Hyper-IgE syndrome (HIES) is a complex PID characterized by recurrent staphylococcal infections beginning early in infancy, predominantly involving the skin and lungs, chronic eczema, and markedly high serum IgE concentrations [325–327]. Skin infections due to S. aureus lack the usual local or systemic features of inflammation, forming so-called cold abscesses [328]. Recurrent sinopulmonary infections, resulting in bronchiectasis and pneumatocele formation frequently superimposed with bacterial and fungal infections, are the major causes of morbidity and mortality in patients with HIES [329]. Despite having extremely high serum IgE levels and eosinophilia, patients with HIES are usually free from other allergic manifestations, recognized as a marked difference from DOCK8 deficiency [325, 327]. In patients with HIES, serum IgG, IgM, and IgA levels are usually normal; however, most have impaired antigen-specific Ab response to immunization [330]. Diminished circulating memory B cells and defects in the differentiation of Th17 cells have also been demonstrated [330–332]. The multisystem nature of the disease extends beyond the immune system and accounts for the characteristics craniofacial, musculoskeletal, dental, and vascular abnormalities [333–336].

Dominant negative mutations in STAT3 (OMIM*102582) have been identified as the major molecular etiology of autosomal dominant and sporadic cases of HIES [337, 338]. STAT3, one of the seven STAT proteins in the human, is a transcription factor and plays a critical role in responses to many cytokines and growth factors through the shared signal-transducing molecule gp130 [326, 327]. It is crucial for cell proliferation, survival, migration, apoptosis, and inflammation in various tissues [339], probably explaining the diverse clinical findings in patients with HIES.

STAT3 deficiency is associated with an increased risk of LPDs, most notably HL and NHL (relative risk: 259), with the majority of B-cell origin and aggressive histology [340–342]. Other cancers described in patients with HIES include leukemia and cancers of the vulva, liver, and lung [343]. The underlying mechanisms, however, remain unclear. The higher risk of tumor formation has been attributed to defective immunosurveillance and chronic B-cell stimulation, resulting in an increased turnover of B cells and accumulating genetic aberrations, giving rise to malignant B-cell clones [99].

Wiskott–Aldrich syndrome (WAS) is a rare X-linked immunodeficiency with highly variable manifestations characterized by thrombocytopenia with small platelets, eczema, and humoral and cellular immunodeficiency with increased susceptibility to pyogenic and opportunistic infections. Patients with WAS may also manifest with an increased incidence of autoimmunity and malignancies [344–349].

The disease is caused by mutations in the WAS gene (OMIM*300392), which is expressed exclusively in hematopoietic cells. Around 300 unique mutations spanning the WAS gene have been described. The effect of a given mutation on WASp expression correlates with the disease severity: mutations that cause decreased WASp levels result in the mild variant X-linked thrombocytopenia (XLT), characterized mainly by thrombocytopenia [350, 351], whereas mutations that abolish WASp expression or result in the expression of a truncated protein are associated with classic WAS. In addition, a third disorder termed X-linked neutropenia (XLN), characterized by neutropenia and variable myelodysplasia, has been attributed to activating mutations in the GTPase-binding domain of WASp [178, 352, 353].

The WAS protein (WASp) is a multifaceted protein which exists in complex with several partners involved in relaying signals from cell surface receptors to the actin cytoskeleton; lack of WASp results in cytoskeletal defects that compromise multiple aspects of normal cellular activity including proliferation, phagocytosis, immune synapse formation, adhesion, and directed migration [347]. It is therefore not surprising that lack of WASp results in a wide range of defects in cellular function involving all hematopoietic cell lineages [347].

Malignancies are relatively common in older patients (adolescent and young adults), especially in those with autoimmune manifestations, and are frequently associated with a poor prognosis [345, 348, 354]. The most frequent malignancy reported is B-cell lymphoma, which often occurs in EBV-positive patients [345, 349]. In a report of 154 patients with WAS, 21 (13 %) developed malignancies, mostly of lymphoreticular origin, with the average age at onset of 9.5 years [345]. Nonlymphoid malignancies, including glioma, acoustic neuroma, testicular carcinoma, and Kaposi sarcoma, have infrequently been reported [345, 355]. The development of hematological malignancies in WAS patients is at least partly due to NK cell and cytotoxic T-lymphocyte dysfunction [356–358], absent of invariant NKT cells [359, 360], and chronic stimulation of autoreactive cells and ineffective clearance of virally infected cells [361, 362]. It has been reported that despite normal expression levels of lytic molecules, the cytotoxic CD8⁺ T cells from WAS patients failed to effectively kill B-cell lymphoma target cells due to inefficient polarization of cytotoxic granules toward the target tumor cells [356]. Recently, activating mutations in WASp (which give rise to XLN) have been found to lead to genetic instability through dysregulation of actin polymerization. Enhanced and delocalized actin polymerization throughout the cell was shown to inhibit myelopoiesis through defective mitosis and cytokinesis, with micronuclei formation indicative of genomic instability [363]. Despite lack of direct evidence, genomic instability might contribute to the development of malignancies in WAS patients [347].

Early HSCT is the treatment of choice for patients with classic WAS, preferably from a matched related donor [364]. Furthermore, immune reconstitution in WAS patients following HSCT leads to a decrease in cancer risk [364]. Gene therapy is an alternative to HSCT in the treatment of WAS [365]; however, the long-term outcome needs to be further monitored. This could be explained by the fact that the viruses used for therapy integrate in the host genome, with preferential insertion at transcription start sites, promoter and enhancer regions of active genes, and at conserved noncoding DNA, resulting in a high rate of transformations and the development of secondary malignancies [366, 367]. Acute T-cell leukemia due to vector insertion in the vicinity of the T-cell oncogene LMO2 has been reported in one patient [368, 369].

Chromosome 22q11.2 deletion syndrome is relatively common (estimated in 1 in 4,000 births) [370], and about 6 % of newly diagnosed cases are familial [371]. The presenting symptoms of chromosome 22q11.2 deletion syndrome vary depending on the patients’ age. While developmental delay and speech issues are the usual presenting symptoms in older children and adults, cardiac anomalies, hypocalcemia, and infection are the major manifestations in infants. Cardiac defects are seen in approximately 80 % of patients; on the other hand, tetralogy of Fallot and interrupted aortic arch type B have a strong positive predictive value for chromosome 22q11.2 deletion syndrome [372, 373]. Palatal dysfunction, feeding problems, facial dysmorphism, renal anomalies, and gastrointestinal manifestations also are seen in most of these patients [374]. Patients are also at an increased risk of atopy and autoimmune disease development [375, 376].

The immune system is affected in approximately 75 % of the patients [374, 376, 377]. The severity ranges from absent thymic tissue and no circulating T cells to completely normal T-cell counts. Many infants with low T-cell counts will demonstrate improvement in the first year of life, but after that, T-cell counts decline [378]. Patients may also suffer from variable degrees of B-cell defects [379, 380]. In a cohort of 687 patients with chromosome 22q11.2 deletion syndrome, six cases of malignancy were identified. This gives an overall frequency of 0.9 % (900 per 100,000) in this large pediatric group of patients, whereas the overall risk of malignancy in children under the age of 14 years is 3.4 per 100,000 children [381]. As reported in the literature, patients with chromosome 22q11.2 deletion syndrome have a clearly increased risk of lymphoma, particularly B-cell lymphoma [382–385]. This is a general phenomenon in patients with severe immunodeficiency. There have also been reports of myelodysplasia, acute lymphoblastic leukemia, SCC, astrocytoma, neuroblastoma, hepatoblastoma, renal cell carcinoma, and rhabdoid tumors [381, 386–390].