Clinical Profile of Adults with Inherited Bone Marrow Failure Syndromes: Results of an Ambispective Clinical Single-Center Study

Abstract

BACKGROUND. Inherited bone marrow failure syndromes (IBMFS) is a heterogenous group of rare genetically determined diseases with variable hematologic and nonhematologic manifestations. The implementation of highly specific methods of genetic diagnosis advanced the understanding of IBMFS and allowed its application also beyond pediatrics. That presupposes an awareness of clinical features and reference points for recognizing IBMFS in adults.

AIM. To describe the clinical profile of adult IBMFS patients.

MATERIALS & METHODS. This ambispective single-center study enrolled 35 patients (10 women and 25 men) with IBMFS. Patients were aged 18–51 years (median 26 years). The following IBMFS were identified: congenital dyskeratosis (n = 10; 28 %), Diamond-Blackfan anemia (n = 9; 26 %), Fanconi anemia (n = 7; 20 %), GATA2 deficiency (n = 3; 8 %), Shwachman-Diamond syndrome (n = 1; 3 %), GATA2 deficiency (n = 1; 3 %), amegakaryocytic thrombocytopenia (n = 1; 3 %), bone marrow failure syndrome type 3 (n = 1; 3 %), severe congenital neutropenia (n = 1; 3 %), bone marrow failure with SAMD9 mutation (n = 1; 3 %). These diseases were analyzed in terms of hematologic and nonhematologic manifestations as well as main diagnosis stages and factors that contribute to recognizing IBMFS.

RESULTS. Monolinear cytopenia, bilinear cytopenia, and pancytopenia were identified at hematologic onset in 18 (52 %), 6 (17 %), and 11 (31 %) patients, respectively. The median age of patients by hematologic onset was 15 years (range 0–43 years), in 14 (40 %) patients cytopenia was newly diagnosed at the age of > 18 years. In 23 (63 %) patients hypocellular bone marrow was reported, 7 (20 %) and 5 (14 %) patients had pure red cell aplasia and multilineage myelodysplasia, respectively. Chromosomal aberrations were identified in 2 patients. Paroxysmal nocturnal hemoglobinuria clone was detected in none of 27 examined patients. In 12 (34 %) patients, the criteria for non-severe aplastic anemia were met. Temporary partial or complete spontaneous hematologic recovery was observed in 6 (17 %) patients. Abnormalities with partial or complete organ dysfunctions were identified in 14 patients, whereas all patients showed minor congenital defects. All 7 Fanconi anemia patients and 9 out of 10 congenital dyskeratosis patients demonstrated organ damage specific to these diseases. Family history predominantly showing malignant neoplasms in relatives was reported in 15 (43 %) patients. Initial hematological examination yielded suspect of IBMFS in 12 (34 %) patients with the median time to diagnosis of 6 months. In 23 (66 %) patients, hematologic defects with cytopenia were erroneously accounted for by various acquired diseases, which led to a delayed correct diagnosis (median 7 years). The key factors in suspecting IBMFS were organ abnormalities and positive family history. The IBMFS diagnosis was verified by the next-generation sequencing (NGS) in 29 (83 %) patients and by other specific methods in 4 (11 %) patients. In 2 patients, the diagnosis was established on the basis of complete clinical criteria alone.

CONCLUSION. IBMFS is a matter of current concern and a difficult-to-recognize clinical challenge in adult hematology patients. Differential diagnosis of acquired and congenital bone marrow failure needs to be performed irrespective of patient’s age. A detailed physical examination of patients, family history, and critical analysis of clinical profile and disease course allow for early suspicion of IBMFS. Suspected IBMFS is an indication for referral of patients to specialized centers and performing genetic diagnostics including NGS.