A child is diagnosed with cancer and you have to decide, before the oncologist's first cycle of chemotherapy, whether a hereditary predisposition is in play. Roughly 10% of pediatric cancers have an identifiable germline cause, but the yield is dramatically higher in subsets defined by tumor type, family history, and exam findings. The work is in recognizing which subset you are in.
These features alone justify a germline workup, regardless of family history.
- Any embryonal tumor: Wilms tumor (nephroblastoma), retinoblastoma, hepatoblastoma, adrenocortical carcinoma, atypical teratoid/rhabdoid tumor, pleuropulmonary blastoma. Adrenocortical carcinoma in a child has greater than 50% prevalence of germline TP53 (Li-Fraumeni syndrome).
- Bilateral or multifocal cancer: bilateral retinoblastoma is essentially always germline RB1. Bilateral Wilms points to WT1, 11p15 imprinting disorders, or familial Wilms.
- Cancer plus congenital anomaly or recognizable dysmorphism: the syndrome was usually there before the cancer; the cancer is what brought it to attention.
- Cancer plus first or second-degree family history of cancer: especially when the cancers cluster (sarcoma plus breast plus brain plus adrenocortical fits Li-Fraumeni; colon plus endometrial plus urinary fits Lynch).
- Cancer plus specific syndromic findings: large café-au-lait spots in a child with hematologic malignancy or brain tumor suggests constitutional mismatch repair deficiency.
When the pattern is recognizable, do not start with a 100-gene panel. The targeted test is faster and clearer.
- TP53 (Li-Fraumeni): sarcoma, premenopausal breast cancer, brain tumors, adrenocortical carcinoma, leukemia. Any pediatric adrenocortical carcinoma. Any childhood sarcoma in a family with breast cancer.
- DICER1: pleuropulmonary blastoma, cystic nephroma, Sertoli-Leydig tumor, multinodular goiter and differentiated thyroid carcinoma, cervical embryonal rhabdomyosarcoma. The cluster is the diagnosis.
- RB1: retinoblastoma, especially bilateral; later second primaries (osteosarcoma, soft tissue sarcoma, melanoma).
- 11p15 (BWS / hemihypertrophy region): Wilms in Beckwith-Wiedemann syndrome and isolated hemihypertrophy. Surveillance with abdominal ultrasound until age 8.
- SDHx (SDHB, SDHC, SDHD, SDHA, SDHAF2): paraganglioma, pheochromocytoma, GIST, renal cell carcinoma.
- NF1: optic pathway gliomas, malignant peripheral nerve sheath tumors, juvenile myelomonocytic leukemia in neurofibromatosis type 1.
- Mismatch repair genes (MLH1, MSH2, MSH6, PMS2): Lynch syndrome heterozygotes (adult colon and endometrial) and the homozygous form, CMMRD (childhood brain tumors, hematologic malignancy, GI cancers).
- APC: familial adenomatous polyposis and pediatric hepatoblastoma. Screen infants at risk with alpha-fetoprotein.
Three-generation pedigree with cancer types and ages of onset. Physical exam looking for cafe-au-lait macules, dysmorphism, hemihypertrophy, congenital anomalies. Pathology re-review with the molecular features (LFS-associated tumors often have a characteristic mutational signature; rhabdoid tumors stain for SMARCB1 loss). Then targeted germline test, or comprehensive cancer panel when the phenotype is not pinpointable.
- Adrenocortical carcinoma in a child = TP53 until proven otherwise. Counsel the family before the result comes back.
- Bilateral Wilms = germline. WT1, 11p15, or familial.
- Bilateral retinoblastoma = germline RB1. Trilateral retinoblastoma adds a pineal primitive neuroectodermal tumor.
- Childhood cancer plus large café-au-lait spots is CMMRD until ruled out; the macules are larger and more numerous than in classic NF1.
- The pedigree is the highest-yield single intervention. The panel is downstream of the pedigree.