Embryonal tumors

A child is diagnosed with a tumor arising from immature embryonic tissue. These are the cancers of early childhood: Wilms, retinoblastoma, hepatoblastoma, medulloblastoma, pleuropulmonary blastoma, neuroblastoma, adrenocortical carcinoma, atypical teratoid/rhabdoid tumor. Each has its own short list of predisposition syndromes, and pattern recognition gets you to the right germline test fast.

Tumor type plus laterality plus age plus extratumoral features. Bilateral tumors are essentially always germline. Tumors in the predisposition-associated lateralities (adrenocortical in a child, retinoblastoma at any age, pleuropulmonary blastoma) trigger germline testing regardless of family history.

Wilms tumor (nephroblastoma)

• WT1-related syndromes: WAGR (11p13 contiguous deletion, with aniridia, GU anomalies, intellectual disability), Denys-Drash (early-onset nephrotic syndrome plus DSD plus Wilms), Frasier (FSGS plus DSD plus gonadoblastoma).
• 11p15 imprinting: Beckwith-Wiedemann syndrome and isolated hemihypertrophy. Surveillance with abdominal ultrasound every 3 months until age 8 reduces stage at diagnosis.
• DICER1, Bloom syndrome, Fanconi anemia (subset), Perlman, Simpson-Golabi-Behmel.

Retinoblastoma

• Germline RB1 (retinoblastoma). Bilateral is essentially always germline. Trilateral retinoblastoma adds a pineal primitive neuroectodermal tumor. Carriers carry a 100-fold lifetime risk of osteosarcoma and increased risk of soft-tissue sarcoma and melanoma.

Hepatoblastoma

• Beckwith-Wiedemann syndrome (~1000-fold increased risk).
• Familial adenomatous polyposis (APC). Screen at-risk infants with serum alpha-fetoprotein every 3 months in the first 5 years.
• Simpson-Golabi-Behmel.

Medulloblastoma and other SHH-pathway tumors

• Gorlin syndrome (PTCH1): basal cell carcinomas, jaw odontogenic keratocysts, medulloblastoma (desmoplastic, SHH subgroup), macrocephaly, calcified falx. Avoid radiation if possible (induces basal cell carcinomas).
• Li-Fraumeni syndrome (TP53).
• Fanconi anemia.

Pleuropulmonary blastoma

• DICER1 syndrome. Type I (cystic) presents in infants; types II and III in older children. Associated tumors: cystic nephroma, Sertoli-Leydig tumor, multinodular goiter, cervical embryonal rhabdomyosarcoma.

Adrenocortical carcinoma

• Li-Fraumeni syndrome (TP53): more than half of pediatric ACC. In southern Brazil the founder TP53 R337H variant explains the cluster.
• Beckwith-Wiedemann syndrome.

Atypical teratoid/rhabdoid tumor (ATRT) and other rhabdoid tumors

• SMARCB1 (more rarely SMARCA4) rhabdoid tumor predisposition syndrome. Tumor IHC shows loss of SMARCB1 nuclear staining.