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CHaPTEr 35 Primary T-Cell Immunodeficiencies 501

TABLE 35.6 Combined Immunodeficiency With Immunoosseous Dysplasia
Molecular Defect/Presumed
Disease Inheritance Pathogenesis features Treatment
Cartilage hair hypoplasia AR Defect in RMRP gene resulting in impaired Metaphyseal dysplasia; fine Hematopoietic stem cell
ribosomal assembly and cell cycle and sparse hair transplantation (HSCT)
regulation
Schimke immunoosseous AR Impaired DNA stress response enzyme Epiphyseal dysplasia; renal Supportive
dysplasia dysfunction; autoimmunity;
non-Hodgkin lymphoma
Roifman immunoskeletal AR Impaired tartrate-resistant phosphatase Spondyloenchondrodysplasia; Supportive
syndrome (SPENCD) (TRAP) enzyme function, accumulation of autoimmunity; neurological
phosphorylated osteopontin abnormalities

with lack of central pigment core, and skin hypopigmentation. Infections are controlled with immunoglobulin replacement
There is an increased risk of non-Hodgkin lymphoma and basal in these patients.
cell carcinoma with this syndrome. HSCT has proven curative
of the immune abnormalities in these patients. SPENCDI–Roifman Immunoskeletal Syndrome
This syndrome was first described in 2000 as a novel combina-
Schimke Immunoosseous Dysplasia tion of features encompassing combined immunodeficiency,
The major features of Schimke immunoosseous dysplasia autoimmunity, and spondylometaphyseal dysplasia (OMIM #
50
(SIOD; OMIM #242900), an autosomal recessive syndrome, 607944). One patient died of noninfectious encephalopathy,
are spondyloepiphyseal dysplasia, progressive renal failure, and and some others had arthritis, SLE, and thrombocytopenia, in
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moderate cellular immunodeficiency. The disease is caused by addition to lung disease. Renella et al. highlighted the type of
mutations in the SWI/SNF matrix actin-dependent regulator of spondylometaphyseal dysplasia as spondyloenchondrodysplasia
chromatin subfamily A-like gene (SMARCAL1) encoding a DNA (SPENCD), confirming the initial observation of autoimmunity
stress response enzyme. Patients with SIOD present with growth in this syndrome. The spectrum of clinical features was further
retardation before and after birth. In addition to progressive renal expanded to include cerebral calcifications and other neurological
failure, patients may have cerebral vascular accidents, dental and abnormalities. SPENCD is a rare skeletal dysplasia characterized
skin abnormalities, and dysmorphic features. Immune function by metaphyseal and vertebral lesions consisting of chondroid
is variable, with mild to moderate lymphopenia and somewhat tissue. Over the years, evidence for both autosomal dominant and
reduced in vitro responses to mitogens. Consequently, they develop recessive inheritance was proposed. Mice lacking tartrate-resistant
recurrent viral and fungal infections. Treatment is supportive, phosphatase (TRAP) display skeletal abnormalities identical to
and some patients may benefit from renal transplantation. the patients. Consequently, sequencing of the ACP5 gene (OMIM
*171640), which encodes TRAP, identified deleterious biallelic
Roifman Syndrome mutations in humans. 52,53 Immune abnormalities include T-cell
Roifman Syndrome (OMIM #616651) was first described as lymphopenia with reduced responses to mitogens and antigens,
a novel association of immunodeficiency, spondyloepiphyseal and an inability to produce specific antibodies. Patients frequently
chondro-osseous dysplasia, retinal dystrophy, growth and have autoantibodies, such as antinuclear factor (ANF) and anti-
developmental delay, and distinctive facial dysmorphism. 49 DNA. Treatment so far has been limited to replacement of Igs,
This syndrome is caused by distinct mutations in the small antibiotics, and immunomodulation of the various immune
nuclear RNA (snRNA) gene RNU4ATAC (OMIM*601428), which manifestations.
is essential for minor intron splicing. About 800 genes have one
or more minor introns, and these are dependent on the minor COMBINED IMMUNODEFICIENCY WITH BONE
spliceosome for correct splicing. Since many of these genes are MARROW FAILURE
involved in basic cellular functions, such as DNA replication
and repair or RNA processing, incorrect splicing can alter cell Immune deficiencies associated with bone marrow failure are
function and survival. Mutations in the Stem II domain of the presented in Table 35.7.
gene appear obligatory for this syndrome. Patients with Roifman
Syndrome frequently suffer repeated microbial infections such IKAROS Deficiency
as otitis media, cellulitis and pneumonia as well as viral and IKAROS deficiency is extremely rare combined immunodeficiency
fungal infections (HSV, PJP). associated with bone marrow failure (OMIM #616873). IKAROS
Atopy and autoimmune manifestations are also common, is a hematopoietic-specific transcription factor (OMIM *603023)
including eczema, asthma, arthritis, hemolytic anemia, colitis, affecting pluripotent stem cells that control T-cell differentiation,
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and autoimmune hepatitis. Antibody deficiency and hypogam- B-cell V(D)J recombination, and NK-cell development. Patients
maglobulinemia are present in all cases, and circulating B cells may present with recurrent pulmonary infections or disseminated
are usually reduced, especially memory B cells. T cell lymphopenia, viral infections in teenage years, or during infancy with bone
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low CD8+ T cells, abnormal T cell repertoire, as well as low in marrow aplasia and near absent B and NK cells. T cells can be
vitro responses to antigens are also recorded. normal in number, but the response to mitogens is absent