Chromosomal Instability Syndromes Associated with Immunodeficiency
Chromosomal instability syndromes have in common increased spontaneous or induced DNA breaks, susceptibility to infections secondary to immune deficiency, and an increased risk of malignancies. Disease-specific abnormalities involving growth and development, the central nervous system, and the skin provide useful diagnostic clues. The classic chromosomal instability syndromes include ataxia-telangiectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome (BS), and ataxia-telangiectasia–like disorder (ATLD). The genes responsible for these syndromes protect human genome integrity by contributing to the complex task of double-strand break repair. Together with the proteins associated with Fanconi anemia, the gene products of the chromosomal instability syndromes form or regulate a large protein complex which is active in the surveillance and maintenance of genomic integrity.171 The triad of immunodeficiency, neoplasia, and infertility is the direct consequence of defective double-strand break repair, and involves nonhomologous end-joining or homologous rejoining. Because nonhomologous end-joining is crucial for the generation of T-cell receptor diversity and polyclonal immunoglobulins, any interruption of this process will predictably result in defective adaptive immunity. Tumor development and infertility may be a direct consequence of defective DNA repair during miotic recombination of lymphocytes, other somatic cells, or germ cells, respectively.
AT is a multisystem disorder, characterized by immunodeficiency, progressive neurologic impairment, and ocular and cutaneous telangiectasia.
The immune deficiency in AT is highly variable, involving both cellular and humoral immunity. Respiratory infections are common and often result in chronic lung disease. Opportunistic infections are rare. The majority of AT patients have low or absent IgA and IgE, often combined with IgG2 and IgG4 deficiency.172 Specific antibody responses may be depressed or normal. The number of circulating lymphocytes is often reduced, and proliferation in response to mitogens is variably depressed. Spontaneous cytogenetic abnormalities include chromosomal breaks, translocations, rearrangements, and inversions; these defects increase following in vitro exposure to radiation. The thymus is often small, showing marked paucity of thymocytes and absence of Hassall corpuscles. The most consistent laboratory abnormality, an elevation of serum -fetoprotein, is diagnostic in adults and children older than age 8 months as it is not observed in the other chromosomal instability syndromes.
Cancer is the second most common cause of death, after infections. Most malignancies are non-Hodgkin lymphomas (40%), leukemias (25%), and solid tumors (25%); 10 percent are Hodgkin lymphoma. In contrast to other immune deficiency syndromes with increased incidence of malignancies, the leukemias and lymphomas observed in AT are predominantly of T-cell origin. The solid tumors in AT patients include adenocarcinoma, dysgerminoma, gonadoblastoma, and medulloblastoma.
Cerebellar ataxia is the earliest clinical manifestation of AT and becomes evident when a child begins to walk at the end of the first year of life. The ataxic gait persists, and most patients never develop normal speech. Eventually, involuntary movements become a major handicap and the child may require a wheelchair by the end of the first decade of life. Cortical cerebellar degeneration involves primarily Purkinje and granular cells; progressive changes to the central nervous system also occur.
A variety of other features have been reported. Growth retardation is present in 30 percent of the patients. Female hypogonadism is common and associated with hypoplasia of the ovaries. Hypogonadism is also observed in male AT patients.
The AT gene (AT mutated [ATM]) encodes a large transcript that predicts a protein of 3056 amino acids.173 ATM is a predominantly nuclear protein with a strong serine-threonine kinase activity. Its major function is to rapidly respond to the induction of double-stranded breaks in DNA. The activation of ATM leads to phosphorylation of an extensive array of target proteins, each of which plays a key role in a unique damage response pathway. Specifically, ATM is involved in cell-cycle checkpoint control and delays the passage of cells through the various phases of the cell cycle, allowing time for DNA damage repair. Additionally, ATM is functionally linked to telomere maintenance, a process crucial to aging and cancer.174 The more than 400 unique mutations of ATM described to date are distributed throughout the gene with a majority predicted to cause premature termination resulting in unstable truncated proteins.
An AT-like disorder(ATLD) that has many features of AT175 is the result of mutations in the hMre11 protein which is part of the DNA-repair complex (Mre11/Rad50/Nbs1).176 Affected patients have progressive ataxia, but show less-severe neurodegeneration and may be ambulatory until their early twenties. They do not develop telangiectasia and -fetoprotein levels are normal. However, similar to AT, ATLD patients have increased spontaneous chromosomal abnormalities in blood lymphocytes and show increased radiation sensitivity.
Nijmegen Breakage Syndrome
NBS is characterized by short stature, microcephaly, a bird-like face, immunodeficiency, chromosomal instability, increased radiosensitivity, and a high percentage of malignancies.177 Although NBS shares many characteristics with AT and ATLD, it can be distinguished from these disorders by an absence of neurodegeneration, impressive microcephaly with mild to moderate mental retardation, and absence of telangiectasia.
Most NBS patients develop respiratory tract infections, including recurrent pneumonia that may result in bronchiectasis and premature death from respiratory failure. Both humoral and cellular immunity are defective and include hypogammaglobulinemia, except for normal or elevated IgM, abnormal antibody responses to protein and polysaccharide antigens, suggesting a defect in class switch recombination, reduced numbers of T lymphocytes, and abnormal lymphoproliferation to mitogens and specific antigens.171
NBS lymphocytes show the typical features of chromosomal instability syndromes characterized by increased chromatid and chromosome breaks, rearrangement/translocations of chromosome 7 and 14, telomere fusions, radio-resistant DNA synthesis, and hypersensitivity to ionizing radiation and radiomimetic agents.
The extensive immunodeficiency and the chromosomal instability explain the high incidence of lymphoid malignancies, including non-Hodgkin lymphoma (both of B- and T-cell origin), lymphoblastic leukemia/lymphoma, and less frequently Hodgkin lymphoma and acute myeloblastic leukemia. Solid tumors are less frequent and include medulloblastoma and rhabdomyosarcoma. Because of hypersensitivity to radiation and radiomimetic/alkylating agents, tumor therapy is limited. However, several patients have been successfully treated with allogeneic hematopoietic stem cell transplantation. Prophylactic therapy with antibiotics and IVIg is indicated in patients with recurrent infections.
BS is characterized by short stature, hypersensitivity to sunlight, increased susceptibility to infections, and a predisposition to early development of a variety of cancers.171 Susceptibility to bacterial infections, affecting mainly the upper and lower respiratory tract, is associated with hypogammaglobulinemia and variable T-cell deficiency. Most affected patients have decreased fertility and some may develop early onset type II diabetes mellitus. By age 25 years, approximately half of the patients with BS will have developed one or more malignancies. Leukemia and non-Hodgkin lymphoma predominate during the first two decades; later, carcinoma affecting the colon, skin, and breast are common. The diagnosis of BS can be confirmed by demonstrating excessive numbers of sister-chromatid exchanges, increased chromatid gaps and breaks, and the presence of quadriradial configuration composed of two homologous chromosomes. The causative gene, BLM, encodes a 1417-amino-acid protein with homology to the RecQ family of helicases. This family of helicases include the WRN protein, which is mutated in Werner syndrome. BLM is a member of a group of proteins that associate with BRCA1 to form a large complex that colocalizes to large nuclear foci if cells are treated with agents that interfere with DNA synthesis. As part of this complex, BLM plays a role in sensing DNA damage and contributes to the maintenance and genomic integrity during the process of DNA replication and repair. More than 60 unique mutations in the BLM gene have been identified. The most common mutation is a 6bp deletion/7bp insertion in exon 10 causing BS in Ashkenazi Jews.
Patients with chromosomal instability may benefit from antibiotic prophylaxis and IVIg therapy, if immune deficiency is documented. Because of increased radiation sensitivity, exposure to any form of irradiation should be restricted.