Research Highlights

Gutierrez-Rodrigues F, Munger E, Ma X, et al. Differential diagnosis of bone marrow failure syndromes guided by machine learning. Blood. 2022 Dec 21:blood.2022017518. doi: 10.1182/blood.2022017518. Epub ahead of print.

Through this large collaborative study, we developed a machine learning algorithm to distinguish patients with inherited bone marrow failure syndromes from acquired bone marrow failures using comprehensive history, physical findings, and laboratory evaluations at baseline. Our tool can be used by health care providers to prioritize patients with marrow failure for genetic testing or for expeditious treatment.

Alter BP, Giri N, Savage SA, et al. Cancer in the National Cancer Institute inherited bone marrow failure syndrome cohort after fifteen years of follow-up. Haematologica. 2018 Jan;103(1):30-39. doi: 10.3324/haematol.2017.178111. Epub 2017 Oct 19.

This study updated estimates of the types and risks of cancer associated with IBMFS. Continued follow-up will help identify effective methods for cancer prevention and surveillance in individuals with IBMFS.

Giri N, Reed HD, Stratton P, et al. Pregnancy outcomes in mothers of offspring with inherited bone marrow failure syndromes. Pediatr Blood Cancer. 2018 Jan;65(1):10.1002/pbc.26757. doi: 10.1002/pbc.26757. Epub 2017 Aug 12.

Women with any IBMFS experience higher rates of complications during pregnancy, including increased premature births and C-sections. Their pregnancies should be considered high-risk and would benefit from the care of a multidisciplinary team of maternal-fetal specialists with experience in bone marrow failure disorders.

Shankar RK, Giri N, Lodish MB, et al. Bone mineral density in individuals with inherited bone marrow failure syndromes. Pediatr Res. 2017 Sep;82(3):458-464. doi: 10.1038/pr.2017.117. Epub 2017 May 31.

Adults and children with IBMFS often have low bone mineral density. Prompt recognition of risk factors (including hypogonadism, iron overload, and glucocorticoid use) and management are essential to optimize bone health.

Cole S, Giri N, Alter BP, et al. Variable Clinical Features in a Large Family With Diamond Blackfan Anemia Caused by a Pathogenic Missense Mutation in RPS19. Front Genet. 2022 Jul 18;13:914141. doi: 10.3389/fgene.2022.914141.

Family studies inform that family members who have the same disease-causing gene mutation can present differently, and some individuals may not have disease-associated findings. Long term follow-up is important to identify late complications even in people with no disease-related features.

Gianferante MD, Wlodarski MW, Atsidaftos E, et al. Genotype-phenotype association and variant characterization in Diamond-Blackfan anemia caused by pathogenic variants in RPL35A. Haematologica. 2021 May 1;106(5):1303-1310. doi: 10.3324/haematol.2020.246629.

This paper shows that patients with DBA caused by large deletions involving RPL35A can have complex problems involving multiple systems and require comprehensive care by multiple specialists.

Mirabello L, Khincha PP, Ellis SR, et al. Novel and known ribosomal causes of Diamond Blackfan anaemia identified through comprehensive genomic characterization. J Med Genet. 2017 Jun;54(6):417-425. doi: 10.1136/jmedgenet-2016-104346. Epub 2017 Mar 9.

This study discovered novel pathogenic genetic variants in people with DBA and provided additional information about known genetic causes of DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.

Altintas B, Giri N, McReynolds LJ, et al. Genotype-phenotype and outcome associations in patients with Fanconi anemia: the National Cancer Institute cohort. Haematologica. 2023 Jan 1;108(1):69-82. doi: 10.3324/haematol.2021.279981.

This comprehensive study of a large cohort of patients with Fanconi anemia provides a detailed assessment of physical abnormalities and clinical outcomes in relation to Fanconi anemia genes, mutation pathways and type of genetic variants.

Bourke G, Wilks D, Kinsey S, et al. The incidence and spectrum of congenital hand differences in patients with Fanconi anaemia: analysis of 48 patients. J Hand Surg Eur Vol. 2022 Jul;47(7):711-715. doi: 10.1177/17531934221087521. Epub 2022 Mar 31.

This study demonstrates the broad spectrum of radial ray anomalies seen in patients with Fanconi anemia and suggests screening for Fanconi anemia in newborns with radial ray anomaly.

Alter BP, Giri N, McReynolds LJ, et al. Fanconi anaemia: A syndrome with distinct subgroups. Br J Haematol. 2022 May;197(4):467-474. doi: 10.1111/bjh.18091. Epub 2022 Feb 22.

This study discusses that people with Fanconi anemia who are diagnosed as adults are distinct from those diagnosed during childhood. People diagnosed with FA as adults may not have hematological problems or obvious physical findings that are characteristics of FA diagnosed during childhood but may have come to attention through family studies or due to early onset cancer or severe complication of cancer treatment.

McReynolds LJ, Giri N, Leathwood L, et al. Risk of cancer in heterozygous relatives of patients with Fanconi anemia. Genet Med. 2022 Jan;24(1):245-250. doi: 10.1016/j.gim.2021.08.013. Epub 2021 Nov 30.

This study of parents, grandparents, and siblings of patients with Fanconi anemia enrolled in our cohort shows that the risk of cancer is not increased in people who carry a single copy of pathogenic variant in FA gene. This does not apply to carriers of gene variants in BRCA1, BRCA2, PALB2, BRIP1, and RAD51C.

McReynolds LJ, Biswas K, Giri N, et al. Genotype-cancer association in patients with Fanconi anemia due to pathogenic variants in FANCD1 (BRCA2) or FANCN (PALB2). Cancer Genet. 2021 Nov;258-259:101-109. doi: 10.1016/j.cancergen.2021.10.001. Epub 2021 Oct 4.

This review of world literature of FA describes the types of early childhood embryonic cancers that are seen only in patients with FA due to pathogenic variants in FANCD1 and FANCN and not in FA caused by pathogenic variants in other FA genes. Surveillance for these specific cancers is recommended for patients with FANCD1 and FANCN genotypes.

Fiesco-Roa MO, Giri N, McReynolds LJ, et al. Genotype-phenotype associations in Fanconi anemia: A literature review. Blood Rev. 2019 Sep;37:100589. doi: 10.1016/j.blre.2019.100589. Epub 2019 Jul 16.

The paper describes various physical findings that have been identified in patients with Fanconi anemia and the findings that are more common. Knowledge of the presence of these findings can facilitate early diagnosis of Fanconi anemia.

Alter BP, Giri N. Serum alpha fetoprotein levels in Fanconi anaemia. Br J Haematol. 2019 Mar;184(6):1074-1076. doi: 10.1111/bjh.15517. Epub 2018 Aug 20.

This study discovered novel pathogenic genetic variants in people with DBA and provided additional information about known genetic causes of DBA. Ongoing studies of DBA genomics will be important to understand this complex disorder.

Thompson AS, Giri N, Gianferante DM, et al. Shwachman Diamond syndrome: narrow genotypic spectrum and variable clinical features. Pediatr Res. 2022 Dec;92(6):1671-1680. doi: 10.1038/s41390-022-02009-8. Epub 2022 Mar 23.

This study of NCI cohort highlights the importance of multidisciplinary team approach in diagnosis and management of patients with Shwachman Diamond Syndrome due to their diverse clinical presentations involving multiple organ systems in spite of a narrow genotype spectrum.

Niewisch MR, Giri N, McReynolds LJ, et al. Disease Progression and Clinical Outcomes in Telomere Biology Disorders. Blood. 2022 Mar 24;139(12):1807-1819. doi: 10.1182/blood.2021013523.

This long-term study of the clinical manifestations of telomere biology disorders (TBD) created a foundation for incorporating the mode of inheritance into evidence-based clinical care guidelines, and risk stratification in patients with TBDs.

Thompson MB, Muldoon D, de Andrade KC, et al. Lipoprotein particle alterations due to androgen therapy in individuals with dyskeratosis congenita. EBioMedicine. 2022 Jan;75:103760. doi: 10.1016/j.ebiom.2021.103760. Epub 2021 Dec 17.

This work describes how androgen treatment for telomere biology disorders can alter a patient’s blood lipids. Individuals receiving androgen therapy should have cardiovascular disease monitoring.

Giri N, Alter BP, Savage SA, et al. Gynaecological and reproductive health of women with telomere biology disorders. Br J Haematol. 2021 Jun;193(6):1238-1246. doi: 10.1111/bjh.17545. Epub 2021 May 21.

This work describes the gynecological and reproductive health complications of telomere biology disorders (TBD). Women with TBDs benefit from multidisciplinary, coordinated care by hematology, gynecology and maternal-fetal medicine consultation.

Toufektchan E, Lejour V, Durand R, et al. Germline mutation of MDM4, a major p53 regulator, in a familial syndrome of defective telomere maintenance. Sci Adv. 2020 Apr 10;6(15):eaay3511. doi: 10.1126/sciadv.aay3511.

This work identified that pathogenic variants in MDM4 causes a dyskeratosis congenita-like syndrome.

Giri N, Ravichandran S, Wang Y, et al. Prognostic significance of pulmonary function tests in dyskeratosis congenita, a telomere biology disorder. ERJ Open Res. 2019 Nov 15;5(4):00209-2019. doi: 10.1183/23120541.00209-2019.

This work showed that pulmonary function abnormalities are common in patients with telomere biology disorders and are associated with progression to significant pulmonary disease.

Bhala S, Best AF, Giri N, et al. CNS manifestations in patients with telomere biology disorders. Neurol Genet. 2019 Oct 29;5(6):370. doi: 10.1212/NXG.0000000000000370.

This work described the structural brain abnormalities, and the neurological and psychiatric complications seen in patients with telomere biology disorders.

Higgs C, Crow YJ, Adams DM, et al. Understanding the evolving phenotype of vascular complications in telomere biology disorders. Angiogenesis. 2019 Feb;22(1):95-102. doi: 10.1007/s10456-018-9640-7. Epub 2018 Aug 25.

This article summarized the findings of the 2017 workshop on vascular abnormalities in patients with telomere biology disorders held at the NCI in conjunction with Team Telomere.

Khincha PP, Bertuch AA, Gadalla SM, et al. Similar telomere attrition rates in androgen treated and untreated individuals with dyskeratosis congenita. Blood Adv. 2018 Jun 12;2(11):1243-1249. doi: 10.1182/bloodadvances.2018016964.

This work showed the rate of telomere attrition is similar in patients telomere biology disorders comparing those patients on and off androgen treatment.

Ward SC, Savage SA, Giri N, et al. Beyond the triad: Inheritance, mucocutaneous phenotype, and mortality in a cohort of individuals with dyskeratosis congenita. J Am Acad Dermatol. 2018 Apr;78(4):804-806. doi: 10.1016/j.jaad.2017.10.017. Epub 2017 Oct 16.

Individuals with more skin, nail and mouth complications of DC were more likely to have certain genes affected and more medical complications. Careful detection of all mucocutaneous features of DC is important for early referral, confirmatory testing, and appropriate clinical management.