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Chapter 51 Congenital Disorders of Lymphocyte Function 717

Supportive treatment for WAS consists of monitoring and treat- Hepatic venoocclusive disease with immunodeficiency is an
ment for bleeding, antimicrobial prophylaxis, immunoglobulin- autosomal recessive condition caused by mutations of the SP110
replacement therapy, and treatment of eczema and autoimmune gene. In addition to liver disease, patients are highly prone to infec-
manifestations with immunosuppressive drugs. Splenectomy can be tions that are often sustained by opportunistic pathogens (CMV,
effective in many to correct thrombocytopenia, but leads to increased Candida, P. jiroveci). Cerebrospinal leukodystrophy has been observed
risk of sepsis. in several cases. The disease is rapidly fatal, unless treated by HCT.
Allogeneic HCT (typically with myeloablative regimens) for WAS Autosomal recessive combined immune deficiency with intestinal
has become standard at many institutions, and may be indicated early atresias is caused by mutations in the TTC7A gene, which encodes
in life, especially in patients with severe mutations that abrogate for a protein involved in maintaining cell polarity in epithelial cells.
protein expression. Variable, but often severe, lymphopenia and panhypogammaglobu-
HCT is usually associated with robust T-cell engraftment, whereas linemia are typical immunological abnormalities. The prognosis is
some patients develop mixed chimerism in the B and myeloid lin- generally severe and is determined by the severity of the gastro-
eages, indicating differential requirement for normal WAS protein to intestinal involvement and of immune deficiency. Small-bowel
promote lineage-specific development or survival. Poor myeloid transplantation is often necessary. In patients with profound immune
chimerism is associated with the risk of persistent thrombocytopenia, deficiency HCT may be required; however, limited data are available
and mixed chimerism favors autoimmune manifestations. on long-term outcome.
Survival after HCT for WAS is influenced by donor type and age The cytidine triphosphate synthase 1 (CTPS1) protein is essential
at transplantation. Optimal results, with approximately 90% survival, for lymphocyte proliferation. Patients with CTPS1 deficiency have a
are obtained after HCT from an HLA-identical sibling donor. Results high risk of recurrent and chronic infections (especially those due to
of HCT from matched unrelated donors are superior if the transplant herpesviruses), and of EBV-related lymphoma.
is performed at a young age (<5 years), but are good overall even A very high risk of EBV-induced lymphoproliferative disease is
when the transplant is performed later in life. However, mixed chi- also observed in patients with CD27 deficiency, who may also present
merism may be associated with increased risk of autoimmunity, and with signs of hemophagocytic lymphohistiocytosis (HLH). These
low myeloid chimerism with persistence of thrombocytopenia. patients lack memory B cells and often develop hypogammaglobu-
Because outcome after HCT is not uniformly good and many linemia after EBV infection.
patients lack matched related or unrelated donors, somatic gene Finally, EBV-associated lymphoma is a common manifestation in
therapy is an attractive treatment option for WAS. In a first trial, 10 patients with magnesium transporter type 1 (MAGT1) deficiency.
boys with WAS were treated with gene therapy by transduction of This condition is inherited as an X-linked trait. The number of naive
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CD34 -selected peripheral blood stem cells using a murine leukemia CD4 T cells is reduced, and expression of NKG2D, an important
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virus-based gammaretroviral vector after low-dose busulfan condi- activating molecule, on the surface of CD8 cytotoxic T cells and
tioning. Immune reconstitution was attained in nine patients; NK lymphocytes, is markedly decreased. HCT can correct the
however, seven of these developed leukemia due to insertional muta- disease.
genesis. More recently, gene therapy for WAS has been performed IL-21 and IL-21R deficiencies are inherited as autosomal recessive
using a self-inactivating lentiviral vector. Results show good immune traits. Gastrointestinal manifestations with colitis and Cryptosporidium-
reconstitution and improved safety (with no leukemic events associated cholangitis have been reported. A single patient with
reported); however, the platelet count, although increased, remains Kaposi sarcoma and OX40 deficiency has been reported.
abnormally low in most patients.
DISORDERS WITH T CELL-MEDIATED
COMBINED IMMUNODEFICIENCIES WITH IMMUNE DYSREGULATION
OSSEOUS DYSPLASIA
Along with generation of a diversified repertoire of T and B lympho-
Cartilage hair hypoplasia (CHH) is an autosomal recessive disorder cytes, purging of self-reactive cells is essential to maintain immune
characterized by short-limbed dwarfism, hair abnormalities, increased homeostasis and prevent autoimmune diseases. We have already
risk of bone marrow dysplasia, malignancies and Hirschsprung reported how autoimmune manifestations are common in severe
disease, and a variable degree of immunodeficiency. The majority of forms of immunodeficiency characterized by oligoclonal expansion
patients show susceptibility to bacterial and viral infections; however, of T lymphocytes (e.g., Omenn syndrome, complete atypical DGS)
some may present with SCID, Omenn syndrome, or selective defi- and in patients with defects of T-cell signaling. Here, we describe
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ciency of CD8 cells. The disease is more common among certain other forms of primary immunodeficiency with faulty control of
ethnic groups (the Amish populations and the Finns), and is caused central or peripheral T-cell tolerance.
by mutations of the gene encoding for the untranslated RNA com-
ponent of the ribonuclease mitochondrial RNA processing (RMRP)
complex, which is involved in cleavage of ribosomal RNA, processing Autoimmune Polyendocrinopathy Candidiasis
of mitochondrial RNA, and cell cycle control. Management of the Ectodermal Dystrophy Syndrome
immunologic problems in CHH depends on their severity. HCT may
be indicated in cases with severe T lymphocyte defects. Also known as autoimmune polyglandular syndrome type 1 (APS1),
Schimke immunoosseous dysplasia is an autosomal recessive autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
disorder that also combines immunologic and skeletal abnormalities. (APECED) is an autosomal recessive disorder characterized by
These children have short stature, skeletal dysplasia, renal dysfunc- autoimmune endocrine manifestations (hypoparathyroidism,
tion and T-cell immunodeficiency caused by mutations in the Addison disease), candidiasis, and nail dystrophy. The disease is
SMARCAL1 gene. caused by mutations of the autoimmune regulator (AIRE) gene,
which encodes for a transcription factor expressed by medullary
TECs (mTECs) where it regulates expression of tissue specific anti-
OTHER COMBINED IMMUNODEFICIENCIES gens that are presented to nascent T cells, thereby promoting clonal
deletion of self-reactive T lymphocytes, or their conversion to natural
Mutations of ICOS, a molecule expressed by activated T cells, were regulatory T cells (nTreg cells).
initially thought to cause a common variable immune deficiency In patients with APECED, mucocutaneous candidiasis usually
(CVID)-like phenotype, but have more recently been shown to cause develops first (in infancy or early childhood), followed by auto-
combined immune deficiency, with recurrent infections of the respi- immune hypoparathyroidism with hypocalcemia and adrenal failure.
ratory and gastrointestinal tracts, and autoimmunity. Around 15% to 20% of patients may develop insulin-dependent