syndrome with Concomitant Fourth Ventricular Ependymoma: True Association or Mere Coincidence?

Familial cerebral cavernous malformation syndromes are most commonly caused by mutations in one of three genes. The overlap of these genetic malformations with other acquired neoplastic lesions and congenital malformations is still under investigation. To the best of our knowledge, the concurrent occurrence of familial cavernous malformations and ependymoma has not been previously reported in the literature. Herein, we describe a patient with familial cerebral cavernous malformation syndrome and posterior fossa ependymoma. A 17-year-old asymptomatic male was referred to our outpatient neurosurgery clinic after genetic testing identified a familial KRIT1 (CCM1) mutation. The patient's sister had presented with a seizure disorder previously; multiple cavernous malformations were discovered, and a symptomatic large cavernous malformation required a craniotomy for resection. Two years later, she was diagnosed with follicular thyroid cancer due to HRAS (c.182A>G) mutation. The patient and his sister were found to have a novel germline KRIT1 disease-causing variant (c.1739deletion, p.ASN580Ilefs*2) and a variant of uncertain significance, potentially pathogenic (c.1988 A>G, p.Asn663Ser) in cis in CCM1 (KRIT1), of paternal inheritance. Due to the presence of genetic abnormalities, the patient underwent screening imaging of his neuraxis. Multiple cavernous malformations were identified, as was an incidental fourth ventricular mass. Resection of the fourth ventricular lesion was performed, and histopathological examination was consistent with ependymoma. We report a unique case of posterior fossa ependymoma in an individual with a familial cerebral cavernous malformation syndrome and a novel genetic abnormality in KRIT1. The association of these two findings may be valuable in determining a potential genetic association between the two pathologies and elucidating the pathogenesis of both cavernous malformations and ependymomas.