Page 94 - Haematologica Vol. 107 - September 2022

ARTICLE - Inherited cytopenias in children O. Gilad et al. Table 7. Clinical characteristics of patients referred with a presumptive diagnosis of severe aplastic anemia.
BM: bone marrow; BMF: bone marrow failure; AD: autosomal dominant; Ht: heterozygous; HSCT: hematopoietic stem cell transplant.
Patient
Ethnic origin/ Consanguinity (+/-)
Gene
Disease/ Inheritance
MHGVS Coding
Age (years) at presentation/ diagnosis
Hematological presentation
BM, cytogenetics and functional tests
Extra hematological manifestations
Outcome
5203
Jewish (-)
GATA2
BMF/AD
NM_001145661.1: c.1186C>T -Ht
11/11
Pancytopenia
Severe hypoplastic marrow
Mild dysmorphic features
Post HSCT
Arab ancestry, and in Yemenite Jews.37 Thirteen of our pa- tients were indeed found to be homozygous for the de- scribed polymorphism. In twelve, the clinical phenotype was compatible with ethnic neutropenia, while one patient had a severe phenotype and underwent successful HSCT, suggesting the presence of a yet undiscovered gene caus- ing congenital neutropenia. Notably,mostpatientsreferredwithprolongedneutropenia had no genetic diagnosis. Using both NGS panels and WES, Blombery et al. did not identify a molecular diagnosis in ten of 11 patients with IBMFS who were referred with suspected SCN.38 Using an NGS panel, Galvez et al. successfully diag- nosed only three of 25 patients with prolonged neutropenia.18 Overlap with primary immunodeficiencies,49 new unrecog- nized genes (estimated to be the cause in about 25% of pa- tients with SCN)50 and acquired neutropenia probably contribute to the low yield of pathogenic variant detection among these patients. The overall poor results that we and others achieved calls for better selection of candidates for genetic diagnosis due to isolated neutropenia.
Severe acquired aplastic anemia
Only one patient of 31 (3. 2%) referred with SAA was found to have IBMFS with a variant in GATA2 (Figure 1; Table 7; Online Supplementary Table S3). Most patients in this group underwent an NGS workup. However, three patients under- went only a partial workup by Sanger sequencing. Keel et al. found that among 98 pediatric and young adult patients who underwent HSCT due to what was considered SAA, five (5.1%) had germline genetic alterations in DKC1, MPL and TP53.15 In their study of germline variants in young adults with aplastic anemia, Feurstein et al. found that six of 39 (15,4%) patients had MDS germline predisposition.17 Our patient was already on immunosuppressive therapy when the genetic test results were received. Immunosup- pressive therapy was discontinued, and he successfully underwent HSCT. Interestingly, asymptomatic neutropenia was documented 2 years prior his development of pan- cytopenia. The low number of patients with SAA diagnosed with an underlying inherited syndrome in our cohort may be related to our routine use of an extensive workup to ex- clude inherited disorders, including chromosomal breakage test and evaluation of telomere length.
A main limitation of this nationwide study is that it was conducted retrospectively and that patients were referred
at the discretion of the treating physicians. All the patients referred during the study period were included in our co- hort, yielding a wide variety of clinical presentations. There- fore, we divided the patients to subgroups according to referral diagnoses and analyzed the results of each sub- group independently.
In summary, using NGS panels, we performed a nationwide study of 189 children who presented with prolonged cytopenias. To the best of our knowledge, this is the first comprehensive genetic study of children presenting with a wide range of clinical manifestations including IBMFS, MDS, SAA, thrombocytopenia, and neutropenia. We were able to identify P/LP variants in 31.2% of the children, the majority in genes predisposing to leukemia. Positive diagnostic re- sults were most often achieved in children with suspected IBMFS and with isolated thrombocytopenia. We conclude that applying Sanger sequencing and NGS panels to children with persistent cytopenias is important for ident- ifying inherited syndromes, especially those predisposing to leukemia. This may direct close monitoring and inter- vention prior to the development of overt leukemia.
Disclosures
No conflicts of interest to disclose.
Contributions
OG, HT and OSS designed the study, analyzed the data and wrote the paper; JY, RR, TG, AK, AAQ, HM, NK, NMS, SS, DH, TBA, EA, CL, SA, RE and SBA provided the clinical data of the patients enrolled; OD, SNY, TK, LCY, YK, NO and MHG per- formed the laboratory research and analyzed the data; SI contributed to data analysis and paper writing. All the authors approved the manuscript and submission.
Funding
This work was supported by grants from the Israeli Cancer Association to HT, OD and OSS; from the Israeli Center for Better Childhood to HT; and from grants of the Israeli Health Ministry (# 3-15001) and the Israeli Ministry of Science (#3- 14354 and #14940-3) to SI.
Data-sharing statement
The authors will make their original data available to future researchers upon request directed to the corresponding author.
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