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

IMMUNOOSSEOUS DYSPLASIAS develop in the second decade of life. Severe neutropenia contrasts with
Cartilage Hair Hypoplasia accumulation of mature neutrophils in the marrow. Spontaneous apop-
tosis of neutrophils has been reported. Lymphopenia, including low
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Cartilage hair hypoplasia is an autosomal recessive condition char- B-cell numbers, is a frequent finding. Hypogammaglobulinemia of vari-
acterized by short-limbed dwarfism and light-colored, hypoplastic able degree can be observed, and immunizations result in short-lived
hair. Patients may also present with marrow cell dysplasia, increased antibody responses and impaired class switch. EBV-positive B-cell
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susceptibility to malignancies, Hirschsprung disease, defects of sper- lymphoma can occur.
matogenesis, and a variable degree of immune deficiency (resembling Immunoglobulin replacement therapy and antibiotic prophylaxis
SCID, Omenn syndrome, partial T-cell deficiency) or may have normal may reduce the incidence of infections. Recombinant G-CSF has been
immune function. The rare disorder is more common in certain pop- used to increase the absolute neutrophil count. Warts are resistant to
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ulations, such as the Amish and Finns, and is caused by mutations in local therapy and need to be monitored for neoplastic transformation.
the gene encoding for untranslated RNA component of the ribonuclease
mitochondrial RNA processing (RMRP) complex, which is involved in
cleavage of ribosomal RNA, processing of mitochondrial RNA, and
cell-cycle control. Decreased numbers of T lymphocytes, especially CHROMOSOMAL INSTABILITY
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of CD8+ cells, and impaired in vitro proliferative responses to mitogens SYNDROMES ASSOCIATED WITH
have been reported and may be from reduced thymic output, cell-cycle
abnormalities, and increased apoptosis. 208,209 Impairment of cellular IMMUNODEFICIENCY
immunity may cause increased susceptibility to severe varicella or other Chromosomal instability syndromes have in common increased
viral diseases, and administration of live-attenuated viral vaccines should spontaneous or induced DNA breaks, susceptibility to infections sec-
be avoided. Defects of humoral immunity are less frequent, and may ondary to immune deficiency, and an increased risk of malignancies.
contribute to recurrent infections. Autoimmune manifestations (hemo- Disease-specific abnormalities involving growth and development, the
lytic anemia, neutropenia, and thrombocytopenia) may also occur. central nervous system, and the skin provide useful diagnostic clues.
Similar to what has been observed in other disorders of ribosomal bio- The classic chromosomal instability syndromes include ataxia-telang-
genesis (Diamond-Blackfan anemia, Shwachman-Diamond syndrome), iectasia (AT), Nijmegen breakage syndrome (NBS), Bloom syndrome
disturbances of hematopoiesis, such as anemia, leukopenia, thrombocy- (BS), and AT-like disorder (ATLD). The genes responsible for these syn-
topenia, and marrow dysplasia, are frequent manifestations of cartilage dromes protect human genome integrity by contributing to the complex
hair hypoplasia. Allogeneic HSCT has been successfully used to cor- task of double-strand break repair. Together with the proteins associ-
rect those forms of cartilage hair hypoplasia presenting with a SCID or ated with Fanconi anemia, the gene products of the chromosomal insta-
Omenn syndrome phenotype. 210
bility syndromes form or regulate a large protein complex that is active
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in the surveillance and maintenance of genomic integrity. The triad of
Schimke Syndrome immunodeficiency, neoplasia, and infertility is the direct consequence
Schimke syndrome is an autosomal recessive condition characterized of defective double-strand break repair, and involves nonhomologous
by dwarfism with short neck and trunk because of spondyloepiphyseal end-joining or homologous rejoining. Because nonhomologous end-
dysplasia, progressive renal impairment evolving to renal failure, facial joining is crucial for the generation of TCR diversity and polyclonal
dysmorphisms, lentigines, immunodeficiency (ranging from T-cell immunoglobulins, any interruption of this process will predictably result
lymphopenia to SCID), and increased occurrence of marrow failure in defective adaptive immunity. Tumor development and infertility may
and of early onset arteriosclerosis associated with cerebral infarcts. be a direct consequence of defective DNA repair during miotic recom-
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Microcephaly and cognitive, motor, or social abnormalities have been bination of lymphocytes, other somatic cells, or germ cells, respectively.
reported in a significant proportion of the patients. The disease is
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caused by mutations of the switch/sucrose nonfermentable (SWI/
SNF)-related matrix-associated actin-dependent regulator of chromatin ATAXIA-TELANGIECTASIA
subfamily A-like protein 1 (SMARCAL1) gene that encodes for a chro-
matin remodeling protein. Recurrent infections of bacterial, viral, and AT is a multisystem disorder, characterized by immunodeficiency,
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fungal origin, and opportunistic infections (P. jirovecii pneumonia) are progressive neurologic impairment, and ocular and cutaneous
seen in half of the patients. Severe presentations lead to death in the first telangiectasia. 220
decade of life, and development of renal failure is common among those The immune deficiency in AT is highly variable, involving both
who survive. Combined HSCT and renal transplantation has been used cellular and humoral immunity. Respiratory infections are common
to correct immune deficiency and renal problems. 213 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 IgG and IgG deficiency. Specific antibody responses
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WHIM SYNDROME may be depressed or normal. The number of circulating lymphocytes
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Warts, hypogammaglobulinemia, infections, and myelokathexis is often reduced, and proliferation in response to mitogens is variably
(WHIM) syndrome is an AD disorder, caused by heterozygous muta- depressed. Spontaneous cytogenetic abnormalities include chromo-
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tions in the CXCR4 gene that encodes for the receptor for the CXCL12 somal breaks, translocations, rearrangements, and inversions; these
chemokine, involved in leukocyte trafficking. The term myelokathexis defects increase following in vitro exposure to radiation. The thymus
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indicates retention of mature neutrophils in the marrow. WHIM muta- is often small, showing marked paucity of thymocytes and absence of
tions result in truncation or structural abnormalities in the intracyto- Hassall corpuscles. The most consistent laboratory abnormality, an ele-
plasmic tail of CXCR4 that interfere with ligand-induced internalization vation of serum α-fetoprotein, is diagnostic in adults and children older
and ultimately cause increased cellular responsiveness to CXCL12. 214 than age 8 months as it is not observed in the other chromosomal insta-
Patients with WHIM syndrome may present with early onset bility syndromes.
recurrent bacterial infections, but the clinical phenotype may vary Cancer is the second most common cause of death, after infec-
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greatly. Warts, caused by human papillomavirus (HPV), tend to tions. Most malignancies are non-Hodgkin lymphomas (40 percent),

Kaushansky_chapter 80_p1211-1238.indd 1226 9/18/15 10:02 AM