Page 93 - Haematologica Vol. 107 - September 2022

ARTICLE - Inherited cytopenias in children
O. Gilad et al.
with variants in ERCC6L2.42 Future studies will help eluci- date the full natural history of this disorder.
Monoallelic nucleotide substitutions at the 5’UTR of the ANKRD26 gene were found in 18% of the patients with IT and are the most common cause of IT with a predisposi- tion to MDS/AML.11,43 These variants cause gain of function and disrupt the downregulation of the expression of ANKRD26 by RUNX1 and FLI1. This causes suppression of megakaryopoiesis, which leads to thrombocytopenia and to MDS/AML later in life.44 We describe here an initiation codon variant in ANKRD26 (c.3G>A), in an 8-year-old boy with mosaic monosomy 21 who presented with MDS. This variant was previously described in two adult patients with AML and was shown to cause ANKRD26 over- expression as well.45
Inherited thrombocytopenia
Of the 33 patients referred with thrombocytopenia, 17 (51.5%) had IT (Figure 1; Table 5; Online Supplementary Table S3). Of them, nine (27.3% of 33) had variants affecting late megakaryopoiesis and platelet production, without a pre- disposition to leukemia (in MYH9, ACTN1, NBEAL2 and CYCS); while eight patients (24.2% of 33) had variants in genes encoding for growth factors involved in early mega- karyopoiesis and a predisposition to leukemia (4 had vari- ants in the 5'UTR of ANKRD26, 2 in ETV6 and 1 in RUNX1; and 1 had a biallelic genetic alteration in GALE). Molecular
diagnosis of IT is essential, not only for identifying patients with a predisposition to leukemia but also for offering ac- curate diagnosis and avoiding the false diagnosis of im- mune thrombocytopenia (ITP), with possible subsequent futile treatment including splenectomy.46,47 Indeed, five of our IT patients (29.4%), diagnosed with ANKRD26, ACTN1, ETV6, CYCS and MYH9 variants, were considered to have chronic ITP and were treated as such (Table 5). These re- sults emphasize that persistence of mild to moderate thrombocytopenia from birth, and a lack of response to ITP therapy should alert physicians to suspect IT.
Congenital neutropenia
In six of 51 (11.8%) pediatric patients with a clinical and lab- oratory diagnosis of congenital neutropenia we detected variants explaining the clinical phenotype (Figure 1; Table 6; Online Supplementary Table S3). Two patients were di- agnosed with SBDS; one patient was diagnosed with a JAGN1 homozygous variant. Two other patients who had negative panel results were later diagnosed by WES, with variants in SRP54 and in UNC13D, a rare cause of neutrope- nia.48 Another patient was diagnosed with SRP54 following its incorporation into the NGS panel.
Since benign ethnic neutropenia is not rare in our popu- lation, we subsequently looked for the known homozygous polymorphism in the DARK promoter (rs2814778, -30 T>C), which was previously described in people of African and
Table 6. Clinical characteristics of patients referred with isolated neutropenia.
Patient
Ethnic
origin/ Consangui nity (+/-)
Gene
Disease/ Inheritance
MHGVS Coding
Age at presentation /diagnosis
Hematological presentation
BM, cytogenetics and functional tests
Extra hematological manifestations
Outcome
3881
Jewish (-)
JAGN1 (CN)
CN/AR
NM_032492.3: c.3G>A -Hm
2y/20y
Neutropenia
Early myeloid maturation arrest
Recurrent infections
Followup
4452**
Jewish (-)
SRP54
CN/AD
NM_003136.3: c.349_351de- lACA
2y/30y
Neutropenia
Hypoplastic marrow, early myeloid arrest
Recurrent Aphthae
Followup
4041
Arab Christian (-)
SRP54
CN/AD
NM_003136.3: c.349_351de- lACA
8-28d/11y
Neutropenia
Late myeloid arrest
Recurrent infec- tions
Followup
5750*
Jewish (-)
SBDS
SBDS/AR
1. NM_016038:
c. 183_184 delTAinsCT - Ht 2. NM_016038: c.258+2 t>c: splice - Ht
0.3y/1y
Neutropenia
Normal marrow, abnormal exocrine pancreatic func- tions
Short stature, shortened long bones, small kid- neys
Followup
4593*
Jewish (-)
SBDS
SBDS/AR
1. NM_016038:
c. 183_184 delTAinsCT - Ht 2. NM_016038: c.258+2 t>c: splice - Ht
0.2y/1.5y
Neutropenia
Normal
Short stature
Followup
3734**
Arab Muslim (+)
UNC13
CN/AD
NM_199242.2: c.679C>T- Hm
8-28d/2.4y
Neutropenia, later pancytopenia
Hypocellular marrow
None
Post HSCT
BM. bone marrow; CN: congenital neutropenia; AR: autosomal recessive; AD: autosomal dominant; y: years; d: days; SBDS: Shwachman-Bo- dian-Diamond syndrome; Ht: heterozygous; Hm: homozygous; HSCT: hematopoietic stem cell transplant. * Diagnosed by Sanger sequencing, **diagnosed by whole exome sequencing.
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