Inherited Forms of Bone Marrow Failure

Published on 04/03/2015 by admin

Filed under Hematology, Oncology and Palliative Medicine

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Chapter 3 Inherited Forms of Bone Marrow Failure

Yigal Dror, Melvin H. Freedman

Table 3-1 Inherited Bone Marrow Failure Syndromes:
Inheritance and Mutated Genes

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AD, Autosomal dominant; AR, autosomal recessive; IBMFSs, inherited bone marrow failure syndromes; UK, unknown; WHIM, warts, hypogammaglobulinemia, infections, and myelokathexis; X-L, X-linked recessive.

Modified from Dror Y: Inherited bone marrow failure syndromes: Genetic complexity of monogenic disorders. In Genetic Disorders. InTech Open Access Publisher. Available at http://www.intechweb.org.

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Figure 3-1 DYSTROPHIC NAILS IN DYSKERATOSIS CONGENITA.

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Figure 3-2 LEUKOPLAKIA OF THE TONGUE IN DYSKERATOSIS CONGENITA.

Table 3-2 Miscellaneous Inherited Thrombocytopenia Disorders and Their Major Hematologic Features

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AD, Autosomal dominant; AML, acute myeloid leukemia; AR, autosomal recessive; MDS, myelodysplastic syndrome; MPV, mean platelet volume; X-L, X-linked recessive.

* Platelet size: small, MPV <7 fL; normal, MPV 7-11 fL; large or giant, MPV >11 fL.

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Figure 3-3 RADIOGRAPH OF A TRIPHALANGEAL THUMB IN DIAMOND-BLACKFAN ANEMIA.

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Figure 3-4 SIMILAR DIAMOND-BLACKFAN FACIES IN TWO UNRELATED GIRLS OF DIFFERENT ANCESTRIES CONSSTING OF A SMALL HEAD, ALMOND-SHAPED EYES WITH A SLIGHT ANTIMONGOLOID SLANT, A “FISH-LIKE” SMILE, AND A POINTED CHIN.

Table 3-3 Hematologic Features in Diamond-Blackfan Anemia at Diagnosis Based on Data on 21 Toronto Cases and on 41 Cases From the Canadian Inherited Marrow Failure Registry

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BM, Bone marrow; HbF, fetal hemoglobin; MCV, mean corpuscular volume; RBC, red blood cell.

Table 3-4 Distinguishing Features Between Diamond–Blackfan Anemia and Transient Erythroblastopenia of Childhood

  DBA TEC
Etiology Genetic Acquired
Immune mediated None Common
Family history ≈10% Occasional siblings with concurrent TEC
Antecedent history None Viral infection
Age at diagnosis 90% by 1 year 6 months-4 years
Physical anomalies ≈50% None
Neurologic findings None Occasional
Transfusion dependence Yes, if steroid refractory None
Course Chronic Full recovery
Risk of cancer Increased Not increased
Risk of MDS or leukemia Increased Not increased
Laboratory findings at diagnosis:    
RBC size Macrocytic Normocytic
HbF Increased Normal*
i Antigen Increased Normal*
RBC enzyme activities Fetal levels Adult levels
RBC adenosine deaminase Increased in 40%-90% Normal

DBA, Diamond–Blackfan Anemia; HbF, fetal hemoglobin; MDS, myelodysplastic syndrome; RBC, red blood cell; TEC, transient erythroblastopenia of childhood.

*During spontaneous recovery, values may be increased.

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Figure 3-5 HIGH-POWER VIEW OF A BONE MARROW ASPIRATE FROM A PATIENT WITH KOSTMANN SYNDROME (CONGENITAL NEUTROPENIA) BEFORE GRANULOCYTE COLONY-STIMULATING FACTOR THERAPY.

The findings are a “maturation arrest” with recognizable myeloblasts, promyelocytes, myelocytes, and occasional metamyelocytes but total absence of band forms and neutrophils.

(Photomicrograph prepared by Dr. Mohamed Abdelhaleem, Toronto.)

Table 3-5 Miscellaneous Inherited Neutropenia Disorders

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AD, Autosomal dominant; AR, autosomal recessive; Ig, immunoglobulin; X-L, X-linked recessive.

Data compiled from Online Mendelian Inheritance in Man (http://ncbi.nlm.nih.gov/omim).

Kostmann/Severe Congenital Neutropenia: Granulocyte Colony-Stimulating Factor Versus Hematopoietic Stem Cell Transplantation as First-Line Therapy

Therapeutic options for newly diagnosed patients with K/SCN must be constantly reevaluated. It is largely accepted that G-CSF induces robust neutrophilic responses and eliminates infections almost completely in more than 90% of K/SCN patients. Therefore, it should be the first treatment choice. HSCT has been regarded as “salvage” therapy for patients who either acquire evidence of malignant myeloid transformation or fail to respond to G-CSF altogether. For KS patients transplanted with a fully matched donor before transforming to MDS/AML and in stable health, the chance for cure is at least 85%, possibly higher. The SCNIR data support this estimate. Not only is the neutropenia fully corrected by HSCT, but the risk of MDS/AML is also eliminated. The onerous burden of daily subcutaneous injections is removed, the financial expense is relieved, and the side effects of G-CSF are prevented. Clearly, an 85% cure rate stacks up favorably against the high cumulative incidence of incurable MDS/AML over time, particularly in patients who require large doses of G-CSF. HSCT is a reasonable option as front-line therapy for selected higher risk patients instead of G-CSF, and the option should be discussed fairly and sensibly with newly diagnosed patients and families.

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Figure 3-6 PERIPHERAL BLOOD SMEAR FROM A PATIENT WITH CONGENITAL DYSERYTHROPOIETIC ANEMIA TYPE II.

Note the marked variation in red blood cell size and shape.

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