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Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond–Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18–6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46–18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3–14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0–8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2–17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57–14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32–11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09–13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57–14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy. [ABSTRACT FROM AUTHOR]

Pediatric myelodysplastic syndromes (MDS) often raise concern for an underlying germline predisposition to hematologic malignancies, referred to as germline predisposition herein. With the availability of genetic testing, it is now clear that syndromic features may be lacking in patients with germline predisposition. Many genetic lesions underlying germline predisposition may also be mutated somatically in de novo MDS and leukemias, making it critical to distinguish their germline origin. The verification of a suspected germline predisposition informs therapeutic considerations, guides monitoring pre- and post-treatment, and allows for family counseling. Presentation of MDS due to germline predisposition is not limited to children and spans a wide age range. In fact, the risk of MDS may increase with age in many germline predisposition conditions and can present in adults who lack classical stigmata in their childhood. Furthermore, germline predisposition associated with DDX41 mutations presents with older adult-onset MDS. Although a higher proportion of pediatric patients with MDS will have a germline predisposition, the greater number of MDS diagnoses in adult patients may result in a larger overall number of those with an underlying germline predisposition. In this review, we present a framework for the evaluation of germline predisposition to MDS across all ages. We discuss characteristics of personal and family history, clinical exam and laboratory findings, and integration of genetic sequencing results to assist in the diagnostic evaluation. We address the implications of a diagnosis of germline predisposition for the individual, for their care after MDS therapy, and for family members. Studies on MDS with germline predisposition have provided unique insights into the pathogenesis of hematologic malignancies and mechanisms of somatic genetic rescue vs. disease progression. Increasing recognition in adult patients will inform medical management and may provide potential opportunities for the prevention or interception of malignancy.

Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA) are inherited bone marrow failure syndromes (IBMFS) with high risks of bone marrow failure, leukemia, and solid tumors. Individuals with FA have reduced fertility. Previously, we showed low levels of anti-Müllerian hormone (AMH), a circulating marker of ovarian reserve, in females with IBMFS. In males, AMH may be a direct marker of Sertoli cell function and an indirect marker of spermatogenesis. In this study, we assessed serum AMH levels in pubertal and postpubertal males with FA, DC/TBD, or DBA and compared this with their unaffected male relatives and unrelated healthy male volunteers. Males with FA had significantly lower levels of AMH (median: 5 ng/mL, range: 1.18-6.75) compared with unaffected male relatives (median: 7.31 ng/mL, range: 3.46-18.82, P = 0.03) or healthy male volunteers (median: 7.66 ng/mL, range: 3.3-14.67, P = 0.008). Males with DC/TBD had lower levels of AMH (median: 3.76 ng/mL, range: 0-8.9) compared with unaffected relatives (median: 5.31 ng/mL, range: 1.2-17.77, P = 0.01) or healthy volunteers (median: 5.995 ng/mL, range: 1.57-14.67, P < 0.001). Males with DBA had similar levels of AMH (median: 3.46 ng/mL, range: 2.32-11.85) as unaffected relatives (median: 4.66 ng/mL, range: 0.09-13.51, P = 0.56) and healthy volunteers (median: 5.81 ng/mL, range: 1.57-14.67, P = 0.10). Our findings suggest a defect in the production of AMH in postpubertal males with FA and DC/TBD, similar to that observed in females. These findings warrant confirmation in larger prospective studies.

• Hematopoietic cell transplantation led to resolution of myelodysplastic syndrome/bone marrow failure and excellent overall survival in SAMD9/SAMD9L patients. • Unique acute posttransplant complications were observed in patients with MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. Germline mutations in SAMD9 and SAMD9L genes cause MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) (OMIM: *610456) and ataxia-pancytopenia (OMIM: *611170) syndromes, respectively, and are associated with chromosome 7 deletions, myelodysplastic syndrome (MDS), and bone marrow failure. In this retrospective series, we report outcomes of allogeneic hematopoietic cell transplantation (HCT) in patients with hematologic disorders associated with SAMD9/SAMD9L mutations. Twelve patients underwent allogeneic HCT for MDS (n = 10), congenital amegakaryocytic thrombocytopenia (n = 1), and dyskeratosis congenita (n = 1). Exome sequencing revealed heterozygous mutations in SAMD9 (n = 6) or SAMD9L (n = 6) genes. Four SAMD9 patients had features of MIRAGE syndrome. Median age at HCT was 2.8 years (range, 1.2 to 12.8 years). Conditioning was myeloablative in 9 cases and reduced intensity in 3 cases. Syndrome-related comorbidities (diarrhea, infections, adrenal insufficiency, malnutrition, and electrolyte imbalance) were present in MIRAGE syndrome cases. One patient with a familial SAMD9L mutation, MDS, and morbid obesity failed to engraft and died of refractory acute myeloid leukemia. The other 11 patients achieved neutrophil engraftment. Acute post-transplant course was complicated by syndrome-related comorbidities in MIRAGE cases. A patient with SAMD9L- associated MDS died of diffuse alveolar hemorrhage. The other 10 patients had resolution of hematologic disorder and sustained peripheral blood donor chimerism. Ten of 12 patients were alive with a median follow-up of 3.1 years (range, 0.1 to 14.7 years). More data are needed to refine transplant approaches in SAMD9/SAMD9L patients with significant comorbidities and to develop guidelines for their long-term follow-up. [ABSTRACT FROM AUTHOR]

Diamond‐Blackfan anemia (DBA) features hypoplastic anemia and congenital malformations, largely caused by mutations in various ribosomal proteins. The aim of this study was to characterize the spectrum of genetic lesions causing DBA and identify genotypes that correlate with phenotypes of clinical significance. Seventy‐four patients with DBA from across Canada were included. Nucleotide‐level mutations or large deletions were identified in 10 ribosomal genes in 45 cases. The RPS19 mutation group was associated with higher requirement for chronic treatment for anemia than other DBA groups. Patients with RPS19 mutations, however, were more likely to maintain long‐term corticosteroid response without requirement for further chronic transfusions. Conversely, patients with RPL11 mutations were less likely to need chronic treatment. Birth defects, including cardiac, skeletal, hand, cleft lip or palate and genitourinary malformations, also varied among the various genetic groups. Patients with RPS19 mutations had the fewest number of defects, while patients with RPL5 had the greatest number of birth defects. This is the first study to show differences between DBA genetic groups with regards to treatment. Previously unreported differences in the rate and types of birth defects were also identified. These data allow better patient counseling, a more personalized monitoring plan, and may also suggest differential functions of DBA genes on ribosome and extra‐ribosomal functions. [ABSTRACT FROM AUTHOR]

Patients with inherited bone marrow failure syndromes (IBMFS), such as Fanconi anemia (FA), dyskeratosis congenita (DC), or Diamond Blackfan anemia (DBA), can have hematologic manifestations cured through hematopoietic cell transplantation (HCT). Subsequent late effects seen in these patients arise from a combination of the underlying disease, the pre-HCT therapy, and the HCT process. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium on late effects screening and recommendations following allogeneic hematopoietic cell transplantation for immune deficiency and nonmalignant hematologic diseases held in Minneapolis, Minnesota in May 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. This multidisciplinary group of experts in rare diseases and transplantation late effects has already published on the state of the science in this area, along with discussion of an agenda for future research. This companion article outlines consensus disease-specific long-term follow-up screening guidelines for patients with IMBFS. [ABSTRACT FROM AUTHOR]

Fanconi anemia (FA), dyskeratosis congenita (DC), and Diamond Blackfan anemia (DBA) are 3 of the most common inherited bone marrow failure syndromes (IBMFS), in which the hematologic manifestations can be cured with hematopoietic cell transplantation (HCT). Later in life, these patients face a variety of medical conditions, which may be a manifestation of underlying disease or due to pre-HCT therapy, the HCT, or a combination of all these elements. Very limited long-term follow-up data exist in these populations, with FA the only IBMFS that has specific published data. During the international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium entitled “Late Effects Screening and Recommendations following Allogeneic Hematopoietic Cell Transplant (HCT) for Immune Deficiency and Nonmalignant Hematologic Disease” held in Minneapolis, Minnesota in May of 2016, a half-day session was focused specifically on the unmet needs for these patients with IBMFS. A multidisciplinary group of experts discussed what is currently known, outlined an agenda for future research, and laid out long-term follow-up guidelines based on a combination of evidence in the literature as well as expert opinion. This article addresses the state of science in that area as well as consensus regarding the agenda for future research, with specific screening guidelines to follow in the next article from this group. [ABSTRACT FROM AUTHOR]

We describe haploidentical bone marrow transplantation with post-transplant cyclophosphamide (PT-CY) for 30 patients with Fanconi anemia (FA). Twenty-six patients were transplanted upfront, and the preparatory regimens included fludarabine 150 mg/m 2  + total body irradiation 200 to 300 cGy ± CY 10 mg/kg without (n = 12) or with rabbit antithymocyte globulin (r-ATG) 4 to 5 mg/kg (n = 14). Four patients were rescued after primary or secondary graft failure after related or unrelated donor transplantation with the above regimen with (n = 2) or without r-ATG (n = 2). PT-CY at 25 mg/kg/day (total dose, 50 mg/kg) followed by cyclosporine and mycophenolate mofetil was given to all patients. All patients engrafted in the subgroup of patients who did not receive r-ATG (n = 14), but their transplant course was complicated by high rates of acute and chronic graft-versus-host disease (GVHD), and only 8 patients are alive. In the subgroup that received r-ATG (n = 16), 14 patients had sustained engraftment, severe GVHD rates were lower, and 13 patients are alive. Hemorrhagic cystitis occurred in 50% of patients, whereas cytomegalovirus reactivation occurred in 75%. One-year overall survival for the entire cohort was 73% (95% CI, 64% to 81%), and all surviving patients achieved full donor chimerism. In conclusion, haploidentical donor transplantation with PT-CY is a suitable option for FA patients without a matched related or unrelated donor. [ABSTRACT FROM AUTHOR]

Hashmi SK, Allen C, Klaassen R, Fernandez CV, Yanofsky R, Shereck E, Champagne J, Silva M, Lipton JH, Brossard J, Samson Y, Abish S, Steele M, Ali K, Dower N, Athale U, Jardine L, Hand JP, Beyene J, Dror Y. Comparative analysis of Shwachman-Diamond syndrome to other inherited bone marrow failure syndromes and genotype-phenotype correlation. Our knowledge of the phenotypes of inherited bone marrow failure syndromes (IBMFSs) derives from case reports or case series in which only one IBMFS was studied. However, the substantial phenotypic overlap necessitates comparative analysis between the IBMFSs. Shwachman-Diamond syndrome (SDS) is an IBMFS that the appreciation of what comprises its clinical phenotype is still evolving. In this analysis we used data on 125 patients from the Canadian Inherited Marrow Failure Study (CIMFS), which is a prospective multicenter population-based study. Thirty-four cases of SDS patients were analyzed and compared to other patients with the four most common IBMFSs on the CIMFS: Diamond Blackfan anemia, Fanconi anemia (FA), Kostmann/severe congenital neutropenia and dyskeratosis congenita (DC). The diagnosis of SDS, FA and DC was often delayed relative to symptoms onset; indicating a major need for improving tools to establish a rapid diagnosis. We identified multiple phenotypic differences between SDS and other IBMFSs, including several novel differences. SBDS biallelic mutations were less frequent than in previous reports (81%). Importantly, compared to patients with biallelic mutations, patients with wild type SBDS had more severe hematological disease but milder pancreatic disease. In conclusion, comprehensive study of the IBMFSs can provide useful comparative data between the disorders. SBDS-negative SDS patients may have more severe hematological failure and milder pancreatic disease. [ABSTRACT FROM AUTHOR]

Somatic runt-related transcription factor 1 ( RUNX1 ) mutations are the most common mutations in various hematological malignancies, such as myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Mono-allelic RUNX1 mutations in germline cells may cause familial platelet disorder (FPD), an inherited bone marrow failure syndrome (IBMFS) associated with an increased lifetime risk of AML. It is suspected that additional RUNX1 mutations may play a role in the pathogenesis of hematological malignancies in IBMFS. This review aims to study the role of RUNX1 mutations in the pathogenesis of hematological malignancies in patients with IBMFS. A PubMed database search was conducted using the following medical subject heading (MeSH) terms: "inherited bone marrow failure syndromes," "hematological neoplasms," "gene expression regulation, leukemic," "RUNX1 protein, human," "RUNX1 protein, mouse," and "Neutropenia, Severe Congenital, Autosomal recessive." Three studies published in 2020 were identified as meeting our inclusion and exclusion criteria. Leukemic progression in severe congenital neutropenia was used as a disease model to evaluate the clinical, molecular, and mechanistic basis of RUNX1 mutations identified in hematological malignancies. Studies in mice and genetically reprogrammed or induced pluripotent stem cells (iPSCs) have shown that isolated RUNX1 mutations are weakly leukemogenic and only initiate hyperproduction of immature hematopoietic cells when in combination with granulocyte colony-stimulating factor 3 receptor ( GCSF3R ) mutations. Despite this, whole-exome sequencing (WES) performed on leukemogenic transformed cells revealed that all AML cells had an additional mutation in the  CXXC finger protein 4 ( CXXC4 ) gene that caused hyperproduction of the ten-eleven translocation (TET2) protein. This protein causes inflammation in cells with RUNX1 mutations. This process is thought to be critical for clonal myeloid malignant transformation (CMMT) of leukemogenic cells. In conclusion, the combinations of GCSF3R and RUNX1 mutations have a prominent effect on myeloid differentiation resulting in the hyperproduction of myeloblasts. In other studies, it has been noted that the mutations in GCSF3R and RUNX1 genes are not sufficient for the full transformation of leukemogenic cells to AML, and an additional clonal mutation in the CXXC4 gene is essential for full transformation to occur. These data have implicitly demonstrated that RUNX1 mutations are critical in the pathogenesis of various hematological malignancies, and further investigations into the role of RUNX1 are paramount for the development of new cancer treatments., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Illango et al.)

Inherited bone marrow failure syndromes (IBMFS) are a group of cancer-prone genetic diseases characterized by hypocellular bone marrow with impairment in one or more hematopoietic lineages. The pathogenesis of IBMFS involves mutations in several genes which encode for proteins involved in DNA repair, telomere biology and ribosome biogenesis. The classical IBMFS include Shwachman–Diamond syndrome (SDS), Diamond–Blackfan anemia (DBA), Fanconi anemia (FA), dyskeratosis congenita (DC), and severe congenital neutropenia (SCN). IBMFS are associated with high risk of myelodysplastic syndrome (MDS), acute myeloid leukemia (AML), and solid tumors. Unfortunately, no specific pharmacological therapies have been highly effective for IBMFS. Hematopoietic stem cell transplantation provides a cure for aplastic or myeloid neoplastic complications. However, it does not affect the risk of solid tumors. Since approximately 28% of FA, 24% of SCN, 21% of DBA, 20% of SDS, and 17% of DC patients harbor nonsense mutations in the respective IBMFS-related genes, we discuss the use of the nonsense suppression therapy in these diseases. We recently described the beneficial effect of ataluren, a nonsense suppressor drug, in SDS bone marrow hematopoietic cells ex vivo. A similar approach could be therefore designed for treating other IBMFS. In this review we explain in detail the new generation of nonsense suppressor molecules and their mechanistic roles. Furthermore, we will discuss strengths and limitations of these molecules which are emerging from preclinical and clinical studies. Finally we discuss the state-of-the-art of preclinical and clinical therapeutic studies carried out for IBMFS. [ABSTRACT FROM AUTHOR]