Overview of inherited bone marrow failure syndromes

Meerim Park

doi:10.5045/br.2022.2022012

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Blood Res 2022; 57(S1):

Published online April 30, 2022

https://doi.org/10.5045/br.2022.2022012

Overview of inherited bone marrow failure syndromes

Meerim Park

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Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, Goyang, Korea

Correspondence to : Meerim Park, M.D., Ph.D.
Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
E-mail: meerim@ncc.re.kr

Received: January 17, 2022; Revised: February 27, 2022; Accepted: March 14, 2022

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

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Abstract

Patients with inherited bone marrow failure syndrome (IBMFS) can develop peripheral blood cytopenia, which can ultimately progress to myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Although some cases of IBMFS are diagnosed based on their typical presentation, variable disease penetrance and expressivity may result in diagnostic dilemmas. With recent advances in genomic evaluation including next-generation sequencing, many suspected cases of IBMFS with atypical presentations can be identified. Identification of the genetic causes of IBMFS has led to important advances in understanding DNA repair, telomere biology, ribosome biogenesis, and hematopoietic stem cell regulation. An overview of this syndromes is summarized in this paper.

Keywords Inherited bone marrow failure syndrome, DNA repair, Telomere, Ribosome, Stem cell regulation

Article

Review Article

Blood Res 2022; 57(S1): S49-S54

Published online April 30, 2022 https://doi.org/10.5045/br.2022.2022012

Overview of inherited bone marrow failure syndromes

Meerim Park

Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, Goyang, Korea

Correspondence to:Meerim Park, M.D., Ph.D.
Department of Pediatrics, Center for Pediatric Cancer, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea
E-mail: meerim@ncc.re.kr

Received: January 17, 2022; Revised: February 27, 2022; Accepted: March 14, 2022

Abstract

Keywords: Inherited bone marrow failure syndrome, DNA repair, Telomere, Ribosome, Stem cell regulation

Abstract

Table 1 . Clinical manifestations and laboratory findings in inherited bone marrow failure syndrome..

Syndrome	Non-hematological clinical manifestations	Laboratory findings	Molecular mechanisms
Fanconi anemia	Short stature, low birth weight, microcephaly, microphthalmia, hearing loss, triangular face, micrognathia, cardiac anomalies, tracheoesophageal fistula, esophageal atresia, kidney anomalies, hypoplastic thenar eminence, clinodactyly, café-au-lait spots	Pancytopenia, macrocytosis, elevated HbF, increased chromosome breakage in clastogenic assay	DNA repair: FA/BRCA pathway
Dyskeratosis congenita	Mucocutaneous triad (skin pigmentation, nail dysplasia, oral leucoplakia), short stature, low birth weight, failure to thrive, pulmonary fibrosis, stenosis of the esophagus, liver fibrosis	Pancytopenia, macrocytosis, elevated HbF, very short telomeres	Telomere shortening
Diamond-Blackfan anemia	Low birth weight, short stature, developmental delay, anomalies in craniofacial skeleton, eyes, heart, visceral organs and limbs	Anemia, elevated red blood cell adenosine deaminase, macrocytosis, elevated HbF	Ribosome biogenesis and processing
Schwachman-Diamond syndrome	Exocrine pancreatic insufficiency, failure to thrive, malabsorption, short stature, neurodevelopment and skeletal abnormalities	Neutropenia, low serum isoamylase, low serum trypsinogen	Ribosome biogenesis and processing
Severe congenital neutropenia	Recurrent infection	Neutropenia	Myeloid lineage growth arrest
Congenital amegakaryocytic thrombocytopenia	Nonsyndromic (occasionally, growth retardation, cardiac anomalies, psychomotor developmental delay)	Thrombocytopenia, reduced megakaryocytes	Hematopoietic stem cell and megakaryocyte regulation
GATA2 deficiency	Lymphedema, immunodeficiency, atypical mycobacterial infections	Neutropenia, anemia, thrombocytopenia	Zinc finger transcription factor
SAMD9/SAMD9L disorders	MIRAGE (SAMD9): MDS, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy	Transient or permanent cytopenia	Defective antiproliferative function
SAMD9/SAMD9L disorders	Ataxia–pancytopenia syndrome (SAMD9L): cerebellar atrophy and white matter hyperintensities, gait disturbance, nystagmus	Transient or permanent cytopenia	Defective antiproliferative function
MECOM-associated syndromes	Radioulnar synostosis, clinodactyly, hearing loss, cardiac/renal malformation	Thrombocytopenia	Zinc finger transcription factor

Abbreviations: HbF, hemoglobin F; MDS, myelodysplastic syndrome..

Table 2 . Genetics and screening of inherited bone marrow failure syndrome..

Syndrome	Genetics	Screening
Fanconi anemia	FANCA, C, G account for 95% of cases	Increased chromosome breakage
Dyskeratosis congenita	DKC1, RTEL1, TERT, TERC, TINF2	Short telomere lengths
Diamond-Blackfan anemia	RPS19, RPL11, RPS26, RPS10, RPL35A, RPS24, RPS17	Elevated erythrocyte adenosine deaminase
Schwachman-Diamond syndrome	SBDS, SRP54, ELF1	Low pancreatic isoamylase (age >3 yr) and low fecal elastase
Severe congenital neutropenia	ELA2 (33–60%), HAX1, G6PC3, GFI1, WAS, CSF3R
Congenital amegakaryocytic thrombocytopenia	MPL
GATA2 deficiency	GATA2
SAMD9/SAMD9L disorders	SAMD9/SAMD9L	Monosomy 7, del 7q and der(1;7)
MECOM-associated syndrome	MECOM	Suspected to have congenital amegakaryocytic thrombocytopenia, but without mutations in the MPL gene