In this document the terms 'child' or 'children' refers to individuals under age 18 years
Some children have a higher risk of developing cancer due to an inherited genetic pathogenic variant. Hereditary cancer predisposition syndromes are identified in at least 8.5% of all children with cancer.r
These syndromes have implications not only for the individual child but also for their family members. If a child is found to carry a pathogenic variant associated with an increased cancer risk, their siblings, parents, and other close relatives may also be at risk. Therefore, referring the child to clinical genetics is essential, as such services provide comprehensive evaluation and counselling for the entire family, enabling early detection and preventive measures for other family members who may be at risk. Clinical genetics services can also offer diagnostic evaluation for children with undiagnosed syndromes.
Currently, many children with cancer will have genomic testing performed as part of routine care and this may include germline sequencing. This document is intended to guide clinicians when to refer paediatric patients to clinical genetics due to a personal or family history of a known or likely hereditary cancer predisposition syndrome.
Abbreviations: CMMRD – constitutional mismatch repair deficiency; MEN – multiple endocrine neoplasia.
| Family history criteria (child with cancer) |
| A child with a cancer and one of the following family history characteristics should be referred to genetics irrespective of other factors |
| 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) |
| General criteria (child with cancer) |
| These features should raise concern for an underlying genetic diagnosis in any child with cancer. Any one of the following features should be considered for referral to genetics unless there is a known alternative explanation for these additional 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 at 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 |
| Cancer/tumour criteria |
| Some cancer types or subtypes are associated with a high risk of germline genetic abnormality. Some services may allow for non-geneticist clinicians to request germline testing after appropriate informed consent has taken place. A child with one of the following cancers/tumours should be considered for testing and/or referred to genetics irrespective of other factors* |
| Adrenocortical carcinoma - TP53 |
Medulloblastoma
1. WNT subtype without documented somatic CTNNB1 mutation - APC
2. SHH subtype under age 18 years - TP53, PTCH1, SUFU, APC, ELP1, PTEN
|
| B acute lymphoblastic leukaemia (ALL) – low hypodiploid (32-39 chromosomes) - TP53 |
Myelodysplastic syndrome (MDS) |
| Cerebellar gangliocytoma (Lhermitte-Duclos disease - PTEN) |
Neuroblastoma (with other features suggestive of germline abnormality) |
| Choroid plexus carcinoma - TP53 |
Optic glioma |
| Colorectal polyps – hamartomatous** - STK11, SMAD4, BMPR1A |
Osteosarcoma |
| Colorectal polyps – multiple adenomatous or serrated/hyperplastic*** - APC, POLE, MUTYH |
Ovarian Sertoli-Leydig cell tumour - DICER1 |
| Cystic nephroma - DICER1 |
Paraganglioma or phaeochromocytoma |
| Desmoid-type fibromatosis (intra-abdominal/abdominal wall location) - APC |
Pineoblastoma - DICER1, RB1 |
| Endolymphatic sac tumour - VHL |
Pituitary blastoma - DICER1 |
| Gastrointestinal stromal tumour (GIST) - KIT |
Pleuropulmonary blastoma - DICER1 |
| Haemangioblastoma - VHL |
Retinoblastoma - RB1 |
| Hepatoblastoma - APC |
Rhabdomyosarcoma (anaplastic subtype at any age, or any subtype under age 3 years) - TP53, DICER1 |
| Infantile myofibromatosis - PDGFRB |
Schwannoma - NF2 |
| Juvenile myelomonocytic leukaemia (JMML) - NF1, RASopathies |
Small cell carcinoma of the ovary hypercalcaemic type (SCCOHT) - SMARCA4 |
| Malignant peripheral nerve sheath tumour - NF1 |
Subependymal giant cell tumour - TSC1, TSC2 |
| Malignant rhabdoid tumour - SMARCB1, SMARCA4 |
Wilms tumour |
| Medullary thyroid cancer - MEN2A/2B |
|
| General |
| Immunohistochemistry 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 |
Abbreviations: CMMRD – constitutional mismatch repair deficiency; MEN – multiple endocrine neoplasia; NGS – next generation sequencing
* 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