Panel testing recommended at Breda Genetics for this condition:
Detailed clinical description
The bone marrow, which is mainly located in the diaphyseal canal of long bones and in the cavities of the spongy tissue of flat bones, it’s the main human tissue dedicated to hematopoietic function, that is the production and maturation of blood cells from their precursors.
Bone marrow consist of three parts:
- structural parenchyma, called stroma, made up of connective cells (reticular cells);
- hematopoietic components, rich in stem cell and cell precursors at various stages of differentiation, from which red blood cells, white blood cells and platelets will originate;
- vascular network, which has a trophic function for the organ and which transports mature blood cells in the bloodstream.
From fetal development to puberty, the bone marrow maintains a marked hematopoietic function and, thanks to the massive presence of blood and red blood cells inside it, takes on a characteristic bright red appearance (red bone marrow). In adults, on the other hand, the hematopoietic function is progressively lost as the component of connective and adipose cells within the bone marrow increases, giving it the yellowish connotation (yellow bone marrow). This means that, with advancing age, the hematopoietic function is restricted to some areas of the cranial vault, the sternum, the ribs and the central parts of some short bones, where red bone marrow is still present.
Bone marrow failure can affect only a single cell type, resulting in the onset of erythropenia (red blood cells deficiency), leukopenia (white blood cells deficiency) or thrombocytopenia (platelets deficiency), or it can involve them all together. In this case, we talk about pancytopenia.
Bone marrow failure can be caused by different causes:
- reduction in the number of the cells in the hematopoietic compartment, resulting in the onset of aplastic/hypoplastic anemia;
- maturation defect of cellular precursors contained in the bone marrow (for instance, due to vitamin B12 or folate deficiency)
- cell differentiation defect (myelodysplasia)
- infiltration of the bone marrow by lymphoma, multiple myeloma, carcinoma or tricoleukemia.
Here, we will talk only about genetic forms.
Aplastic/ Hypoplastic anemia
Aplastic/Hypoplastic anemia is a disorder caused by insufficient erythropoiesis due to bone marrow hypoplasia (reduction in the number of stem cells and blood cells during bone marrow maturation). In the blood, aplastic/hypoplastic anemia causes pancytopenia. Aplastic/Hypoplastic anemia can be both inherited or acquired. Among inherited forms, there are Fanconi anemia, dyskeratosis congenita, Diamond-Blackfan syndrome and Shwachman-Diamond syndrome:
Fanconi anemia is a rare progressive juvenile anemia, combined with growth delay, and skeletal, skin, urogenital, cardiopulmonary, gastrointestinal and central nervous system (CNS) malformations. Patients tend to develop some kind of tumors such as acute myeloid leukemia, head and neck tumors, and genital apparatus in females. Fanconi anemia is characterized by high genetic heterogeneity. To date more than 15 different genes are known: BRCA1, BRCA2, BRIP1, ERCC4, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCN, MAD2L2, PALB2, PFHF9, RAD51, RAD51C, RFWD3, SLX4, UBE2T, XRCC2 and XRCC9. The disorder has autosomal recessive inheritance, with the exceptions of RAD51, which is autosomal dominant and FANCB which is X-linked.
Dyskeratosis congenita is a very rare multisystem disorder, caused by bone marrow failure, characterized by 3 typical mucocutaneous signs: skin pigmentation abnormalities, nail dystrophy and mucosal leukoplakia. Dyskeratosis congenita has genetic heterogeneity and clinical variability. Inheritance can be either autosomal recessive, autosomal dominant or X-linked. The most frequently mutated genes are DKC1 and TERC, which encode for components of the telomerase complex, enzymes that control the entireness of chromosomal extremities, otherwise intended to shorten during each cell DNA replication cycle with consequent loss of stability and genetic information.
Diamond-Blackfan syndrome is a congenital anemia with onset in early infancy (within 2 years of life), mainly associated with erythroblastopenia. Patients have short stature, craniofacial, thumb and urogenital abnormalities. Moreover, they have an increased risk of developing leukemia and tumors. Diamond-Blackfan anemia has autosomal dominant or X-linked inheritance and incomplete penetrance. Causative mutations are identified in about 40-50% of cases. Associated genes are GATA1, TSR2, RPS7, RPS17, RPS19, RPS24, RPL5, RPL11 and RPL35A.
Shwachman-Diamond syndrome is a multisystem disorder with onset in early infancy, mainly characterized by exocrine pancreas hypoplasia, short stature and osseous malformations, ichthyosis, psychomotor retardation. the mutated genes are EFL1 and SBDS and inheritance is autosomal recessive.
Myelodysplastic syndromes
Myelodysplastic syndromes are a heterogeneous group of malignant hematopoietic disorders, characterized by the tendency to evolve towards acute myeloid leukemia. About 10% of myelodysplastic syndromes are secondary to chemo or radio-therapy against tumor onset, particularly against prostate, breast, bladder, lung cancers and non-Hodgkin lymphoma. A small number of cases of myelodysplasia are due to exposure to radiation, benzene and other organic solvents. Clinical signs include petechiae and ecchymosis, pale conjunctiva, tachycardia and splenomegaly.
In myelodysplastic syndrome somatic mutations are often identified in the SF3B1, TET2, SRSF2, ASXL1 and TP53 genes.
Differential diagnosis
Bone marrow failure differential diagnosis include systemic lupus erythematosus, leukemia, and other forms of anemia not dependent on bone marrow deficiency (such as iron deficiency anemia).
Genetic testing strategy
Clinical examinations include CBC, Ham test, MRI, PET, and bone marrow biopsy with needle aspiration for microscope evaluation. In the forms with suspected genetic origin, the execution of a multigene panel, which includes the analysis of all the possible genes involved, is certainly indicated.
Panel testing recommended at Breda Genetics for this condition:
References
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