Pediatric Annals

Special Issue Article 

Recognizing and Managing Children with a Pediatric Cancer Predisposition Syndrome: A Guide for the Pediatrician

Stephanie A. Coury, MS; Katherine A. Schneider, MPH; Jaclyn Schienda, ScM; Wen-Hann Tan, BMBS

Abstract

It is estimated that at least 8% to 10% of children diagnosed with cancer have an inherited cancer predisposition syndrome. Pediatricians may be called upon to (1) identify children with symptoms suggestive of cancer that require further diagnostic testing, (2) identify children who should be referred to cancer genetics based on their personal and family histories, and (3) provide primary care to children who have an inherited cancer syndrome. This review article provides a list of clinical warning signs suggestive of childhood malignancy, discusses the personal and family history “red flags” suggestive of hereditary cancer, offers checklists to help identify patients who are candidates for cancer genetics evaluation, and describes features of the major pediatric cancer syndromes involving solid tumors and surveillance guidelines. This review aims to provide the pediatrician with the tools needed to recognize, refer, and help manage children at risk for pediatric cancer syndromes. [Pediatr Ann. 2018;47(5):e204–e216.]

Abstract

It is estimated that at least 8% to 10% of children diagnosed with cancer have an inherited cancer predisposition syndrome. Pediatricians may be called upon to (1) identify children with symptoms suggestive of cancer that require further diagnostic testing, (2) identify children who should be referred to cancer genetics based on their personal and family histories, and (3) provide primary care to children who have an inherited cancer syndrome. This review article provides a list of clinical warning signs suggestive of childhood malignancy, discusses the personal and family history “red flags” suggestive of hereditary cancer, offers checklists to help identify patients who are candidates for cancer genetics evaluation, and describes features of the major pediatric cancer syndromes involving solid tumors and surveillance guidelines. This review aims to provide the pediatrician with the tools needed to recognize, refer, and help manage children at risk for pediatric cancer syndromes. [Pediatr Ann. 2018;47(5):e204–e216.]

In the course of their practice, pediatricians will likely come across children who have significant personal or family histories of cancer. It is estimated that 8% to 10% of children diagnosed with cancer have an inherited cancer predisposition syndrome.1,2 However, this may be an underestimation, because compared to adult-onset cancers, childhood-onset cancers typically involve less common tumor types and are less likely to be associated with environmental exposures, two features that increase the likelihood of an underlying genetic etiology.1,2 Due to advancements in genetic testing, increased insurance coverage, and federal protections against genetic discrimination in health insurance coverage, the number of children identified with hereditary cancer syndromes has dramatically increased over the past 5 years.3

Identification of a cancer syndrome typically begins with the child who has cancer. Determining whether a child has a hereditary cancer is critically important for the following reasons:

  1. It may change the child's current cancer treatment or surgical plans. For this reason, it is becoming standard of care to offer genetic testing to children with certain solid tumors.3–6

  2. It may give the child an opportunity to participate in a syndrome-specific screening regimen, which may allow for the early detection of additional cancers.4,6,7

  3. It may identify other relatives who are at increased risk for having similar cancers. Parents may also choose to have reproductive genetic counseling prior to additional childbearing.3,4

  4. It may help provide an explanation for why the child has cancer.3,5

Common Signs of Cancer

In the United States, the annual incidence of childhood cancer (ie, cancer that occurs between ages 0 and 14 years) is approximately 150 per million children.8 The major cancer types seen in children include leukemias, lymphomas, brain and spinal tumors, sympathetic nervous system tumors, retinoblastoma, kidney tumors, liver tumors, bone tumors, soft-tissue sarcomas, gonadal tumors, and epithelial tumors.8 Childhood cancers remain the leading cause of disease-related death in children age 1 to 19 years; however, childhood cancer survival rates have improved greatly over the past 2 decades, with an average 5-year survival rate of 70% to 80% when all types of cancer are considered.9 Early diagnosis and treatment of pediatric cancers is of paramount importance and can reduce morbidity or complications, resulting in higher cure rates.7,10

Being on the frontline, pediatricians are in a unique position to identify pediatric patients who might have cancer. The first step in the evaluation for childhood cancer is to obtain a detailed medical history.11 Clinical “red flags” for childhood malignancy may include any combination of the following: fatigue, fever, recurrent infections, weight loss, lymphadenopathy, hemorrhagic manifestations, headaches, palpable masses, hepatosplenomegaly, vomiting, or bone pain (Table 1).12

Warning Signs of Childhood Cancer that Indicate Need for Further Evaluation

Table 1:

Warning Signs of Childhood Cancer that Indicate Need for Further Evaluation

It can be difficult to readily identify childhood cancer as many of the initial signs and symptoms overlap with other common childhood illnesses. Although a malignant tumor is low on the differential diagnosis for the average child, this is not the case for children with inherited cancer predisposition.4,10 For these reasons, extra cancer surveillance should begin in early childhood for many of the hereditary cancer syndromes (Table 2). Parents of children with increased risks of cancer need to know that providers will take reports of health status changes seriously and arrange prompt evaluations.

Pediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance GuidelinesPediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance GuidelinesPediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance GuidelinesPediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance GuidelinesPediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance GuidelinesPediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance Guidelines

Table 2:

Pediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance Guidelines

Personal and Family History Indicators Appropriate for Cancer Genetics Referral

One study found that more than 25% of pediatric cancer survivors were appropriate candidates for referral to a cancer genetics clinic.13 Therefore, it is useful for pediatricians to be aware of the indicators or red flags that increase the likelihood that a child could have a cancer syndrome. Jongmans et al.6 have developed a tool to identify pediatric cancer patients who may benefit from a genetics evaluation. This tool assesses for the presence of at least 1 of 5 characteristics: family history of cancer, tumors that are more often associated with a cancer syndrome, multiple tumors, congenital or developmental abnormalities, and excessive treatment toxicity.6 A child with cancer who meets one of these criteria, as discussed below, should be evaluated for a cancer syndrome.3

Features in a Child's Personal or Family History that Increase the Likelihood of an Inherited Cancer Syndrome

A rare tumor or a tumor with a known association with a cancer syndrome. See Table 3 for tumor types that are more likely to be hereditary and see Table 2 for the tumors associated with specific hereditary cancer syndromes. Please note that this article focuses on solid tumors, not leukemias, lymphomas, or bone marrow failure syndromes.

Tumors that Warrant Cancer Genetics Referral If They Occur in Childhood

Table 3:

Tumors that Warrant Cancer Genetics Referral If They Occur in Childhood

Two or more tumors. A child who has two or more tumors (including bilateral tumors), either simultaneously or at different times, warrants a genetic evaluation. Although some second tumors are complications of treatment for the original neoplasm, others may be indicative of an underlying genetic predisposition to cancer.6 In addition, tumors that have occurred in paired organs, such as bilateral retinoblastoma or Wilms' tumor, have a high likelihood (often close to 100%) of being due to a cancer syndrome.

Diagnosed at an unusually young age. A hallmark feature of hereditary cancer syndromes is that the tumors tend to occur at younger than typical ages for that tumor type.4 Examples include children diagnosed with cancer within the first 12 months of life and children diagnosed with tumors, such as colon polyps or cancer, which are typically seen in adults.

Child has a mutation in the tumor tissue that could also be hereditary. Genetic tumor profiling characterizes the genetic composition of the tumor to determine the best treatment approach. Most of the mutations identified are confined to the tumor (ie, not in the germline); however, certain mutations may be present in both the tumor and the germline.

Child with excessive treatment toxicity. Whereas most cancer treatments are known to cause adverse side effects, people with certain cancer genetic syndromes may experience more significant complications.4 For example, in Li-Fraumeni syndrome (LFS), children with cancer may experience adverse radiation-related side effects or secondary tumors.14

Child has both cancer and congenital anomalies or other medical problems. See Table 2 and Table 4 for examples of additional noncancerous features that can be associated with hereditary cancer syndromes.

Noncancerous Features in Hereditary Cancer Syndromes

Table 4:

Noncancerous Features in Hereditary Cancer Syndromes

Personal and family history of cancer. A child who has a personal and family history of cancer, especially if it involves the same or related tumor, other childhood tumors, or two or more relatives with cancer diagnosed at younger than age 45 years, should raise concerns about a possible cancer syndrome. For example, a child with an osteosarcoma whose mother had breast cancer should be evaluated for LFS.

Benign tumor(s) or cysts that are associated with a cancer syndrome. Many of the hereditary cancer syndromes are associated with specific benign tumors or cysts. Examples include neurofibromas in neurofibromatosis type 1 (NF1),15 cystic nephromas in DICER1 syndrome,16 and kidney cysts in von Hippel-Lindau syndrome (VHL).17

Family history of cancer and/or a mutation in a cancer syndrome gene. If the family history includes a significant history of cancer and/or a mutation in a cancer-susceptibility gene, then the child may be at increased risk.

It is important to note that in a recent study, only 40% of pediatric cancer patients who had a germline pathogenic or likely pathogenic variant in a cancer predisposition gene had a family history of cancer.1 Thus, the lack of a family history of cancer does not preclude the existence of a cancer syndrome, especially in the setting of the additional red flags.3,6

Tumor Risks Associated with Pediatric Cancer Syndromes

Tumor predisposition syndromes are associated with increased risks of specific benign and malignant tumors during childhood, adolescence, and often adulthood (Table 2). Children with these syndromes typically have increased risks of developing multiple tumor types, often spanning more than one organ system. The syndrome-related tumors include malignant tumors such as pleuropulmonary blastoma in DICER1 syndrome16 and medullary thyroid cancer in multiple endocrine neoplasia type 2 (MEN2),18 and benign tumors such as cortical tubers in tuberous sclerosis complex,19 and dysplastic nevi in familial atypical multiple mole melanoma syndrome.20

A few of the syndromes, namely familial adenomatous polyposis (FAP),21 MEN2,18 and possibly constitutional mismatch repair deficiency syndrome (CMMRD),22 confer close to 100% risk of cancer, but most syndromes confer cancer risks that are below 100% (range of 5%–90% depending on the specific syndrome). In addition, some associated tumors seldom occur, such as hepatoblastoma in FAP21 and gastrointestinal stromal tumors in hereditary paraganglioma-pheochromocytoma.17

Variable Penetrance and Expressivity

Tumor predisposition syndromes vary in terms of penetrance and expressivity. Penetrance is the likelihood that a person with the genetic mutation will have features of the associated syndrome. Some hereditary cancer syndromes such as FAP, MEN2, and hereditary retinoblastoma are highly penetrant, whereas other cancer syndromes have lower penetrance, which implies that there may be people in the family who have the mutation but will never develop any syndrome-related tumors or other features.

Expressivity is the variability in the severity and spectrum of clinical manifestations associated with a syndrome among affected people. The tumor predisposition syndromes can have variable expressivity even within the same family. For example, a person with VHL might develop spinal hemangioblastoma, pheochromocytoma, and renal cancer whereas his relative may only develop a few renal cysts.

Nontumor Manifestations of Pediatric Cancer Syndromes

Some syndromes are characterized by their nontumor features as much as their associated tumors. Because these features may be the initial red flag of a specific cancer syndrome, it is important to be aware of them. Some of these nontumor features include macrocephaly in PTEN hamartoma tumor syndrome16 and asymmetrical growth in Beckwith-Wiedemann syndrome (BWS).23 For details on specific tumor predisposition syndromes, refer to Table 2 and the resources in Table 5.

Additional Resources about Pediatric Cancer and Pediatric Cancer Predisposition Syndromes

Table 5:

Additional Resources about Pediatric Cancer and Pediatric Cancer Predisposition Syndromes

Inheritance of Pediatric Cancer Syndromes

One of the benefits of determining whether a child has a mutation in a cancer susceptibility gene is to clarify whether other family members may also be at risk. Tumor predisposition syndromes tend to follow one of two inheritance patterns: autosomal dominant and recessive inheritance (although in rare instances, other inheritance patterns are possible).

Autosomal Dominant Inheritance

Most tumor predisposition syndromes are inherited in an autosomal dominant manner. “Autosomal” refers to the fact that the mutation lies on one of the 22 numbered chromosomes rather than the X or Y chromosome. Thus, the mutation can be passed on to the child from either parent. Children have a 50% chance of inheriting the mutation and having the tumor predisposition syndrome. Some of these mutations are de novo (ie, a new mutation that occurred in the egg or sperm that combined for conception of the child and, therefore, are not present in either parent). Some cancer syndromes, such as NF1, have high de novo rates. However, once a child is born with the mutation, there is a 50% risk that it will be passed onto his or her future offspring, similar to other autosomal dominant syndromes.

Autosomal Recessive Inheritance

A few cancer syndromes, such as CMMRD, are inherited in an autosomal recessive manner. This means that both parents are “carriers” (ie, each of them carries a mutation in the same gene) and each child has a 25% risk of inheriting both mutations and having the cancer syndrome. For recessive conditions, it is important to offer testing to partners of people who are carriers of the condition to determine the risks to their offspring. If only one parent is a carrier of a recessive disorder, then there is very little risk of having a child with the disorder (although 50% of the children will be “carriers” like their parent).

Genetic Testing

Increasingly, the best way to diagnose a specific cancer predisposition syndrome is to perform genetic testing. Often, 75% or more of the children meeting clinical criteria for a cancer syndrome will be found to carry a pathogenic variant in a specific cancer susceptibility gene.5

Gene-specific testing can be performed if the history or physical examination is highly suggestive of a specific cancer syndrome, but multigene panel testing may be more time and cost-efficient if the differential diagnosis is broad. Prior to testing, the family will be given information about the possible test results, the implications of the results to the child and family, and the risks and benefits of testing.3

The possible results are positive (pathogenic or likely pathogenic variant; often referred to as a mutation), negative (benign or likely benign variant, or no variants found), or variant of uncertain significance (VUS) (ie, there are insufficient data to determine whether the variant identified is benign or pathogenic). With the advent of multigene panel testing, VUS results have become common. VUS results are not mutations and, therefore, are rarely treated as actionable results.3

Given the complexity of ordering genetic testing, interpreting the results, and coordinating appropriate follow-up, it is recommended that testing be performed within the auspices of a cancer genetic testing program (which is often available in many major medical centers) that offers both medical and psychological support.3 Resources to find such programs can be found in Table 5.

Surveillance and Management

Published criteria for surveillance and management are currently available for many cancer syndromes (Table 2). The American Association of Clinical Research held a summit workshop in 2016 that culminated with the publication of screening and surveillance guidelines for the major childhood cancer-predisposition syndromes.24 We summarize these guidelines in Table 2, but we acknowledge that there are also other groups offering syndrome-specific guidelines that may differ.

The current guidelines, which are based mainly on expert opinion as opposed to evidence-based data, are rapidly evolving.24 Therefore, it is important for families to stay connected to a cancer genetics program so they can learn of any updates or changes in surveillance and management.

For two cancer syndromes, specifically FAP21 (colorectal) and MEN218 (thyroid), the associated lifetime risks of cancer are 100%, so prophylactic surgery of the at-risk organs is recommended. However, for most pediatric cancer syndromes, surveillance through a comprehensive physical examination with or without MRI of the relevant body regions, is the goal.

Comprehensive Physical Examination

For each of the cancer syndromes, it is important to perform a comprehensive physical examination, including careful neurologic and skin examinations. These physical examinations are generally recommended 1 to 2 times per year, and the frequency or type of examination may change depending on the age of the child, the specific syndrome, and the child's current symptoms. Parents of a child with a pediatric cancer syndrome should pay attention to specific warning signs and should be encouraged to bring these concerns to the child's pediatrician.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) imaging is an excellent screening modality for solid tumors and has the advantage of providing multiorgan screening, which is often needed for children at risk for multiple tumors.25 Annual MRI screening is recommended for many of the cancer syndromes, especially at age 10 years or older when children are usually able to remain still for the procedure. The disadvantages of MRI include having to sedate young children for the procedure, having an increased risk of incidental findings that need follow-up, and not being covered by insurance.

Summary

Children with an inherited cancer syndrome often have high risks for developing specific tumors. Early identification of malignancy, which provides the best chance for successful treatment, relies heavily on parental reports of any symptoms and the pediatrician's careful evaluation. For children with pathogenic variants in a cancer predisposition gene, there needs to be a low threshold for pursuing further testing for possible cancer.

Pediatricians are important providers in referring children for cancer testing and/or to cancer genetics for evaluation of cancer susceptibility. At least 8% to 10% of children with cancer have an inherited cancer predisposition syndrome, which has implications for their current and future care and for their biological relatives, especially their siblings and parents. Children who have been diagnosed with rare solid tumors, have relatives who have developed cancer, or have other red flags in their personal and/or family histories are appropriate candidates for referral for cancer genetic counseling and testing.

It is important for pediatricians to become aware of the tumor and nontumor features of the major inherited cancer syndromes. Cancer genetic testing programs, pediatricians, and other pediatric care providers need to work together as a unified team to provide children with inherited susceptibilities of cancer the best possible care.

References

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Warning Signs of Childhood Cancer that Indicate Need for Further Evaluation

Anemia or other blood count anomalies

Bruising more easily or often

Changes in bowel habits or blood in the stool

Frequent headaches, often with vomiting

Limping with or without pain

Mole that has increased in size or changed appearance

Ongoing pain in one area of the body, especially bone or joint pain that wakes the child up at night or has lasted longer than 2 weeks

Persistent lymph nodes

Sudden changes in vision

Unexplained fever or illness that does not resolve in a typical time frame

Unexplained paleness and loss of energy

Unexplained weight loss

Unusual lump or swelling (palpable mass), especially in the abdomen

Urine retention/enuresis or blood in the urine

Pediatric Cancer Predisposition Syndromes: Related Tumors, Inheritance, and Surveillance Guidelines

SyndromeMalignant TumorsaNonmalignant Tumorsa,bNontumor FeaturesaGene/LocusInheritanceSurveillance Guidelinesc
Beckwith-Wiedemann syndrome5,23Adrenocortical carcinoma, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, Wilms' tumorPheochromocytomaAdrenocortical cytomegaly, ear creases/pits, hemihypertrophy, macroglossia, macrosomia, neonatal hypoglycemia, nevus flammeus, renal abnormalities, omphalocele, visceromegalyEpigenetic and genomic alterations at 11p15 or mutations in CDKN1CSporadic or AD (CDKN1C)From birth to 4 y: serum AFP and abdominal U/S q 3 m From 4–7 y: abdominal U/S q 3 m CDKN1C: From birth to 6 y: NB screening, abdominal U/S, urine VMA and HVA, chest X-ray q 3 m then q 6 m from 6–10 y
Constitutional mismatch repair deficiency syndrome5,22Brain tumors (often anaplastic astrocytoma, glioblastoma, medulloblastoma, primitive neuroectodermal tumors), leukemia, lymphoma (often T-cell lymphoblastic), neuroblastoma, osteosarcoma, rhabdomyosarcoma, Wilms' tumor. Lynch syndrome associated cancers: colorectal, endometrial, small bowel, urinary tract (ureter, renal pelvis, bladder), biliary tract, stomach, ovaryColorectal and small bowel adenomatous polyposis, neurofibroma, pilomatricomaCafé-au-lait macules and other hyper-/hypopigmented skin lesions, mild immunodeficiencyBiallelic: MLH1, MSH2, MSH6, PMS2, EPCAMARAt diagnosis: brain MRI q 6 m At 1 y: consider abdominal U/S and CBC q 6m At 6 y: colonoscopy q 1 y, then q 6 m when polyps detected, WBMRI q 1 y At 8 y: upper gastrointestinal endoscopy and VCE q 1 y At 20 y: gynecologic examination, transvaginal U/S, pipelle curettage, urine cytology, dipstick q 1 y
DICER1 syndrome5,16Differentiated thyroid cancer, embryonal rhabdomyosarcoma of cervix/bladder/ovary, pleuropulmonary blastoma, pineoblastoma, pituitary blastoma, Sertoli-Leydig cell tumor of ovary, Wilms' tumorCiliary body medulloepithelioma, cystic nephroma, juvenile hamartomatous intestinal polyp, multinodular goiter, nasal chondromesenchymal hamartomaMacrocephaly reportedDICER1ADFrom birth to 8 y: abdominal U/S q 6 m then q 1 y At 3–6 m: chest CT At 2.5–3 y: repeat chest CT From 3 m–8 y: consider chest X-ray q 6 m, then q 1 y from 8–12 y At 8 y: thyroid U/S q 3 y From early childhood to adulthood: consider pelvic U/S q 6 m–1 y
Familial adenomatous polyposis5,21,26Ampullary adenocarcinoma, colorectal cancer, differentiated thyroid cancer (often papillary), hepatoblastoma, medulloblastoma, pancreatic cancer, small bowel cancer, stomach cancerColorectal adenomatous polyposis, desmoid tumor, epidermal cyst, fundic gland polyp (stomach), Nuchal fibroma (Gardner associated fibroma), osteoma (often jaw, skull), small bowel adenomaCongenital hypertrophy of the retinal pigment epithelium or pigmented ocular fundus lesions of FAP, extranumerary teeth/dental anomaliesAPCADFrom birth to 7 y: abdominal U/S and serum AFP q 4–6 m At 10–15 y until surgery: colonoscopy q 1 y At 15–19 y: thyroid cervical palpation q 1 y Consider abdominopelvic MRI (if family history of desmoids) q 1–3 y after surgery, then 5–10 y Adults: see NCCN
Familial atypical multiple mole melanoma syndrome5,20Astrocytoma, melanoma, pancreatic cancerMultiple dysplastic neviNoneCDKN2AADAt 10 y: dermatologic examination q 6 m, self-examination q 1–3 m
Gorlin (aka nevoid basal cell carcinoma syndrome)5,27,28Basal cell carcinoma (multiple), ependymoma, medulloblastoma, ovarian fibrosarcoma, rhabdomyosarcomaCardiac fibroma, meningioma, ovarian fibroma, jaw keratocyst, rhabdomyomaCalcified falx, coarse face, facial milia, frontal bossing, macrocephaly, pits in palms of hands or soles of feet, skeletal anomalies (ribs/vertebrae)PTCH1, SUFU, PTCHADIn infancy: echocardiogram At 8 y: dental examination s with jaw X-ray q 12–18 m By 10 y: dermatologic examination q 1 y By 18 y: ovarian U/S SUFU: No jaw X-rays From birth to 3 y: consider brain MRI q 4 m, then q 6 m until 5 y
Hereditary leiomyomatosis and renal cell carcinoma5,16,27Cutaneous or uterine leiomyosarcoma, type II papillary renal cell carcinomaCutaneous leiomyoma, uterine leiomyoma (fibroids)NoneFHADAt diagnosis: skin examinations q 1 y At 8 y: MRI with renal protocol q 1 y At 20 y: gynecologic examination with U/S as needed q 1y
Hereditary paraganglioma-pheochromocytoma5,17Renal cell carcinoma (especially clear cell), gastrointestinal stromal tumors, papillary thyroid carcinoma, paraganglioma, pheochromocytomaParaganglioma, pheochromocytomaNoneSDHA, SDHB, SDHC, SDHD, SDHAF2, TMEM127, MAXADAt 6–8 y: blood pressure at all medical visits, biochemical testing (PFM and/or 24-h UFM, plasma methoxytyramine, optional serum chromogranin A), and CBC (w/RBC indices) q 1 y WBMRI (skull base to pelvis) with optional dedicated neck MRI q 2 y
Hereditary retinoblastoma5,27,29Retinoblastoma (often bilateral), melanoma, osteosarcoma, soft-tissue sarcomas, pineoblastomaRetinomaNoneRB1ADFrom birth to 8 wks: nonsedated exams q 2–4 wks From 8 wks–12 m: EUA q 1 m From 1–2 y: EUA q 2 m From 2–3 y: EUA q 3 m From 3–4 y: EUA q 4 m From 4–5 y: EUA q 6 m From 5–7 y: nonsedated examinations q 6 m At 7 y: consider examinations q 1–2 y At retinoblastoma diagnosis: brain MRI, regular skin examinations by pediatrician At 18 y: skin examinations by primary care physician or dermatologist q 1 y
Juvenile polyposis syndrome5,21,26,27Colorectal, small bowel, pancreatic and stomach cancersJuvenile polyps of the colon, small intestine, stomach, and rectumSMAD4: thoracic aortic disease, HHT: multiple arteriovenous malformations, telangiectasias, epistaxis, cerebral aneurysm, and digital clubbingBMPR1A, SMAD4ADAt 12–15 y: colonoscopy q 1 y until no polyps found, can reduce to q 3 y At 15 y: CBC q 1 y, upper endoscopy and VCE q 1–2 y SMAD4: Screening for HHT-related features Adults: see NCCN
Li-Fraumeni syndrome5,14,27,30Acute lymphoblastic leukemia (often hypodiploid), ACC, brain tumors (astrocytoma, choroid plexus carcinoma, glioma, medulloblastoma), breast cancer, colorectal cancer, differentiated thyroid cancer, kidney cancer, lung cancer, melanoma, neuroblastoma, sarcoma (osteosarcoma, rhabdomyosarcoma, soft-tissue sarcomas)Colon polypsNoneTP53ADBirth to 18 y: physical examination q 3–4 m, including blood pressure, growth, neurologic assessment Abdominal/pelvic U/S q 3–4 m Brain MRI (first w/contrast) q 1 y WBMRI q 1 y Some also include laboratory tests for ACC and hematopoietic malignancies q 1 y Adults: see NCCN
Multiple endocrine neoplasia, type 15,18,27EpendymomaAdrenocortical tumors, collagenoma, carcinoid tumors, facial angiofibroma, leiomyoma, lipoma, meningioma, parathyroid adenoma, pituitary tumors (including prolactinoma, growth hormone, TSH, or ACTH-secreting adenomas), well differentiated endocrine tumors of the gastro-entero-pancreatic tract (including gastrinoma, insulinoma, vasoactive intestinal peptide (Verner-Morrison syndrome), glucagonoma)Primary hyperparathyroidism, hypercalcemiaMEN1ADBiochemical tests q 1 y: At 5 y: prolactin, IGF-1, fasting glucose, and insulin At 8 y: calcium At 10 y: chromogranin-A, pancreatic polypeptide, glucagon, proinsulin, vasoactive intestinal peptide At 20 y: fasting gastrin Imaging: from 5 y: brain MRI q 3 y From 10 y: abdominal MRI q 1 y From 20 y: CT/MRI chest and abdomen q 1–2 y
Multiple endocrine neoplasia, types 2A (MEN2A) and 2B (MEN2B)5,18,27Medullary thyroid cancerPheochromocytomaMEN2A: Parathyroid adenoma or hyperplasia MEN2B: Mucosal ganglioneuromas of the gastrointestinal tract, mucosal neuromasMEN2A: Primary hyperparathyroidism, cutaneous lichen amyloidosis, Hirschsprung disease MEN2B: Marfanoid habitusRETADRisks and age recommendations vary by RET mutation At birth to 3 y: PE to include neck, U/S of neck, serum carcinoembryonic antigen and calcitonin q 6 m for first year, then q 1 y Within first few months of life, by 5 y, or childhood: thyroidectomy At 11 y or 16 y: PFM and normetanephrines or 24-h UFM, serum calcium, and consider intact parathyroid hormone q 1 y
Neurofibromatosis, type 1Breast cancer, glioma (especially optic glioma), gastrointestinal stromal tumor, juvenile myelomonocytic leukemia, embryonal rhabdomyosarcoma, malignant peripheral nerve sheath tumors, neuroblastomaCutaneous/subcutaneous neurofibroma (often multiple), duodenal carcinoid, Lisch nodules of the iris, pheochromocytoma, plexiform neurofibromaAxillary/inguinal freckling, Café-au-lait macules (multiple), learning disabilities, macrocephaly, seizures, skeletal anomalies (scoliosis, sphenoid wing dysplasia, tibial pseudoarthrosis/bowing/dysplasia, vertebral dysplasia), vasculopathyNF1ADFrom birth to 8 y: ophthalmology assessment q 6 m to 1 y From 8–20 y: ophthalmology assessment q 1–2 y At 16–20 y: consider WBMRI PE to include neurologic and skin, blood pressure, height, weight, and pubertal development q 1 y Adult women: See NCCN
Neurofibromatosis, type 2Astrocytoma, ependymoma, glioma, malignant peripheral nerve sheath tumor (rare)Meningioma, neurofibroma (rare), schwannoma (especially vestibular)Balance dysfunction, café-au-lait macules (less common than NF1), hearing loss, posterior subcapsular opacities, tinnitusNF2ADAt diagnosis: PE to include neurologic and audiologic q 1 y; routine eye examinations At 10 y: brain MRI with gadolinium q 1 y, consider 2 MRIs in first year of diagnosis, consider reducing to q 2 y if normal Spinal MRI q 2–3 y; consider WBMRI
Peutz-Jeghers syndrome5,21,26,27Cancers of the breast, cervix (adenoma malignum), colon, lung, ovary (especially ovarian sex cord tumors with annular tubules), pancreas, small bowel, stomach, testes (large-cell calcifying Sertoli cell tumor), uterusGastrointestinal hamartomatous polyps (often small bowel), extraintestinal hamartomatous polypsHyperpigmented macules on fingers, intussusception from polyps, mucocutaneous pigmentation around vermillion border of lips, eyes, nostrils, buccal mucosal, perianal areaSTK11ADAt 8 y: gastroduodenal endoscopy, VCE, colonoscopy q 3 y if polyps, or repeat at 18 y if no polyps PE to include testicular and attention for gynecomastia, precocious puberty q 1 y Adults: See NCCN
PTEN hamartoma syndrome, includes Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome5,16,27,30Breast cancer, colorectal cancer, differentiated thyroid cancer (especially follicular), endometrial cancer, melanoma, renal cell carcinomaFibroma, fibrocystic breast, gastrointestinal polyposis (adenomas, ganglioneuromas, hamartomas), hamartoma, lipoma, Lhermitte-Duclos disease/cerebellar dysplastic gangliocytoma (adult onset), mucocutaneous lesions (acral keratoses, mucosal lesion, papillomatous papule, trichilemmoma), multinodular goiter, uterine fibroidsAutism, developmental delay, macrocephaly, penile freckling, vascular anomaliesPTENADAt 7 y: thyroid U/S q 1–2 y Adults: See NCCN
Rhabdoid tumor predisposition syndrome, types 1 and 25,28Atypical teratoid/rhabdoid tumor, malignant rhabdoid tumorType 1: Malignant peripheral nerve sheath tumor Type 2: small cell carcinoma of the ovary, hypercalcemic typeType 1: congenital neurovascular hamartoma of skin, meningioma, schwannomaNoneType 1: SMARCB1Type 2: SMARCA4ADType 1 SMARCB1: from birth to 5 y: brain MRI and abdominal U/S q 3 m Consider WBMRI Type 2 SMARCA4: no formal recommendations; younger women could consider abdominal U/S q 6 m
Tuberous sclerosis complex, types 1 and 25,19,27Neuroendocrine tumors (pituitary, pancreatic, parathyroid), renal cell carcinoma, subependymal giant cell astrocytomaCardiac rhabdomyoma, cortical tuber, facial angiofibroma, intraoral fibroma, lymphangiomyomatosis, renal angiomyolipoma, renal oncocytoma, retinal hamartoma, subependymal nodule, ungual fibromasBone cysts, dental enamel pits, neurologic issues (autism, behavioral concerns, cortical dysplasia, learning disability, seizures), renal cysts, retinal achromic patch, skin lesions(“confetti” hypopigmented skin lesions, hypomelanotic macules, shagreen patch)TSC1, TSC2ADMultidisciplinary care needed. From infancy to childhood: echocardiogram q 1–3y until regression of rhabdomyoma At diagnosis: abdominal MRI q 1–3 y Brain MRI q 1–3 y until 25 y Routine EEG if known or suspected seizures Skin and ophthalmologic examinations q 1 y Renal function laboratory tests and blood pressure q 1 y Dental examination q 6 m with panoramic X-ray by 7 y Adults: monitoring for LAM
Von Hippel-Lindau syndrome5,17,27Endolymphatic sac tumor, pancreatic islet cell carcinoma, renal cell carcinoma (clear cell)Cyst of kidney, liver, pancreas, spleen; cystadenoma of the broad ligament, epididymis or pancreas; hemangioblastoma of CNS, retina (aka retina angioma), pancreatic neuroendocrine tumors, pheochromocytoma, paragangliomaPolycythemiaVHLADAt birth: eye examination including retina q 1 y At 2 y: blood pressure at all medical visits, PFM or 24-h UFM q 1 y At 5 y: audiogram q 2 y At 8 y: brain MRI with and without contrast, spine MRI with contrast q 2 y At 10 y: abdominal MRI with dedicated renal sequences q 1y

Tumors that Warrant Cancer Genetics Referral If They Occur in Childhood

Adrenocortical carcinoma

Atypical teratoid rhabdoid tumor

Basal cell carcinoma

Cardiac rhabdomyoma

Cerebellar gangliocytoma

Choroid plexus carcinoma

Colon cancer

Cystic nephroma

Desmoid tumor

Endolymphatic sac tumors

Ependymoma

Gastrointestinal stromal tumor

Hemangioblastoma

Hepatoblastoma

Hepatocellular carcinoma

Juvenile granulosa cell tumor

Juvenile myelomonocytic leukemia

Hypodiploid acute lymphoblastic leukemia

Malignant peripheral nerve sheath tumor

Medullary thyroid carcinoma

Medulloblastoma

Melanoma

Neurofibroma

Optic glioma

Ovarian Sertoli-Leydig cell tumor

Pancreatic islet cell tumor

Paraganglioma/pheochromocytoma

Pleuropulmonary blastoma

Pituitary blastoma

Pineoblastoma

Renal cell carcinoma

Retinoblastoma

Rhabdoid tumor

Sarcoma (bone or soft tissue)

Schwannoma

Subependymal giant cell tumor

Wilms' tumor (especially if bilateral)

Noncancerous Features in Hereditary Cancer Syndromes

FeatureExamples
Congenital anomaliesAbnormal hearing or vision, cleft lip/palate, dental anomalies, radial ray or other skeletal anomalies, congenital heart defect, urogenital abnormalities, or congenital anomalies of other organs
Cutaneous and subcutaneous lesionsHyper- or hypopigmentation (such as multiple café-au-lait macules, mucocutaneous pigmentation, axillary or inguinal freckling), shagreen patch, butterfly rash, photosensitivity, multiple benign tumors of the skin (such as dysplastic nevi, neurofibromas, lipomas), palmar/plantar pitting, nevus flammeus or other vascular anomalies
Dysmorphic featuresEar creases/pits, coarse facial features, frontal bossing, broad forehead, abnormal placement of eyes or ears
Endocrine anomaliesCushing syndrome, gigantism/acromegaly, precocious puberty, primary hyperparathyroidism, hypercalcemia
Growth abnormalitiesOvergrowth, poor/stunted growth, asymmetric growth/hemihypertrophy, macro- or microcephaly, macroglossia, organomegaly
Hematologic disordersPancytopenia, anemia, thrombocytopenia, neutropenia, leukopenia, polycythemia
Immune deficiencyFrequent or persistent infections, lymphopenia, autoimmune disorders
Neurodevelopmental or neurologic concernsAutism spectrum disorder, behavioral abnormalities, developmental delay, intellectual disability, learning difficulties, seizures
Ophthalmologic anomaliesCongenital hypertrophy of the retinal pigment epithelium, anirida, coloboma

Additional Resources about Pediatric Cancer and Pediatric Cancer Predisposition Syndromes

American Cancer Societya (www.cancer.org/cancer/cancer-in-children)

Children's Oncology Groupa (www.childrensoncologygroup.org)

National Comprehensive Cancer Networka (www.nccn.org)

PDQ (Physician Data Query): National Cancer Institute's comprehensive source of cancer informationa (www.cancer.gov/publications/pdq)

GeneReviews (www.genereviews.org)

Online Mendelian Inheritance in Man (www.omim.org)

Familial Cancer Database (www.facd.info)

National Society of Genetic Counselors find a genetic counselor tool (www.nsgc.org/findageneticcounselor)

American College of Medical Genetics and Genomics: genetics clinics database (www.acmg.net)

Authors

Stephanie A. Coury, MS, is a Senior Genetic Counselor, Division of Genetics and Genomics, Boston Children's Hospital. Katherine A. Schneider, MPH, is a Senior Genetic Counselor, Center for Cancer Genetics and Prevention, Dana-Farber Cancer Institute. Jaclyn Schienda, ScM, is a Senior Genetic Counselor, Pediatric Cancer Genetic Risk Program, Dana-Farber Cancer Institute. Wen-Hann Tan, BMBS, is an Attending Physician, Division of Genetics and Genomics, Boston Children's Hospital.

Address correspondence to Wen-Hann Tan, BMBS, Division of Genetics and Genomics, Boston Children's Hospital, Fegan 4, 300 Longwood Avenue, Boston, MA 02115; email: wen-hann.tan@childrens.harvard.edu.

Disclaimer: Stephanie A. Coury and Katherine A. Schneider contributed equally to this work.

Disclosure: The authors have no relevant financial relationships to disclose.

10.3928/19382359-20180424-02

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