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1226 Part IX: Lymphocytes and Plasma Cells Chapter 80: Immunodeficiency Diseases 1227

leukemias (25 percent), and solid tumors (25 percent); 10 percent are NBS lymphocytes show the typical features of chromosomal insta-
Hodgkin lymphoma. In contrast to other immune deficiency syn- bility syndromes characterized by increased chromatid and chromo-
dromes with increased incidence of malignancies, the leukemias and some breaks, rearrangement/translocations of chromosome 7 and 14,
lymphomas observed in AT are predominantly of T-cell origin. The telomere fusions, radioresistant DNA synthesis, and hypersensitivity to
solid tumors in AT patients include adenocarcinoma, dysgerminoma, ionizing radiation and radiomimetic agents. 226
gonadoblastoma, and medulloblastoma. The extensive immunodeficiency and the chromosomal instabil-
Cerebellar ataxia is the earliest clinical manifestation of AT and ity explain the high incidence of lymphoid malignancies, including
becomes evident when a child begins to walk at the end of the first year non-Hodgkin lymphoma (both of B- and T-cell origin), lymphoblas-
of life. The ataxic gait persists, and most patients never develop normal tic leukemia/lymphoma, and, less frequently, Hodgkin lymphoma and
speech. Eventually, involuntary movements become a major handicap and acute myeloblastic leukemia. Solid tumors are less frequent and include
the child may require a wheelchair by the end of the first decade of life. medulloblastoma and rhabdomyosarcoma. Because of hypersensitivity
Cortical cerebellar degeneration involves primarily Purkinje and granular to radiation and radiomimetic/alkylating agents, tumor therapy is lim-
cells; progressive changes to the central nervous system also occur. ited. Magnetic resonance imaging and ultrasound examinations are the
A variety of other features have been reported. Growth retardation preferred imaging techniques, rather than x-ray and CT scan. Prophy-
is present in 30 percent of the patients. Female hypogonadism is com- lactic therapy with antibiotics and IVIG is indicated in patients with
mon and associated with hypoplasia of the ovaries. Hypogonadism is recurrent infections. Several patients have been successfully treated
also observed in male AT patients. with allogeneic HSCT. 227
The AT gene (AT mutated [ATM]) encodes a large transcript that
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predicts a protein of 3056 amino acids. ATM is a predominantly BLOOM SYNDROME
nuclear protein with a strong serine-threonine kinase activity. Its major BS is characterized by short stature, hypersensitivity to sunlight, increased
function is to rapidly respond to the induction of double-stranded susceptibility to infections, and a predisposition to early development of a
breaks in DNA. The activation of ATM leads to phosphorylation of an variety of cancers. Susceptibility to bacterial infections, affecting mainly
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extensive array of target proteins, each of which plays a key role in a the upper and lower respiratory tract, is associated with hypogamma-
unique damage response pathway. Specifically, ATM is involved in cell- globulinemia and variable T-cell deficiency. Most affected patients have
cycle checkpoint control and delays the passage of cells through the decreased fertility and some may develop early onset type II diabetes
various phases of the cell cycle, allowing time for DNA damage repair. mellitus. By age 25 years, approximately half of the patients with BS will
Additionally, ATM is functionally linked to telomere maintenance, a have developed one or more malignancies. Leukemia and non-Hodgkin
process crucial to aging and cancer. The more than 400 unique muta- lymphoma predominate during the first two decades; later, carcinoma
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tions of ATM described to date are distributed throughout the gene with affecting the colon, skin, and breast are common. The diagnosis of BS
a majority predicted to cause premature termination resulting in unsta- can be confirmed by demonstrating excessive numbers of sister-chro-
ble truncated proteins. matid exchanges, increased chromatid gaps and breaks, and the presence
AT patients should avoid X-radiation and chemotherapeutic of quadriradial configuration composed of two homologous chromo-
agents. Treatment is symptomatic and includes prophylactic antibiotics somes. The causative gene, BLM, encodes a 1417-amino-acid protein
for those with recurrent pulmonary infections and IVIG for those with with homology to the RecQ family of helicases. This family of helicases
antibody deficiency.
includes the Werner syndrome, RecQ helicase-like (WRN) protein, which
is mutated in Werner syndrome. BLM is a member of a group of proteins
ATAXIA-TELANGIECTASIA–LIKE DISORDER that associate with BRCA1 to form a large complex that co-localizes to
ATLD has many features of AT and is the result of mutations in the large nuclear foci if cells are treated with agents that interfere with DNA
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synthesis. As part of this complex, BLM plays a role in sensing DNA dam-
Mre11 protein, which is part of the DNA-repair complex (Mre11/ age and contributes to the maintenance and genomic integrity during the
Rad50/Nbs1). Affected patients have progressive ataxia, but show process of DNA replication and repair. More than 60 unique mutations in
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less-severe neurodegeneration and may be ambulatory until their early the BLM gene have been identified. The most common mutation is a 6-bp
twenties. They do not develop telangiectasia and α-fetoprotein levels are deletion/7-bp insertion in exon 10, which is the homozygous mutation
normal. However, similar to AT, ATLD patients have increased spon- causing BS in Ashkenazi Jews.
taneous chromosomal abnormalities in blood lymphocytes and show BS patients with significant antibody deficiency may benefit from
increased radiation sensitivity.
antibiotic prophylaxis and IVIG therapy. Because of increased radiation
sensitivity, exposure to any form of irradiation should be restricted.
NIJMEGEN BREAKAGE SYNDROME
NBS is characterized by short stature, microcephaly, a bird-like face, RARE SYNDROMES WITH CHROMOSOMAL
immunodeficiency, chromosomal instability, increased radiosensitivity, INSTABILITY
and a high incidence of malignancies. Although NBS shares many NBS-like phenotypes have been linked to mutations in LIG4, RAD50,
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characteristics with AT and ATLD, it can be distinguished from these and nonhomologous end-joining factor 1 (NHEJ1). Other syndromes
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disorders by an absence of neurodegeneration, impressive microcephaly with chromosomal instability include Werner syndrome, Riddle syn-
with mild to moderate mental retardation, and absence of telangiectasia. drome and immunodeficiency with centromere instability and facial
Most NBS patients develop respiratory tract infections, including anomalies (ICF) syndrome.
recurrent pneumonia that may result in bronchiectasis and premature
death from respiratory failure. Both humoral and cellular immunity are CYTOTOXICITY DISORDERS
defective and include hypogammaglobulinemia, except for normal or ele-
vated IgM, abnormal antibody responses to protein and polysaccharide Defense against viruses is primarily dependent on cell-mediated cyto-
antigens, suggesting a defect in CSR, reduced numbers of T lymphocytes, toxicity. Cytotoxic T lymphocytes (CTLs) and NK cells are capable
and abnormal lymphoproliferation to mitogens and specific antigens. 226 of killing virus-infected target cells using pore-forming perforin and

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