Inherited Bone Marrow Failure Disorders

What is Inherited Bone Marrow Failure Syndromes (IBMFS)?

The inherited bone marrow failure syndromes are a heterogeneous group of disorders characterized by bone marrow failure usually in association with one or more physical abnormalities. It is often present in childhood but may not present till adulthood in some of patients.

Most of the disorders are Autosomal Recessive (needs defective gene from both parents to develop the disease) but few are Autosomal Dominant (needs defective gene from any one parent to develop the disease) or X-Linked (only the male child will develop the disease).

What are the signs and symptoms of Inherited Bone Marrow Failure Syndromes?

The symptoms are usually in the form of unilineage (only anemia or Neutropenia or thrombocytopenia) or multilineage cytopenias (presence of more than one cell line affection) and infections. A lot of patients have physical abnormalities like short stature, darkening of skin, bone abnormalities, heart defects etc.

Most common signs and symptoms of bone marrow failure in children are:

• Bleeding and Bruising
• Blood in gums, nose or the skin, and tend to last longer than normal.
• Blood in urine or stools, which results in digestive problems with an unpleasant scent.
• Tooth loss or tooth decay.
• Feeling tired most of the time
• Shortness of breath
• Recurring cold

How do we classify Inherited Bone Marrow Failure Syndromes?

Commonly found diseases are:-

FANCONI ANEMIA (FA)

Children with FA have characteristic physical abnormalities as listed above.
FA is characterised by the defect in DNA repair leading to extensive chromosomal breakage. Affected individual have mutation in the FANC family of genes. FA is usually inherited as Autosomal recessive disease but can be X linked recessive disorder. FA mostly presents at early school age. Most patients mostly present with thrombocytopenia with anemia and neutropenia and later with progressive bone marrow failure. Upto 20% of patients develop MDS or AML and another 20% can develop solid cancers by the age of 40 years.

DYSKERATOSIS CONGENITA (DKC)

DKC is characterised by the triad of abnormal nails, reticular skin pigmentation and oral leukoplakia. Bone marrow failure occurs during early adulthood and is associated with high risk of development of Aplastic Anemia, Myelodysplastic Syndrome (MDS), Leukemia and solid tumors. The disease is characterised by abnormalities in the telomere gene. They have very short germ line telomers.

SHWACHMAN- DIAMOND SYNDROME (SDS)

It includes bone marrow failure with exocrine pancreatic insufficiency, short stature, metaphyseal dysplasia with typical mild to moderate Neutropenia. Intestinal malabsorption with failure to thrive commonly occurs in infancy and in early childhood. Affected patients also have increased risk of Myelodysplastic Syndrome or Acute Myeloid Leukemia.

SEVERE CONGENITAL NEUTROPENIA (SCN) INCLUDING KOSTMANN SYNDROME

SCN, as its name indicates, is characterized by profound peripheral neutropenia. Patients usually present with recurrent, life-threatening infections in infancy. Bone marrow examination usually reveals a maturation arrest in the myeloid lineage. The disease can progress to myelodysplasia and leukemia, usually with acquisition of secondary mutations. Heterozygous mutations in the neutrophil elastase gene (ELA2) have been demonstrated in the majority of patients.

The original family described by Kostmann, had autosomal recessive severe congenital neutropenia, which has been shown to be associated with biallelic mutations in the HAX1 gene, predicted to lead to defects in cell death.

CONGENITAL AMEGAKARYOCYTIC THROMBOCYTOPENIA (CAMT)

CAMT usually presents in infancy and is characterized by isolated thrombocytopenia and a reduction or absence of megakaryocytes in the bone marrow, but usually there are no somatic abnormalities. Approximately 50% of patients develop Aplastic anemia, usually by the age of 5 years. CAMT can also evolve into myelodysplasia or leukemia. Diagnosis is based on markedly reduced megakaryocytic precursors in the Bone Marrow with normal erythroid and myeloid lineages with elevated TPO levels.

DIAMOND-BLACKFAN ANEMIA (DBA)

DBA usually presents in early infancy, with features of anemia. The hallmark of classical DBA is a selective decrease in erythroid precursors and normochromic macrocytic anemia associated with a variable number of somatic abnormalities such as craniofacial, thumb, cardiac and urogenital malformations. Myelodysplastic syndrome and acute myeloid leukemia have been reported in a few patients, suggesting an increased predisposition to hematologic malignancies or sometime aplastic anemia. Thus, although Diamond-Blackfan anemia has been regarded classically as a pure red cell aplasia, a more global hematopoietic defect can be observed. Patients usually respond with steroids initially but on withdrawal the disease reappears.

How do we Diagnose Inherited Bone Marrow Failure Syndromes (IBMFS)?

• Complete Blood Count: The characteristic findings of IBMFS are unilineage or multilineage cytopenia which varies with the individual diseases. Examination of the blood gives the diagnosis.
• Bone Marrow Study: mainly marrow biopsy is done to confirm the hypocellularity of the marrow.
• Flow Cytometry: This is often performed to detect early changes of leukemia and Myelodysplastic syndrome.
• Cytogenetics: This is testing for abnormalities in the chromosomes. Certain genes are mutated which leads to complete or partial defect in the cells.
• Antenatal Screening: For mothers who have already had a child with a IBMFS, prenatal testing can be done for subsequent pregnancies. Samples of amniotic fluid, blood or cells from the placenta are tested for IBMFS.

How do we treat Inherited Bone Marrow Failure Syndromes (IBMFS)?

Definitive cure is generally only achieved by ALLOGENEIC BMT, some disease may respond with steroids. But the Diseases reappears once they are withdrawn.

When is BMT needed for children with Inherited Bone Marrow Failure Syndromes (IBMFS)?

Best results are obtained when BMT is carried out at the earliest, before the onset of leukemia, Myelodysplastic syndrome or severe Aplastic anemia.

How is Conditioning for BMT done in Inherited Bone Marrow Failure Syndromes (IBMFS)?

Reduced Intensity Conditioning with low doses of chemotherapy or radiation is the preferred option. Otherwise these patients develop severe organ toxicity.

Who can be a donor for BMT?

Although we prefer a matched family donor, a Half Matched (Haploidentical) family donor or a Matched unrelated donor ( PBSC or BM) or cord blood are suitable alternatives. As BMT is required as an emergency procedure in this condition, Haploidentical Family Donor is often the preferred option if a matched family donor is not available.

What are the results of BMT in Inherited Bone Marrow Failure Syndromes (IBMFS)?

With improved results with alternate donors and safer conditioning regimens, cure rates of 70-80% can be expected if ALLOGENEIC BMT is performed in time.