a) T cell primary immunodeficiencies. Reticular dysgenesis, a rare severe combined immunodeficiency (SCID) characterized by T lymphopenia and agranulocytosis, can cause sensorineural deafness. Coronin A deficiency is another SCID variant that can be associated with behavioral disorders because the Coronin A gene is located in a genome area known to have been deleted in some patients with this disorder. The lack of enzymes of purine metabolism (adenosine deaminase [ADA] and purine nucleoside phosphorylase) provokes not only profound T cell lymphocytopenia but also neurologic impairment, including dysautonomia and abnormalities of cognitive development of variable intensity, in many patients. The neurologic impairment can persist after hematopoietic stem cell transplantation (HSCT). Mild chondrodysplasia is a common finding in ADA deficiency and, indeed, can help the physician arrive at a final diagnosis.
b) Primary thymic defects. DiGeorge’s syndrome is a complex embryopathy that is caused by hemizygous interstitial deletion of chromosome 22, leading to multiple developmental defects, including conotruncal defects, hypoparathyroidism, and dysmorphic syndrome. Although a profound T cell immunodeficiency is rare in DiGeorge’s syndrome (~1% of cases), failure to recognize this feature is likely to have a fatal outcome. Similarly, some forms of the related CHARGE syndrome (mutation of the CHD7 gene) also cause a profound T cell immunodeficiency.
c) T cell primary immunodeficiencies related to calcium influx defects. Recently, rare T cell PIDs were found to be caused by defective store-operated entry of calcium ions into T and B lymphocytes after antigen stimulation. These defects (caused by ORA-1 and STIM-1 deficiencies) also lead to anhydrotic ectodermal dysplasia, abnormal teeth, and, above all, a nonprogressive muscle disease characterized by excessive fatigue.
d) DNA repair defects. Several genetic defects impair DNA repair pathways. Many lead to combined T and B lymphocyte PIDs in a syndromal setting of varying complexity. The most common is ataxia-telangiectasia (AT), an autosomal recessive disorder with an incidence of 1 in 40,000 live births; AT causes a B cell immunodeficiency (low IgA, IgG2 deficiency, and low antibody production) that often requires immunoglobulin replacement therapy.
AT is associated with a progressive T cell immunodeficiency. As the condition’s name suggests, the hallmark features are telangiectasia and cerebellar ataxia.
These manifestations may not be detectable before age 3–4 years, and so AT should be considered in young children with IgA deficiency and problematic infections. Diagnosis is based on a cytogenetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. AT is caused by mutation of the gene encoding the ATM protein, a kinase that plays a major role in the detection of DNA lesions and the organization of DNA repair (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that carries a very high risk of lymphoma, leukemia, and (during adulthood) carcinomas. A variant of AT (AT-like disease) is caused by mutation of the MRE11 gene.
Nijmegen breakage syndrome (NBS) is a less common condition that also results from chromosome instability (and the same cytogenetic abnormalities as in AT). It is characterized by a severe T and B cell combined immunodeficiency with autosomal recessive inheritance. Subjects with NBS exhibit microcephaly and a birdlike face but neither ataxia nor telangiectasia. The risk of malignancies is also very high. NBS results from a deficiency in Nibrin (NBS1, a protein associated with MRE11 and Rad50 that is involved in checking DNA lesions) caused by hypomorphic mutations.
Severe forms of dyskeratosis congenita (also known as Hoyeraal-Hreidarsson syndrome) combine a progressive immunodeficiency that can include an absence of B and natural killer cell (NK) lymphocytes, progressive bone marrow failure, microcephaly, in utero growth retardation, and gut disease. The disease can be X-linked or, more rarely, autosomal recessive. It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1).
Bloom’s syndrome (helicase deficiency) combines a typical dysmorphic syndrome with growth retardation, skin lesions, and a mild immunodeficiency that also can be found in some patients with Fanconi’s anemia.
Rare forms of combined T and B cell immunodeficiencies with autosomal recessive inheritance are associated in more complex syndromes with microcephaly, failure to grow, and a variable dysmorphic syndrome. These disorders are caused by mutation of the genes that encode DNA ligase 4 and Cernunnos (XLF), both of which are members of the nonhomologous end-joining DNA repair pathway.
The Vici syndrome combines callosal agenesis, cataracts, cardiomyopathy, hyperpigmentation, and a combined immunodeficiency. It is caused by biallelic EPG5 gene mutation that results in defective autophagy.
Lastly, immunodeficiency, centromere instability, and facial anomalies (ICF) syndrome is a complex autosomal recessive syndrome that variably combines a mild T cell immunodeficiency and a more severe B cell immunodeficiency with a coarse face, intestinal disease, and mild mental retardation. A cytogenetic diagnostic feature is the presence of multiradial chromosomes (most frequently chromosomes 1, 9, and 16) caused by DNA defective methylation. The syndrome is a result of either DNA methyltransferase DNMT3B deficiency or ZBTB24 deficiency.
e) Growth hormone insensitivity syndrome (Laron dwarfism) with combined PID. Mutations in the STAT5b gene, which encodes a transcription factor involved in signaling downstream of the growth hormone receptor and the interleukin 2 (IL-2) receptor, lead to susceptibility to infection because of a partial, functional T cell immunodeficiency associated with autoimmune manifestations. The autoimmune manifestations probably result from defective generation/activation of regulatory T cells.
f) Hyper-IgE syndrome (autosomal dominant form). Hyper-IgE syndrome is a complex disorder that combines skin infections, inflammation, and susceptibility to bacterial and fungal infections of skin and lungs, often with pneumatoceles, with characteristic syndromic signs such as facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels are typical of hyper-IgE syndrome. The recently reported defects in TH17 effector responses account, at least in part, for the vulnerability to specific infections. This condition is caused by heterozygous (dominant) mutation of the gene encoding the transcription factor STAT3, which is required in a number of signaling pathways downstream of cytokine/cytokine receptor interactions (notably for IL-6 and IL21).
g) Primary immunodeficiencies with bone disease. The autosomal recessive cartilage hair hypoplasia (CHH) disease is characterized by short-limb dwarfism, metaphyseal dysostosis, and sparse hair, together with a combined T and B cell PID of variable intensity, ranging from quasi-SCID to an absence of clinically significant immunodeficiency. The condition can predispose to erythroblastopenia, autoimmunity, and tumors. It is caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA.
Schimke immunoosseous dysplasia is a rare autosomal recessive condition characterized by severe T and B cell immunodeficiency with spondyloepiphyseal dysplasia, growth retardation, and kidney and vascular diseases. It is the consequence of mutations in the SMARCAL1 gene. The function of the gene product may be related to DNA repair.
h) Venoocclusive disease with immunodeficiency (VODI syndrome) is a rare autosomal recessive condition predominantly found in populations originating from Lebanon. It combines severe hepatic venoocclusive disease with usually mild T cell immunodeficiency and panhypogammaglobulinemia. It is caused by a deficiency in a nuclear protein, Sp110.