Table 3.

Recommendations for the clinical care and surveillance of patients with pathogenic germline hereditary myeloid malignancy syndrome variants

Syndrome	At diagnosis	At follow-up	Research questions
All inherited MDS and/or AL syndromes	CBC with differential	CBC with differential every 6-12 mo3,38,72,78	What drives progression from the carrier state to overt malignancy development?
	Clinical examination	Clinical examination every 6-12 mo
	BM biopsy with aspirate and cytogenetic/molecular analysis3,38,72,78	BM biopsy with aspirate and cytogenetic/molecular analysis at the time of any significant, persistent change in blood counts3,38,72,78	What are useful clinical biomarkers of impending malignancy development?
	Educate the patient regarding signs and symptoms of MDS/AL and to alert his/her physician promptly for evaluation if any develop	If MDS or AL develops, consider risks and benefits of allogeneic transplant in first remission given risk of future second primary leukemias
	Consider HLA typing patient and all full siblings
	Site-specific testing for pathogenic germ line mutation in potential related donors
	Careful consideration of matched related stem cell donors: avoid donors known to carry pathogenic germ line mutations or those with cytopenia(s) or donors who fail to mobilize well in whom a germ line mutation is not identifiable
	Offer genetic counseling and site-specific testing for the familial mutation to all at-risk individuals
Familial MDS/AL with mutated DDX41			How effective is lenalidomide for MDS/AML or other hematologic malignancies in the setting of a germ line DDX41 mutation?13
			What is the risk of lymphoma development and autoimmunity in those with germ line DDX41 mutations and does it vary by mutation type?14
Familial aplastic anemia/MDS with SRP72 mutation	Screen newborns for congenital sensorineural deafness20
Inherited syndromes associated with thrombocytopenia and platelet dysfunction	Educate the patient and his/her physicians that no specific treatment is required for asymptomatic thrombocytopenia	Provide platelet transfusions prior to major surgery or childbirth and consider HLA-matched platelets to avoid alloimmunization	ANKRD26: Do MEK inhibitors effectively improve platelet counts without limiting toxicities in patients with thrombocytopenia 2?80
Thrombocytopenia 2 (ANKRD26)	Treatments for ITP, such as steroids and splenectomy, are ineffective and should be avoided10,11,17-19,28
Thrombocytopenia 5 (ETV6)	Education regarding possible excessive bleeding risk with surgery, childbirth, or injury due to platelet dysfunction and to inform his/her hematologist prior to any invasive procedure for management recommendations	Consider allogeneic HSCT if a patient develops a regular transfusion requirement, clonal cytogenetic abnormality, dysplasia, or an overt hematologic malignancy	ETV6: Are colon cancer, GERD, myopathy and/or autoimmune disorders part of the clinical phenotype?17-19
FPD/AML (RUNX1)	Consider platelet aggregation assays to evaluate platelet function		RUNX1: Can gene-corrected induced pluripotent stem cells reconstitute hematopoiesis and cure the BM manifestations?81
GATA2 deficiency syndromes (GATA2)	Screen for HPV infection and HPV-related cervical, head and neck, and anogenital cancers76	Screen for HPV infections and HPV-related malignancies at least every 12 mo76	Consider systemic interferon α for patients with refractory HPV or herpesvirus infections76
	Consider HPV vaccination76	Repeat pulmonary function testing annually or sooner if new symptoms develop76
	Perform baseline pulmonary evaluation with pulmonary function testing. Include CT scan if symptoms warrant76	Consider allogeneic transplant if a patient develops: a regular transfusion requirement, clonal cytogenetic abnormality, dysplasia, overt BM malignancy or recurrent severe infections
	Educate the patient and his/her physicians regarding the increased risk of opportunistic infections (especially mycobacterial infections) due to immunodeficiency	Consider allogeneic transplant if patient shows somatic ASXL1 mutations and/or elevated (or increasingly elevated) FLT3 ligand39
	Consider azithromycin prophylaxis76
	Replace immunoglobulins if low and repeated infections
	Screen for congenital deafness and avoid ototoxic drugs
Telomere syndromes due to TERC or TERT mutation	Consider telomere length measurement by flowFISH as first diagnostic test or to aid in diagnosis in those without an identifiable telomere-related mutation and/or variant of uncertain significance	If BM failure develops and warrants treatment,
		•avoid immunosuppression as a therapeutic strategy for telomere syndrome-associated AA given lack of efficacy (refer to DC guidelines statement77)
		•carefully consider allogeneic HSCT
		•androgens may lead to hematologic response82,83
	Educate patient to avoid smoking and pulmonary and BM toxic medications and to report any disease associated symptoms promptly for evaluation
	Perform baseline pulmonary evaluation including pulmonary function tests ± CT scan for all with symptoms (eg, chronic cough or dyspnea) and asymptomatic carriers at age 40 y or 5-10 y earlier than the earliest pulmonary fibrosis or emphysema case in the family	Repeat pulmonary function tests every 1-3 y or sooner if any symptoms develop
	Assess liver function tests; if abnormal, perform hepatic ultrasound and consider hepatology evaluation with telomere syndrome experienced physician	Assess liver function tests annually or with symptoms; perform hepatic ultrasound and consider hepatology evaluation if abnormal
	Screen for clinical symptoms of head and neck cancer and perform baseline dental and head and neck exam	Screen for head and neck cancer via thorough dental evaluations every 6 mo ± otolaryngology evaluation annually or with symptoms
	Screen for clinical symptoms of anogenital cancer; for females, perform pap/pelvic exam	Screen for clinical symptoms of anogenital cancer; for females, perform pap/pelvic exam annually
	Consider HPV vaccination
	Awareness that younger generations may present with more severe disease at earlier ages (anticipation)	If HSCT is warranted, choose a conditioning regimen with known efficacy and lack of excess toxicity in patients with telomere syndromes (eg, avoid busulfan-based regimens)73-75
Li-Fraumeni syndrome	CBC with differential and ESR/LDH every 4 mo32,71	Follow chosen Li-Fraumeni syndrome screening protocol (interval for exams and screening tests every 4-6 mo)32,71
	Consider a comprehensive screening program, ideally on a clinical trial, for the core Li-Fraumeni syndrome cancers (eg, breast, brain, and sarcoma)
	Avoid unnecessary radiation to prevent radiation-induced malignancies79

CT, computed tomography; DC, dyskeratosis congenita; ESR, erythrocyte sedimentation rate; flowFISH, fluorescent in situ hybridization with flow cytometry; GERD, gastroesophageal reflux disease; HPV, human papillomavirus; LDH, lactate dehydrogenase.