The Hematologist

September-October 2017, Volume 14, Issue 5

Recommendations and Research Growing for Pediatric Cancer Predisposition Syndromes

Joshua Schiffman, MD Professor of Pediatrics & Adjunct Professor of Oncological Sciences
Huntsman Cancer Institute/University of Utah, Salt Lake City, UT
Luke Maese, DO Assistance Professor of Pediatrics
Huntsman Cancer Institute/University of Utah, Salt Lake City, UT

Published on: August 22, 2017

In October 2016, a panel of experts including pediatric hematologist-oncologists, endocrinologists, radiologists, geneticists, and genetic counselors from around the world convened on behalf of the American Association for Cancer Research (AACR) for a first-of-its-kind workshop dedicated to pediatric cancer predisposition conditions. This workshop produced 17 publications on a variety of topics related to pediatric cancer predisposition including recommendations on the approach to diagnosis and management of children with a genetic predisposition for malignant hematopoietic disease. It is essential for practicing pediatric and medical hematologists/oncologists to be aware of these hereditary conditions as prompt recognition may not only have implications for treatment, but more importantly, may lead to earlier diagnosis of future malignancy with decreased morbidity/mortality through implementation of surveillance techniques. Below we review some of the pediatric cancer susceptibility disorders and their relevance to hematology as highlighted in the recent AACR workshop.

Technological advancements including development of large-scale biologic databases, techniques for examining tissue, and methods for characterizing data have enabled incorporation of precision medicine into all aspects of cancer care.1 Although often overlooked, disease prevention through incorporation of individual variability is perhaps one of the most positive impacts resulting from these recent genomic and technological innovations. Specifically, preventative precision medicine in oncology can be achieved through identification of cancer predisposition syndromes (CPS). CPS diagnoses have multiple beneficial effects on patients including enhancement of diagnostic clarity, preemptively alerting family members who would otherwise be unaware of cancer risk, and allowing for potential utilization of surveillance techniques. Perhaps the greatest impact of CPS diagnosis is seen in the pediatric population given their lack of understanding of oncogenesis and otherwise extended life expectancy. There are many nuances included in the presentation, diagnosis, and management of CPS in the pediatric population. For a comprehensive review of this topic we encourage reading the reference publications from the AACR workshop.


Clinical suspicion for CPS (Table 1) is a prerequisite step to establishing a diagnosis. Heightened suspicion is necessary in certain scenarios including: (1) strong, relevant family history of cancer at an early age, (2) individual with multiple cancers, (3) specific cancer diagnoses, (4) certain physical exam findings, and as treatment progresses, (5) excessive treatment toxicity.2 In pediatric oncology, family history is often neglected. However, it should be emphasized as part of a new complete cancer diagnosis and follow up.3 The possibility of treatment-related second malignancies in patients with multiple, separate cancers can camouflage a CPS. Unless the second malignancy is consistent in timing and/or histology, the patient should be referred for genetic evaluation.2 This is especially important to the hematologist as a significant portion of second malignancies are of hematopoietic origin. The list of specific cancer diagnoses associated with CPS is becoming essential knowledge for the practicing pediatric hematologist/oncologist. The extensive list is made up of a variety of central and peripheral nervous system tumors, non-nervous system solid tumors, genitourinary solid tumors, and liquid tumors4,5; the CPS-related tumors include the most common pediatric cancers like acute lymphoblastic leukemia and gliomas, as well as the exceedingly rare juvenile myelomonocytic leukemia and choroid plexus carcinomas. Not every initial presentation of CPS will be apparent at first malignancy diagnosis, but family history changes and identification of mutations in the tumor reflecting germline mutations can be a common tip-off. The possibility of a CPS should be considered throughout and even after completion of treatment. However, a significant number of patients will harbor cancer predisposition mutations outside of these higher risk scenarios. De novo variants, parental germline mosaicism, penetrance variability, and variants of uncertain significance (VUS) are just a few of the situations that make the diagnosis of CPS challenging.5

Diagnosis/Diagnostic Methods

Diagnostic confirmation with genetic testing often follows the suspected identification of CPS in children. A prerequisite to testing is a consultation with a certified genetic counselor, as failure to do this has been associated with an assortment of negative testing outcomes for both early tumor surveillance and psychosocial issues.6 A variety of genetic testing approaches exist for CPS confirmation including single gene testing, multigene panel, whole exome/whole genome sequencing (WES/WGS), and single nucleotide polymorphism (SNP) microarray. Each method has its strengths, weaknesses and limitations that make the clinical context and genetic counselor consultation essential for proper selection. For instance, when a known familial mutation is present performing WES or WGS is not necessary and could possibly lead to false negative results. On the contrary, in a patient with suspected CPS but no previously identified familial mutation, a broader interrogation approach such as multigene panel or WES/WGS may be preferred given the limitations of single gene testing. Whereas previously cost was a limiting factor with genetic testing, the continued decreasing costs of next-generation sequencing (NGS) techniques have paved the way for greater employment of these methods.7 However, as the cost has become less of a barrier to testing, the generation/storage of data and interpretation of results has now arisen as the rate-limiting step in the CPS diagnostic process.8

The distinction between somatic and germline testing is extremely important in genetic testing interpretation. As NGS of tumors becomes an increasingly popular testing methodology, demonstrating the ability to identify pathogenic germline mutations, the number of unexpected and/or potential CPS diagnoses will increase,9 further emphasizing the need for proper informed consent and genetic counseling prior to any genetic testing.


There are two primary aspects to management of CPS: genetic counseling and cancer surveillance, and in pediatrics these are both interventions employed throughout one’s life. It is imperative, especially in young children, that genetic counseling be revisited throughout major stages of development: adolescence, family-planning, and older adulthood; this is important not only to allow for additional understanding but also to review the ever-changing landscape of CPS.5 At the AACR Childhood Cancer Predisposition Workshop, CPS screening recommendations for early tumor surveillance varied according to the risk of developing cancer during the first 20 years of life: (1) 5 percent or greater risk, screening is indicated, (2) 1 to 5 percent risk, screening discussed on individual basis, and (3) less than 1 percent, no surveillance at this time.10 Recommendations for cancer surveillance screening including regular/focused physical exams, specific laboratory studies, and an assortment of imaging procedures varied for each syndrome (Table 1), and many have already demonstrated benefits in several CPS.11,12 Although surveillance allows for early cancer detection, its primary benefit is most realized in solid tumors that can be excised prior to excessive growth or metastases. Conversely, while early diagnosis of hematopoietic neoplasm may be beneficial and makes sense from an intuitive perspective, the evidence that it alters patient outcomes is still lacking for many of the leukemic diagnoses (in the absence of a previous myelodysplastic prodrome). In some scenarios, prophylactic treatment with allogenic hematopoietic stem cell transplant (HSCT) has been employed in select populations with predisposition to hematopoietic malignancy, and has demonstrated superior outcomes.13

In fact, the panel for CPS with leukemia-predisposition was one of the most exciting and perhaps challenging groups of hereditary disorders discussed at the AACR workshop14 due to limited evidence to support clear management recommendations for children at genetic risk to develop leukemia despite strongly held beliefs that some type of early surveillance and intervention could be beneficial.15 Indeed, for several of the hematology-based predisposition syndromes, there was agreement that routine monitoring with complete blood counts and bone marrow evaluations will help to identify disease evolution and permit early HSCT – although the exact timing for such routine surveillance could vary from monthly to yearly, to even longer. The risks of procedures like bone marrow aspirates and marrows need to be weighed against the still being determined benefits. The pediatric hematology panel recognized that their recommendations are based on opinion and local experience; revisions are expected over time with continued input from experts in the field. Everyone on the panel agreed that CPS registries and clinical trials will be critical for gathering more data to help improve surveillance recommendations and patient outcome for those at genetic risk for leukemia and other hematological malignancies.

Future Endeavors

Similarly, a focused European effort to consolidate information and recommendations on CPS directed by the Society for Pediatric Oncology and Hematology (GPOH) was held in January of 2016.4 Followed by the AACR workshop, these two symposiums were a significant step forward in formalizing the diagnosis and management of childhood cancer predisposition. The challenge to the pediatric oncology community remains that given the rarity of the these syndromes, an essential need exists now for greater collaborative research in order to improve on current recommendations.10 To that end, many discussions are taking place about continuing to formalize special interest groups on the topic of pediatric predisposition syndromes in the major pediatric hematology and oncology professional societies. These types of CPS interest groups by practicing clinicians will allow for greater support, enhance understanding, and incite research in this growing field of pediatric cancer predisposition. Finally, the role of parent and family advocacy groups will continue to play a vital role in the identification of those at risk for both solid and hematological cancers, and importantly, in the enrollment of participants into registries and clinical trials. The field of pediatric CPS is still relatively young but making great strides in early cancer identification and improving the long-term outcome for high risk children and family members.

Primary AssociationsSyndromeAssociated Hematopoietic MalignancyOther Associated MalignancyMutation(s)Clinical FeaturesScreening Recommendations
Solid tumorsLFSAML, ALLSoft tissue sarcoma, osteosarcoma, breast, choroid plexus carcinoma, medulloblastoma, ACC, neuroblastoma, gastric, colorectalTP53N/AChildren (Birth to 18 y/o)
Leukemia: CBC annually
ACC: Abd/pelvic US q 3-4 mo, if US insufficient then serum total testosterone, DHEA-S, and androstenedione q 3-4 mo
Brain tumor: Brain MRI annually
Sarcoma: WBMRI annually
Leukemia: CBC annually
Breast: clinical breast examination biannually (≥18 y/o), breast MRI annually (20-75 y/o), consider bilateral mastectomy
Brain: Brain MRI annually
Sarcoma: WBMRI annually, abd/pelvis US q 12 mo
GI: Upper endoscopy and colonoscopy q 2-5 yrs
Melanoma: skin examination annually
CMMRDNHL, T-ALL, B-ALL, AMLGI, endometrial, brainMLH1, MSH2, MSH6, PMS2, EPCAMcafé au lait macules, hyper-and hypopigmented skin alterations, venous anomalies, corpus callosum agenesis, mild immunodeficiency, early onset cancer Leukemia: CBC q 6 mo starting at 1 y/o, consider BM evaluation
Lymphoma: Abd US q 6 mo starting at 1 y/o
Brain: MRI brain at diagnosis q 6 mo
GI: upper endoscopy/ileocolonoscopy annually starting at 4-6 y/o
GU: Gyn exam, transvaginal US, pipelle curettage, urine cytology, dipstick annually starting at 20 y/o
All tumors: WBMRI annually starting at 6 y/o 
RAS-activating syndromesJMML, ALL, AML, TAMneurofibroma, schwannoma, low grade glioma/high grade glioma, MPNST, RMSNF1, PTPN11, KRAS, CBLNF1: café-au-lait spots, axillary/inguinal freckling, Lisch nodules, learning disabilities
PTPN11: dysmorphic facies, congenital hearing anomalies, short stature
CBL: dysmorphic features, JXG, learning difficulties
Brain tumor: ophthalmic assessments q 6-12 mo from birth to 8 y/o, baseline assessment of color vision and visual fields
Solid tumor: consider baseline WB MRI ages 16-20 y/o for internal tumor burden assessment
Leukemia: consider physical exams with spleen size assessment and CBC q 3-6 mo until 5 y/o; thereafter annual CBCs and consideration of BM evaluation
DNA repairFanconi anemiaAML, ALL, MDSHead and neck SCC, anogenitalFANCA-E, RAD51D, BRCAShort stature, microcephaly, hypoplastic/aplastic thumb, small or absent radius, hyperpigmented skin macules, bone marrow failureLeukemia: CBCs q 4 mo, BM evaluations annually
Head and neck SCC: ENT screening annually starting 10 y/o
Dyskeratosis congenitaAML, MDSHead and neck SCC, anogenitalDKC1, TERT, TERC, othersNail dystrophy, lacy skin pigmentation, oral leukoplakia, pulmonary fibrosis, hepatic fibrosisLeukemia: CBCs annually, consider BM evaluation
Head and neck SCC: ENT screening annually starting at 16 y/o
BloomNHL, AML, MDS, ALLSarcoma, GI, breast, GU carcinoma, WT, medulloblastoma, retinoblastomaBLMShort stature, photosensitivity, gastroesophageal reflux, decreased fertility, insulin resistance, immunodeficiencyLeukemia: CBC q 3-4 months, consider BM evaluation
WT: Renal US q 3 mo until age 8
GI: colonoscopy annually and fecal immunochemical testing q 6 mo starting at 15 y/o
Breast: MRI breast starting at 18 y/o
Nijmegen breakage syndromeNHLMedulloblastoma, glioma, RMS, breast, prostateNBNCraniofacial dysmorphology, immunodeficiencyNHL: CBCs, metabolic profile, LDH annually
Ataxia-telangiectasiaT-ALL, NHL, HL, AMLOvarian, breast, prostate, gastric, pancreatic, melanoma, leiomyoma, sarcomaATMCerebellar ataxia, conjunctival talangiectasia, oculomotor apraxia, choreoathetosis, immunodeficiencyLeukemia: CBC, metabolic profile, LDH annually, consider BM evaluation
Chromosomal changesDown syndromeALL, TAM, AMLN/ATrisomy 21Short stature, developmental delay, congenital heart defect, muscular hypotonia, single transverse palmar crease, characteristic facial appearance (epicanthal folds, upslanting palpebral fissures, protruding tongue)Leukemia: CBC annually, consider BM evaluation
Monosomy 7MDS, AMLN/AChromosome 7 Annual CBCs/BM evaluations
LeukemiaGATA2MDS/AMLN/AGATA2Immunodeficiency, lymphedema, deafness, hypertelorism, hydrocele, other congenital anomaliesAnnual CBCs/BM evaluations
Susceptibility to ALL 3B-ALLN/APAX5N/ACBCs annually, consider BM evaluation
CEBPA associated predisposition to AMLAMLN/ACEBPA Annual CBCs/BM evaluations
ThrombocytopeniaThrombocytopenia, type 5B-ALL, MDS, AML, multiple myelomaSolid tumors, GIETV6Thrombocytopenia, red cell macrocytosis, esophageal dysmotilityLeukemia: CBCs annually, consider BM evaluation
FPD/AMMAML, T-ALLN/ARUNX1Thrombocytopenia, eczemaAnnual CBCs/BM evaluations
CytopeniaSevere congenital neutropeniaAML, MDSN/AELANE, HAX1, GFI1, othersNeutropenia, recurrent infections, neurocognitive abnormalitiesAnnual CBCs/BM evaluations
Shwachman-DiamondMDS, AMLN/ASBDSCytopenia (neutropenia), short stature, pancreatic insufficiencyAnnual CBCs/BM evaluations
Diamond-Blackfan anemiaMDS, AMLOsteogenic sarcoma, other solid tumorsRPS19, RPL5, RPL11,othersMacrocytic anemia, short stature, congenital anomaliesLeukemia: CBCs annually, consider BM evaluation
Newly describedMIRAGEMDSN/ASAMD9Myelodysplasia, severe infections, growth restriction, adrenal hypoplasia, genital underdevelopment, chronic diarrhea, thrombocytopenia, anemiaAnnual CBCs/BM evaluations
Ataxia-pancytopeniaMDS, AMLN/ASAMD9LAtaxiaAnnual CBCs/BM evaluations
LFS, Li-Fraumeni syndrome; AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; ACC, adrenocortical carcinoma; CBC, complete blood count; Abd, abdomen; US, ultrasound; DHEAS, dehydroepiandrosterone sulfate; MRI, magnetic resonance imaging; WBMRI, whole-body MRI; GI, gastrointestinal; CMMRD, constitutional mismatch repair deficiency; NHL, non-Hodgkin lymphoma; BM, bone marrow; GU, genitourinary; Gyn, gynecologic; JMML, juvenile myelomonocytic leukemia; MPNST, malignant peripheral nerve sheath tumor; RMS, rhabdomyosarcoma; JXG, juvenile xanthogranuloma; MDS, myelodysplastic syndrome; SCC, squamous-cell carcinoma; ENT, ear-nose-throat; WT, Wilms tumor; LDH, lactate dehydrogenase; HL, Hodgkin lymphoma; TAM; transient abnormal myelopoiesis; FPD/AMM, familial platelet disorder with predisposition to acute myelogenous malignancy.


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Conflict of Interests

Dr. Schiffman and Dr. Maese indicated no relevant conflicts of interest. back to top