| Genetic testing for childhood cancer predisposition syndromes: Controversies and recommendations from the SIOPE Host Genome Working Group meeting 2022 (Bakhuizen JJ, Bourdeaut F et al., 2024)42 | All children with cancer should undergo clinical screening for their risk of harboring a CPS. | It is recommended to use targeted genetic testing based on clinical indication.Comprehensive CPS gene panels containing over 100–150 genes for all pediatric cancer should rather be used in research contexts than routine practice.Smaller actionable gene panels can be considered when they include genes that supporting diagnosis or have a direct impact on therapeutic management. |
| Paediatric cancers or tumours – when a genetic assessment is indicated (Cancer Institute NSW, 2020)43 | Family history criteria (child unaffected)An unaffected child may (being at risk of a known cancer predisposition condition) before age 18 years.- Condition: familial adenomatous polyposis, neurofibromatosis type 1, neurofibromatosis type 2, Gorlin, PTEN hamartoma/Cowden, MEN2, SDHx-related familial paraganglioma-phaeochromocytoma, juvenile polyposis, rhabdoid tumour predisposition syndrome, Peutz-Jeghers, Li-Fraumeni, von Hippel-Lindau disease- Gene: AIP, ALK or PHOX2B, APC, CDC73, CMMRD, DICER1, MEN1, CDKN1B, NF1, NF2, PTCH1, SUFU, PTEN, RB1, RET, SDHx-, SMAD4, SMARCA4, SMARCB1, STK11, TP53, VHL | Family history criteria (child unaffected)- predictive genetic testing before age 18 years |
| Family history criteria (child with cancer)A child with a cancer and one of the following family history characteristics:- Another relative with a cancer diagnosed under age 18 years- 1 or more first degree relative(s) (parent or sibling) with a cancer diagnosed under age 45 years- 2 or more first/second degree relatives in the same lineage with a cancer diagnosed under age 45 years- Parents are genetically related (i.e. consanguineous) | Family history criteria (child with cancer)- considered for testing and/or referred to genetics |
| General criteria (child with cancer)A child with cancer and any one of the following features:- Growth abnormalities (e.g. short stature, microcephaly, macrocephaly, overgrowth)- Congenital anomalies (e.g. oral clefting, structural cardiac defects, microphthalmia, microcephaly, urinary tract anomalies)- Facial dysmorphism- Skin features (e.g. unusual pigmentation, multiple café-au-lait macules, UV hypersensitivity)- Haematological abnormalities not explained by the cancer diagnosis or treatment (e.g. thrombocytopenia, anaemia, pancytopenia)- Immunodeficiency not explained by the cancer diagnosis or treatment- Excessive treatment toxicity- Multiple primary cancers (unless the second malignancy is consistent in time and/or tissue type with those expected from their treatment regime); includes multiple or bilateral primary cancers of the same type- Unusual age of onset. Either a cancer usually diagnosed in adulthood (e.g. basal cell carcinoma, colorectal cancer, ovarian cancer, meningioma, renal cell carcinoma); or a cancer diagnosed in a prepubertal child, when the usual age at diagnosis is teenage or young adult years | General criteria (child with cancer)- should be considered for testing and/or referred to genetics unless there is a known alternative explanation for these additional features |
| Cancer/tumour criteriaA child with one of the following cancers/tumours*:(* This list is not all inclusive. There are other rare tumours/cancers where referral to a clinical genetics service is indicated. Clinical judgement should be used** 5 or more juvenile polyps or any number of Peutz-Jeghers polyps*** 3 or more under age 10 years; 5 or more over 10 years)- Adrenocortical carcinoma- Medulloblastoma1. WNT subtype without documented somatic CTNNB1 mutation2. SHH subtype under age 18 years- B acute lymphoblastic leukaemia (ALL) – low hypodiploid (32-39 chromosomes)- Myelodysplastic syndrome (MDS)- Cerebellar gangliocytoma (Lhermitte-Duclos disease)- Neuroblastoma (with other features suggestive of germline abnormality)- Choroid plexus carcinoma- Optic glioma- Colorectal polyps – hamartomatous**- Osteosarcoma- Colorectal polyps – multiple adenomatous or serrated/hyperplastic***- Ovarian Sertoli-Leydig cell tumour- Cystic nephroma- Paraganglioma or phaeochromocytoma- Desmoid-type fibromatosis (intra-abdominal/abdominal wall location)- Pineoblastoma- Endolymphatic sac tumour- Pituitary blastoma | - Gastrointestinal stromal tumour (GIST)- Pleuropulmonary blastoma- Haemangioblastoma- Retinoblastoma- Hepatoblastoma- Rhabdomyosarcoma (anaplastic subtype at any age, or any subtype under age 3 years)- Infantile myofibromatosis- Schwannoma- Juvenile myelomonocytic leukaemia (JMML)- Small cell carcinoma of the ovary hypercalcaemic type (SCCOHT)- Malignant peripheral nerve sheath tumour- Subependymal giant cell tumour- Malignant rhabdoid tumour- Wilms tumour- Medullary thyroid cancerGeneralImmunohistochemistry or NGS of tumour DNA raises the possibility of a heritable pathogenic variant in a cancer predisposition gene e.g. CMMRD, Li Fraumeni and others | Cancer/tumour criteria should be considered for testing and/or referred to genetics irrespective of other factors |
| Childhood cancer: Indication for genetic counseling?**updated Jongmans criteria[Jongmans et al., 2016](supporting document to Ripperger et al., 2017)44 | At least one criterion fulfilled - patient may benefit from genetic counselling: |
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| 1. Family history (3 generation pedigree)- ≥2 malignancies occurred in family members before age 18 years, including index patient- Parent or sibling with current or history of cancer before age 45 years- ≥2 first or second degree relatives in the same parental lineage with cancer before age 45 years- The parents of the child with cancer are consanguineous |
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| 2. One of the following Neoplasms was diagnosed:- Adrenocortical carcinoma / adenoma- ALL (low hypodiploid)- ALL (ring chromosome 21)- ALL (Robertsonian translocation 15;21)- ALL relapse (TP53 mutated)- AML (Monosomy 7)- Basal cell carcinoma- Botryoid rhabdomyosarcoma of the urogenital tract (fusion-negative)- Chondromesenchymal harmatoma- Choroid plexus carcinoma / tumor- Colorectal carcinoma- Cystic nephroma- Endolymphatic sac tumor- Fetal rhabdomyoma- Gastrointestinal stromal tumor- Glioma of the optic pathway (with signs of NF1)- Gonadoblastoma- Hemangioblastoma- Hepatoblastoma (CTNNB1 wildtype)- Hepatocellular carcinoma- Infantile myofibromatosis- Juvenile myelomonocytic leukemia- Keratocystic odontogenic tumor- Large cell calcifying Sertoli-cell-tumor- Malignant peripheral nerve sheath tumor- Medullary thyroid carcinoma- Medulloblastoma (SHH activated)- Medulloblastoma (WNT activated, CTNNB1 wildtype) | - Medullary renal cell carcinoma- Medulloepithelioma- Melanoma- Meningioma- Myelodysplastic syndrome- Myeloproliferative neoplasms (except CML)- Myxoma- Neuroendocrine tumor- Paraganglioma / pheochromocytoma- Parathyroid carcinoma / adenoma- Pineoblastoma- Pituitary adenoma / tumor- Pituitary blastoma- Pleuropulmonary blastoma- Renal cell carcinoma- Retinoblastoma- Rhabdoid tumor- Rhabdomyosarcoma with diffuse anaplasia- Schwannoma- Schwannomatosis- Sertoli-Leydig cell tumor- Sex cord stromal tumor with annular tubules- Small cell carcin, of the ovary hypercalcemic type- Squamous cell carcinoma- Subependymal giant cell astrocytoma- Thyroid carcinoma (non-medullary)- Transient myeloproliferative disease- Other rare cancers or cancers that typically occur in adults, unusually early manifestation age |
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| 3. Genetic tumor analysis reveals defect suggesting a germline predisposition |
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| 4. A patient with ≥2 malignancies (e.g. secondary, bilateral, multifocal, metachronous) |
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| 5. A child with cancer and congenital or other anomaliesSign:- Congenital anomalies: Abnormal organs, skeletal anomalies, oral clefting, abnormal teeth, urogenital anomalies, abnormal hearing or vision, etc.- Facial dysmorphism- Mental impairment, developmental delay: Abnormal behavior, learning difficulties- Abnormal growth: Height, head circumference, birth weight, hemihyperplasia, growth chart- Skin anomalies: Abnormal pigmentation such as ≥2 café-au-lait spots, vascular lesions, hypersensitivity to sun, benign tumors, etc.- Hematological abnormalities (not explained by current cancer): Pancytopenia, anemia, thrombocytopenia, neutropenia, leukopenia, macrocytic erythrocytes- Immune deficiency: Frequency of infections, lymphopenia- Endocrine anomalies: Primary hyperparathyroidism, precocious puberty, gigantism/acromegaly, Cushing syndrome |
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| 6. The patient suffers from excessive toxicity of cancer therapy |
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| The McGill Interactive Pediatric OncoGenetic Guidelines (MIPOGG) (Supplementary Online Content to Gouide C. et al. 2021)45 | Tumor-specific criteriaCharacteristic that increases the likelihood of having an underlying CPS in the setting of a specific tumor type. These questions can refer to one or more CPS types. | A referral to genetics is recommended. |
| Universal criteriaCharacteristic that increases the likelihood of having an underlying CPS, independent of the tumor type. These questions do not refer to a specific CPS type.The universal criteria specify the existence of the following conditions:1. More than 1 primary tumor (asynchronous or synchronous)2. Dysmorphism or congenital anomaly that, according to the practitioner's judgment, may be related to the cancer3. Cancer occurring at age <50 years in a parent/sibling4. Cancer occurring at age <18 years in an aunt/uncle/first cousin/grandparent5. Same cancer type or same organ affected by cancer in a close relative6. Close relative with multiple primary tumors (excluding non-melanoma skin cancer) at age <60 years |
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| Direct Referrals Included in MIPOGGMyelodysplastic syndromes including JMMLAdrenocortical carcinomaChondrosarcomaGISTLeiomyosarcomaLiposarcomaAtypical lipomatous tumor / well differentiated liposarcomaMPNST Breast tumorsPhyllodes tumorCardiac myxomaCardiac rhabdomyomaHepatoblastomaPleuropulmonary blastomaMedulloepitheliomaRetinoblastomaKeratocystic odontogenic tumorParathyroid tumorMedullary thyroid carcinomaOvarian SLCTOvarian sex cord-stromal tumor with annular tubulesCystic nephromaRenal cell carcinomaAnaplastic sarcoma of the kidneyMesothelioma | Pheochromocytoma / ParagangliomaRhabdoid tumorAngiomyolipomaGardner fibroma / nuchal-type fibromaLymphangioleiomyomatosisNasal chondromesenchymal hamartomaSchwannoma / Acoustic neuromaFibrofolliculomaMucosal neuromaTrichodiscomaCarcinomas that typically present in adult age (e.g., breast, gastrointestinal, squamous cell carcinoma, pancreatic, uterine, vaginal, ovarian)Atypical teratoid rhabdoid tumorChoroid plexus carcinomaDysplastic cerebellar gangliocytomaEndolymphatic sack tumorHemangioblastomaMedulloepitheliomaMeningiomaPineoblastomaPituitary blastomaSchwannomaSubependymal giant cell tumor |
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| SWEDISH APPROACHWhole genome sequencing becomes clinical routine for all cases of pediatric cancer (Karolinska university hospital, 2024)46Childhood Cancer in Sweden (European Partnership for Personalised Medicine - EP PerMed)47 | All children in Sweden diagnosed with cancer (since 2021) | precision medicine diagnostics through WGS |
| All children in Sweden with cancer (since May 2024) | WGS and whole-transcriptome sequencing (WTS) as part of the standard of care at diagnosis |
| Recognition of genetic predisposition in pediatric cancer patients: An easy-to-use selection tool (Jongmans et al., 2016)48 | fulfilling one or more of the criteria: | may benefit from referral to a clinical geneticist. |
| 1. Family history of the child with cancer- ≥2 malignancies at childhood age (≤18 years)- a first degree relative (parent or sibling) with cancer <45 years- ≥2 second degree relatives with cancer <45 years of age on the same side of the family- the parents of the child with cancer are related |
| 2. One of tumors in childhood:- Adrenocortical carcinoma- Atypical teratoid rhabdoid tumor- Cerebellar gangliocytoma- Choroid plexus carcinoma- Endolymphatic sac tumors- Hemangioblastoma- Hepatoblastoma- JMML- Low hypodiploid ALL- Malignant peripheral nerve sheath tumor- Medullary thyroid carcinoma- Medulloblastoma | - Optic glioma- Ovarian sertoli-leydig cell tumor- Pleuropulmonary blastoma- Pituitary blastoma- Pineoblastoma- Retinoblastoma- Schwannoma- Subependymal giant cell tumorsOrA cancer of adult age, i.e. colorectal cancer, ovarian cancer, basal cell carcinoma etc. |
| 3. A child with two malignancies one of those with onset <18 years of age (unless the 2nd malignancy is consistent in time and/or tissue type with these expected from their treatment regimen). |
| 4. A child with cancer and congenital anomalies or other specific symptoms |
| Sign | Think of |
| Congenital anomalies | Organs, bones, oral clefting, teeth, eyes, ears, brain, urogenital anomalies, etc. |
| Facial dysmorphisms |
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| Intellectual disability |
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| Aberrant growth | Length, head circumference, birth weight, asymmetric growth |
| Skin anomalies | Aberrant pigmentation i.e. >2 café-au-lait spots, vascular skin changes, hypersensitivity for sunlight, multiple benign tumors of the skin |
| Hematological disorders | Pancytopenia, anemia, thrombocytopenia, neutropenia |
| 5. A child with excessive treatment toxicity. |
