Bone Marrow Failure Syndrome 4

A number sign (#) is used with this entry because of evidence that bone marrow failure syndrome-4 (BMFS4) is caused by homozygous mutation in the MYSM1 gene (612176) on chromosome 1p32.

Description

BMFS4 is an autosomal recessive disorder characterized by early-onset anemia, leukopenia, and decreased B cells, resulting in the necessity for red cell transfusion and sometimes causing an increased susceptibility to infection. Some patients may have thrombocytopenia or variable additional nonhematologic features, such as facial dysmorphism, skeletal anomalies, and mild developmental delay. Bone marrow transplantation is curative (summary by Bahrami et al., 2017).

For a discussion of genetic heterogeneity of BMFS, see BMFS1 (614675).

Clinical Features

Alsultan et al. (2013) reported 2 sibs, born of consanguineous Saudi Arabian parents, with transfusion-dependent anemia, mild thrombocytopenia, and low NK and B cells. The patients presented with severe anemia in infancy. Bone marrow biopsy in 1 child showed hypocellular marrow, whereas bone marrow biopsy in the sib showed reduced granulopoiesis and megakaryopoiesis, as well as dysplastic changes, particularly in erythroid precursors. One patient was noted to have nonspecific dysmorphic facial features.

Le Guen et al. (2015) reported a 3-year-old boy, born of consanguineous Turkish parents, with BMFS4. At birth, he was noted to have red cell anemia with low reticulocytes and leukopenia of granulocytes and lymphocytes, as well as agammaglobulinemia. NK cells were moderately reduced. Bone marrow aspirate showed an absence of erythroid precursors with normal granulocyte maturation, but a reduction in granulomonocyte progenitors. Flow cytometric analysis of bone marrow cells showed a 3-fold decrease in CD34+ hematopoietic progenitors compared to controls. Additional features in this patient included small head circumference, choanal atresia, and deafness due to agenesis of the cochlear nerve. During follow-up of this patient, Le Guen et al. (2015) found that circulating B cells returned to normal levels at ages 33 and 39 months compared to age 4 months, and genetic analysis of B cells showed that they were heterozygous for the MYSM1 mutation, indicating that genetic reversion to the normal sequence (a 'back mutation') had occurred on 1 allele. Further analysis showed that 100% of the patient's hematopoietic stem cells had genetic reversion, which ultimately led to correction of all the patient's immunohematologic defects. The findings suggested a strong in vivo selective advantage provided by wildtype MYSM1.

Bahrami et al. (2017) reported 2 sibs, born of consanguineous Arab parents, with BMFS4. Both were born prematurely and had severe anemia requiring transfusion. The patients had recurrent upper respiratory infections in early childhood, but could be managed with prophylactic antibiotics. Laboratory studies showed anemia, mild thrombocytopenia, lymphopenia, decreased B cells, impaired antibody response to vaccination, and neutropenia. T-cell immunity was not affected, although CD4+ and CD8+ cells were decreased at several time points. Bone marrow biopsy showed decreased cellularity and dysplastic red and white cell precursors with myelodysplastic features, including bi- and tri-nucleated erythroblasts and cytoplasmic bridges. Additional features included neurodevelopmental delay with decreased cerebral volume on brain imaging, short stature, rhizomelic shortening of the arms, short fingers, thoracic asymmetry, dry skin, eczema, midface hypoplasia, low-set ears, gingival hyperplasia, and delayed dentition. One had cataracts and the other had noncompaction cardiomyopathy. Both patients underwent bone marrow transplantation in childhood and achieved full donor chimerism with resolution of the symptoms 2 years after transplant.

Inheritance

The transmission pattern of BMFS4 in the family reported by Alsultan et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 2 sibs, born of consanguineous Saudi parents, with BMFS4, Alsultan et al. (2013) identified a homozygous nonsense mutation in the MYSM1 gene (E390X; 612176.0001). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the family. Functional studies of the variant were not performed.

Bahrami et al. (2017) identified a homozygous E390X mutation in 2 sibs, born of consanguineous Arab parents, with BMFS4. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells did not detect the expected size of the MYSM1 protein, suggesting that the mutation leads to protein instability. Patient peripheral blood cells showed increased levels of phosphohistone H2AX, indicative of DNA damage. Upon UV-induced cellular stress, patient cells had delayed re-equilibrium of stress-associated markers, increased reactive oxygen species, defective cell-cycle progression, increased apoptosis, and decreased clonogenic survival compared to controls. These findings were consistent with increased susceptibility to genotoxic stress.

In a boy, born of consanguineous Turkish parents, with BFMS4, Le Guen et al. (2015) identified a homozygous missense mutation in the MYSM1 gene (H656R; 612176.0002). The mutation, which was found by a combination of linkage analysis and whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation occurred at a residue in the highly conserved catalytic JAMM domain, which has isopeptidase activity and allows the removal of ubiquitin from conjugated substrates. Analysis of patient cells showed reduced amounts of MYSM1 protein compared to controls, suggesting that the mutation causes protein instability. Although the patient had spontaneous reversion of the mutation to the wildtype state, the findings indicated that MYSM1 is required for B-cell differentiation and proper immunohematologic development in humans.