Page 520 - Clinical Immunology_ Principles and Practice ( PDFDrive )

500 ParT fOur Immunological Deficiencies

of the TBX1 gene (OMIM *602054), which is localized within involved in protecting DNA repair. ATM is a serine/threonine
the deleted region, can be solely responsible for this disorder. protein kinase that activates signaling pathways upon double-
Less frequently, DGS can be caused by defects in other chromo- strand breaks, which occur naturally during Ig and TCR rear-
somes, notably 10p13. DGS is one form of several phenotypically rangement or upon stress posed by ionizing radiation. It is also
overlapping disorders, including conotruncal anomaly and involved in cell cycle control and may act as a tumor suppressor
velocardiofacial syndrome. Clinically, patients may present with gene.
neonatal hypocalcemia and susceptibility to opportunistic infec- Affected individuals present in early childhood with progressive
tions. Cardiac malfunctions typically include tetralogy of Fallot, truncal ataxia, which is frequently misdiagnosed in infancy as
truncus arteriosus, and interrupted aortic arch. Facial signs consist cerebral palsy. Choreoathetosis and dystonia, ocular motor apraxia,
of retromicrognathia, small teeth, short filtrum, hypertelorism, and dysarthria are common. At 3–5 years of age telangiectasias
and low-set and malformed ears. Pulmonary, renal, skeletal, become increasingly prominent in the eyes and ear lobes. Typically,
ophthalmological, and GI defects can also occur. patients become wheelchair dependent during the second decade
Molecular diagnosis is made by using chromosomal microarray of life. Most patients die by the age of 30 years, with rare survivors
or array comparative genomic hybridization or by sequencing who live to the end of the fourth decade. Patients die of progressive
the TBX1 gene. Because of the poor development of the thymic restrictive lung disease, infections, or cancer. Lymphoma, leukemia,
gland, patients with DGS usually have T-cell lymphopenia, which and ovarian and stomach cancers are the most common malignan-
frequently improves with age but may never reach normal levels. cies associated with AT, and a high risk of developing breast
A small group of patients are born with little to no detectable cancer is a prominent feature of heterozygotes.
circulating T cells and are therefore designated as suffering from Diagnosis of this condition is supported by demonstrating
“complete DGS.” Management is dictated by the presenting increased frequency of chromosomal breakage and elevated levels
features of this heterogeneous syndrome. Calcium supplements of alpha-fetoprotein, which reflect the defect in DNA repair and
and 1,25-cholecalciferol may be needed to treat hypocalcemia. liver tissue immaturity, respectively. Immune investigations show
Blood products, if needed (normally during heart surgery), should decreased circulating T cells and abnormal in vitro response
be CMV-free and irradiated to eliminate allogeneic T-cell transfer to mitogens. The thymus is dysplastic, and TREC levels are
and to prevent GvHD. Thymic tissue transplantation has been markedly reduced. IgA is low in about 50% of patients, and
attempted in cases with complete DGS, although the effects are IgG levels vary from extremely low to normal levels. IgM may
difficult to evaluate, since children with DGS tend to improve be increased, a phenotype mimicking hyper-IgM syndrome
spontaneously with age. (HIGM). The diagnosis is confirmed by identifying mutations
in the ATM gene. Treatment is mostly supportive and limited
Wiskott-Aldrich Syndrome to intravenous immunoglobulin (IVIG) and antibiotics, when
Wiskott-Aldrich syndrome (WAS; OMIM #301000) is a rare indicated, as well as physiotherapy. Nijmegen breakage syndrome
X-linked recessive condition caused by mutations in the WAS (OMIM #251260), an AT-like syndrome, is caused by biallelic
gene. The WAS encoded protein is predominately expressed in hypomorphic mutations in MRE11, which encodes a protein
hematopoietic cells, and its main function is to activate actin involved in cell cycle control and double-strand DNA repair. In
assembly by binding to the Arp2/3 complex. The WAS protein addition to the typical AT feature, Nijmegen breakage syndrome
(WASP) is required for TCR-mediated formation of the immu- is characterized by microcephaly, bird-like facial features, and
nological synapse, which is a process dependent on actin rear- growth retardation.
rangement. Patients are typically diagnosed in infancy, and their
condition is characterized by thrombocytopenia, eczema, and COMBINED IMMUNODEFICIENCY WITH
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recurrent infections. Platelet volume is reduced and appears IMMUNOOSSEOUS DYSPLASIA
to be rapidly cleared from the circulation. The abnormal coagula-
tion in these patients is associated with bloody stools and life- This group of combined immunodeficiencies characterized by
threatening intracranial bleeding. Patients with this syndrome walking and growth disturbances is summarized in Table 35.6.
occasionally have increased susceptibility to bacterial, viral, and
opportunistic organisms, including P. jiroveci pneumonia. Cartilage Hair Hypoplasia
Autoimmunity and malignancy, particularly lymphoma, have McKusick-type metaphyseal chondrodysplasia, also known as
been frequently reported in these patients. T-cell numbers tend cartilage hair hypoplasia (OMIM #250250), is an autosomal
to decrease over time, resulting in mild-to-moderate lymphopenia, recessive syndrome that was first recognized in the Amish and
and in vitro responses to mitogens are frequently normal. Typically, later in the Finnish population. The condition is characterized by
IgM is low, IgG is normal, whereas IgA and IgE are elevated. short-limb dwarfism, various degrees of T-cell immunodeficiency,
Splenectomy should be avoided. HSCT successfully cures these fine and sparse hair, Hirschsprung disease, and increased risk of
patients. Gene therapy for this condition is currently being malignancy. This syndrome is caused by mutations in the RNase
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studied. Recently, a patient with a similar phenotype to WAS MRP (RMRP) gene (OMIM *157660), a ribonuclease that is
was shown to have a mutation in the WASP-interacting protein present in both the nucleus and mitochondria. Uniquely, this gene
(WIP). WIP stabilizes WASP, preventing its degradation. product does not undergo translation but functions as a protein in
the cleavage of RNA during mitochondrial DNA synthesis, as well
Ataxia Telangiectasia (Louis-Bar Syndrome) as clearing of nuclear pre-rRNA. Immune function is variable, and
Ataxia telangiectasia (AT; OMIM #208900) is an autosomal patients may present with profound T-cell lymphopenia, depressed
recessive multisystem disorder characterized by cerebellar ataxia, mitogenic responses, and a dysplastic thymus. Some cases present
+ +
telangiectasias, immunodeficiency, and highly increased predis- with Omenn syndrome (T B SCID). Other patients have various
position to malignancy. AT is a result of deleterious mutations degrees of T-cell lymphopenia. Nonimmune features consist of
in the ATM gene (OMIM *607585), which encodes a key protein spondylometaphyseal dysplasia, small caliber and hypoplastic hair