FA is a chromosomal instability disorder caused by germline mutations in the DNA repair genes of the FA/BRCA pathway. Currently, pathogenic variants of at least 22 genes are known to cause FA in humans [4]. Proteins encoded by FA genes play important roles in numerous cellular functions, including DNA repair, detoxification of reactive oxygen species and aldehydes, energy metabolism, and both proinflammatory and myelosuppressive cytokine homeostasis [5-7]. Patients with FA usually develop variable degrees of pancytopenia in childhood and often have short stature, hypopigmented or café au lait spots, thumb or radial ray abnormalities, micro- or hydrocephaly, structural renal anomalies, hypogonadism, and developmental delays. However, up to one-third of the patients with FA do not have congenital anomalies.

Approximately 40% of patients with FA develop severe BMF by the age of 20 years, and half of the patients with FA develop BMF by the age of 50 years. The risk of solid tumors and AML by the age of 50 years in FA is estimated to be 30% and 10%, respectively [8]. The major cancers in FA include head and neck squamous cell cancer, AML, and cancers of the vulva, esophagus, and brain [9]. The incidence of cancer among various IBMFS is highest in patients with FA. Given the impact of a diagnosis of FA has on treatment and surveillance strategies, a chromosomal breakage test is indicated in all patients with BMF [10]. The increased risk of cancer in patients with FA is related to defective DNA repair, which makes somatic cells more susceptible to mutations that could initiate the carcinogenic process [11]. BMF in FA has been proposed to be a consequence of cumulative DNA damage in hematopoietic stem cells, leading to cell death due to genomic instability [12].

Classic DC is characterized by a triad of abnormal skin pigmentation, oral leukoplakia, and nail dystrophy, but there is wide variability in clinical presentations. A growing number of older adults have been diagnosed with DC after the development of pulmonary fibrosis or hepatic disease, coupled with the expansion of genetic testing and appreciation of a broader clinical spectrum. DC is caused by germline mutations in telomere biology genes, which lead to dysfunctional telomere maintenance. Germline mutations in telomere components may result in short telomere length, which is associated with BMF, hepatic and pulmonary fibrosis, and cancer predisposition [13]. The term “DC” is now used interchangeably with telomere biology disorders (TBD) and short telomere syndromes (STSs). DC and the spectrum of DC-related TBDs are diagnosed by leukocyte telomere lengths less than the first percentile for the age when measured by flow cytometry with fluorescence in situ hybridization (flow FISH) [14]. Telomere length testing using flow-FISH is the gold standard because of its high reproducibility. Telomere shortening is highly sensitive but not specific to the diagnosis of these disorders and has been observed in other inherited disorders [15]. Currently, telomere length assessment is recommended in the initial diagnostic workup for BMF to rule out constitutional STS [10]. Overall, unlike in DC, telomere lengths in patients with non-DC IBMFS are usually within the normal range, albeit shorter than those in unaffected individuals [16]. Occasionally, telomere lengths below the age-adjusted first percentile have been reported in patients with IBMFSs other than DC, including FA and SDS; therefore, consideration of the clinical presentation and additional genetic testing results is necessary to establish the correct diagnosis [14, 17].

Pathogenic variants of genes essential for ribosome assembly and function are associated with two IBMFS, DBA and SDS [18]. Although these two IBMFS share a common underlying biology, there are distinct biological and clinical differences between DBA and SDS.

DBA is usually diagnosed based on the early childhood onset of severe, persistent, and often macrocytic anemia with reticulocytopenia [19]. The BM of patients with DBA is usually normocellular or slightly hypocellular and shows characteristic erythroblastopenia with normal lymphoid, granulocytic, and megakaryocytic lineages. Inherited mutations in RPS19 are the most commonly known cause of DBA, accounting for approximately 25% of DBA cases. Elevated erythrocyte adenosine deaminase (eADA) supports the diagnosis of DBA [20].

SDS is characterized by congenital anomalies, BMF with neutropenia being the most prominent feature, and exocrine pancreatic insufficiency. Failure to thrive during infancy may be the first presenting feature of SDS due to pancreatic insufficiency [21]. Biallelic mutations in the SBDS gene are the most common [22]. Approximately 20–30% of patients develop AML/MDS, which is frequently accompanied by a complex karyotype [23].

Severe congenital neutropenia (SCN) is characterized by absolute neutrophil counts consistently less than 200/mL with recurrent severe infections, which often develop within the first few months of life [24]. The most common cause is ELANE gene mutations (∼50%), followed by HAX1 and G6PC3 mutations (10–20%) [25]. Maturation arrest of the myeloid lineage occurs at the promyelocyte and myelocyte stages. Patients with SCN usually do not have congenital anomalies suggestive of an inherited disorder. Patients with SCN have significantly elevated risks of MDS and AML, which appear to be related to their response to granulocyte colony stimulating factor (G-CSF) [26]. Somatic mutations in CSF3R (encoding the G-CSF receptor) and RUNX1 have been frequently observed in those who developed MDS/AML [25].

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare autosomal recessive disease characterized by an isolated and, severe hypomegakaryocytic thrombocytopenia that presents in infancy and progresses to pancytopenia and BMF in later childhood. CAMT occurs most commonly due to mutations in MPL, which encodes for the thrombopoietin receptor. CAMT mutations lead to diminished or absent thrombopoietin receptor signaling. In general, loss-of-function mutations are associated with more severe thrombocytopenia and early-onset pancytopenia [27].

Diseases such as GATA2 deficiency, SAMD9, and MECOM syndrome are increasingly being diagnosed with advancements in precision genomics.

The GATA2 protein is a transcription factor that is critical for embryonic development, maintenance, and functionality of blood-forming, lymphatic-forming, and other tissue-forming stem cells. GATA2 mutation causes deficiency at the cellular levels of GATA2 proteins and the affected individuals may develop hematological, immunological, lymphatic, or other presentations over time that may begin as benign abnormalities but commonly progress to organ (e.g. lung) failure, opportunistic infections, viral infection-induced cancers, AA, MDS, and/or leukemia. GATA2 deficiency is a life- threatening precancerous condition.

Germline SAMD9 and SAMD9L mutations are associated with a clinical spectrum of disorders including MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital problems, and enteropathy) syndrome (SAMD9), ataxia–pancytopenia syndrome (SAMD9L), and myelodysplasia and leukemia syndrome with monosomy 7 [28]. Affected individuals display a highly variable clinical course that ranges from mild and transient dyspoietic changes in the BM to rapid progression to MDS/AML with monosomy 7.

MECOM (MDS1 and EVI1 complex locus) -associated syndromes can range from isolated radioulnar synostosis without hematopoietic defects to severe BMF with normal skeletal development. MECOM-associated syndrome was first described in the context of amegakaryocytic thrombocytopenia-2; however, congenital variants in the MECOM/EVI1 complex on chromosome 3q26.2 have been associated with hematologic defects (e.g., B cell deficiency, BMF, and MDS) and various systemic manifestations (e.g., radioulnar synostosis, clinodactyly, presenile hearing loss, and cardiac/renal malformations) [29, 30]. A range of genetic variants has been identified, including gene deletions and point mutations [31].