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. 2022 Nov 22;6(22):5829-5834.
doi: 10.1182/bloodadvances.2022007233.

Megalobastic anemia, infantile leukemia, and immunodeficiency caused by a novel homozygous mutation in the DHFR gene

Taco W Kuijpers  1   2 , Andrica C H de Vries  3 , Ester M van Leeuwen  4   5 , A Ton A M Ermens  6 , Saskia de Pont  7 , Desirée E C Smith  8 , Mirjam M C Wamelink  8 , Arjen R Mensenkamp  9 , Marcel R Nelen  9 , Hana Lango Allen  10   11 , Steven T Pals  12 , Berna H B Beverloo  13 , Hidde H Huidekoper  13 , Anja Wagner  14
Affiliations

Megalobastic anemia, infantile leukemia, and immunodeficiency caused by a novel homozygous mutation in the DHFR gene

Taco W Kuijpers et al. Blood Adv. .
No abstract available

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Conflict of interest statement

The authors declare no competing financial interests.

A complete list of the members of the NBR-RD PID Consortium appears in “Appendix.”

Figures

Figure 1
Figure 1
The presence of major symptoms in DHFR deficiency. (A) Bone marrow biopsy showing a severely impaired erythroid outgrowth and a myeloid differentiation defect with marked megaloblastic features (hematoxylin and eosin; bar, 20 μm). (B) Immunohistochemistry with antiglycophorin A, demonstrating the presence of multiple megaloblasts and an almost complete absence of late-stage erythroid precursors. Among the unstained (myeloid) cells, several giant bands are identified (arrows). (C) AML was suggested in the second case. Immunohistochemically stained slide of the spleen. CD33-positive blasts marked as (b) can be observed in lytic tissue of the spleen. Some of these blasts are located in capillaries. The nuclei of the endothelial cells lining the wall of these capillaries are indicated with an arrow. Similar infiltration of MPO/CD33+ myeloid blasts was observed in the liver and bone marrow. The child died at presentation in the emergency room. The diagnosis of infantile AML was made post mortem from the obtained autopsy samples. (D) T2 magnetic resonance imaging in patient 3 demonstrating both cerebral and cerebellar atrophy and hypoplasia of the cerebellar vermis.
Figure 2
Figure 2
Pedigree with 3 cases affected by a novel pathogenic DHFR gene mutation. (A) Pedigree of the index case in 1 branch and 2 additional cases diagnosed in another branch of the same family. Segregation studies showed full penetrance in the case of homozygosity, whereas heterozygous carriers had neither clinical symptoms nor any abnormality in the hematological and immunological parameters. Individuals with the year of birth indicated in the extended pedigree have been tested. Filled symbols indicate the 3 homozygous cases in the family (also marked by 1/1 as determined by WGS [whole-genome sequencing]). Carriership of the DHFR mutation is indicated by 0/1, as was confirmed by Sanger sequencing. (B) NGS demonstrating the homozygous mutation in DHFR (NM_000791.3; c.61G>A; p.Gly21Arg) at chromosome 5q14.1 [OMIM 126060]. (C) Absent activity of DHFR in EBV-transformed lymphoblasts from patient 3 vs control (measured in duplicate according to the exact methods as reported by Cario et al).
See this image and copyright information in PMC

References

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