Residency · Residency · Medical Genetics Genomics

Hereditary Cancer Predisposition in Pediatrics

Overview

Approximately 8-10% of childhood cancers are associated with a recognized cancer predisposition syndrome (CPS), and recent germline sequencing studies suggest the proportion may be higher, with pathogenic variants found in 10-18% of children with cancer. Over 100 cancer predisposition genes have been identified, many relevant to pediatric oncology. Recognition of these syndromes is critical for surveillance, treatment modification, family counseling, and cascade testing. Many pediatric CPS present with specific tumor types, congenital anomalies, or distinctive family history patterns.

When to Suspect a Cancer Predisposition Syndrome

Clinicians should consider a cancer predisposition syndrome when a child presents with bilateral or multifocal tumors, an unusually young age at diagnosis for that tumor type, or multiple primary cancers. Cancer in the context of known congenital anomalies or overgrowth syndromes should raise suspicion, as should a family history of cancer (especially the same tumor type or a recognized CPS pattern). Certain tumor histologies are highly suggestive, including pleuropulmonary blastoma, adrenocortical carcinoma, and optic pathway glioma. Consanguinity in the family and excessive toxicity from cancer treatment (suggesting DNA repair deficiency) are additional red flags.

<image>Flowchart for clinical decision-making when evaluating a child with cancer for potential hereditary cancer predisposition syndrome, including key clinical features and family history triggers</image>

Retinoblastoma and RB1

Genetics

The RB1 gene at 13q14 encodes the retinoblastoma protein (pRb), a critical cell cycle regulator. Retinoblastoma provided the foundation for Knudson's "two-hit" hypothesis: the heritable form requires one germline hit plus one somatic hit, while the sporadic form requires two somatic hits in the same cell. Approximately 40% of retinoblastoma cases are heritable (carrying a germline RB1 mutation). Among heritable cases, roughly 75% are bilateral and 25% are unilateral. De novo germline mutations account for approximately 90% of heritable cases, meaning there is no family history. Mosaicism explains some apparently sporadic unilateral cases.

Clinical Features and Management

Retinoblastoma is the most common intraocular malignancy of childhood, with a median age at diagnosis of 12 months for bilateral disease and 24 months for unilateral disease. Presentation typically involves leukocoria (white pupillary reflex), strabismus, or eye pain. Heritable RB1 mutation carriers face a lifetime risk of second primary malignancies (osteosarcoma, soft tissue sarcomas, melanoma) of approximately 36% by age 50. Radiation therapy further increases second cancer risk and should be avoided when possible. Surveillance involves dilated fundoscopy under anesthesia from birth through age 5-7.

Genetic Testing and Counseling

All children with bilateral retinoblastoma should undergo germline RB1 testing. Unilateral cases also merit consideration for germline testing, as approximately 15% carry germline mutations. When the proband's germline mutation is identified, at-risk relatives can undergo targeted testing. Children of heritable RB1 carriers face a 50% risk and should begin ophthalmic surveillance at birth.

Wilms Tumor Predisposition

WT1-Associated Syndromes

The WT1 gene at 11p13 encodes a zinc finger transcription factor critical for kidney and gonadal development. WAGR syndrome results from a contiguous gene deletion affecting both WT1 and PAX6, producing Wilms tumor, aniridia, genitourinary anomalies, and a range of developmental delays, with approximately 50% risk of Wilms tumor. Denys-Drash syndrome involves dominant-negative WT1 missense mutations in exons 8-9, causing diffuse mesangial sclerosis leading to early renal failure, ambiguous genitalia in 46,XY individuals, and Wilms tumor risk approaching 90%. Frasier syndrome results from WT1 splice site mutations in intron 9, producing focal segmental glomerulosclerosis, 46,XY complete gonadal dysgenesis, and gonadoblastoma risk.

Beckwith-Wiedemann Syndrome (BWS)

BWS is an imprinting disorder at 11p15.5 involving CDKN1C, H19, and IGF2. Features include macrosomia, macroglossia, omphalocele, hemihyperplasia, and ear creases or pits. Embryonal tumor risk is approximately 8%, encompassing Wilms tumor, hepatoblastoma, neuroblastoma, and rhabdomyosarcoma. Tumor risk correlates with molecular subtype: IC1 gain of methylation carries the highest risk at approximately 28%, followed by paternal UPD11 at approximately 16%, and IC2 loss of methylation at approximately 2.6%. Screening involves abdominal ultrasound and AFP every 3 months until age 4, then renal ultrasound every 3 months until age 7-8.

DICER1 Syndrome

DICER1 syndrome is an autosomal dominant condition caused by mutations in DICER1 at 14q32.13, which encodes an RNase III endoribonuclease essential for microRNA processing. The tumor spectrum includes pleuropulmonary blastoma (PPB), cystic nephroma, ovarian sex cord-stromal tumors (particularly Sertoli-Leydig cell tumors), multinodular goiter, differentiated thyroid cancer, nasal chondromesenchymal hamartoma, pineoblastoma, pituitary blastoma, and ciliary body medulloepithelioma. PPB progresses from Type I (cystic, best prognosis) to Type II (cystic-solid) and Type III (solid). Surveillance includes chest CT, thyroid ultrasound, and pelvic ultrasound in females.

<image>Diagram showing the spectrum of tumors associated with DICER1 syndrome mapped to anatomical locations, including pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumor, cystic nephroma, and thyroid nodules</image>

Neurofibromatosis Type 1 (NF1)

Genetics and Diagnosis

NF1 results from mutations in the NF1 gene at 17q11.2, which encodes neurofibromin, a RAS-GTPase activating protein. The condition is autosomal dominant with 50% de novo mutations and an incidence of 1 in 2,500-3,000. Clinical diagnosis follows the revised NIH diagnostic criteria (2021), requiring two or more of the following: six or more cafe-au-lait macules (5 mm or greater prepubertal, 15 mm or greater postpubertal), two or more neurofibromas or one plexiform neurofibroma, axillary or inguinal freckling (Crowe sign), optic pathway glioma, two or more Lisch nodules or two or more choroidal abnormalities, a distinctive osseous lesion (sphenoid dysplasia, long bone bowing/pseudarthrosis), a heterozygous NF1 pathogenic variant (now included as a standalone criterion), or a first-degree relative with NF1.

Cancer Risks

Optic pathway glioma occurs in approximately 15-20% of NF1 children, usually as low-grade pilocytic astrocytomas, many of which are asymptomatic. Malignant peripheral nerve sheath tumor (MPNST) carries a lifetime risk of 8-13% and arises from pre-existing plexiform neurofibromas. Other tumors include juvenile myelomonocytic leukemia (JMML, which may spontaneously regress in some NF1 cases), rhabdomyosarcoma, pheochromocytoma, and breast cancer in women over 30 years.

Surveillance

Annual physical examination with attention to neurofibroma growth, blood pressure, and pubertal development is standard. Ophthalmologic examination occurs annually through age 8, then every 2 years. Brain MRI is performed only if symptomatic rather than as routine screening. Whole-body MRI for MPNST screening in adults is under investigation. Breast cancer screening with annual mammography and breast MRI begins at age 30.

Constitutional Mismatch Repair Deficiency (CMMRD)

Genetics

CMMRD results from biallelic (homozygous or compound heterozygous) pathogenic variants in mismatch repair genes: MLH1, MSH2, MSH6, or PMS2. Inheritance is autosomal recessive, and parents are obligate heterozygous Lynch syndrome carriers. The condition is extremely rare but increasingly recognized.

Clinical Features

Children with CMMRD present with cafe-au-lait macules that resemble NF1 (but without neurofibromas -- an important differential). They develop very early-onset cancers including brain tumors (high-grade gliomas, medulloblastoma), GI cancers (colorectal, small bowel), and hematologic malignancies (T-cell lymphoma, leukemia), often in the first decade of life. Tumors display a hypermutation phenotype and may respond to immune checkpoint inhibitors.

Diagnosis and Surveillance

Diagnosis relies on immunohistochemistry for MMR proteins in normal tissue showing loss of expression, microsatellite instability testing in non-neoplastic tissue, and functional assays such as ex vivo MSI assessment in blood lymphocytes. Surveillance is intensive: annual brain MRI, colonoscopy every 6-12 months starting at age 6, upper GI endoscopy, and whole-body MRI.

<image>Comparison table of cafe-au-lait macule-associated cancer predisposition syndromes: NF1, constitutional mismatch repair deficiency, and Legius syndrome, showing distinguishing features and tumor risks</image>

Summary of Major Pediatric Cancer Predisposition Syndromes

Other Important Pediatric Cancer Predisposition Syndromes

Li-Fraumeni Syndrome (TP53)

Pediatric tumors in LFS include adrenocortical carcinoma, choroid plexus carcinoma, rhabdomyosarcoma, osteosarcoma, and brain tumors. Adrenocortical carcinoma in a child is virtually pathognomonic for germline TP53 mutation.

Gorlin Syndrome (PTCH1)

This autosomal dominant condition (basal cell nevus syndrome) produces multiple basal cell carcinomas (often before age 20), medulloblastoma (desmoplastic type, usually by age 3), ovarian fibroma, and keratocystic odontogenic tumors. Skeletal anomalies include bifid ribs, spina bifida occulta, and calcified falx cerebri. Radiation therapy must be avoided as it triggers basal cell carcinomas in the radiation field.

Hereditary Paraganglioma-Pheochromocytoma Syndromes (SDHx)

Germline mutations in SDHA, SDHB, SDHC, SDHD, and SDHAF2 cause these syndromes. SDHB carries the highest risk of malignant paraganglioma at 30-40%. The condition can present in childhood, with screening recommended from age 5-10 depending on the specific gene involved. Biochemical screening uses plasma metanephrines combined with imaging.

Rhabdoid Tumor Predisposition (SMARCB1/SMARCA4)

SMARCB1 (INI1) mutations produce atypical teratoid/rhabdoid tumors of the brain, malignant rhabdoid tumors of the kidney, and other extracranial rhabdoid tumors. These are extremely aggressive tumors, typically diagnosed in infancy. Approximately 35% of rhabdoid tumor patients carry germline mutations. Schwannomatosis is also associated with SMARCB1 but involves a different mutation spectrum.

Approach to Genetic Testing in Pediatric Oncology

The field is moving toward considering germline genetic testing for all children with cancer. Multigene panel testing is increasingly used as a first-line approach, and tumor-normal paired sequencing identifies both somatic and germline variants simultaneously. Pre-test genetic counseling is essential and must address implications for both the child and family. Results may directly influence treatment decisions (for example, avoiding radiation in Li-Fraumeni or Gorlin syndromes). Cascade testing of at-risk family members represents a critical follow-up step.

Clinical Pearls

Adrenocortical carcinoma in a child warrants TP53 testing regardless of family history, as over 50% carry germline mutations (with the R337H founder mutation prevalent in southern Brazil). Cafe-au-lait macules without neurofibromas in a child with cancer should prompt consideration of CMMRD (biallelic MMR mutations) or Legius syndrome (SPRED1). Pleuropulmonary blastoma, especially a cystic lung lesion in a young child, is pathognomonic for DICER1 syndrome. Multifocal or bilateral Wilms tumor requires evaluation for WT1 mutations, 11p15 imprinting abnormalities, and DICER1. Hypodiploid ALL in a child is associated with germline TP53 mutations in approximately 50% of cases. Treatment planning must always assess secondary cancer risks, as radiation avoidance may be critical. Genetic testing results may affect eligibility for clinical trials and may alter chemotherapy regimens.

References

• Zhang J, Walsh MF, Wu G, et al. "Germline mutations in predisposition genes in pediatric cancer." New England Journal of Medicine. 2015;373(24):2336-2346.
• Brodeur GM, Nichols KE, Plon SE, et al. "Pediatric cancer predisposition and surveillance: an overview, and a tribute to Alfred G. Knudson Jr." Clinical Cancer Research. 2017;23(11):e116-e122.
• Druker H, Zelley K, McGee RB, et al. "Genetic counselor recommendations for cancer predisposition evaluation and surveillance in the pediatric oncology patient." Clinical Cancer Research. 2017;23(13):e91-e97.
• Foulkes WD, Priest JR, Duchaine TF. "DICER1: mutations, microRNAs and mechanisms." Nature Reviews Cancer. 2014;14(10):662-672.
• Tabori U, Hansford JR, Achatz MI, et al. "Clinical management and tumor surveillance recommendations of inherited mismatch repair deficiency in childhood." Clinical Cancer Research. 2017;23(11):e32-e37.

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