Infections in DNA Repair Defects: Comparison
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Please note this is a comparison between Version 1 by Yesim Yilmaz Demirdag and Version 2 by Rita Xu.

DNA repair defects are rare heterogeneous conditions typically present with an increased risk of cancer, accelerated aging, and defects in the development of various organs and systems. The immune system can be affected in a subset of these disorders leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may occur due to primary defects in T, B, or NK cells and other factors such as anatomic defects, neurologic disorders, or during chemotherapy. 

  • inborn errors of immunity
  • immunodeficiency
  • DNA repair disorders
  • ataxia telangiectasia

1. Introduction

DNA damage can occur spontaneously or because of environmental exposure to various agents such as ultraviolet radiation, ionizing radiation, and chemicals, including alkylating agents, aromatic amines, and cross-linking agents [1]. Cells utilize several DNA repair mechanisms to avoid deleterious consequences of DNA damage, which may result in mutations and genomic instability. These mechanisms include DNA mismatch repair (MMR), base excision repair (BER), nucleotide excision repair (NER), single-strand break repair (SSBR), and double-strand break repair (DSBR) [2]. In general, DNA repair starts with damage recognition, activation of checkpoint proteins, and finally, activation of repair enzymes such as nucleases, helicases, polymerases, and ligases. Double-strand breaks are the most toxic DNA breaks resulting in cell death or large-scale gene rearrangement, causing cancer if not properly repaired. The two main DSBR pathways are homologous recombination (HR) and nonhomologous end-joining (NHEJ) pathways. HR is the most accurate because it uses the homologous sister chromatid as a template. Disorders of DNA repair mechanisms may result from alterations in these repair pathways, causing genomic instability and various disease phenotypes ranging from neurodevelopmental syndromes, immunodeficienciencies, increased risk of a variety of malignancies, to premature aging [3].
In addition to a spontaneous occurrence or triggered by environmental factors, in some cells, DNA breaks are programmable and necessary. A classic example of programmed DNA breaks occurs during somatic rearrangement of T cell receptors (TCR) and immunoglobulin receptor (or B cell receptors-BCR) genes, a process called V(D)J recombination, which is essential in the generation of diverse antigenic repertoire. DNA repair mechanisms play a crucial role in the development of these antigen receptors, which are critical for normal immune response. Defects in DNA repair pathways may lead to various alterations in the development and maturation of T and B cells, causing susceptibility to recurrent or severe infections [4]. The majority of DNA repair defects that are most associated with immunodeficiencies are due to defects in 3 repair pathways: DSBR, MMR (such as LIG4 deficiency, ataxia telangiectasia, and Nijmegen Breakage syndrome) and BER (UNG deficiency).

2. Ataxia-Telangiectasia

Ataxia Telangiectasia (AT) is a rare autosomal recessive (AR) disorder affecting multiple systems, primarily the nervous system, and immune system, with a median life expectancy of 25 years [5][8]. It is caused by mutations in the ATM (ataxia–telangiectasia, mutated) gene that encodes the protein ATM, a protein kinase that plays a critical role in DSBR. In addition to the result of exposure to ionizing radiation and other external factors, double-strand breaks (DSB) occur during TCR as well as BCR gene rearrangements. When ATM does not function properly, the cell cycle does not stop to repair DSB. This results in defects in T cell receptor (TCR) and B cell receptor (BCR) rearrangement, which ultimately causes defects in the development of T and B cells [6][7][9,10]. Prevalence, severity, and type of immunologic abnormalities in AT are highly variable and usually associated with lymphopenia, low immunoglobulin levels (IgG/IgA or IgM), low IgG2 or IgG3 and suboptimal polysaccharide antibody responses. Despite low CD4+ T cell counts, T cell function is usually preserved [7][8][9][10,11,12]. About 10–20% of patients with AT present with hyper-IgM phenotype, which is likely due to a blockade in early B cell development resulting in immunoglobulin class-switching defect (CSD) [10][11][13,14]. Importantly, the hyper-IgM phenotype is associated with more severe infectious manifestations and lower survival rates [10][12][13,15]. The symptoms of AT usually develop early in the first 1–2 years of life and include progressive cerebellar ataxia, which is the most reported presentation [13][16]. Other neurologic symptoms include the progressive development of dysarthria, dysphagia, oculomotor apraxia, dystonia, tremor, and peripheral neuropathy. Some patients may also have progressive cognitive impairment. By 10 years of age, the majority of children are unable to walk. Telangiectasia often involves the bulbar conjunctivae, pinna of the ears, and other places in the body starting around 3–4 years of age. Frequent infections may start as early as the first months of life and mostly involves infections of the upper and lower respiratory tracts requiring prophylactic antibiotic therapy as well as immunoglobulin replacement therapy [7][8][10,11]. In contrast to progressive neurologic disease, progressive immunodeficiency is very rare in AT [7][14][10,17]. In addition to neurologic deterioration and infections, increased risk of malignancies, particularly leukemia, and lymphoma, and increased risk of toxicity associated with chemo- and radiation therapies further impact life expectancy in AT [13][15][16,18].

2.1. Respiratory Tract Infections in AT

In a large cohort of patients with AT, recurrent upper respiratory tract infections were reported by more than one-third of patients. Due to progressive neurologic disease, which results in respiratory failure, the prevalence of lower respiratory tract infections increases with age and may be seen in up to 38% of patients older than 20 years [7][8][16][10,11,19]. The major causes of death in AT include bacterial pneumonia and chronic lung disease [5][17][8,20]. A retrospective study analyzed 101 patients who did not have cancer and had chronic respiratory symptoms [18][21]. This included 36 patients with AT who were alive and 65 patients who died secondary to lung disease. Clinical symptoms included cough, fever, adventitial breath sounds, weight loss, post-tussive emesis, hemoptysis, and pleuritic chest pain. Radiological findings included but were not limited to bronchiectasis, hilar adenopathy, pneumothorax, pleural thickening, and sinusitis. Of the 101 patients, 79 had at least one microbial evaluation of their respiratory secretions, and 61 were positive. Bacterial pathogens isolated included Pseudomonas aeruginosa, Hemophilus influenzae, Staphylococcus aureus, Streptococcus pneumoniae, Escherichia coli, Streptococcus viridians, Candida albicans. Of seven patients in whom viral pneumonia was suspected, three had respiratory syncytial virus (RSV) infections, two had clinical and radiological pictures consistent with Varicella pneumonia, and the remaining two had serological evidence of acute EBV infection in association with new pulmonary infiltrates. No opportunistic or fungal pathogens were isolated, with the exception of Candida albicans, which was always found in conjunction with other microbes. A single-center study on 12 patients with AT demonstrated that while patients with low IgG2 had recurrent infections due to S. pneumoniae, bacterial pathogens were not demonstrated in the airways of 4 patients with IgG3 deficiency [9][12]. Interestingly, other studies found no correlation between the frequency of respiratory tract infections and immunoglobulin deficiencies [7][14][10,17]. On the other hand, patients with hyper IgM phenotype, where serum IgM levels are normal or elevated and IgG and/or IgA levels are low, presented with a more severe course and shorter survival due to recurrent and severe respiratory infections [10][13].

2.2. Bacterial Sepsis and Meningitis in AT

Bacterial sepsis and meningitis are seen as relatively rare in AT. Other factors, such as [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80]malignancy, chemotherapy, and indwelling catheters, contribute to the development of invasive infections caused by Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa [7][10].

2.3. Viral Infections in AT

In one cohort, 44% of patients reported varicella infection, and severe varicella infection requiring hospitalization was reported in 5% of these patients. Warts were reported in 17%, and refractory warts were seen in 7% of total patients [7][10]. No patient had a cytomegalovirus infection in this cohort. In addition to chronic EBV infection, EBV-associated tumors such as smooth muscle tumors in the liver and nodular sclerosing Hodgkin lymphoma and mucosa-associated lymphoid tissue (MALT Lymphoma) in the parotid gland have been reported in AT [9][19][20][21][12,22,23,24]. Complications associated with live-viral vaccines for polio, measles, mumps, or varicella zoster have not been reported except for one vaccine-associated poliomyelitis case [22][25]. However, although causality is unclear, vaccine-strain rubella virus has been isolated in some cutaneous granulomas in patients with primary immunodeficiencies, specifically in DNA repair disorders, including AT [23][24][25][26,27,28].

2.4. Fungal Infections in AT

Interestingly, despite the high rate of low T cells, infections associated with cellular immunodeficiency are only rarely seen in AT. Moreover, despite the use of frequent antibiotics for respiratory infections, candida infections were reported only occasionally and mostly in the setting of chemotherapy. For example, candida esophagitis was reported in 3 of 100 patients with AT, and in one patient, it was associated with chemotherapy, in another patient, it was concurrent with EBV infection. Additionally, one patient developed candida esophagitis during severe varicella infection [7][10]. P. jiroveci pneumonia was extremely rare in AT [26][29].

3. Nijmegen Breakage Syndrome

Nijmegen breakage syndrome (NBS) is another rare AR defect in DSBR. It is most commonly seen in Slavic populations due to a founder mutation in the gene NBS-1, encoding protein named “nibrin” [27][30]. Nibrin is part of a trimeric complex which also includes MRE11 and RAD50 (the MRN complex). The MRN complex is involved in DSBR by both homologous recombination and nonhomologous end joining. Nibrin recognizes DSB and initiates the relocation of the MRN complex to the sites of DSBs. In addition to a direct role in DNA repair, the MRN complex is also involved in the activation of ATM [28][29][31,32]. The hallmark of NBS is microcephaly, usually since birth, with normal or mildly impaired psychomotor development. Other cardinal features include a typical facial appearance with a prominent midface, recurrent respiratory infections, chromosomal instability, radiation hypersensitivity, and predisposition to malignancy [27][30][30,33]. Some patients may also have café au lait spots, clinodactyly and syndactyly. Combined humoral and cellular immunodeficiencies are extremely common and highly variable in NBS. In a large cohort, abnormal levels of total serum immunoglobulins were found only in 32 out of 40 patients (80%). The most common immunoglobulin deficiency was combined IgG and IgA deficiency (25%). Interestingly, 36·8% of patients with normal total IgG levels had low IgG subclasses (mainly IgG2 and/or IgG4). Five of 40 patients had markedly elevated concentrations of IgM. Reduced absolute counts of CD4+ T cells were found in 95% and CD8+ T cells in 80% of patients. An elevated number of NK cells was seen in 62.5% of patients. In contrast to AT, in more than 50% of patients with NBS, immunodeficiency may progress over time [31][34]. Patients with recurrent infections are treated with immunoglobulin replacement therapy and prophylactic antibiotics. Despite confirmed immunodeficiency, some patients do not develop frequent infections and do not require prophylactic antibiotics or immunoglobulin treatment for many years or until the development of a malignancy.

3.1. Bacterial Infections in NBS

The most common infections in NBS include bacterial respiratory tract infections which have been reported in more than 50% of patients [27][30][31][32][30,33,34,35]. Mycobacterial infections have been reported in only a few patients [32][33][34][35,36,37].

3.2. Viral Infections in NBS

Herpes simplex infections with recurrent relapses may be seen in up to 30% of patients with NBS, some of which may be associated with chemotherapy [35][38]. In a large retrospective study, chronic hepatitis infections were reported in 23% of patients, including 14 children with HBV, three with HCV, two with co-infection with HCV and HBV, and five children with severe and recurrent HZV infection [32][35]. Other studies also showed that severe or chronic viral infections, especially those caused by lymphotropic and/or hepatotropic viruses such as EBV, CMV, HBV, and HCV, may occur, and they may mimic lymphoma or leukemia [36][37][39,40]. In some patients, two and even three viral infections co-existed [32][36][35,39]. The median maximum load of EBV DNA was higher in patients with CD3+ T cells of <300 cells/μL compared with those with normal CD3+ T cell levels [36][39]. In a large prospective study, 38.6% of 57 children with NBS developed lymphatic malignancies [36][39]. In 68.2% of these patients, viral genetic material was demonstrated before the development of malignancy, including EBV in 63.6%, HBV in 31.8%, HCV in 13.6%, and co-infection with two or three viruses in 8 children. There were statistically significant correlations between monoclonal gammopathy and the persistent presence of EBV DNA and HCV RNA. Although the exact mechanism was not investigated, these findings may suggest that chronic viral (such as EBV or HCV) stimulation may contribute to the development of monoclonal malignancies. Like in AT, the vaccine-strain rubella virus has been isolated in some cutaneous granulomas in patients with NBS, and hematopoietic stem cell transplantation resulted in scarring resolution of granuloma in two patients [23][26].

3.3. Fungal Infections in NBS

Mucosal candidiasis was reported in as many as 50% of patients with NBS, and some of these patients were on chemotherapy [35][38][38,41]. For example, pulmonary fungal infections were suspected in 2.7% of patients and recurrent oral candidiasis in 4.5% [32][35].

4. Bloom Syndrome

Bloom syndrome, a rare AR syndrome, is associated with strong genetic instability characterized by cytogenetic abnormalities such as numerous chromosomal breaks and predisposition to all types of cancers starting at an early age. It is caused by mutations in the BLM gene, which encodes a 3′-5′DNA helicase [39][42]. This is an extremely rare condition of <300 cases registered in the Bloom Syndrome registry. It is more prevalent in populations with high consanguinity rates, such as among Ashkenazi Jews whose ancestors were from Poland or Ukraine. Clinical features of Bloom syndrome include prenatal and postnatal growth retardation, microcephaly, and butterfly-shaped facial erythema due to photosensitivity. The most significant manifestation of Bloom syndrome is the development of cancer of any type starting at an early age, including more than one type of independent cancer [40][43]. Patients with Bloom syndrome have variable immunodeficiencies, mostly mild antibody deficiencies. Although they develop recurrent infections of the respiratory and gastrointestinal tracts, they are not susceptible to severe or opportunistic infections [41][42][44,45]. Treatment includes immunoglobulin replacement and/or prophylactic antibiotics in patients with recurrent infections.

5. Immunodeficiency, Centromeric Instability and Facial Anomalies (ICF) Syndrome

ICF syndrome is a heterogenous autosomal recessive disorder. The number of genes associated with ICF increased from 1 to 4 in the past couple of years, and they include DNA methyltransferase 3B (DNMT3B), zinc-finger and BTB domain-containing 24 (ZBTB24), cell division cycle associated 7 (CDCA7), and helicase, lymphoid specific (HELLS). About 50% of patients with ICF carry biallelic mutations in the DNMT3B gene. In addition to 3 characteristic findings (variable immunodeficiency, cytogenetic abnormalities, and facial dysmorphism), patients with ICF may present with prenatal and postnasal growth retardation, neurodevelopmental abnormalities, and hematological malignancies [43][44][46,47]. Facial features include hypertelorism, flat nasal bridge, epicanthal folds, macroglossia, and micrognathia. In one study, hypogammaglobulinemia/agammaglobulinemia was seen in almost all patients regardless of the genotype [44][45][47,48]. As a result, recurrent and severe respiratory, gastrointestinal, and skin infections with common organisms are very common in ICF. On the other hand, T cell numbers are normal in the majority of patients during the early years of life, and some patients may develop progressive T cell lymphopenia [44][46][47,49]. Opportunistic infections (Candida albicans, Pneumocystis jiroveci) have been reported in a small number of patients [44][45][47][47,48,50]. ICF rarely presented with severe combined immunodeficiency, and one of those patients died from rubella pneumonia [48][49][51,52].

6. POLE1 Deficiency (FILS Syndrome and IMAGe Syndrome)

Facial dysmorphism, immunodeficiency, livedo, and short stature (FILS) syndrome is a recently described autosomal recessive DNA breakage syndrome caused by a single homozygous intronic variant in POLE1, which encodes the catalytic subunit of polymerase E [50][51][53,54]. Patients may have intrauterine growth restriction, short limbs, dysmorphic features including malar and mandibular hypoplasia, lacy reticular pigmentation of the face and extremities, recurrent pruritic papular eruptions, small and dysplastic teeth, and feeding aversion [50][53]. Normal total B, T cells, low class-switched and non-switched memory B cells, and high memory T cells, low NK cells, high IgA, normal total IgG, and low IgM, IgG2, and IgG4 have been reported [50][52][53,55]. Recurrent or severe infections were observed in some but not all patients and include chronic rhinosinusitis, purulent otitis media, pulmonary infections, as well as acute CMV infection associated with pancytopenia, splenomegaly, and hepatitis. One patient had recurrent meningitis caused by Streptococcus pneumonia [51][54]. Recently a different intronic variant (c.1686+32C > G) in POLE1 as part of a common haplotype in combination with different loss-of-function variants in trans was described in 15 patients from 12 families [53][56]. They had clinical features similar to IMAGe syndrome (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, and genitourinary anomalies in males), a disorder previously associated with gain-of-function mutations in CDKN1C. Five of those patients had increased susceptibility to respiratory infections with lymphopenia and/or low IgM levels. Three patients had low NK cell levels, and one of these patients developed CMV pneumonia and then EBV-associated hemophagocytic lymphohistiocytosis (HLH), requiring allogeneic bone marrow transplantation. Another patient died from an HSV infection at 22 months.

References

  1. Chatterjee, N.; Walker, G.C. Mechanisms of DNA damage, repair, and mutagenesis. Environ. Mol. Mutagen. 2017, 58, 235–263. References
  2. Sancar, A.; Lindsey-Boltz, L.A.; Unsal-Kacmaz, K.; Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu. Rev. Biochem. 2004, 73, 39–85. Chatterjee, N.; Walker, G.C. Mechanisms of DNA damage, repair, and mutagenesis. Environ Mol Mutagen 2017, 58, 235-263, doi:10.1002/em.22087.
  3. Tiwari, V.; Wilson, D.M., 3rd. DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging. Am. J. Hum. Genet. 2019, 105, 237–257. Sancar, A.; Lindsey-Boltz, L.A.; Unsal-Kacmaz, K.; Linn, S. Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints. Annu Rev Biochem 2004, 73, 39-85, doi:10.1146/annurev.biochem.73.011303.073723.
  4. Gennery, A.R.; Cant, A.J.; Jeggo, P.A. Immunodeficiency associated with DNA repair defects. Clin. Exp. Immunol. 2000, 121, 1–7. Tiwari, V.; Wilson, D.M., 3rd. DNA Damage and Associated DNA Repair Defects in Disease and Premature Aging. Am J Hum Genet 2019, 105, 237-257, doi:10.1016/j.ajhg.2019.06.005.
  5. Crawford, T.O.; Skolasky, R.L.; Fernandez, R.; Rosquist, K.J.; Lederman, H.M. Survival probability in ataxia telangiectasia. Arch. Dis. Child. 2006, 91, 610–611. Gennery, A.R.; Cant, A.J.; Jeggo, P.A. Immunodeficiency associated with DNA repair defects. Clin Exp Immunol 2000, 121, 1-7, doi:10.1046/j.1365-2249.2000.01257.x.
  6. Lavin, M.F.; Shiloh, Y. The genetic defect in ataxia-telangiectasia. Annu. Rev. Immunol. 1997, 15, 177–202. Tangye, S.G.; Al-Herz, W.; Bousfiha, A.; Cunningham-Rundles, C.; Franco, J.L.; Holland, S.M.; Klein, C.; Morio, T.; Oksenhendler, E.; Picard, C.; et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022, 42, 1473-1507, doi:10.1007/s10875-022-01289-3.
  7. Nowak-Wegrzyn, A.; Crawford, T.O.; Winkelstein, J.A.; Carson, K.A.; Lederman, H.M. Immunodeficiency and infections in ataxia-telangiectasia. J. Pediatr. 2004, 144, 505–511. Peron, S.; Metin, A.; Gardes, P.; Alyanakian, M.A.; Sheridan, E.; Kratz, C.P.; Fischer, A.; Durandy, A. Human PMS2 deficiency is associated with impaired immunoglobulin class switch recombination. J Exp Med 2008, 205, 2465-2472, doi:10.1084/jem.20080789.
  8. Pashankar, F.; Singhal, V.; Akabogu, I.; Gatti, R.A.; Goldman, F.D. Intact T cell responses in ataxia telangiectasia. Clin. Immunol. 2006, 120, 156–162. Zhang, S.; Pondarre, C.; Pennarun, G.; Labussiere-Wallet, H.; Vera, G.; France, B.; Chansel, M.; Rouvet, I.; Revy, P.; Lopez, B.; et al. A nonsense mutation in the DNA repair factor Hebo causes mild bone marrow failure and microcephaly. J Exp Med 2016, 213, 1011-1028, doi:10.1084/jem.20151183.
  9. Szczawinska-Poplonyk, A.; Tapolska-Jozwiak, K.; Schwartzmann, E.; Pietrucha, B. Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience. Front. Pediatr. 2022, 10, 972952. Crawford, T.O.; Skolasky, R.L.; Fernandez, R.; Rosquist, K.J.; Lederman, H.M. Survival probability in ataxia telangiectasia. Arch Dis Child 2006, 91, 610-611, doi:10.1136/adc.2006.094268.
  10. Ghiasy, S.; Parvaneh, L.; Azizi, G.; Sadri, G.; Zaki Dizaji, M.; Abolhassani, H.; Aghamohammadi, A. The clinical significance of complete class switching defect in Ataxia telangiectasia patients. Expert Rev. Clin. Immunol. 2017, 13, 499–505. Lavin, M.F.; Shiloh, Y. The genetic defect in ataxia-telangiectasia. Annu Rev Immunol 1997, 15, 177-202, doi:10.1146/annurev.immunol.15.1.177.
  11. Noordzij, J.G.; Wulffraat, N.M.; Haraldsson, A.; Meyts, I.; van’t Veer, L.J.; Hogervorst, F.B.; Warris, A.; Weemaes, C.M. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch. Dis. Child. 2009, 94, 448–449. Nowak-Wegrzyn, A.; Crawford, T.O.; Winkelstein, J.A.; Carson, K.A.; Lederman, H.M. Immunodeficiency and infections in ataxia-telangiectasia. J Pediatr 2004, 144, 505-511, doi:10.1016/j.jpeds.2003.12.046.
  12. Amirifar, P.; Mozdarani, H.; Yazdani, R.; Kiaei, F.; Moeini Shad, T.; Shahkarami, S.; Abolhassani, H.; Delavari, S.; Sohani, M.; Rezaei, A.; et al. Effect of Class Switch Recombination Defect on the Phenotype of Ataxia-Telangiectasia Patients. Immunol. Investig. 2021, 50, 201–215. Pashankar, F.; Singhal, V.; Akabogu, I.; Gatti, R.A.; Goldman, F.D. Intact T cell responses in ataxia telangiectasia. Clin Immunol 2006, 120, 156-162, doi:10.1016/j.clim.2006.04.568.
  13. Petley, E.; Yule, A.; Alexander, S.; Ojha, S.; Whitehouse, W.P. The natural history of ataxia-telangiectasia (A-T): A systematic review. PLoS ONE 2022, 17, e0264177. Szczawinska-Poplonyk, A.; Tapolska-Jozwiak, K.; Schwartzmann, E.; Pietrucha, B. Infections and immune dysregulation in ataxia-telangiectasia children with hyper-IgM and non-hyper-IgM phenotypes: A single-center experience. Front Pediatr 2022, 10, 972952, doi:10.3389/fped.2022.972952.
  14. Chopra, C.; Davies, G.; Taylor, M.; Anderson, M.; Bainbridge, S.; Tighe, P.; McDermott, E.M. Immune deficiency in Ataxia-Telangiectasia: A longitudinal study of 44 patients. Clin. Exp. Immunol. 2014, 176, 275–282. Ghiasy, S.; Parvaneh, L.; Azizi, G.; Sadri, G.; Zaki Dizaji, M.; Abolhassani, H.; Aghamohammadi, A. The clinical significance of complete class switching defect in Ataxia telangiectasia patients. Expert Rev Clin Immunol 2017, 13, 499-505, doi:10.1080/1744666X.2017.1292131.
  15. Suarez, F.; Mahlaoui, N.; Canioni, D.; Andriamanga, C.; Dubois d’Enghien, C.; Brousse, N.; Jais, J.P.; Fischer, A.; Hermine, O.; Stoppa-Lyonnet, D. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: A report from the French national registry of primary immune deficiencies. J. Clin. Oncol. 2015, 33, 202–208. Noordzij, J.G.; Wulffraat, N.M.; Haraldsson, A.; Meyts, I.; van't Veer, L.J.; Hogervorst, F.B.; Warris, A.; Weemaes, C.M. Ataxia-telangiectasia patients presenting with hyper-IgM syndrome. Arch Dis Child 2009, 94, 448-449, doi:10.1136/adc.2008.149351.
  16. Lefton-Greif, M.A.; Crawford, T.O.; Winkelstein, J.A.; Loughlin, G.M.; Koerner, C.B.; Zahurak, M.; Lederman, H.M. Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. J. Pediatr. 2000, 136, 225–231. Amirifar, P.; Mozdarani, H.; Yazdani, R.; Kiaei, F.; Moeini Shad, T.; Shahkarami, S.; Abolhassani, H.; Delavari, S.; Sohani, M.; Rezaei, A.; et al. Effect of Class Switch Recombination Defect on the Phenotype of Ataxia-Telangiectasia Patients. Immunol Invest 2021, 50, 201-215, doi:10.1080/08820139.2020.1723104.
  17. Ersoy, F.; Berkel, A.I.; Sanal, O.; Oktay, H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia. Turk. J. Pediatr. 1991, 33, 205–215. Petley, E.; Yule, A.; Alexander, S.; Ojha, S.; Whitehouse, W.P. The natural history of ataxia-telangiectasia (A-T): A systematic review. PLoS One 2022, 17, e0264177, doi:10.1371/journal.pone.0264177.
  18. Schroeder, S.A.; Zielen, S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr. Pulmonol. 2014, 49, 389–399. Chopra, C.; Davies, G.; Taylor, M.; Anderson, M.; Bainbridge, S.; Tighe, P.; McDermott, E.M. Immune deficiency in Ataxia-Telangiectasia: a longitudinal study of 44 patients. Clin Exp Immunol 2014, 176, 275-282, doi:10.1111/cei.12262.
  19. Meister, M.T.; Voss, S.; Schwabe, D. Treatment of EBV-associated nodular sclerosing Hodgkin lymphoma in a patient with ataxia telangiectasia with brentuximab vedotin and reduced COPP plus rituximab. Pediatr. Blood Cancer 2015, 62, 2018–2020. Suarez, F.; Mahlaoui, N.; Canioni, D.; Andriamanga, C.; Dubois d'Enghien, C.; Brousse, N.; Jais, J.P.; Fischer, A.; Hermine, O.; Stoppa-Lyonnet, D. Incidence, presentation, and prognosis of malignancies in ataxia-telangiectasia: a report from the French national registry of primary immune deficiencies. J Clin Oncol 2015, 33, 202-208, doi:10.1200/JCO.2014.56.5101.
  20. Rawat, A.; Tyagi, R.; Chaudhary, H.; Pandiarajan, V.; Jindal, A.K.; Suri, D.; Gupta, A.; Sharma, M.; Arora, K.; Bal, A.; et al. Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India. Sci. Rep. 2022, 12, 4036. Lefton-Greif, M.A.; Crawford, T.O.; Winkelstein, J.A.; Loughlin, G.M.; Koerner, C.B.; Zahurak, M.; Lederman, H.M. Oropharyngeal dysphagia and aspiration in patients with ataxia-telangiectasia. J Pediatr 2000, 136, 225-231, doi:10.1016/s0022-3476(00)70106-5.
  21. Bennett, J.A.; Bayerl, M.G. Epstein-barr virus-associated extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT Lymphoma) arising in the parotid gland of a child with ataxia telangiectasia. J. Pediatr. Hematol. Oncol. 2015, 37, e114–e117. Ersoy, F.; Berkel, A.I.; Sanal, O.; Oktay, H. Twenty-year follow-up of 160 patients with ataxia-telangiectasia. Turk J Pediatr 1991, 33, 205-215.
  22. Pohl, K.R.; Farley, J.D.; Jan, J.E.; Junker, A.K. Ataxia-telangiectasia in a child with vaccine-associated paralytic poliomyelitis. J. Pediatr. 1992, 121, 405–407. Schroeder, S.A.; Zielen, S. Infections of the respiratory system in patients with ataxia-telangiectasia. Pediatr Pulmonol 2014, 49, 389-399, doi:10.1002/ppul.22817.
  23. Buchbinder, D.; Hauck, F.; Albert, M.H.; Rack, A.; Bakhtiar, S.; Shcherbina, A.; Deripapa, E.; Sullivan, K.E.; Perelygina, L.; Eloit, M.; et al. Rubella Virus-Associated Cutaneous Granulomatous Disease: A Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders. J. Clin. Immunol. 2019, 39, 81–89. Meister, M.T.; Voss, S.; Schwabe, D. Treatment of EBV-associated nodular sclerosing Hodgkin lymphoma in a patient with ataxia telangiectasia with brentuximab vedotin and reduced COPP plus rituximab. Pediatr Blood Cancer 2015, 62, 2018-2020, doi:10.1002/pbc.25621.
  24. Chiam, L.Y.; Verhagen, M.M.; Haraldsson, A.; Wulffraat, N.; Driessen, G.J.; Netea, M.G.; Weemaes, C.M.; Seyger, M.M.; van Deuren, M. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: Reflection of inappropriate immune regulation? Dermatology 2011, 223, 13–19. Rawat, A.; Tyagi, R.; Chaudhary, H.; Pandiarajan, V.; Jindal, A.K.; Suri, D.; Gupta, A.; Sharma, M.; Arora, K.; Bal, A.; et al. Unusual clinical manifestations and predominant stopgain ATM gene variants in a single centre cohort of ataxia telangiectasia from North India. Sci Rep 2022, 12, 4036, doi:10.1038/s41598-022-08019-0.
  25. Browne, R.; Cliffe, L.; Ip, W.; Brown, K.; McDermott, E. A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia. Pediatr. Dermatol. 2022, 39, 619–621. Bennett, J.A.; Bayerl, M.G. Epstein-barr virus-associated extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT Lymphoma) arising in the parotid gland of a child with ataxia telangiectasia. J Pediatr Hematol Oncol 2015, 37, e114-117, doi:10.1097/MPH.0b013e31829f3496.
  26. Tsukahara, M.; Masuda, M.; Ohshiro, K.; Kobayashi, K.; Kajii, T.; Ejima, Y.; Sasaki, M.S. Ataxia telangiectasia with generalized skin pigmentation and early death. Eur. J. Pediatr. 1986, 145, 121–124. Pohl, K.R.; Farley, J.D.; Jan, J.E.; Junker, A.K. Ataxia-telangiectasia in a child with vaccine-associated paralytic poliomyelitis. J Pediatr 1992, 121, 405-407, doi:10.1016/s0022-3476(05)81795-0.
  27. The International Nijmegen Breakage Syndrome Study Group. Nijmegen breakage syndrome. Arch. Dis. Child. 2000, 82, 400–406. Buchbinder, D.; Hauck, F.; Albert, M.H.; Rack, A.; Bakhtiar, S.; Shcherbina, A.; Deripapa, E.; Sullivan, K.E.; Perelygina, L.; Eloit, M.; et al. Rubella Virus-Associated Cutaneous Granulomatous Disease: a Unique Complication in Immune-Deficient Patients, Not Limited to DNA Repair Disorders. J Clin Immunol 2019, 39, 81-89, doi:10.1007/s10875-018-0581-0.
  28. Carney, J.P.; Maser, R.S.; Olivares, H.; Davis, E.M.; Le Beau, M.; Yates, J.R., 3rd; Hays, L.; Morgan, W.F.; Petrini, J.H. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: Linkage of double-strand break repair to the cellular DNA damage response. Cell 1998, 93, 477–486. Chiam, L.Y.; Verhagen, M.M.; Haraldsson, A.; Wulffraat, N.; Driessen, G.J.; Netea, M.G.; Weemaes, C.M.; Seyger, M.M.; van Deuren, M. Cutaneous granulomas in ataxia telangiectasia and other primary immunodeficiencies: reflection of inappropriate immune regulation? Dermatology 2011, 223, 13-19, doi:10.1159/000330335.
  29. Lee, J.H.; Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005, 308, 551–554. Browne, R.; Cliffe, L.; Ip, W.; Brown, K.; McDermott, E. A case of wild-type rubella-associated cutaneous granuloma in ataxia telangiectasia. Pediatr Dermatol 2022, 39, 619-621, doi:10.1111/pde.15032.
  30. Hasbaoui, B.E.; Elyajouri, A.; Abilkassem, R.; Agadr, A. Nijmegen breakage syndrome: Case report and review of literature. Pan Afr. Med. J. 2020, 35, 85. Tsukahara, M.; Masuda, M.; Ohshiro, K.; Kobayashi, K.; Kajii, T.; Ejima, Y.; Sasaki, M.S. Ataxia telangiectasia with generalized skin pigmentation and early death. Eur J Pediatr 1986, 145, 121-124, doi:10.1007/BF00441871.
  31. Gregorek, H.; Chrzanowska, K.H.; Michalkiewicz, J.; Syczewska, M.; Madalinski, K. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: An 8-year follow-up study in a single centre. Clin. Exp. Immunol. 2002, 130, 319–324. The, I. Nijmegen breakage syndrome. The International Nijmegen Breakage Syndrome Study Group. Arch Dis Child 2000, 82, 400-406, doi:10.1136/adc.82.5.400.
  32. Wolska-Kusnierz, B.; Gregorek, H.; Chrzanowska, K.; Piatosa, B.; Pietrucha, B.; Heropolitanska-Pliszka, E.; Pac, M.; Klaudel-Dreszler, M.; Kostyuchenko, L.; Pasic, S.; et al. Nijmegen Breakage Syndrome: Clinical and Immunological Features, Long-Term Outcome and Treatment Options—A Retrospective Analysis. J. Clin. Immunol. 2015, 35, 538–549. Carney, J.P.; Maser, R.S.; Olivares, H.; Davis, E.M.; Le Beau, M.; Yates, J.R., 3rd; Hays, L.; Morgan, W.F.; Petrini, J.H. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 1998, 93, 477-486, doi:10.1016/s0092-8674(00)81175-7.
  33. Erdos, M.; Toth, B.; Veres, I.; Kiss, M.; Remenyik, E.; Marodi, L. Nijmegen breakage syndrome complicated with primary cutaneous tuberculosis. Pediatr. Infect. Dis. J. 2011, 30, 359–360. Lee, J.H.; Paull, T.T. ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005, 308, 551-554, doi:10.1126/science.1108297.
  34. Resnick, I.B.; Kondratenko, I.; Togoev, O.; Vasserman, N.; Shagina, I.; Evgrafov, O.; Tverskaya, S.; Cerosaletti, K.M.; Gatti, R.A.; Concannon, P. Nijmegen breakage syndrome: Clinical characteristics and mutation analysis in eight unrelated Russian families. J. Pediatr. 2002, 140, 355–361. Hasbaoui, B.E.; Elyajouri, A.; Abilkassem, R.; Agadr, A. Nijmegen breakage syndrome: case report and review of literature. Pan Afr Med J 2020, 35, 85, doi:10.11604/pamj.2020.35.85.14746.
  35. Kondratenko, I.; Paschenko, O.; Polyakov, A.; Bologov, A. Nijmegen breakage syndrome. Adv. Exp. Med. Biol. 2007, 601, 61–67. Gregorek, H.; Chrzanowska, K.H.; Michalkiewicz, J.; Syczewska, M.; Madalinski, K. Heterogeneity of humoral immune abnormalities in children with Nijmegen breakage syndrome: an 8-year follow-up study in a single centre. Clin Exp Immunol 2002, 130, 319-324, doi:10.1046/j.1365-2249.2002.01971.x.
  36. Gregorek, H.; Chrzanowska, K.H.; Dzierzanowska-Fangrat, K.; Wakulinska, A.; Pietrucha, B.; Zapasnik, A.; Zborowska, M.; Pac, M.; Smolka-Afifi, D.; Kasztelewicz, B.; et al. Nijmegen breakage syndrome: Long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin. Immunol. 2010, 135, 440–447. Wolska-Kusnierz, B.; Gregorek, H.; Chrzanowska, K.; Piatosa, B.; Pietrucha, B.; Heropolitanska-Pliszka, E.; Pac, M.; Klaudel-Dreszler, M.; Kostyuchenko, L.; Pasic, S.; et al. Nijmegen Breakage Syndrome: Clinical and Immunological Features, Long-Term Outcome and Treatment Options - a Retrospective Analysis. J Clin Immunol 2015, 35, 538-549, doi:10.1007/s10875-015-0186-9.
  37. Lim, S.T.; Fei, G.; Quek, R.; Lim, L.C.; Lee, L.H.; Yap, S.P.; Loong, S.; Tao, M. The relationship of hepatitis B virus infection and non-Hodgkin’s lymphoma and its impact on clinical characteristics and prognosis. Eur. J. Haematol. 2007, 79, 132–137. Erdos, M.; Toth, B.; Veres, I.; Kiss, M.; Remenyik, E.; Marodi, L. Nijmegen breakage syndrome complicated with primary cutaneous tuberculosis. Pediatr Infect Dis J 2011, 30, 359-360, doi:10.1097/INF.0b013e3181faa941.
  38. Gregorek, H.; Olczak-Kowalczyk, D.; Dembowska-Baginska, B.; Pietrucha, B.; Wakulinska, A.; Gozdowski, D.; Chrzanowska, K.H. Oral findings in patients with Nijmegen breakage syndrome: A preliminary study. Oral Surg. Oral Med. Oral Pathol. Oral Radiol. Endod. 2009, 108, e39–e45. Resnick, I.B.; Kondratenko, I.; Togoev, O.; Vasserman, N.; Shagina, I.; Evgrafov, O.; Tverskaya, S.; Cerosaletti, K.M.; Gatti, R.A.; Concannon, P. Nijmegen breakage syndrome: clinical characteristics and mutation analysis in eight unrelated Russian families. J Pediatr 2002, 140, 355-361, doi:10.1067/mpd.2002.122724.
  39. Ellis, N.A.; Groden, J.; Ye, T.Z.; Straughen, J.; Lennon, D.J.; Ciocci, S.; Proytcheva, M.; German, J. The Bloom’s syndrome gene product is homologous to RecQ helicases. Cell 1995, 83, 655–666. Kondratenko, I.; Paschenko, O.; Polyakov, A.; Bologov, A. Nijmegen breakage syndrome. Adv Exp Med Biol 2007, 601, 61-67, doi:10.1007/978-0-387-72005-0_6.
  40. German, J. Bloom’s syndrome. XX. The first 100 cancers. Cancer Genet. Cytogenet. 1997, 93, 100–106. Gregorek, H.; Chrzanowska, K.H.; Dzierzanowska-Fangrat, K.; Wakulinska, A.; Pietrucha, B.; Zapasnik, A.; Zborowska, M.; Pac, M.; Smolka-Afifi, D.; Kasztelewicz, B.; et al. Nijmegen breakage syndrome: Long-term monitoring of viral and immunological biomarkers in peripheral blood before development of malignancy. Clin Immunol 2010, 135, 440-447, doi:10.1016/j.clim.2010.01.008.
  41. Schoenaker, M.H.D.; Henriet, S.S.; Zonderland, J.; van Deuren, M.; Pan-Hammarstrom, Q.; Posthumus-van Sluijs, S.J.; Pico-Knijnenburg, I.; Weemaes, C.M.R.; Hanna, I.J. Immunodeficiency in Bloom’s Syndrome. J. Clin. Immunol. 2018, 38, 35–44. Lim, S.T.; Fei, G.; Quek, R.; Lim, L.C.; Lee, L.H.; Yap, S.P.; Loong, S.; Tao, M. The relationship of hepatitis B virus infection and non-Hodgkin's lymphoma and its impact on clinical characteristics and prognosis. Eur J Haematol 2007, 79, 132-137, doi:10.1111/j.1600-0609.2007.00878.x.
  42. Kondo, N.; Motoyoshi, F.; Mori, S.; Kuwabara, N.; Orii, T.; German, J. Long-term study of the immunodeficiency of Bloom’s syndrome. Acta Paediatr. 1992, 81, 86–90. Gregorek, H.; Olczak-Kowalczyk, D.; Dembowska-Baginska, B.; Pietrucha, B.; Wakulinska, A.; Gozdowski, D.; Chrzanowska, K.H. Oral findings in patients with Nijmegen breakage syndrome: a preliminary study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2009, 108, e39-45, doi:10.1016/j.tripleo.2009.06.032.
  43. Maraschio, P.; Zuffardi, O.; Dalla Fior, T.; Tiepolo, L. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: The ICF syndrome. J. Med. Genet. 1988, 25, 173–180. Ellis, N.A.; Groden, J.; Ye, T.Z.; Straughen, J.; Lennon, D.J.; Ciocci, S.; Proytcheva, M.; German, J. The Bloom's syndrome gene product is homologous to RecQ helicases. Cell 1995, 83, 655-666, doi:10.1016/0092-8674(95)90105-1.
  44. Weemaes, C.M.; van Tol, M.J.; Wang, J.; van Ostaijen-ten Dam, M.M.; van Eggermond, M.C.; Thijssen, P.E.; Aytekin, C.; Brunetti-Pierri, N.; van der Burg, M.; Graham Davies, E.; et al. Heterogeneous clinical presentation in ICF syndrome: Correlation with underlying gene defects. Eur. J. Hum. Genet. 2013, 21, 1219–1225. German, J. Bloom's syndrome. XX. The first 100 cancers. Cancer Genet Cytogenet 1997, 93, 100-106, doi:10.1016/s0165-4608(96)00336-6.
  45. Thijssen, P.E.; Ito, Y.; Grillo, G.; Wang, J.; Velasco, G.; Nitta, H.; Unoki, M.; Yoshihara, M.; Suyama, M.; Sun, Y.; et al. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat. Commun. 2015, 6, 7870. Schoenaker, M.H.D.; Henriet, S.S.; Zonderland, J.; van Deuren, M.; Pan-Hammarstrom, Q.; Posthumus-van Sluijs, S.J.; Pico-Knijnenburg, I.; Weemaes, C.M.R.; H, I.J. Immunodeficiency in Bloom's Syndrome. J Clin Immunol 2018, 38, 35-44, doi:10.1007/s10875-017-0454-y.
  46. Von Bernuth, H.; Ravindran, E.; Du, H.; Frohler, S.; Strehl, K.; Kramer, N.; Issa-Jahns, L.; Amulic, B.; Ninnemann, O.; Xiao, M.S.; et al. Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2). Orphanet J. Rare Dis. 2014, 9, 116. Kondo, N.; Motoyoshi, F.; Mori, S.; Kuwabara, N.; Orii, T.; German, J. Long-term study of the immunodeficiency of Bloom's syndrome. Acta Paediatr 1992, 81, 86-90, doi:10.1111/j.1651-2227.1992.tb12088.x.
  47. Van den Boogaard, M.L.; Thijssen, P.E.; Aytekin, C.; Licciardi, F.; Kiykim, A.A.; Spossito, L.; Dalm, V.; Driessen, G.J.; Kersseboom, R.; de Vries, F.; et al. Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2. Clin. Genet. 2017, 92, 380–387. Maraschio, P.; Zuffardi, O.; Dalla Fior, T.; Tiepolo, L. Immunodeficiency, centromeric heterochromatin instability of chromosomes 1, 9, and 16, and facial anomalies: the ICF syndrome. J Med Genet 1988, 25, 173-180, doi:10.1136/jmg.25.3.173.
  48. Mehawej, C.; Khalife, H.; Hanna-Wakim, R.; Dbaibo, G.; Farra, C. DNMT3B deficiency presenting as severe combined immune deficiency: A case report. Clin. Immunol. 2020, 215, 108453. Weemaes, C.M.; van Tol, M.J.; Wang, J.; van Ostaijen-ten Dam, M.M.; van Eggermond, M.C.; Thijssen, P.E.; Aytekin, C.; Brunetti-Pierri, N.; van der Burg, M.; Graham Davies, E.; et al. Heterogeneous clinical presentation in ICF syndrome: correlation with underlying gene defects. Eur J Hum Genet 2013, 21, 1219-1225, doi:10.1038/ejhg.2013.40.
  49. Reisli, I.; Yildirim, M.S.; Koksal, Y.; Avunduk, M.C.; Acar, A. A case with ICF syndrome lost to rubella pneumonitis. Turk. J. Pediatr. 2005, 47, 85–88. Thijssen, P.E.; Ito, Y.; Grillo, G.; Wang, J.; Velasco, G.; Nitta, H.; Unoki, M.; Yoshihara, M.; Suyama, M.; Sun, Y.; et al. Mutations in CDCA7 and HELLS cause immunodeficiency-centromeric instability-facial anomalies syndrome. Nat Commun 2015, 6, 7870, doi:10.1038/ncomms8870.
  50. Thiffault, I.; Saunders, C.; Jenkins, J.; Raje, N.; Canty, K.; Sharma, M.; Grote, L.; Welsh, H.I.; Farrow, E.; Twist, G.; et al. A patient with polymerase E1 deficiency (POLE1): Clinical features and overlap with DNA breakage/instability syndromes. BMC Med. Genet. 2015, 16, 31. von Bernuth, H.; Ravindran, E.; Du, H.; Frohler, S.; Strehl, K.; Kramer, N.; Issa-Jahns, L.; Amulic, B.; Ninnemann, O.; Xiao, M.S.; et al. Combined immunodeficiency develops with age in Immunodeficiency-centromeric instability-facial anomalies syndrome 2 (ICF2). Orphanet J Rare Dis 2014, 9, 116, doi:10.1186/s13023-014-0116-6.
  51. Pachlopnik Schmid, J.; Lemoine, R.; Nehme, N.; Cormier-Daire, V.; Revy, P.; Debeurme, F.; Debre, M.; Nitschke, P.; Bole-Feysot, C.; Legeai-Mallet, L.; et al. Polymerase epsilon1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature (“FILS syndrome”). J. Exp. Med. 2012, 209, 2323–2330. van den Boogaard, M.L.; Thijssen, P.E.; Aytekin, C.; Licciardi, F.; Kiykim, A.A.; Spossito, L.; Dalm, V.; Driessen, G.J.; Kersseboom, R.; de Vries, F.; et al. Expanding the mutation spectrum in ICF syndrome: Evidence for a gender bias in ICF2. Clin Genet 2017, 92, 380-387, doi:10.1111/cge.12979.
  52. Jiang, L.; Chen, X.; Zheng, J.; Wang, M.; Bo, H.; Liu, G. Case report: A Chinese boy with facial dysmorphism, immunodeficiency, livedo, and short stature syndrome. Front. Pediatr. 2022, 10, 933108. Mehawej, C.; Khalife, H.; Hanna-Wakim, R.; Dbaibo, G.; Farra, C. DNMT3B deficiency presenting as severe combined immune deficiency: A case report. Clin Immunol 2020, 215, 108453, doi:10.1016/j.clim.2020.108453.
  53. Logan, C.V.; Murray, J.E.; Parry, D.A.; Robertson, A.; Bellelli, R.; Tarnauskaite, Z.; Challis, R.; Cleal, L.; Borel, V.; Fluteau, A.; et al. DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency. Am. J. Hum. Genet. 2018, 103, 1038–1044. Reisli, I.; Yildirim, M.S.; Koksal, Y.; Avunduk, M.C.; Acar, A. A case with ICF syndrome lost to rubella pneumonitis. Turk J Pediatr 2005, 47, 85-88.
  54. Thiffault, I.; Saunders, C.; Jenkins, J.; Raje, N.; Canty, K.; Sharma, M.; Grote, L.; Welsh, H.I.; Farrow, E.; Twist, G.; et al. A patient with polymerase E1 deficiency (POLE1): clinical features and overlap with DNA breakage/instability syndromes. BMC Med Genet 2015, 16, 31, doi:10.1186/s12881-015-0177-y.
  55. Pachlopnik Schmid, J.; Lemoine, R.; Nehme, N.; Cormier-Daire, V.; Revy, P.; Debeurme, F.; Debre, M.; Nitschke, P.; Bole-Feysot, C.; Legeai-Mallet, L.; et al. Polymerase epsilon1 mutation in a human syndrome with facial dysmorphism, immunodeficiency, livedo, and short stature ("FILS syndrome"). J Exp Med 2012, 209, 2323-2330, doi:10.1084/jem.20121303.
  56. Jiang, L.; Chen, X.; Zheng, J.; Wang, M.; Bo, H.; Liu, G. Case report: A Chinese boy with facial dysmorphism, immunodeficiency, livedo, and short stature syndrome. Front Pediatr 2022, 10, 933108, doi:10.3389/fped.2022.933108.
  57. Logan, C.V.; Murray, J.E.; Parry, D.A.; Robertson, A.; Bellelli, R.; Tarnauskaite, Z.; Challis, R.; Cleal, L.; Borel, V.; Fluteau, A.; et al. DNA Polymerase Epsilon Deficiency Causes IMAGe Syndrome with Variable Immunodeficiency. Am J Hum Genet 2018, 103, 1038-1044, doi:10.1016/j.ajhg.2018.10.024.
  58. Pezzani, L.; Brena, M.; Callea, M.; Colombi, M.; Tadini, G. X-linked reticulate pigmentary disorder with systemic manifestations: a new family and review of the literature. Am J Med Genet A 2013, 161A, 1414-1420, doi:10.1002/ajmg.a.35882.
  59. Starokadomskyy, P.; Escala Perez-Reyes, A.; Burstein, E. Immune Dysfunction in Mendelian Disorders of POLA1 Deficiency. J Clin Immunol 2021, 41, 285-293, doi:10.1007/s10875-020-00953-w.
  60. Starokadomskyy, P.; Gemelli, T.; Rios, J.J.; Xing, C.; Wang, R.C.; Li, H.; Pokatayev, V.; Dozmorov, I.; Khan, S.; Miyata, N.; et al. DNA polymerase-alpha regulates the activation of type I interferons through cytosolic RNA:DNA synthesis. Nat Immunol 2016, 17, 495-504, doi:10.1038/ni.3409.
  61. Anderson, R.C.; Zinn, A.R.; Kim, J.; Carder, K.R. X-linked reticulate pigmentary disorder with systemic manifestations: report of a third family and literature review. Pediatr Dermatol 2005, 22, 122-126, doi:10.1111/j.1525-1470.2005.22206.x.
  62. Casey, J.P.; Nobbs, M.; McGettigan, P.; Lynch, S.; Ennis, S. Recessive mutations in MCM4/PRKDC cause a novel syndrome involving a primary immunodeficiency and a disorder of DNA repair. J Med Genet 2012, 49, 242-245, doi:10.1136/jmedgenet-2012-100803.
  63. Hughes, C.R.; Guasti, L.; Meimaridou, E.; Chuang, C.H.; Schimenti, J.C.; King, P.J.; Costigan, C.; Clark, A.J.; Metherell, L.A. MCM4 mutation causes adrenal failure, short stature, and natural killer cell deficiency in humans. J Clin Invest 2012, 122, 814-820, doi:10.1172/JCI60224.
  64. Gineau, L.; Cognet, C.; Kara, N.; Lach, F.P.; Dunne, J.; Veturi, U.; Picard, C.; Trouillet, C.; Eidenschenk, C.; Aoufouchi, S.; et al. Partial MCM4 deficiency in patients with growth retardation, adrenal insufficiency, and natural killer cell deficiency. J Clin Invest 2012, 122, 821-832, doi:10.1172/JCI61014.
  65. Gatti, M.; Pinato, S.; Maiolica, A.; Rocchio, F.; Prato, M.G.; Aebersold, R.; Penengo, L. RNF168 promotes noncanonical K27 ubiquitination to signal DNA damage. Cell Rep 2015, 10, 226-238, doi:10.1016/j.celrep.2014.12.021.
  66. Pietrucha, B.; Heropolitanska-Pliszka, E.; Geffers, R.; Enssen, J.; Wieland, B.; Bogdanova, N.V.; Dork, T. Clinical and Biological Manifestation of RNF168 Deficiency in Two Polish Siblings. Front Immunol 2017, 8, 1683, doi:10.3389/fimmu.2017.01683.
  67. Devgan, S.S.; Sanal, O.; Doil, C.; Nakamura, K.; Nahas, S.A.; Pettijohn, K.; Bartek, J.; Lukas, C.; Lukas, J.; Gatti, R.A. Homozygous deficiency of ubiquitin-ligase ring-finger protein RNF168 mimics the radiosensitivity syndrome of ataxia-telangiectasia. Cell Death Differ 2011, 18, 1500-1506, doi:10.1038/cdd.2011.18.
  68. Barnes, D.E.; Tomkinson, A.E.; Lehmann, A.R.; Webster, A.D.; Lindahl, T. Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents. Cell 1992, 69, 495-503, doi:10.1016/0092-8674(92)90450-q.
  69. Maffucci, P.; Chavez, J.; Jurkiw, T.J.; O'Brien, P.J.; Abbott, J.K.; Reynolds, P.R.; Worth, A.; Notarangelo, L.D.; Felgentreff, K.; Cortes, P.; et al. Biallelic mutations in DNA ligase 1 underlie a spectrum of immune deficiencies. J Clin Invest 2018, 128, 5489-5504, doi:10.1172/JCI99629.
  70. Dabrowska-Leonik, N.; Pastorczak, A.K.; Babol-Pokora, K.; Bernat-Sitarz, K.; Piatosa, B.; Heropolitanska-Pliszka, E.; Kacprzak, M.M.; Kalwak, K.; Gul, K.; van der Burg, M.; et al. Case report: Severe combined immunodeficiency with ligase 1 deficiency and Omenn-like manifestation. Front Immunol 2022, 13, 1033338, doi:10.3389/fimmu.2022.1033338.
  71. Silva, J.M.F.; Jones, A.; Sibson, K.; Bibi, S.; Jeggo, P.; Woodbine, L.; Ahsan, G.; Gilmour, K.C.; Rao, K.; Chiesa, R.; et al. Haematopoietic Stem Cell Transplantation for DNA Ligase 1 Deficiency. J Clin Immunol 2021, 41, 238-242, doi:10.1007/s10875-020-00871-x.
  72. Chang, Y.P.; Wang, G.; Bermudez, V.; Hurwitz, J.; Chen, X.S. Crystal structure of the GINS complex and functional insights into its role in DNA replication. Proc Natl Acad Sci U S A 2007, 104, 12685-12690, doi:10.1073/pnas.0705558104.
  73. Cottineau, J.; Kottemann, M.C.; Lach, F.P.; Kang, Y.H.; Vely, F.; Deenick, E.K.; Lazarov, T.; Gineau, L.; Wang, Y.; Farina, A.; et al. Inherited GINS1 deficiency underlies growth retardation along with neutropenia and NK cell deficiency. J Clin Invest 2017, 127, 1991-2006, doi:10.1172/JCI90727.
  74. van der Crabben, S.N.; Hennus, M.P.; McGregor, G.A.; Ritter, D.I.; Nagamani, S.C.; Wells, O.S.; Harakalova, M.; Chinn, I.K.; Alt, A.; Vondrova, L.; et al. Destabilized SMC5/6 complex leads to chromosome breakage syndrome with severe lung disease. J Clin Invest 2016, 126, 2881-2892, doi:10.1172/JCI82890.
  75. Mace, E.M.; Paust, S.; Conte, M.I.; Baxley, R.M.; Schmit, M.M.; Patil, S.L.; Guilz, N.C.; Mukherjee, M.; Pezzi, A.E.; Chmielowiec, J.; et al. Human NK cell deficiency as a result of biallelic mutations in MCM10. J Clin Invest 2020, 130, 5272-5286, doi:10.1172/JCI134966.
  76. Frugoni, F.; Dobbs, K.; Felgentreff, K.; Aldhekri, H.; Al Saud, B.K.; Arnaout, R.; Ali, A.A.; Abhyankar, A.; Alroqi, F.; Giliani, S.; et al. A novel mutation in the POLE2 gene causing combined immunodeficiency. J Allergy Clin Immunol 2016, 137, 635-638 e631, doi:10.1016/j.jaci.2015.06.049.
  77. Staples, E.R.; McDermott, E.M.; Reiman, A.; Byrd, P.J.; Ritchie, S.; Taylor, A.M.; Davies, E.G. Immunodeficiency in ataxia telangiectasia is correlated strongly with the presence of two null mutations in the ataxia telangiectasia mutated gene. Clin Exp Immunol 2008, 153, 214-220, doi:10.1111/j.1365-2249.2008.03684.x.
  78. Alghamdi, H.A.; Tashkandi, S.A.; Alidrissi, E.M.; Aledielah, R.D.; AlSaidi, K.A.; Alharbi, E.S.; Habazi, M.K.; Alzahrani, M.S. Three Types of Immunodeficiency, Centromeric Instability, and Facial Anomalies (ICF) Syndrome Identified by Whole-Exome Sequencing in Saudi Hypogammaglobulinemia Patients: Clinical, Molecular, and Cytogenetic Features. J Clin Immunol 2018, 38, 847-853, doi:10.1007/s10875-018-0569-9.
  79. Hagleitner, M.M.; Lankester, A.; Maraschio, P.; Hulten, M.; Fryns, J.P.; Schuetz, C.; Gimelli, G.; Davies, E.G.; Gennery, A.; Belohradsky, B.H.; et al. Clinical spectrum of immunodeficiency, centromeric instability and facial dysmorphism (ICF syndrome). J Med Genet 2008, 45, 93-99, doi:10.1136/jmg.2007.053397.
  80. Gennery, A.R.; Slatter, M.A.; Bredius, R.G.; Hagleitner, M.M.; Weemaes, C.; Cant, A.J.; Lankester, A.C. Hematopoietic stem cell transplantation corrects the immunologic abnormalities associated with immunodeficiency-centromeric instability-facial dysmorphism syndrome. Pediatrics 2007, 120, e1341-1344, doi:10.1542/peds.2007-0640.
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