Research Highlights

Stratton P, Giri N, Bhala S, Sklavos MM, Alter BP, Savage SA, Pinto LA. Reduced anti-Müllerian hormone levels in males with inherited bone marrow failure syndromes. Endocr Connect. 2024 Aug 7;13(9):e230510. doi: 10.1530/EC-23-0510. Print 2024 Sep 1.

The study investigates serum anti-Müllerian hormone (AMH) levels in pubertal and postpubertal males with inherited bone marrow failure syndromes (IBMFS) including Fanconi anemia (FA), dyskeratosis congenita-related telomere biology disorders (DC/TBD), and Diamond-Blackfan anemia (DBA). Results indicate that males with FA and DC/TBD have significantly lower AMH levels compared to unaffected relatives and healthy volunteers, suggesting a defect in AMH production similar to that observed in females with IBMFS.

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.

Gianferante DM, Mendez KJW, Cole S, Gadalla SM, Alter BP, Savage SA, Giri N. Genotype-phenotype associations in individuals with Diamond Blackfan anaemia. EJHaem. 2022 Jul 18;13:914141. doi: 10.3389/fgene.2022.914141.

This study examines the genotype-phenotype correlations and outcomes in 121 patients with Diamond Blackfan anemia (DBA), identifying pathogenic germline variants in 71% of cases. Results show that patients with large ribosomal protein subunit variants have a higher prevalence of intellectual disability and gastrointestinal abnormalities, while no significant differences were found in overall survival or cancer incidence between large and small ribosomal subunit gene variants. This detailed genotype-phenotype study of DBA improves our understanding of the role of germline genetics in the clinical manifestations that may help guide the management of people with DBA.

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.

Enache A, Sajjad B, Altintas B, Giri N, McReynolds LJ, Cowen EW. Benign tumors and non-melanoma skin cancers in patients with Fanconi anemia. Fam Cancer. 2024 Nov;23(4):583-590. doi: 10.1007/s10689-024-00410-2. Epub 2024 Jun 21.

This study examines the occurrence of non-melanoma skin cancers (NMSC) and benign tumors (BT) in 200 patients with Fanconi anemia (FA) enrolled in a National Cancer Institute IBMFS study. Results highlight the early onset of NMSC and the diverse anatomical locations of benign tumors, emphasizing the need for consistent and comprehensive monitoring to manage cancer risk and symptoms in FA patients.

Kastellan S, Kalb R, Sajjad B, McReynolds LJ, Giri N, Samuel D, Milde T, Elbracht M, Holzhauer S, Niewisch MR, Kratz CP. Germline biallelic BRCA2 pathogenic variants and medulloblastoma: an international cohort study. J Hematol Oncol. 2024 Apr 29;17(1):26. doi: 10.1186/s13045-024-01547-4.

This study details the genetic, clinical, pathological, and treatment characteristics of eight international patients with Fanconi anemia (FA) due to biallelic BRCA2 pathogenic variants who developed medulloblastoma (MB). Findings indicate a poor prognosis, with all patients succumbing shortly after MB diagnosis, underscoring the need for future experimental treatments to improve outcomes for this lethal condition.

Deng J, Altintas B, Haley JS, Kim J, Ramos M, Carey DJ, Stewart DR, McReynolds LJ. Most Fanconi anemia heterozygotes are not at increased cancer risk: A genome-first DiscovEHR cohort population study. Genet Med. 2024 Mar;26(3):101042. doi: 10.1016/j.gim.2023.101042. Epub 2023 Dec 5.

This study investigated the cancer risk associated with single pathogenic variants in Fanconi anemia (FA) genes using the DiscovEHR cohort of 170,503 individuals. Elevated cancer risk was confirmed for five known cancer predisposition genes, while signals for cancer risk in three additional genes were not validated in secondary cohorts. These findings suggest a need on clinical surveillance given how common pathogenic FA variants are in the population.

Altintas B, Giri N, McReynolds LJ, Best A, Alter BP. 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 study examined the genotype-phenotype correlations and outcomes in 203 patients with Fanconi anemia (FA), focusing on differences across FA/BRCA DNA repair pathway genes and types of pathogenic variants. Findings revealed that patients with upstream complex variants had a less severe phenotype and better survival compared to those with ID or downstream complex variants, while associations between specific phenotypes (e.g., PHENOS and VACTERL-H) and clinical outcomes (e.g., bone marrow failure, cancer risk) were identified, providing valuable insights for understanding and managing FA.

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.

Thompson AS, Niewisch MR, Giri N, McReynolds LJ, Savage SA. Germline RTEL1 Variants in Telomere Biology Disorders. Am J Med Genet A. 2025 Feb;197(2):e63882. doi: 10.1002/ajmg.a.63882. Epub 2024 Sep 16.

This study analyzed 44 individuals from 14 families with mono- or biallelic RTEL1 variants, highlighting significant differences in age at diagnosis and overall survival between heterozygous and biallelic variant carriers, with biallelic carriers presenting earlier and having worse outcomes. The study reviewed 257 RTEL1 variants from literature, finding that only 38.3% met pathogenic/likely pathogenic criteria, and emphasized the need for systematic functional studies and standardized variant curation to better inform clinical management of telomere biology disorders (TBDs) associated with RTEL1 variants.

Niewisch MR, Kim J, Giri N, Lunger JC, McReynolds LJ, Savage SA. Genotype and Associated Cancer Risk in Individuals With Telomere Biology Disorders. JAMA Netw Open. 2024 Dec 2;7(12):e2450111. doi: 10.1001/jamanetworkopen.2024.50111.

This longitudinal cohort study assessed cancer risks among 230 individuals with telomere biology disorders (TBDs) from 2002 to 2022, revealing a 3-fold higher cancer risk compared to the general population. Findings showed that the highest cancer risk and earliest onset were in individuals with autosomal-recessive/X-linked (AR/XLR) inheritance, particularly for head and neck squamous cell carcinomas, while hematologic malignancy risk was highest in those with autosomal-dominant non-TINF2 (AD-non-TINF2) variants; cancer risks increased further after organ transplant across all genetic subgroups, highlighting the need for genotype-tailored cancer screening.

Pearce E, Majid A, Brown T, Wilsnack C, Rising C, Thompson AS, Shepherd RF, Niknafs A, Werner-Lin A, Gilkey MB, Ribisl KM, Hutson SP, Han PKJ, Savage SA. A "rotating menu" of medical uncertainty for families affected by telomere biology disorders: A qualitative interview study. SSM Qual Res Health. 2024 Dec;6:100486. doi: 10.1016/j.ssmqr.2024.100486. Epub 2024 Oct 5.

This qualitative-descriptive study explored the experience and management of medical uncertainty among 32 participants, including individuals with telomere biology disorders (TBDs) and their caregivers. Findings revealed that medical uncertainty in TBDs is a chronic burden with interrelated sources, including scientific, practical, and personal uncertainties, which complicate medical decision-making and relationship formation; participants employed multiple strategies such as information-seeking and community-building, though these could sometimes exacerbate uncertainty rather than alleviate it, highlighting the need for further research and tailored psychosocial interventions.

Wilsnack C, Rising CJ, Pearce EE, Forbes Shepherd R, Thompson AS, Majid A, Werner-Lin A, Savage SA, Hutson SP. Defining the complex needs of families with rare diseases-the example of telomere biology disorders. Eur J Hum Genet. 2024 Dec;32(12):1615-1623. doi: 10.1038/s41431-024-01697-6. Epub 2024 Oct 1.

This study aimed to identify the perceived unmet needs of adults and family caregivers of individuals with telomere biology disorders (TBDs), revealing significant gaps in psychosocial, medical, financial, and daily activity domains. Through an online survey and interviews with 67 participants, findings highlighted chronic family distress and poor coordination of specialty care as critical issues, underscoring the necessity for tailored, multi-disciplinary interventions to address the comprehensive care needs for families dealing with rare diseases like TBDs.

Vittal A, Niewisch MR, Bhala S, Kudaravalli P, Rahman F, Hercun J, Kleiner DE, Savage SA, Koh C, Heller T, Giri N. Progression of liver disease and portal hypertension in dyskeratosis congenita and related telomere biology disorders. Hepatology. 2023 Dec 1;78(6):1777-1787. doi: 10.1097/HEP.0000000000000461. Epub 2023 May 16.

This retrospective study of 58 patients with dyskeratosis congenita (DC) and related telomere biology disorders (TBD) evaluated from 2002 to 2019 revealed a high prevalence (72.4%) of liver abnormalities (defined at baseline assessment by laboratory and/or radiological findings), predominantly cholestatic pattern of liver enzyme elevation. Over six years, 17.2% developed clinically significant liver disease and portal hypertension, especially among those with recessive or TINF2-associated DC. Pulmonary and vascular diseases were significant risk factors for liver disease progression, highlighting the necessity for vigilant monitoring of these complications in DC/TBD patients.