Abstract
Genomic instability disorders are characterized by DNA or chromosomal instability, resulting in various clinical manifestations, including developmental anomalies, immunodeficiency, and increased risk of developing cancers beginning in childhood. Many of these genomic instability disorders also present with exquisite sensitivity to anticancer treatments such as ionizing radiation and chemotherapy, which may further increase the risk of second cancers. In July 2023, the American Association for Cancer Research held the second Childhood Cancer Predisposition Workshop, where multidisciplinary international experts discussed, reviewed, and updated recommendations for children with cancer predisposition syndromes. This article discusses childhood cancer risks and surveillance recommendations for the group of genomic instability disorders with predominantly recessive inheritance, including the DNA repair disorders ataxia telangiectasia, Nijmegen breakage syndrome, Fanconi anemia, xeroderma pigmentosum, Bloom syndrome, and Rothmund–Thomson syndrome, as well as the telomere biology disorders and mosaic variegated aneuploidy. Recognition of children with genomic instability disorders is important in order to make the proper diagnosis, enable genetic counseling, and inform cancer screening, cancer risk reduction, and choice of anticancer therapy.
Introduction
Maintaining genomic stability is important for cell division, proliferation, and function as well as for preventing malignant transformation. A variety of mechanisms cooperate to monitor and repair DNA and chromosome damage and reduce genomic instability. Biallelic germline pathogenic variants (PV) in genes involved in these pathways can cause genomic instability disorders. Individuals with these disorders develop cancers at earlier ages and higher frequencies than the general population. In addition, they typically present with other manifestations affecting multiple systems and organs, such as congenital anomalies, developmental delay, neurologic manifestations, endocrine problems, and immunodeficiency. The diagnosis of genomic instability disorders is based on clinical manifestations, laboratory testing to assess DNA instability such as chromosome breakage analysis or telomere length, biochemical screening [e.g., measuring serum alpha–fetoprotein (AFP) levels], and germline genetic testing. In some cases, diagnosis is made only after cancer has developed and an individual presents with exquisite sensitivities to chemotherapy or radiation. Overall, the penetrance and expressivity of genomic instability disorders can vary widely and, therefore, comprehensive individualized and multidisciplinary approaches are required, preferably at centers with a specific understanding of these disorders.
An international team of multidisciplinary experts met at the AACR Childhood Cancer Predisposition Workshop in 2016 and formulated surveillance recommendations for children with DNA repair disorders (1). In July 2023, this working group reconvened to update these recommendations. The group of syndromes that were discussed, here referred to as genomic instability disorders, was expanded compared with the earlier report (Tables 1 and 2). We provide a basic description of the primary manifestations of each of these disorders and discuss the tumor risks and surveillance recommendations during childhood and adolescence. Our updated recommendations are meant to serve as the basis for the development of a multidisciplinary care plan for providers caring for these patients.
Genetic features of genomic instability disorders.
Disorder . | Biological pathway . | Inheritance: gene(s) . | Diagnostic testing and other laboratory abnormalities . |
---|---|---|---|
Ataxia telangiectasia | DNA double-strand break repair cell cycle checkpoint | AR: ATM | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Chromosome breakage analysis | |||
▪ Immunoblotting | |||
▪ Elevated alpha-fetoprotein | |||
▪ Abnormal karyotype involving chromosomes 7 and 14 | |||
▪ Immunodeficiency (lymphopenia, low levels of immunoglobulin, reduced TREC in newborn screening) | |||
Bloom syndrome | Homologous recombination | AR: BLM | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Sister chromosome exchange analysis | |||
▪ Immunodeficiency (low levels of immunoglobulin) | |||
Dyskeratosis congenita and related telomere biology disorders | Telomere biology | XLR: DKC1 | ▪ Genetic testing (sequencing, including/deletion/, duplication assessment) |
AD or AR: ACD, PARN, RTEL1, and TERT | |||
AD: TERC, TINF2, NAF1, RPA1, and ZCCHC8 | |||
▪ Lymphocyte telomere length measurement using flow cytometry with in situ hybridization | |||
AR: CTC1, DCLRE1B, NOP10, NHP2, POT1, STN1, and WRAP3 | |||
▪ Bone marrow failure | |||
Fanconi anemia | DNA interstrand crosslink repair | XLR: FANCB | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
AD: FANCR/RAD51 | |||
AR: FANCA, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCN/PALB2, FANCO/RAD51C, FANCV/REV7, FANCP/SLX4, FANCQ/ERCC4, FANCS/BRCA1, FANCT/UBET2, FANCU/XRCC2, and FANCW/RFWD3 | |||
▪ Chromosome breakage study | |||
▪ Bone marrow failure | |||
Nijmegen breakage syndrome | DNA double-strand break repair | AR: NBN | ▪ Genetic testing (targeted sequencing for c.657_661del5 variant, sequencing, including deletion/duplication assessment) |
▪ Abnormal karyotype involving chromosomes 7 and 14 | |||
▪ Radiation hypersensitivity | |||
▪ Immunoblotting | |||
▪ Immunodeficiency (lymphopenia, low levels of immunoglobulin, reduced TREC in newborn screening) | |||
Rothmund–Thomson syndrome | DNA replication repair | AR: RECQL4, ANAPC1, CRIPT, and DNA2 | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
Xeroderma pigmentosa | Nucleotide excision repair | AR: XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ERCC4, XPG/ERCC5, POLH(XP-variant), and ERCC1 | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Measurement of unscheduled DNA synthesis | |||
Mosaic variegated aneuploidy | Cell division (mitosis) | AR: BUB1B, CEP57, and TRIP13 | ▪ Genetic testing |
▪ Karyotype analysis on nonmalignant metaphases |
Disorder . | Biological pathway . | Inheritance: gene(s) . | Diagnostic testing and other laboratory abnormalities . |
---|---|---|---|
Ataxia telangiectasia | DNA double-strand break repair cell cycle checkpoint | AR: ATM | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Chromosome breakage analysis | |||
▪ Immunoblotting | |||
▪ Elevated alpha-fetoprotein | |||
▪ Abnormal karyotype involving chromosomes 7 and 14 | |||
▪ Immunodeficiency (lymphopenia, low levels of immunoglobulin, reduced TREC in newborn screening) | |||
Bloom syndrome | Homologous recombination | AR: BLM | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Sister chromosome exchange analysis | |||
▪ Immunodeficiency (low levels of immunoglobulin) | |||
Dyskeratosis congenita and related telomere biology disorders | Telomere biology | XLR: DKC1 | ▪ Genetic testing (sequencing, including/deletion/, duplication assessment) |
AD or AR: ACD, PARN, RTEL1, and TERT | |||
AD: TERC, TINF2, NAF1, RPA1, and ZCCHC8 | |||
▪ Lymphocyte telomere length measurement using flow cytometry with in situ hybridization | |||
AR: CTC1, DCLRE1B, NOP10, NHP2, POT1, STN1, and WRAP3 | |||
▪ Bone marrow failure | |||
Fanconi anemia | DNA interstrand crosslink repair | XLR: FANCB | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
AD: FANCR/RAD51 | |||
AR: FANCA, FANCC, FANCD1/BRCA2, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ/BRIP1, FANCL, FANCN/PALB2, FANCO/RAD51C, FANCV/REV7, FANCP/SLX4, FANCQ/ERCC4, FANCS/BRCA1, FANCT/UBET2, FANCU/XRCC2, and FANCW/RFWD3 | |||
▪ Chromosome breakage study | |||
▪ Bone marrow failure | |||
Nijmegen breakage syndrome | DNA double-strand break repair | AR: NBN | ▪ Genetic testing (targeted sequencing for c.657_661del5 variant, sequencing, including deletion/duplication assessment) |
▪ Abnormal karyotype involving chromosomes 7 and 14 | |||
▪ Radiation hypersensitivity | |||
▪ Immunoblotting | |||
▪ Immunodeficiency (lymphopenia, low levels of immunoglobulin, reduced TREC in newborn screening) | |||
Rothmund–Thomson syndrome | DNA replication repair | AR: RECQL4, ANAPC1, CRIPT, and DNA2 | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
Xeroderma pigmentosa | Nucleotide excision repair | AR: XPA, XPB/ERCC3, XPC, XPD/ERCC2, XPE/DDB2, XPF/ERCC4, XPG/ERCC5, POLH(XP-variant), and ERCC1 | ▪ Genetic testing (sequencing, including deletion/duplication assessment) |
▪ Measurement of unscheduled DNA synthesis | |||
Mosaic variegated aneuploidy | Cell division (mitosis) | AR: BUB1B, CEP57, and TRIP13 | ▪ Genetic testing |
▪ Karyotype analysis on nonmalignant metaphases |
Oncologic manifestations, surveillance recommendations for pediatric patients, and non-cancer manifestations.
Oncologic manifestations . | Cancer surveillance/prevention for children . | Non-cancer manifestations . |
---|---|---|
More frequent evaluations are required for patients with abnormal results and/or certain pathogenic variants. | Presence and severities of manifestations vary among patients. | |
Multidisciplinary team and assessments by specialists in each field are required. | ||
Ataxia telangiectasia | ||
(Pediatric—) | Starting at diagnosis | ▪ Neurologic manifestation (ataxia and abnormal eye movement) |
Lymphoma, leukemia | ▪ Aware of tumor-related symptoms | ▪ Telangiectasia |
(Adult‒) | ▪ ROS and physical assessment including skin exam q 1 year | ▪ Immunodeficiency |
Breast cancer, leukemia, lymphoma, and thyroid cancer | Starting at age 25a | ▪ Slow growth |
Hepatocellular carcinoma, gastrointestinal cancer, and pancreatic cancer | Breast MRI | ▪ Nutrition and feeding problems |
Prevention | ▪ Pulmonary (infection, muscle weakness) | |
Radiation avoidance and sun protection | ▪ Endocrine (insulin resistance and abnormal puberty) | |
▪ Leaning, speech, and cognitive problems | ||
Bloom syndrome | ||
(Pediatric‒) | Starting at diagnosis | |
Lymphoma, leukemia | ▪ Aware of tumor-related symptoms | ▪ Small gestational age and slow growth |
Colorectal polyps/cancer | ▪ ROS and physical assessment q 1 year | ▪ Dermatologic manifestation |
Wilms tumor | ▪ Abdominal US q 3 months (to age 8) | ▪ Nutrition and feeding problems |
(Adult‒) | Starting at age 12–13 | ▪ Immunodeficiency |
Skin cancer | ▪ Colonoscopy q 1 year and fecal immunochemical testing q 6 months | ▪ Nutrition and feeding |
Breast cancer | Starting at the age of 18a | ▪ Endocrine (growth, insulin resistance, and hypothyroidism) |
Leukemia, lymphoma, | ▪ Breast MRI q 1 year | ▪ Infertility |
Colorectal polyps/cancer | Prevention | |
Oropharyngeal cancer | Radiation avoidance, sun protection, and HPV vaccine | |
Dyskeratosis congenita and related telomere biology disorders | ||
(Pediatric‒) | Starting at diagnosis | |
MDS/AML | ▪ Aware of tumor-related symptoms | ▪ Dermatologic manifestations |
▪ ROS and physical assessment q 1 year | ||
HNSCC | ▪ CBC yearly or more frequently based on clinical indications | ▪ Bone marrow failure |
(Adult‒) | ▪ Bone marrow exam (baseline at diagnosis) Consider q 1 year based on clinical manifestations | ▪ Ophthalmologic manifestations (e.g., lacrimal duct stenosis and vascular retinal abnormalities) |
MDS/AML | ▪ Dental assessment q 6 months | ▪ Dental manifestations (e.g., short tooth roots) |
HNSCC | Starting at age 5 | ▪ IUGR |
Anogenital SCC | ▪ Dermatologist screening q 1 year | ▪ Developmental delay of variable severity |
Skin cancer | Starting at age 10 | ▪ Mental health problems (e.g., anxiety and depression) |
▪ Naso laryngoscopy q 1 year | ▪ Endocrine (growth and bone health) | |
Starting at the age of 18 | ▪ Pulmonary (pulmonary fibrosis) | |
▪ Females, starting at age 18 or after becoming sexually active, whichever is first, annual gynecology exam | ▪ Liver disease, including hepatopulmonary syndrome | |
Prevention | ▪ Arteriovenous malformations, usually microscopic of the lungs and/or GI tract | |
Radiation avoidance, sun protection, HPV vaccination, and oral hygiene maintenance | ||
Fanconi anemia | ||
(Pediatric‒) | Starting at diagnosis | |
MDS/AML | ▪ Aware of tumor-related symptoms | ▪ Dermatologic manifestations |
HNSCC | ▪ ROS and physical assessment q 1 year | ▪ Bone marrow failure |
(PVs in FAND1/BRCA2 or FANCN/PALB2) | ▪ CBC q 3–4 months based on clinical features | ▪ Congenital anomalies (microcephaly, skeletal, genitourinary, cardiac) |
Wilms tumor, brain tumor (medulloblastoma) | ▪ Bone marrow exam (baseline at diagnosis, if baseline is normal start annual exam from age 2 years, baseline could be delayed in pts with PVs in FANCA, FANCC, and FANCG until after third birthday) | ▪ Ophthalmologic manifestations (small eyes) |
(Adult‒) | ▪ Dental screening q 6 months | ▪ Endocrine (hypothyroid and insulin resistance) |
MDS/AML | *For pts with PV in FANCD1/BRACA2 or FANCN/PALB2 | ▪ Developmental delay |
HNSCC | ▪ Renal US q 3–4 months (to age 7) | ▪ Hearing loss |
Breast cancer, liver cancer, esophageal cancer, vaginal cancer, brain tumor | ▪ Brain MRI q 3 months (to age 3), q 6 months (to age 5) | |
Starting at age 10 | ||
ENT evaluation with nasolaryngoscopy | ||
(female) Starting at age 13 | ||
▪ Visual exam of the external genitalia | ||
Females, starting at age 18 or after becoming sexually active, whichever is the first annual gynecology exam. | ||
Starting at age 18 or earlier based on clinical manifestations. | ||
▪ Annual skin exam | ||
Prevention | ||
Radiation avoidance, sun protection, HPV vaccination, and oral hygiene maintenance | ||
Nijmegen breakage syndrome | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Microcephaly and dysmorphic facial feature |
▪ Aware of tumor-related symptoms. | ||
▪ Small gestational age and slow growth | ||
▪ Physical assessment and ROS q 1 year | ||
▪ Dermatologic and hair manifestations | ||
Leukemia/lymphoma | Prevention | |
▪ Immunodeficiency (and respiratory infections) | ||
Radiation avoidance, sun protection, and HPV vaccination | ||
▪ Ovarian insufficiency | ||
Rothmund–Thomson Syndrome | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Dermatologic manifestations (poikiloderma) |
▪ Aware of tumor-related symptoms. | ||
▪ Spare hair, eyebrows, and/or eyelashes | ||
(PVs in RECQL4) | ||
▪ Skeletal and nail abnormalities | ||
▪ Physical assessment and ROS q 1 year | ||
▪ Small stature | ||
Osteosarcoma | ||
(Adult‒) | ▪ Consider WBMRI# q 1 year in pts with PVs in RECQL4 | ▪ Dental abnormalities |
▪ Gastrointestinal disorders | ||
Skin cancer | ▪ Dermatologic assessment q 1 year | |
▪ Ophthalmologic manifestations | ||
Prevention | ||
SCC of the tongue | Radiation avoidance, sun protection, and HPV vaccination | |
Xeroderma pigmentosa | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Dermatologic manifestations (severe sun sensitivity) |
Skin cancer | ||
▪ Aware of tumor-related symptoms. | ||
Mucocutaneous oral cancer | ||
▪ Neurologic manifestations | ||
Ocular surface cancer (PVs in XPC) hematologic malignancies (AML/MDS) | ▪ Dermatologic assessment q 3 months | |
▪ Ophthalmologic manifestation | ||
▪ Ophthalmologic and ENT exam q 6–12 months | ||
▪ Hearing loss | ||
Brain tumors, thyroid nodule/cancer | ▪ CBC q 3–6 months and bone marrow assessment q 1 year | |
Prevention | ||
Radiation avoidance, sun protection and avoidance, and HPV vaccination | ||
Mosaic variegated aneuploidy | ||
(Pediatric) | Starting at diagnosis | ▪ Microcephaly |
Wilms tumor | ▪ Renal ultrasound q 3 months until age 7 | |
▪ Growth retardation | ||
Rhabdomyosarcoma | Prevention | |
Hematologic malignancies | ||
▪ Congenital heart defects | ||
HPV vaccine | ||
▪ Intellectual disability | ||
▪ Skeletal malformations |
Oncologic manifestations . | Cancer surveillance/prevention for children . | Non-cancer manifestations . |
---|---|---|
More frequent evaluations are required for patients with abnormal results and/or certain pathogenic variants. | Presence and severities of manifestations vary among patients. | |
Multidisciplinary team and assessments by specialists in each field are required. | ||
Ataxia telangiectasia | ||
(Pediatric—) | Starting at diagnosis | ▪ Neurologic manifestation (ataxia and abnormal eye movement) |
Lymphoma, leukemia | ▪ Aware of tumor-related symptoms | ▪ Telangiectasia |
(Adult‒) | ▪ ROS and physical assessment including skin exam q 1 year | ▪ Immunodeficiency |
Breast cancer, leukemia, lymphoma, and thyroid cancer | Starting at age 25a | ▪ Slow growth |
Hepatocellular carcinoma, gastrointestinal cancer, and pancreatic cancer | Breast MRI | ▪ Nutrition and feeding problems |
Prevention | ▪ Pulmonary (infection, muscle weakness) | |
Radiation avoidance and sun protection | ▪ Endocrine (insulin resistance and abnormal puberty) | |
▪ Leaning, speech, and cognitive problems | ||
Bloom syndrome | ||
(Pediatric‒) | Starting at diagnosis | |
Lymphoma, leukemia | ▪ Aware of tumor-related symptoms | ▪ Small gestational age and slow growth |
Colorectal polyps/cancer | ▪ ROS and physical assessment q 1 year | ▪ Dermatologic manifestation |
Wilms tumor | ▪ Abdominal US q 3 months (to age 8) | ▪ Nutrition and feeding problems |
(Adult‒) | Starting at age 12–13 | ▪ Immunodeficiency |
Skin cancer | ▪ Colonoscopy q 1 year and fecal immunochemical testing q 6 months | ▪ Nutrition and feeding |
Breast cancer | Starting at the age of 18a | ▪ Endocrine (growth, insulin resistance, and hypothyroidism) |
Leukemia, lymphoma, | ▪ Breast MRI q 1 year | ▪ Infertility |
Colorectal polyps/cancer | Prevention | |
Oropharyngeal cancer | Radiation avoidance, sun protection, and HPV vaccine | |
Dyskeratosis congenita and related telomere biology disorders | ||
(Pediatric‒) | Starting at diagnosis | |
MDS/AML | ▪ Aware of tumor-related symptoms | ▪ Dermatologic manifestations |
▪ ROS and physical assessment q 1 year | ||
HNSCC | ▪ CBC yearly or more frequently based on clinical indications | ▪ Bone marrow failure |
(Adult‒) | ▪ Bone marrow exam (baseline at diagnosis) Consider q 1 year based on clinical manifestations | ▪ Ophthalmologic manifestations (e.g., lacrimal duct stenosis and vascular retinal abnormalities) |
MDS/AML | ▪ Dental assessment q 6 months | ▪ Dental manifestations (e.g., short tooth roots) |
HNSCC | Starting at age 5 | ▪ IUGR |
Anogenital SCC | ▪ Dermatologist screening q 1 year | ▪ Developmental delay of variable severity |
Skin cancer | Starting at age 10 | ▪ Mental health problems (e.g., anxiety and depression) |
▪ Naso laryngoscopy q 1 year | ▪ Endocrine (growth and bone health) | |
Starting at the age of 18 | ▪ Pulmonary (pulmonary fibrosis) | |
▪ Females, starting at age 18 or after becoming sexually active, whichever is first, annual gynecology exam | ▪ Liver disease, including hepatopulmonary syndrome | |
Prevention | ▪ Arteriovenous malformations, usually microscopic of the lungs and/or GI tract | |
Radiation avoidance, sun protection, HPV vaccination, and oral hygiene maintenance | ||
Fanconi anemia | ||
(Pediatric‒) | Starting at diagnosis | |
MDS/AML | ▪ Aware of tumor-related symptoms | ▪ Dermatologic manifestations |
HNSCC | ▪ ROS and physical assessment q 1 year | ▪ Bone marrow failure |
(PVs in FAND1/BRCA2 or FANCN/PALB2) | ▪ CBC q 3–4 months based on clinical features | ▪ Congenital anomalies (microcephaly, skeletal, genitourinary, cardiac) |
Wilms tumor, brain tumor (medulloblastoma) | ▪ Bone marrow exam (baseline at diagnosis, if baseline is normal start annual exam from age 2 years, baseline could be delayed in pts with PVs in FANCA, FANCC, and FANCG until after third birthday) | ▪ Ophthalmologic manifestations (small eyes) |
(Adult‒) | ▪ Dental screening q 6 months | ▪ Endocrine (hypothyroid and insulin resistance) |
MDS/AML | *For pts with PV in FANCD1/BRACA2 or FANCN/PALB2 | ▪ Developmental delay |
HNSCC | ▪ Renal US q 3–4 months (to age 7) | ▪ Hearing loss |
Breast cancer, liver cancer, esophageal cancer, vaginal cancer, brain tumor | ▪ Brain MRI q 3 months (to age 3), q 6 months (to age 5) | |
Starting at age 10 | ||
ENT evaluation with nasolaryngoscopy | ||
(female) Starting at age 13 | ||
▪ Visual exam of the external genitalia | ||
Females, starting at age 18 or after becoming sexually active, whichever is the first annual gynecology exam. | ||
Starting at age 18 or earlier based on clinical manifestations. | ||
▪ Annual skin exam | ||
Prevention | ||
Radiation avoidance, sun protection, HPV vaccination, and oral hygiene maintenance | ||
Nijmegen breakage syndrome | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Microcephaly and dysmorphic facial feature |
▪ Aware of tumor-related symptoms. | ||
▪ Small gestational age and slow growth | ||
▪ Physical assessment and ROS q 1 year | ||
▪ Dermatologic and hair manifestations | ||
Leukemia/lymphoma | Prevention | |
▪ Immunodeficiency (and respiratory infections) | ||
Radiation avoidance, sun protection, and HPV vaccination | ||
▪ Ovarian insufficiency | ||
Rothmund–Thomson Syndrome | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Dermatologic manifestations (poikiloderma) |
▪ Aware of tumor-related symptoms. | ||
▪ Spare hair, eyebrows, and/or eyelashes | ||
(PVs in RECQL4) | ||
▪ Skeletal and nail abnormalities | ||
▪ Physical assessment and ROS q 1 year | ||
▪ Small stature | ||
Osteosarcoma | ||
(Adult‒) | ▪ Consider WBMRI# q 1 year in pts with PVs in RECQL4 | ▪ Dental abnormalities |
▪ Gastrointestinal disorders | ||
Skin cancer | ▪ Dermatologic assessment q 1 year | |
▪ Ophthalmologic manifestations | ||
Prevention | ||
SCC of the tongue | Radiation avoidance, sun protection, and HPV vaccination | |
Xeroderma pigmentosa | ||
(Pediatric and adult) | Starting at diagnosis | ▪ Dermatologic manifestations (severe sun sensitivity) |
Skin cancer | ||
▪ Aware of tumor-related symptoms. | ||
Mucocutaneous oral cancer | ||
▪ Neurologic manifestations | ||
Ocular surface cancer (PVs in XPC) hematologic malignancies (AML/MDS) | ▪ Dermatologic assessment q 3 months | |
▪ Ophthalmologic manifestation | ||
▪ Ophthalmologic and ENT exam q 6–12 months | ||
▪ Hearing loss | ||
Brain tumors, thyroid nodule/cancer | ▪ CBC q 3–6 months and bone marrow assessment q 1 year | |
Prevention | ||
Radiation avoidance, sun protection and avoidance, and HPV vaccination | ||
Mosaic variegated aneuploidy | ||
(Pediatric) | Starting at diagnosis | ▪ Microcephaly |
Wilms tumor | ▪ Renal ultrasound q 3 months until age 7 | |
▪ Growth retardation | ||
Rhabdomyosarcoma | Prevention | |
Hematologic malignancies | ||
▪ Congenital heart defects | ||
HPV vaccine | ||
▪ Intellectual disability | ||
▪ Skeletal malformations |
Abbreviations: AML, acute myeloid leukemia; CBC, complete blood count; ENT, ear, nose, and throat; HNSCC, head and neck squamous cell carcinoma; HPV, human papillomavirus; IUGR, intrauterine growth restriction; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging; PV, pathogenic variant; ROS, review of system; SCC, squamous cell carcinoma; US, ultrasound; WBMRI, whole-body MRI. #, head to feet.
Cancer surveillance for adult-onset tumors should be discussed at the time of the transition to and provided by adult service.
Ataxia Telangiectasia
Ataxia telangiectasia (A-T) is an autosomal recessive (AR) multisystem disorder caused by biallelic PVs in the ATM gene. ATM encodes a serine/threonine protein kinase that evokes the DNA damage response on double-strand DNA breaks (1–4). Patients with A-T manifest have neurologic manifestations including ataxia, oculomotor apraxia and cognitive difficulties, telangiectasia, immune deficiency, pulmonary disease, endocrine dysfunctions, and increased risk of malignancy. Abnormal laboratory findings include increased levels of serum AFP, and somatic rearrangements of chromosomes 7 and 14 visible on peripheral blood karyotype analysis (1, 5). Neurologic signs and symptoms are typically the earliest findings leading to the diagnosis of A-T, whereas some patients are diagnosed through newborn screening tests developed for severe combined immunodeficiency (6). Cancer is a major cause of death in patients with A-T (5). The incidence of cancer in patients with A-T is approximately 15% by the age of 18% and 38% by the age of 40 (7, 8). Compared with patients with truncating ATM variants (classic A-T), patients with less deleterious missense/splice-site ATM variants resulting in residual ATM activity (variant A-T) seem to present with milder phenotypes and lower risk of developing hematologic malignancies in childhood, but they are still at high risk of solid tumors such as breast cancer, liver cancer, and gastrointestinal and thyroid cancers, at later ages (9–11).
Cancer screening/surveillance/management protocols
In children with A-T, lymphoma and leukemia are the most common tumors, and approximately 60% of them are non-Hodgkin lymphoma (7, 8). Some patients require routine blood work for the purpose of monitoring their immunologic status. However, after discussion at the 2023 Workshop, we no longer recommend annual blood work, such as complete blood count and lactate dehydrogenase for early detection of hematologic malignancies (1). Different from myeloid leukemia following myelodysplastic syndrome (MDS) and/or bone marrow failure (BMF) syndromes, there is no evidence to support the benefit of routine blood work for early detection of acute lymphoblastic leukemia (ALL) and lymphoma in patients with A-T. However, prompt evaluation should be performed for patients showing signs and symptoms suggestive of leukemia and lymphoma. Patients with A-T are also at risk of developing other tumors including breast cancers, liver cancer, gastrointestinal cancer, and skin cancer at earlier ages than the general population (5, 7, 8). Pediatric cases of brain tumors are also reported. With an estimated incidence of these solid tumors in children of less than 5%, regular surveillance for these cancers including whole-body MRI (WBMRI) is generally not indicated. Therefore, from a pediatric oncological perspective, we recommend an annual physical with skin examination, attention to any concerning signs and symptoms that could indicate an underlying malignancy, as well as avoidance of excess sun exposure and use of sun protective measures.
The treatment of cancers in patients with A-T requires special consideration. Because of their genetic condition and preexisting comorbidities including respiratory and immunologic problems, patients with A-T are highly susceptible to the side effects of cytotoxic chemotherapy and radiotherapy. Reducing the dose of chemotherapy, avoiding radiotherapy, and considering the use of immunotherapy such as rituximab, are recommended (12, 13). Minimizing the use of X-ray and CT is also important. The overall management of patients with A-T requires a multidisciplinary care team that includes neurology, immunology, pulmonology, genetics, oncology, nutrition, occupational therapy, and physiotherapy (14). A-T Children’s Project and AT Society provide information and resources for patients, family members, and medical providers (Table 3).
Resources for patients, families, and caregivers.
Disorder . | Resources . |
---|---|
Ataxia telangiectasia | AT Children’s Project (https://www.atcp.org) |
| Ataxia Telangiectasia Society (https://atsociety.org.uk/) |
Bloom syndrome | Bloom syndrome registry (https://pediatrics.weill.cornell.edu/research/bloom-syndrome-registry) |
Dyskeratosis congenita and telomere biology disorders | Team Telomere (https://teamtelomere.org/) |
Fanconi anemia | Fanconi anemia research fund (https://www.fanconi.org/) |
Rothmund–Thomson syndrome | Rothmund–Thomson Syndrome Foundation (https://www.rtsplace.org/) |
Xeroderma pigmentosa | Xeroderma pigmentosa society (https://www.xps.org/) |
| XP family support group (https://xpfamilysupport.org/) |
Disorder . | Resources . |
---|---|
Ataxia telangiectasia | AT Children’s Project (https://www.atcp.org) |
| Ataxia Telangiectasia Society (https://atsociety.org.uk/) |
Bloom syndrome | Bloom syndrome registry (https://pediatrics.weill.cornell.edu/research/bloom-syndrome-registry) |
Dyskeratosis congenita and telomere biology disorders | Team Telomere (https://teamtelomere.org/) |
Fanconi anemia | Fanconi anemia research fund (https://www.fanconi.org/) |
Rothmund–Thomson syndrome | Rothmund–Thomson Syndrome Foundation (https://www.rtsplace.org/) |
Xeroderma pigmentosa | Xeroderma pigmentosa society (https://www.xps.org/) |
| XP family support group (https://xpfamilysupport.org/) |
Nijmegen Breakage Syndrome
Nijmegen breakage syndrome (NBS) is an AR disorder caused by biallelic PVs in the NBN gene encoding nibrin (2, 15). Nibrin is involved in DNA double-strand break repair, cell cycle checkpoint control, and telomere stability. The c.657_661del5 (p. K219fsX19) PV, which originates from the Slavic population, comprises approximately 100% of PVs detected in patients from Slavic countries and more than 70% of PVs in patients from the United States (15–17). Similar to patients with A-T, patients with NBS typically show hypersensitivity to radiation and are at high risk of developing tumors, particularly lymphomas. Somatic rearrangements, involving chromosomes 7 and 14, are also often detected by peripheral blood karyotypes of patients with NBS. In addition, these patients show an impaired immunologic profile such as a reduced number of CD4-positive T cells and B cells and hypogammaglobulinemia or low levels of one or more immunoglobulin or IgG subclasses. Unlike patients with A-T, elevated AFP levels are not observed in patients with NBS (16). Other common clinical manifestations include microcephaly and dysmorphic facial features (sloping forehead, receding mandible, prominent nose, relatively large ears, and upward slant of the palpebral fissures), café au lait macules, and growth deficiency, particularly in the first 2 years of life and premature ovarian insufficiency. Approximately half of patients with NBS show borderline to mild intellectual disability. Malignancies are the most common cause of early death, followed by pulmonary infection with respiratory insufficiency (16–19).
Cancer screening/surveillance/management protocols
The incidence of malignancies in patients with NBS is approximately 40% to 70% by age 20 (15–17). Most malignancies are of lymphoid origin, including B cell or T cell non-Hodgkin lymphomas and T cell ALL. The incidence of subsequent malignancy is also high in patients with NBS (13%–19%; refs. 19, 20). Other malignancies, such as medulloblastoma and rhabdomyosarcoma, have been reported (16). Similar to the rationale for A-T, we no longer recommend routine blood work for patients with NBS. It is important for patients and caregivers to recognize the cancer risks associated with NBS and its suggestive signs and symptoms. Sun protection and minimizing the use of radiation is recommended.
Cancer treatments for patients with NBS require special consideration and careful monitoring and support, as these patients are at increased risk of toxicities, such as severe infections and respiratory complications (13). Studies have shown that patients with NBS who receive allogeneic hematopoietic cell transplantation (HCT) for hematologic malignancies had better survival than those who did not (19, 20). Although data are limited for standardizing recommendation of HCT for patients with NBS, HCT can be considered for patients in their first remission of hematologic malignancy and also for those who present with clinically apparent immunodeficiency, such as recurrent infections to restore their immune function (13, 21, 22). General management for patients with NBS requires experts from multiple disciplines including genetics, immunology, oncology, endocrinology, and pulmonary medicine, and careful baseline assessment and monitoring for the risk of complications of cancer therapy are recommended (13, 15).
Bloom Syndrome
Bloom syndrome (BS) is a rare disorder caused by biallelic PVs in BLM (1, 2, 23, 24). BLM encodes the RecQ-like DNA helicase BLM, a member of the RecQ helicase family, which plays a crucial role in maintaining genome stability. It unwinds double-stranded DNA into single-strand DNA, suppresses excess sister chromatid exchange in DNA replication, and is involved in double-strand break repair. Increased Sister chromatid exchanges is a characteristic finding in patients with BS, although it is not sufficient to confirm a diagnosis because it is also observed in patients with Bloom-like syndromes caused by PVs in genes other than BLM, such as TOP3A (24). BLM c.2281delATCTGAinsTAGATTC p. (Tyr736fs) is, a common founder variant in individuals of Ashkenazi Jewish ancestry, and founder variants in other ethnicities are reported (23).
Patients with BS are small for gestational age and experience persistent growth problems, dermatologic conditions (e.g., sun-sensitive facial rash and café au lait macules), gastrointestinal and feeding problems, endocrine issues (e.g., hypothyroidism and diabetes mellitus), early-onset cancer, immunodeficiency, chronic lung disease, and impaired fertility (23, 24). A variety of malignancies are reported in patients with BS, and the cumulative incidence of any cancer is 52% by age 30% and 82.5% by age 40 (25). Hematologic malignancies, including ALL, acute myeloid leukemia (AML), and lymphoma, account for approximately one-third of tumors in patients with BS and occur from childhood to young adulthood (25). Gastrointestinal tumors are the second most common neoplasms, with colorectal polyps and cancer occurring at higher prevalence and younger age than in the general population (26). Other tumors that frequently occur in patients with BS include oropharyngeal tumors, breast cancer, skin cancer, and Wilms tumor (25). It should also be noted that sarcoma is recurrently reported in pediatric patients with BS. However, as the reported incidence is 1.4%, we do not recommend routine surveillance (25).
Cancer screening/surveillance/management protocols
A recommended surveillance protocol was published in 2018 based on data from the Bloom Syndrome Registry (26). Here, based on referring to recommendations for patients with autoimmune lymphoproliferative syndrome, annual to biannual WBMRI was recommended for early detection of lymphoma (26, 27). However, in the absence of data to support this approach and because patients with BS do not typically experience progressive lymphadenopathy prior to symptomatic presentation of lymphoma, our group does not recommend routine WBMRI for lymphoma in children. As for the risk of Wilms tumor, routine ultrasound (US) until age 8 has been included in that protocol from the registry and also in our previous recommendations (1, 26). However, as the reported incidence of Wilms tumor is 3%, our group no longer recommends routine US, which is in accordance with recommendations from SIOP-Europe Host Genome Working Group and SIOP Renal Tumor Study Group published in 2021 (25, 28). We endorse at least an annual clinical assessment from diagnosis of BLM and family education about signs and symptoms of hematologic malignancies and Wilms tumor as well. About the risk of colorectal carcinoma, annual colonoscopy and immunochemical fecal occult blood test were recommended every 6 months starting at age 10 to 12 years (26). This is earlier than the youngest age of colorectal carcinoma diagnosis in patients with BS (age 16), because some patients develop polyps before cancer, and early polypectomy is thought to be beneficial for these patients. In line with this, we have also advanced the starting age of colonoscopy from age 15 to 10 to 12 years. However, screening frequency could be extended to less frequent intervals for patients under the age of 16 if no abnormalities have been detected at baseline colonoscopy. Chemotherapy for patients with BS requires special consideration and dose reduction of standard regimens along with an alkylating agent-sparing regimen are encouraged (26, 29). Protection from sun exposure, avoiding radiation, and annual skin exams for a risk of skin cancer are recommended. The care and management of patients with BS requires a multidisciplinary team that includes specialists in genetics, endocrinology, immunology, feeding and nutrition, and oncology. Information for patients with BS, family members, and caregivers is also provided by the Bloom Syndrome Registry (Table 3).
Rothmund–Thomson Syndrome
Rothmund–Thomson syndrome (RTS) is an AR syndrome clinically diagnosed by characteristic skin rash, poikiloderma, in combination with multiple other findings (1, 30, 31). RTS results from biallelic PVs in multiple genes including RECQL4 for RTS type 2. A member of the RecQ helicase family, RECQL4 mainly participates in DNA replication, repair, and recombination and is crucial in maintaining genome stability. PVs in ANAPC1 have been identified in patients with RTS type 1 in 2019 and are associated with a high incidence of juvenile cataracts (32). Additionally, biallelic PVs in CRIPT and DNA2 have recently been identified in several patients clinically diagnosed with RTS without PVs in RECQL4 or ANAPC1 (33, 34). RAPADILINO syndrome and Baller–Gerold syndrome are other overlapping AR disorders caused by PVs in RECQL4 (30, 31). RAPADILINO syndrome does not show the same skin manifestations as RTS. The distinguishing clinical features of Baller–Gerold syndrome are craniosynostosis and radial abnormalities.
Patients with RTS type 2 are at increased risk of osteosarcoma (2, 31, 35). The reported prevalence is 30%, and the median age of onset is 9 to 10 years (35, 36). It is also reported that the estimated probability of osteosarcoma by the age of 20 is about 50% and more than 60% by the age of 40 (37). The estimated survival of osteosarcoma in patients with RTS is not inferior to that in patients without RTS; thus, patients with RTS should receive full-dose treatment regimens unless toxicity develops (30, 36). Patients with RTS are also at high risk of developing skin cancer. The estimated prevalence is 5%, and onset occurs at a younger age than in the general population. Lymphomas are prevalent in RAPADILINO syndrome (30).
Cancer screening/surveillance/management protocols
Due to the high risk of osteosarcoma in patients with PV in RECQL4, head-to-foot WBMRI could be used as a surveillance modality. However, potential risks and benefits should be considered carefully and discussed with patients. The clinical benefit of early detection of asymptomatic osteosarcoma is still uncertain. Furthermore, patients with RTS type 2 often have nonmalignant skeletal abnormalities, which could potentially lead to false-positive findings on WBMRI (38). Considering the median age of onset of osteosarcoma in RTS type 2 is around 10 years, general anesthesia may be needed if WBMRI screening is initiated earlier. Patients’ and caregivers’ awareness of the signs and symptoms of osteosarcoma, such as bone pain and swelling, is highly important. Avoiding excessive sun exposure and use of sun protective measures are recommended to decrease the risk of skin cancer. Obtaining baseline radiographs with a skeletal survey by the age of 5 years is recommended to evaluate underlying skeletal abnormalities in patients with RTS. About the use of X-ray and CT, risks and benefits and the possibility of using alternate imaging should be discussed with patients and families. Annual physical assessments, eye screening, and dermatologic exams are recommended (30). The RTS Foundation provides information and support for patients and family members (Table 3; ref. 39).
Telomere Biology Disorders
Dyskeratosis congenita (DC) and related telomere biology disorders (TBD) are caused by PVs in genes involved in maintaining telomere length and function. At least 18 genes with various inheritance patterns have been reported as causative genes of DC/TBD. DKC1 (X-linked), RTEL1 (AD or AR), TERT (AD or AR), TERC (AD), and TINF2 (AD) are relatively common, whereas PVs in other genes, including ACD (AD or AR), PARN (AD or AR), NAF1 (AD), ZCCHC8 (AD), CTC1 (AR), DCLRE1B (AR), NOP10 (AR), NHP2 (AR), POT1 (AR), RPA1 (AD), STN1 (AR), and WRAP53 (AR), are rare (<1%–5%; refs. 40–45). Impaired function of these genes leads either (or both) to significant shortening or in rare cases lengthening of telomeres. Although the onset of TBDs associated with very short telomeres can be pediatric or adult, long telomeres (e.g., POT1-tumor predisposition) are associated with an increased risk of cancers in adults. Males with PVs in genes associated with X-linked disorders, males or females with biallelic PVs in genes associated with AR disorders, and males or females with heterozygous PVs in TINF2 (usually de novo) develop manifestations in childhood, whereas patients with PVs in genes associated with AD disorders, excluding TINF2, typically develop manifestations in adulthood and have a better prognosis (45, 46).
The classic DC mucocutaneous triad consists of nail dystrophy, reticulated skin pigmentation, and oral leukoplakia. However, many patients do not have all three findings and these findings often develop/progress with age (47). About half of patients with DC develop severe BMF by the age of 40, making it the leading cause of mortality (46, 48). Patients are also at high risk of developing MDS/AML, and solid tumors, including head and neck squamous cell carcinoma (HNSCC), anogenital cancer, lymphoma, and skin cancer, at a younger age than the general population. The risk of MDS/AML and solid tumors starts in the late teens, with a reported median age of onset in 40 seconds for MDS/AML and 20 to 30 for solid tumors. The cumulative incidence of solid tumors by age 50 is 20% to 30%, the risk becomes higher in patients after HCT (42). Other clinical features include ophthalmologic manifestations (epiphora and blepharitis), lung diseases (pulmonary fibrosis and arteriovenous malformations), early graying hair/spare hair, gastrointestinal and hepatic diseases (enterocolitis, gastrointestinal telangiectasias, and liver cirrhosis), developmental delay, neurologic manifestations, and impaired immunologic functions (40–42). Developmental delay, immunodeficiency, enterocolitis, and BMF are major issues from birth or childhood. Pulmonary fibrosis and liver cirrhosis are typically observed in adulthood. However, it should be noted that clinical manifestations, age of onset of these manifestations, and severity of disease phenotypes can vary broadly even within the same family. Hoyeraal–Hreidarsson (HH) syndrome, Revesz syndrome, and Coats plus syndrome are considered rare variants and severe forms of DC/TBD (42). The causative genes and manifestations overlap with DC/TBD. In addition to common features of DC, patients with HH syndrome show cerebellar hypoplasia, intrauterine growth retardation, immunodeficiency, and early-onset BMF. Several genes, including DKC1, TINF2, RTEL1 (biallelic), and TERT (biallelic), have been reported to cause HH syndrome. Meanwhile, Revesz syndrome is characterized by the presence of intrauterine growth retardation, bilateral exudative retinopathy, intracranial calcifications, and early-onset BMF and is usually associated with TINF2 (49).
Cancer screening/surveillance/management protocols
The lymphocyte telomere length measured by flow cytometry with in situ hybridization is a valuable clinical test when diagnosing and assessing the severity of these disorders (45). Patients with typical clinical manifestations of DC/TBD, PVs in genes at high risk of developing manifestations in pediatric age, and/or very short telomeres (<1%ile), require intensive clinical care and screening. Guidelines for the management of patients with TBDs were recently updated (42). For the risk of progressive BMF and MDS/leukemia, at least every 6 months CBC and annual bone marrow monitoring should be considered with the frequency adapted based on the patient’s clinical picture. However, less intensive care would be considered for pediatric patients with limited features of TBD and heterozygous PVs in genes associated with adult-onset manifestations (as detailed above). For example, if baseline bone marrow results show no pathologic abnormalities, further bone marrow monitoring may not be necessary during childhood unless a patient’s CBC shows abnormal findings, or they present with new clinical findings suggestive of severe DC/TBD or hematologic diseases. About the risk of HNSCC evaluation for premalignant lesions by an otolaryngologist is recommended starting at age 10 and continuing annually. A dental assessment every 6 months is recommended to maintain oral hygiene and screen for premalignant lesions. Annual evaluation by dermatologists starting at age five or earlier and sun protection from the time of diagnosis are recommended to reduce the risk of developing skin cancer. As patients with DC/TBD can develop manifestations in multiple organs and systems, baseline evaluation and regular follow-up by a multidisciplinary team are crucial (42, 50, 51). Individuals with DC/TBDs are at risk of severe chemotherapy and radiation therapy complications and dose reductions are usually required (42). Non-myeloablative HCT regimens are required for TBD-related BMF (42). Ionizing radiation is used for the diagnosis and treatment of cancer when the benefit outweighs the possible harm in consideration of potentially high sensitivity to radiation for patients with cancer predisposition disorders, particularly children. Thus, it is important to adjust exposure parameters for pediatric CT based on the individual patient’s size, smallest necessary area, and organs to be scanned (52). Nevertheless, major national and international organizations responsible for evaluating radiation risks agree that there probably is no low-dose radiation “threshold” for inducing cancers. In other words, no amount of radiation should be considered absolutely safe. Team Telomere provides information and resources for patients, family members, and medical providers (Table 3).
Fanconi Anemia
Fanconi anemia (FA) is an inherited BMF syndrome caused by PVs in genes involved in the FA-BRCA pathway, which repairs interstrand cross-links and maintains genome instability (53–57). FA cells show hypersensitivity to agents that cause interstrand cross-links. Diagnosis of FA is confirmed by chromosomal breakage studies measuring DNA breaks after exposure to dieboxybutane or mitomycin C and germline sequencing. Twenty-one FA genes have been identified that operate in distinct functional complexes. PVs in FANCA are most frequently (60%–70%), followed by those in FANCC (10%–14%) and FANCG (8%–10%). The inheritance pattern for FA is AR, except for complementation groups FA-B (X-linked) and FA-R (AD). Approximately 60% to 75% of patients show physical abnormalities, and they are heterogeneous and multisystemic. Common clinical findings include abnormal skin pigmentation, short stature, skeletal malformation of the upper limbs, ophthalmic manifestations, renal anomalies, cardiac malformations, gonadal anomalies, and endocrine disorders (e.g., growth hormone deficiency, hypothyroidism, and diabetes). More than 95% of patients with FA develop BMF, with the majority diagnosed in childhood. The risk of severe BMF by age 50 is 70% (48). However, the absence of BMF does not exclude the diagnosis of FA, and the diagnosis of malignancy can precede the diagnosis of FA. Patients with FA are at increased risk of developing MDS/AML and various solid tumors, particularly HNSCC, which develop much earlier than in the general population. Eleven percent of patients with FA develop cancer at pediatric age, and the cumulative incidence of MDS, leukemia, and solid tumors by the age of 50 years is approximately 50%, 10%, and 20%–30%, respectively (8, 48, 55, 57). The risk of developing solid tumors is higher in patients who receive HCT (48, 58). PVs in FANCD1/BRCA2 or FANCN/PALB2 are associated with a high risk of developing brain tumors (medulloblastoma and others), particularly before the age of 6 years and Wilms tumor (59, 60). As for FANCD1/BRCA2, it is reported that patients who have PV upstream or in exon 11, which encodes the RAD51-binding domain, are more highly susceptible to cancer from infancy and young childhood compared with patients who have both biallelic variants downstream of exon11 (61). In addition to FANCD1/BRCA2 and FANCN/PALB2, recent reports suggest that patients with FANCS/BRCA1 are at high risk of developing pediatric tumors from a very early age. Four of 10 patients with FANCS/BRCA1 developed tumors under the age of 6 years including brain tumors, neuroblastoma, and leukemia (62).
Cancer screening/surveillance/management protocols
From the diagnosis of FA, a CBC every 3 to 6 months and a bone marrow evaluation at least annually are recommended but should be adapted based on the patient’s genotype and clinical manifestations (53, 57, 63). In patients with complementation groups FA-A, FA-C, and FA-G myeloid neoplasms typically do not arise before the age of 4 years (8). Thus, starting bone marrow surveillance after the third birthday is recommended. Patients with homozygous ALDH2 genotype [i.e., GA or AA genotype (rs671) found in the East Asian population] may have early onset of BMF and AML regardless of their complementation group but ALDH2 is not clinically used to guide screening at this time (64). It is also important to distinguish MDS without excess blasts in patients with FA from FA with aberrations of indeterminate potential because the latter group may remain stable without treatment (65). Surveillance of HNSCC, including careful examination of all mucosal surfaces of the head and neck regions, is recommended every 6 months from the age of 10 years. Brush biopsy using cytology and analysis of DNA ploidy is highly sensitive and specific for the early diagnosis of oral cancer without biopsy but is not yet approved for widespread clinical use (66). Abstinence from alcohol and tobacco and maintaining good oral hygiene are also important for reducing the risk of HNSCC. Skin protection and sun avoidance are essential to reduce the risk of skin cancer. Ionizing radiation such as X-ray and CT can be used with consideration of benefit and potential harm. Female patients should receive a visual examination of the external genitalia starting at age 13 years and a comprehensive gynecologic exam starting at age 18 years. For patients with FA-D1 (BRCA2) or FA-N (PALB2), we recommend brain MRI until the age of 5 years (every 3 months until age 3 and every 6 months until age 5) and abdominal US (every 3–4 months) until age 7 years for the risk of medulloblastoma and Wilms tumors, respectively.
The curative therapy for severe BMF is HCT. Considering their acute therapy-related toxicity and late effects, including a high risk of secondary malignancy, the indication, timing of HCT, and conditioning regimen should be carefully considered by FA specialists (63). Long-term follow-up after HCT is required given the continued risk of second malignancies. As described earlier, besides the risk of cancers, patients with FA can have multiple complications, including congenital anomalies, ophthalmic manifestations, and development and endocrine problems. Therefore, regular follow-up by various experts is required. Detailed guidelines for the diagnosis and management of FA are available from the Fanconi Anemia Research Fund (Table 3).
Xeroderma Pigmentosum
Xeroderma pigmentosum (XP) is caused by PVs in genes related to nucleotide excision repair including XPA, XPB (ERCC3), XPC, XPD (ERCC2), XPE (DDB2), XPF (ERCC4), XPG (ERCC5) and ERCC1, and XPV (POLH) which is involved in translation DNA synthesis (67, 68). The incidence of XP and frequency of PVs in each gene vary by ancestry. The estimated rate of XP is 1 in 1,000,000 in the United States, 2.3 in 1,000,000 in Western Europe, and even substantially higher in Japan (1 in 22,000), the Middle East, and North Africa (68, 69). PVs in XPC are the most common form of XP in the United States, Europe, and North Africa, whereas XPA is the most frequently affected gene in Japanese patients. Patients with XP show extreme sun sensitivity. They are at high risk of severe sunburn, poikiloderma, and early-onset skin cancer (basal cell carcinoma, squamous cell carcinoma, and melanoma), oral cancers, and ocular manifestations (photophobia, conjunctival injection conjunctival melanosis, and ocular tumors; refs. 68–72). Although clinical manifestations and sensitivity to UV vary among causative genes, overall, in patients with XP under the age of 20, the risk of melanoma and nonmelanoma skin cancers is 2,000 and 10,000 times higher, respectively than the general population. The median age of nonmelanoma skin cancer diagnosis is 9 years (range from 1 to 32 years; refs. 71, 72). These patients are also at higher risk of developing other cancers including central nervous system tumors, and hematologic malignancies. In particular, PVs in XPC, the majority of which are founder homozygous variants c.1643_1644, are associated with more than a 1,000-fold increased risk of AML in pediatric and young adult ages (73–75). Approximately 25% of patients with XP also show neurologic manifestations including progressive sensory-neural hearing loss, cognitive impairment, neuropathy, and contracture. Patients with PVs in XPC rarely show neurologic manifestations, whereas patients with XPA commonly develop neurologic symptoms.
Cancer screening/surveillance/management protocols
Avoidance of and protection from exposure to ultraviolet (UV)A and UVB are highly important. Patients should reduce sun exposure and indoor-emitted UV, such as uncovered fluorescent light (67, 68). UV meters can be used to assess UV levels in their daily environment. Use of sunscreen with a high sun protection factor, UV-protective clothing and glasses, and UV-resistant films on windows are necessary. Patients with XP need a multidisciplinary team approach to care, including dermatology, ophthalmology, otolaryngology, and neurology assessments and follow-up. In terms of cancer surveillance, dermatologic exams every 3 months and ophthalmologic and oral exams by specialists at least twice a year are recommended. Consuming foods and supplements rich in vitamin D is recommended to prevent vitamin D deficiency. For the risk of AML in patients with PVs in XPC, CBC (once or twice yearly) and annual bone marrow should be considered. Further information for patients with XP and their family members is available at Xeroderma Pigmentosum Society and XP Support Group (Table 3).
Mosaic Variegated Aneuploidy
Mosaic variegated aneuploidy (MVA) syndrome is a rare AR genetic disorder characterized by the presence of constitutional mosaic patterns of variegated aneuploidy, including trisomies and, to a lesser extent, monosomies (76, 77). Individuals with MVA generally present with severe microcephaly, growth deficiency, congenital heart defects, skeletal malformations, and intellectual disability (78). Three major types of MVA have been described, which are caused by biallelic germline PVs in BUB1B (MVA1), CEP57 (MVA2), and TRIP13 (MVA3), respectively (79–81). All three genes encode proteins that promote spindle assembly checkpoint functioning. In addition, other genes causing MVA in patients have recently been reported including CENATAC, SLF2, SMC5, and MAD2L1B, of which the latter is also involved in spindle assembly checkpoint functioning (82–84). A convincing increased cancer risk particularly during childhood has been described only for MVA1 and MVA3. Cancer types in MVA1 include predominantly Wilms tumor and rhabdomyosarcoma, but MDS, AML, and ALL have also been reported (79, 85–87). The limited number of reported families with MVA3 predominantly presented with Wilms tumors, but the cancer spectrum may be broader (81). The two reported siblings of consanguineous parents with biallelic mutations in MAD2l1B developed juvenile granulosa cell tumors of the ovary and testis, respectively. However, a third of unrelated affected individuals did not develop cancer, and other (modifying) genetic cancer risk factors in the siblings cannot be excluded (84). CEP57 has been reported as a haploinsufficient tumor suppressor (88), but at the time of writing, none of the 15 individuals with MVA2 described in the literature developed cancer (80, 89).
Cancer screening/surveillance/management protocols
Although cancer risk is clearly increased in MVA, the rarity of the syndrome hampers the establishment of an accurate risk assessment, particularly when considering the different MVA subtypes. Therefore, we recommend increased awareness in MVA families for early signs of potential tumor development. These include abnormal mass or swelling, hematuria, hypertension, pain, and discomfort. Recommendations for cancer screening and surveillance guidelines for Wilms tumor in children have recently been presented by the SIOP-Europe Host Genome Working Group and SIOP Renal Tumor Study Group (28). This group recommended renal US surveillance every 3 months from birth until the age of 7, for all MVA conditions including those with an unknown genetic cause. Radiation exposure should be avoided. This AACR study group supports these recommendations. Although some of the MVA subtypes, including MVA2, do not show indications for increased cancer risk, the numbers of patients with MVA other than MVA1 and MVA3 are currently too small to recommend against screening. We recommend regular clinical assessment including review of systems to identify signs of rhabdomyosarcoma and other malignancies.
Heterozygous Carriers of Pathogenic Variants
Most of the genomic instability disorders discussed here are caused by biallelic PVs. However, heterozygous PVs in ATM and a subset of the FA genes (FNCS/BRCA1, FANCD1/BRCA2, FANCJ/BRIP1, FNCN/PALB2, or FNCO/RAD51C) are associated with an increased risk of cancers that typically arise in adulthood (breast cancer, epithelial ovarian cancers, and others) and are generally not encountered at childhood (90). Systematic germline (with or without tumor) testing of children with cancer, which is performed in more and more centers, increasingly reveals carriership of germline PVs in these adult-onset cancer predisposition genes. Recent data suggest an association between childhood high-grade glioma and Lynch syndrome, BARD1, and neuroblastoma as well as BRCA2 and rhabdomyosarcoma (91). Although the prevalence of PVs in these genes may be increased in childhood cancer, evidence for causality is currently limited (92).
We do not recommend surveillance during childhood for individuals with a heterozygous carrier of a PV in genes associated with an AR genomic instability disorder. Therefore, cascade testing for pediatric siblings may be deferred if there is no concern that the sibling has the recessive disorder until established evidenced-based guidelines are available. Germline testing must be offered to (biological) relatives of patients who become potential HCT donors to rule out the possibility of having the disorder as a recipient. However, individuals who have monoallelic PV can be donors, although it should be evaluated on a case-by-case basis (93). Furthermore, it has been reported that patients with heterozygous PV in certain DNA damage repair pathway genes may have an increased risk of second cancers (94, 95). Further research is needed to determine the impact of these heterozygous PVs on pediatric patients with cancer and to propose personalized approaches based on the findings. A detailed discussion of adult tumor syndromes in children with cancer is available in a perspective article of this series.
Conclusions
Patients with genomic instability disorders present with a variety of medical complications and elevated risk of cancer beginning in childhood. Therefore, a multidisciplinary team approach is essential. Although recommendations for cancer surveillance and therapeutic approaches should be followed, management should be tailored to the clinical situation of each patient. In addition to routine cancer screening, education for patients and family members about potential signs and symptoms of cancers and recommendations for cancer prevention (e.g., avoidance of UV) are essential. Sharing the latest information and the limitations of current knowledge with patients and their families can help their decision-making. Prospective research on surveillance and a better understanding of genotype–phenotype correlations and modifying factors are expected to lead to further optimization of surveillance including more individualized approaches.
Authors’ Disclosures
H. Lesmana reports other support from Pharming outside the submitted work. C.P. Kratz reports grants from Deutsche Kinderkrebsstiftung during the conduct of the study. L.D. Maese reports grants from St. Baldrick’s Foundation during the conduct of the study, as well as other support from Jazz Pharmaceuticals and Servier Pharmaceuticals outside the submitted work. M.I. Achatz reports personal fees from AstraZeneca and MSD outside the submitted work. A.S. Doria reports grants from Terry Fox Foundation, PSI Foundation, Society of Pediatric Radiology, CARRA Foundation, and Access to Insight outside the submitted work. M.-L.C. Greer reports nonfinancial support from Alimentiv and grants from AbbVie outside the submitted work. S.E. Plon reports membership on a scientific advisory panel for Baylor Genetics. No disclosures were reported by the other authors.
Acknowledgments
Y. Nakano is supported by a Jeffery Brock Cancer Genetics Research Fellowship and Tokyo Children’s Cancer Study Group scholarship of the Gold Ribbons Network. K.E. Nichols, S.E. Plon, and C.C. Porter are supported in part by the St. Baldrick’s Foundation. C.P. Kratz has been supported by the BMBF ADDRess (01GM2205A) and by the Deutsche Kinderkrebsstiftung (DKS 2024.03). The work of SAS is supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute.