Inherited bone marrow failure in the pediatric patient

Abstract

The inherited bone marrow (BM) failure syndromes are a diverse group of disorders characterized by BM failure usually in association with one or more extra-hematopoietic abnormality. The BM failure, which can involve one or more cell lineages, often presents in the pediatric age group. Furthermore, some children initially labelled as having "idiopathic aplastic anemia" or "myelodysplasia" represent cryptic presentations of these syndromes. Significant advances in the genetics of these syndromes have been made with more than 100 disease genes identified. These advances have given insights into normal hematopoiesis and how this is disrupted in patients with BM failure. They have also provided important information on fundamental biological pathways: DNA repair-Fanconi anemia (FA) genes; telomere maintenance-dyskeratosis congenita (DC) genes; ribosome biogenesis-Shwachman Diamond syndrome and Diamond-Blackfan anemia genes. Additionally, as these disorders are usually associated with extra-hematopoietic abnormalities and an increased risk of cancer they have provided insights into human development and the genesis of cancer. In the clinic, genetic tests stemming from the recent advances are facilitating diagnosis especially when clinical features may not be sufficient to make an accurate classification. Hematopoietic stem cell transplantation using fludarabine based protocols has improved outcomes significantly particularly for patients with FA and DC. Management of some of the other complications, such as cancer, remains a challenge. Recent studies suggest the possibility of new and potentially more efficacious therapies. This includes renewed focus on hematopoietic gene therapy and drugs (TGF-b inhibitors for FA and PAPD5 inhibitors for DC) that target disease specific defects.

Germline thymidylate synthase deficiency impacts nucleotide metabolism and causes dyskeratosis congenita

“…A clinically diagnosed individual with dyskeratosis congenita (DC [MIM: 305000]) classically presents with a combination of muco-cutaneous features comprising abnormal skin pigmentation, nail dystrophy, and oral leucoplakia, 1 as initially described by Zinsser in 1910. 2 Bone-marrow failure, predisposition to cancer, and pulmonary abnormalities are reported to be major causes of death in DCaffected individuals.…”

“…A major subset of individuals (n ¼ [MIM:179835]). 1 Five of these genes encode components of the enzyme telomerase (TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; DKC1, dyskerin pseudouridine synthase 1; NOP10, NOP10 ribonucleoprotein; or NHP2, NHP2 ribonucleoprotein) contributing to its catalytic function. Poly (A)-specific ribonuclease (PARN), zinc finger CCHC-type containing 8 (ZCCHC8), and nuclear assembly factor 1 ribonucleoprotein (NAF1) are involved in TERC maturation.…”

Cell Type-Specific Regulation by a Heptad of Transcription Factors in Human Hematopoietic Stem and Progenitor Cells

“…Numerous bone marrow failure syndromes have an underlying germline genetic cause (Dokal et al, 2022) and may therefore be amenable to gene therapy approaches. Such therapies would ideally target the most primitive HSCs to enable long term clinical benefits.…”

Genetic Polymorphisms of Xenobiotics-Metabolizing Enzymes Contributing to Leukemia

“…Despite the fact that leukemogenesis research has been going on for a long time, the mechanisms underlying the development of this hematologic malignancy are still unknown [1]. Leukemia is known to be caused by a number of risk factors, including genetic variables such as constitutional genetic variation in components of DNA damage response pathways, which have become the focus of research [4,5].…”