Page 91 - Haematologica Vol. 107 - September 2022

ARTICLE - Inherited cytopenias in children
referred with MDS and one with a suspected IBMF. Simi- larly, of the five patients with variants in ANKRD26, four had isolated thrombocytopenia and one had MDS (Table 1; Figure 1). This emphasizes the variable phenotypic pres- entation of children with inherited cytopenias and sup- ports an unbiased diagnostic approach.
Inherited bone marrow failure syndromes
Of the 48 patients referred for an NGS workup with a di- agnosis of IBMFS, 60.4% were genetically diagnosed. All but two had classical IBMFS, including FA, DBA and DC (Figure 1; Table 2; Table 3; Online Supplementary Table S3). These results are similar to those obtained in recent studies, in which the diagnosis rate of IBMFS was 48- 59%.38,39 The relatively high accurate referral diagnosis of patients with IBMFS is probably related to the classical clinical presentation, including typical congenital anomalies (in 70.8% of the patients in this group; Online Supplementary Table S2), as well as to the availability of functional screening tests for FA (chromosomal breakage
O. Gilad et al. test) and DC (telomere length) that support the diagno-
sis.
Myelodysplastic syndromes
Of 26 children referred with MDS, based on cytopenias and BM morphology, with or without cytogenetic abnor- malities, six (23.1%) were found to have germline variants: three in SAMD9L, two in ERCC6L2 and one in ANKRD26 (Figure 1; Table 4; Online Supplementary Table S3). Inter- estingly, although germline variants in GATA2 are com- monly found in pediatric patients with MDS,9 none of our patients referred with MDS had genetic alterations in this gene. Feurstein et al. recently found that 19% (13/68) of young adults with MDS/AML had sequence variants in leukemia predisposition genes,17 including in GATA2, ERCC6L2, RUNX1, ANKRD26, CSF3R, DC genes, FANCA and PARN. None of them had SAMD9/L variants; the latter have been commonly described in children with MDS.9 In our study, all pathogenic variants were found in patients with RCC, while none of the seven patients with MDS-EB car-
Table 4. Clinical characteristics of patients referred with a diagnosis of myelodysplastic syndrome.
Patient
Ethnic origin/ Consanguinity (+/-)
Gene
Disease/ Inheritance
MHGVS Coding
Age at presentation/ diagnosis
Hematological presentation
BM, cytogenetics and functional tests
Extra hematological manifestations
Outcome
5467
Jewish (-)
SAMD9L
MDS/AD
NM_152703: c.4736A>G-Ht
0.4y/0.8y
Pancytopenia
Hypocellular with myelodysplasia, monosomy 7
None
Followup
5096
Jewish (-)
SAMD9L
MDS/AD
NM_152703.4: c.4045C>G-Ht
0.9y/5.5y
Pancytopenia
Hypocellular mar- row, monosomy 7 -re- solved
None
Followup
5371
Eritrean (-)
SAMD9L
MDS/AD
NM_152703.2: c.2957G>A -Ht
1.2y/2y
Pancytopenia
Hypocellular, dysplastic megakarycytes, monosomy 7 -re- solved
None
Followup
5418
Arab Muslim (+)
ERCC6L2
BMF/AR
NM 001010895.2: c.535A>G- Hm
20y/27y
Anemia, followed by pancytopenia
Dysplastic red cell precursors
None
Died of sepsis
5249
Druze (+)
ERCC6L2
BMF/AR
NM_020207.7: c.3492+2T>G Hm
16y/16y
Anemia, thrombocyto- penia
Hypercellular dysplasia
None
Died of sepsis
4261
Jewish (-)
ANKRD 26
IT-MDS/AD
NM_001256053.1: c.3G>A -Ht
1-7d/6y
Thrombocytope- nia
Hypocellular mar- row, monosomy 7, monosomy 21 (germline)
Short stature, mildly dysmorphic features, combined immune deficiency, bicuspid aortic valve
Followup
BM: bone marrow; BMF: bone marrow failure; IT: inherited thrombocytopenia; MDS: myelodysplastic syndrome; AR: autosomal recessive; AD: autosomal dominant; y: years; d: days; Ht: heterozygous; Hm: homozygous.
Haematologica | 107 September 2022
2090