Sideroblastic Anemia With B-Cell Immunodeficiency, Periodic Fevers, And Developmental Delay

A number sign (#) is used with this entry because congenital sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is caused by homozygous or compound heterozygous mutation in the TRNT1 gene (612907) on chromosome 3p26.

Description

Sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD) is an autosomal recessive syndromic disorder characterized by onset of severe sideroblastic anemia in the neonatal period or infancy. Affected individuals show delayed psychomotor development with variable neurodegeneration. Recurrent periodic fevers without an infectious etiology occur throughout infancy and childhood; immunologic work-up shows B-cell lymphopenia and hypogammaglobulinemia. Other more variable features include sensorineural hearing loss, retinitis pigmentosa, nephrocalcinosis, and cardiomyopathy. Death in the first decade may occur (summary by Wiseman et al., 2013).

Clinical Features

Wiseman et al. (2013) reported 12 children from 10 families with a syndrome comprising congenital sideroblastic anemia, B-cell deficiency, periodic fevers, and developmental delay. All patients presented in the neonatal period or infancy with severe sideroblastic microcytic anemia; 1 patient presented at age 18 months. Peripheral blood smears typically showed hypochromasia, schistocytosis, and nucleated erythrocytes. Bone marrow biopsy confirmed the diagnosis, and additional studies were consistent with ineffective erythropoiesis. Eleven patients had periodic recurrent febrile episodes with no identified microorganisms throughout infancy and childhood, and immunologic studies showed significant B-cell lymphopenia and hypogammaglobulinemia, as well as a progressive reduction in T and NK cells. One patient who was investigated in detail had high levels of circulating naive B cells, suggesting a defect in B-cell maturation. All patients had variable degrees of delayed psychomotor development, mainly manifest as hypotonia and communication problems. Some patients showed other features, including sensorineural hearing impairment (5 patients), recurrent seizures (5 patients), ataxia (4 patients), brain imaging abnormalities such as cerebral atrophy (6 patients), retinitis pigmentosa (4 patients), nephrocalcinosis (3 patients), and aminoaciduria (6 patients). Most patients required regular blood transfusions, iron chelation, and immunoglobulin replacement. Seven patients died, 6 in the first decade, and death was usually due to cardiac failure. Bone marrow transplantation performed in 1 patient was successful, with apparent cure of the hematologic and immunologic manifestations.

Inheritance

The transmission pattern of SIFD in the families reported by Wiseman et al. (2013) was consistent with autosomal recessive inheritance.

Molecular Genetics

In 15 patients from 13 families with sideroblastic anemia with B-cell immunodeficiency, periodic fevers, and developmental delay, Chakraborty et al. (2014) identified homozygous or compound heterozygous mutations in the TRNT1 gene (see, e.g., 612907.0001-612907.0006). The first mutations were found in consanguineous families by linkage analysis and candidate gene sequencing; subsequent mutations were found by whole-exome analysis of direct sequencing of the TRNT1 gene. There were 3 frameshift alleles, 3 splicing variants, and 7 missense mutations. Knockdown of TRNT1 by siRNA in wildtype human fibroblasts caused cytotoxicity and apoptosis, suggesting that complete loss of TRNT1 function is lethal. In vitro functional expression studies showed that the missense mutants could only partially rescue the growth defect in a yeast strain with a defective ortholog of TRNT1 (cca1), consistent with a partial loss of function. However, there was some variability in residual function of the mutants, suggesting that the phenotypic severity may depend upon the degree of CCA-adding enzyme loss of function.