Abstract
Objective
This case report looks at a child’s ectodermal dysplasia with immunodeficiency (EDA-ID), caused by a mutation in the IKBKG gene, and other relevant cases.
Methods
A pediatric patient diagnosed with EDA-ID was examined at Shanxi Bethune Hospital in July 2025. Clinical data were systematically collected, and whole-exome sequencing (WES) was performed on blood samples from the patient and their family members to identify potential pathogenic variants. Segregation analysis and a comprehensive literature review were performed.
Results
The patient exhibited symptoms including fever, mucoid bloody stools, and atopic dermatitis. WES analysis revealed the presence of a hemizygous variant, designated c.1167dup (p. Glu390ArgfsTer5), within the IKBKG gene. In accordance with the guidelines established by the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genomics Resource (ClinGen), this variant is classified as pathogenic (PVS1+PS4).
Conclusion
In pediatric patients with early-onset findings, immunodeficiency should be considered after excluding infections, rheumatic or malignancies. Key clinical features that raise suspicion include sparse hair, reduced sweating, dry skin, recurrent infections, treatment-refractory atopic dermatitis, persistently elevated acute-phase inflammatory markers, and immune dysfunction. Genetic testing facilitates early diagnosis, thereby supporting treatment planning. In this study, we identified a pathogenic IKBKG variant (c.1167dupC) in a pediatric patient with EDA-ID via WES, expanding the current understanding of genotype-phenotype correlations.
Keywords: children, ectodermal dysplasia with immunodeficiency, IKBKG, immunodeficiency, NF-κB
1. Introduction
Ectodermal dysplasia with immunodeficiency (EDA-ID) is a condition resulting from impaired nuclear factor κB (NF-κB) signaling due to genetic mutations or associated defects. Its clinical presentation is diverse and includes ectodermal dysplasia, lymphedema, osteopetrosis, and multiple immunological abnormalities. Patients may experience recurrent infections, diminished antibody response to polysaccharides, hypogammaglobulinemia, hyper-IgM syndrome, impaired natural killer (NK) cell cytotoxicity, and autoimmune disorders (1). Differential diagnoses include hyper-IgM syndromes, common variable immunodeficiency(CVID), and other combined immunodeficiencies. Diagnosis relies on clinical manifestations, immunological phenotype, and genetic testing. Two genes associated with EDA-ID have been identified: mutations in the IKBKG gene, which encodes the NF-κB essential modulator (NEMO), follow an X-linked inheritance pattern (2); and mutations in the NFKBIA gene, encoding the NF-κB inhibitor α (IκBα), cause autosomal EDA-ID (3). X-linked EDA-ID (XL-EDA-ID) is a relatively uncommon condition. The c.1167dup mutation in IKBKG has been previously reported; however, the clinical phenotype associated with this recurrent variant is not fully characterized. This report describes a pediatric patient with EDA-ID caused by the IKBKG c.1167dup mutation, further expanding the clinical phenotype associated with this variant. By combining a literature review with this case study, we aim to enhance clinicians’ awareness of this condition and improve early diagnosis.
2. Objectives and methods
A four-month-old male infant was admitted to our hospital due to recurrent leukocytosis and bloody stools. After obtaining informed consent from the family, we collected clinical data and drew 5 mL of peripheral blood samples from both the infant and his parents for genetic analysis. We also collected clinical information, including medical history, family history, laboratory findings, imaging studies, and treatment records. A comprehensive literature search was performed using the keywords “ectodermal dysplasia with immunodeficiency”, “X-linked ectodermal dysplasia with immunodeficiency”, “NEMO-ID”, and “IKBKG gene” in CNKI, Wanfang Database, VIP Database, and PubMed from database inception to August 31, 2025. Inclusion criteria were:(1)confirmed IKBKG mutation;(2)clinical diagnosis of EDA-ID, OL-EDA-ID (Osteopetrosis, Lymphedema, Anhidrotic Ectodermal Dysplasia with Immunodeficiency), or isolated immunodeficiency;(3)available clinical or immunological data;(4)age ≤18 years. Only articles published in English or Chinese were included. Exclusion criteria were duplicate publications or lack of original data. The literature screening was conducted in strict accordance with the PRISMA guidelines, and the specific screening procedure is presented in Figure 1 (PRISMA flow diagram).
Figure 1.
PRISMA flow diagram.
3. Case data and literature findings
3.1. Case presentation
Family and personal history: Non-consanguineous parents, no history of infections or infant deaths. The patient was the first-born at 40+6 weeks of gestation; oligohydramnios was noted at 37 weeks but not addressed. Birth was complicated by grade II amniotic fluid contamination and ecchymoses; platelets and coagulation were normal. The infant received antimicrobial and hemostatic therapy and was discharged. At 7 days of life, eczema developed that was unresponsive to topical therapy. Umbilical cord detachment occurred at 45 days with minor discharge. No perianal abscess was noted. The newborn has completed the screening for four conditions (Phenylketonuria, Congenital Hypothyroidism, Congenital Adrenal Hyperplasia, Glucose-6-phosphate dehydrogenase deficiency) and HIV nucleic acid test was normal.
The infant presented with diarrhea at two months of age, with 7 to 10 episodes per day; the stools contained mucus and bloody pus. A thorough stool examination revealed the presence of 3 to 5 red blood cells (RBCs) per high-power field (HPF), along with 10 to 20 white blood cells (WBCs) per HPF. Further investigation was prompted by the patient’s elevated white blood cell count, which exhibited fluctuations and was measured at a range of 15.75-29.53 x 109/L. Given the infant’s concurrent presentation of intractable eczema, the probable etiology was identified as a food protein allergy. Consequently, the therapeutic regimen was modified to encompass lactase, montmorillonite, probiotics, and an amino acid formula. However, the child’s diarrhea showed no improvement, and routine stool examinations continued to– reveal the presence of red and white blood cells. Consequently, the child was admitted to our hospital for treatment at 4 months of age. Upon admission, the patient was examined physically, revealing a height of 68 centimeters, a weight of 6 kilograms, and a BMI of 13.0kg/m2 (3rd–5th percentile by WHO child growth standards). The anterior fontanelle was observed to be flat and soft, with dimensions measuring approximately 1.5 × 1.5 cm. The subject’s scalp hair and eyebrows were sparse, with no other body hair present. Teeth had not yet erupted, and nails appeared normal. In the course of febrile episodes, the occurrence of sweating was reduced or ceased. The rash was characterized by its diffuse appearance, non-pruritic, and a pale red coloration. It was also noted that the rash exhibited a circular configuration and was located in a superficial layer of the skin. Cardiac, pulmonary, and abdominal examinations revealed no abnormalities. The perianal region exhibited no signs of redness, swelling, or ulceration. Post-admission laboratory monitoring revealed an elevated white blood cell count, with red and white blood cells visible in routine stool examinations. Further diagnostic procedures, including stool culture, did not reveal any signs of a specific infection. Normal platelet and coagulation function levels suggest the absence of coagulation disorders for the time being. Abdominal X-ray and ultrasound revealed no congenital intestinal anomalies. The most probable diagnosis was that of infectious diarrhea, and the child was treated with cefotaxime for the infection. The child’s diarrhea exhibited a marginal improvement, with red and white blood cells in the stool returning to normal levels. However, the fecal occult blood test remained positive. The child developed a fever and diarrhea after contact with a sick family member. Inflammatory bowel disease and immunodeficiency were considered as possible causes. Comprehensive respiratory NGS testing revealed Pneumocystis jirovecii pneumonia and parainfluenza virus type 3 infection. The treatment regimen was adjusted to penicillin combined with cefoperazone/sulbactam. Monitoring of immune function revealed hypogammaglobulinaemia, suggesting immunodeficiency, and the patient was transferred to Beijing Children’s Hospital. During hospitalization, the patient underwent bone marrow aspiration, lumbar puncture, bronchoscopic alveolar lavage and genetic testing. The patient was placed on mechanical ventilation and treated with trimethoprim-sulfamethoxazole for infection and intravenous immunoglobulin (IVIG). Genetic testing results confirmed EDA-ID caused by a mutation in the IKBKG gene. In January 2026, the patient underwent allogeneic hematopoietic stem cell transplantation. Currently, the patient is in good health with no post-transplant complications reported, and further evaluation is scheduled for July 2026.
3.2. Laboratory testing
3.2.1. Routine stool examination and occult blood test (March 18-July 28, 2025)
The specific details are provided in Tables 1 and 2.
Table 1.
Dynamic Changes in Routine Stool Parameters.
| Times | Fecal occult blood | Leukocytes/HP | Red blood cells/HP |
|---|---|---|---|
| 2025-07-20 | + | 20-30 | 1-3 |
| 2025-07-22 | + | 5-10 | 3-5 |
| 2025-07-23 | + | 5-10 | 1-3 |
| 2025-07-24 | +- | 5-10 | 0-1 |
| 2025-07-25 | + | 0-1 | 5-10 |
| 2025-07-28 | + | 0 | 0 |
Table 2.
Dynamic Changes in Blood Cell Analysis and C-Reactive Protein.
| Times | WBC*109/L | neutrophil% | hemoglobin(g/l) | Platelets*109/L | C-Reactive Protein (mg/l) |
|---|---|---|---|---|---|
| 2025-03-18 | 29.53 | 70.0% | 190 | 342 | <0.5 |
| 2025-03-23 | 20.50 | 26.2% | 182 | 253 | <0.5 |
| 2025-04-09 | 15.75 | 22.7% | 120 | 334 | <1.0 |
| 2025-04-28 | 16.52 | 18% | 105 | 377 | 15.2 |
| 2025-07-19 | 26.20 | 35.2% | 109 | 512 | 13.17 |
| 2025-07-22 | 29.70 | 42.1% | 108 | 526 | 15.53 |
| 2025-07-24 | 22.22 | 44.0% | 120 | 166 | 4.97 |
| 2025-07-28 | 42.99 | 43.5% | 116 | 275 | 8.34 |
Immunology: Immunoglobulin IgG levels were significantly reduced, while IgA, IgM, and IgE remained within normal ranges; cytokine IL-17 was elevated (47.254 pg/ml). Lymphocyte subset analysis revealed a decreased proportion of CD8+T cells and an increased proportion of B cells. Detailed data are provided in Table 3.
Table 3.
Specific lymphocyte subset data.
| Outcome | Reference Range | |
|---|---|---|
| Percentage of total T-Cells (CD3+CD45+) | 57.3% | 65%-79% |
| Absolute total T-cell count (CD3+CD45+) | 7062/ul | 650-1880/ul |
| Percentage of Th cells (CD3+CD4+) | 46.6% | 34%-52% |
| Absolute Th cell count (CD3+CD4+) | 5745/ul | 340-1072/ul |
| Percentage of CD8+T cells (CD3+CD8+) | 10.2% | 21%-39% |
| Absolute CD8+T cells count (CD3+CD8+) | 1243/ul | 210-742/ul |
| Th/CD8+T cells | 4.61 | 1-2 |
| Percentage of B cells (CD3–CD19+) | 30.2% | 9.02%-14.2% |
| Absolute B cell count (CD3–CD19+) | 3432/ul | 90-660/ul |
| Percentage of NK cells (CD3-CD56+) | 6.6% | 4.6%-16.0% |
| Absolute NK cell count(CD3–CD56+) | 749/ul | 46-590/ul |
| Percentage of NK-like T cells(CD3+CD56+) | 0.9% | 0%-12% |
| Absolute NK-like T cell count (CD3+CD56+) | 107/ul | |
| Immunoglobulin A | 0.13g/l | 0.7-4.0g/l |
| Immunoglobulin M | 0.74g/l | 0.4-2.3g/l |
| Immunoglobulin G | 0.58g/l | 7.0-16.0g/l |
| Immunoglobulin E | 11.8IU/ml | ≤15IU/ml |
Pathogens:
Parainfluenza virus type 3(by tNGS and respiratory panel)
Pneumocystis jirovecii(by blood and bronchoalveolar lavage tNGS)
Throat swab: Enterococcus faecalis(small amount)
Stool culture: negative
Blood culture: negative
Acid-fast bacilli (AFB): negative
Imaging: Abdominal X-ray showed intestinal gas; abdominal and intestinal ultrasound normal; cardiac ultrasound showed patent foramen ovale at birth, closed on follow-up.
Peripheral smear: The morphology of red blood cells varies in size, with some exhibiting enlarged pale staining areas. In terms of white blood cell morphology, certain types of neutrophils have been observed to contain toxic granules in their cytoplasm. Regarding platelet morphology, there were observations of platelet aggregation and elevated platelet counts. The total cell count was 100 cells.
Bone marrow: The morphology of red blood cells varies in size, with some exhibiting enlarged pale staining areas. In terms of white blood cell morphology, certain types of neutrophils have been observed to contain toxic granules in their cytoplasm. Regarding platelet morphology, there were observations of platelet aggregation and elevated platelet counts. The total cell count was 100 cells.
3.2.2. Whole-exome sequencing
WES revealed a hemizygous frameshift mutation in IKBKG (c.1167dup; p.Glu390ArgfsTer5), confirmed by Sanger sequencing: the patient is hemizygous, the mother is a heterozygous carrier, and the father is wild type. This mutation leads to premature translation termination and loss of protein function (PVS1). It has been reported in multiple EDA-ID patients (PS4), is extremely rare in population databases, and follows an X-linked recessive pattern in the family. According to ACMG guidelines, the variant is classified as pathogenic (PVS1+PS4).
In addition, the patient carries a heterozygous pathogenic variant in DUOX2(c.3250C>T; p.Arg1084Ter), inherited from the father (mother wild type). This variant is associated with thyroid secretory disorder type 6(autosomal recessive). It is likely incidental, as no thyroid dysfunction was observed.
Limitation: No functional validation(e.g. NF-κB phosphorylation, IκBα degradation, TNF-α stimulation assays)was performed due to the unavailability of frozen samples. The detailed genetic testing results and the Sanger sequencing chromatograms are shown in Table 4 and Figure 2, respectively.
Table 4.
WES genetic testing results for pediatric patients.
| Genes | Chromosome | Nucleotide variation in transcript numbering | Genotype | Pathogenic classification | Mode of inheritance |
|---|---|---|---|---|---|
| IKBKG | chrX:153792583-153792584 | exon10 c.1167dup | Hemizygous Father: Wild-type Mother: Heterozygous |
pathogenic | X-linked inheritance |
| DUOX2 | chr15:45392025 | exon25 c.3250C>T | Heterozygous Father: heterozygous Mother: wild-type |
pathogenic | Autosomal Recessive |
IKBKG(OMIM:300248); DUOX2(OMIM:606759).
Figure 2.
Sequencing map of the IKBKG gene in each member of the EDA-ID family. Pediatric patient (hemizygous); Mother (heterozygous); Father (wild-type). Arrows indicate variant sites.
3.3. Literature review
The comprehensive literature search identified 56 English-language and 3 Chinese-language publications, reporting 65 EDA-ID patients with IKBKG variants (excluding the present case). Among these, eight cases were identified as OL-EDA-ID, and 11 cases were classified as the non-ectodermal dysplasia subtype, which is characterized by pure immunodeficiency. The c.1167dup mutation identified in this case is one of the most frequently reported pathogenic mutations to date. The detailed list of included references is provided in Table 5.
Table 5.
Clinical manifestations, immunological phenotypes, treatment and prognosis of diseases associated with the IKBKG gene.
| Cases | Nucleotide or amino acid alterations | Family history | EDA | Infectious diseases | Immunological phenotypes | Outcome |
|---|---|---|---|---|---|---|
| 1 (4) | c.1117 + 5G>C | + | – | + | IgA↓, IgG↓ | Death |
| 2 (5) | c.111dupC(p.Met38fsTer48) | – | – | + | IgA↓, IgG↓, IgM↑ | Death |
| 3 (6) | c.1056-1G>A | – | – | + | NK cells↓ | IVIG |
| 4 (7) | c.601C>T (p.Gln201Ter, Q201X) | + | – | + | – | Death |
| 5 (8) | c.931C>G (p.Asp311Glu, D311E) | – | – | + | – | HSCT |
| 6 (9) | c.956G>A (p.Arg319Gln, R319Q) | – | – | + | IgG↑ | Treatment for tuberculosis |
| 7 (10) | c.1238A>G (p.His413Arg, H413R) | – | + | + | All IgG subclasses↓, B cells↓, NK cells↓ | Death |
| 8 (11) | c.1259A>G (p.Ter420Trp, X420W) | + | + | + | Impaired TNF-α response | Death |
| 9 (12) | c.1259A>G (p.Ter420Trp, X420W) | + | + | + | IgG↓, T cell deficiency | Death |
| 10 (13) | c.1259A>G (p.Ter420Trp, X420W) | + | + | + | IgG↓, lack of antibodies to polysaccharide antigens | Death |
| 11 (14) | c.1259A>G (p.Ter420Trp, X420W) | + | + | + | Impaired TNF-α response | Death |
| 12 (15) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | All IgG subclasses↓, CD3+ T cells↑, CD4+ T cells↑, NK cells↓ | HSCT |
| 13 (16) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | IgG↓, NK cell activity↓, B cells↑ | HSCT |
| 14 (17) | c.1167dupC (p.Glu390fs, E390fs) | + | + | Unknown | – | Unknown |
| 15 (18) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | IgA↑, production of polysaccharide-specific antibodies↓ | Unknown |
| 16 (19) | c.169G>A (p.Glu57Lys, E57K) | – | – | + | IgG↓, specific polysaccharide antibody deficiency, B cells↓ | IVIG |
| 17 (20) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | IgG↓ | HSCT |
| 18 (21) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | IgG↓ | HSCT |
| 19 (21) | c.1167dupC (p.Glu390fs, E390fs) | – | + | Unknown | IgG↓, NK cells↓ | Death |
| 20 (21) | c.1167dupC (p.Glu390fs, E390fs) | – | + | + | IgG↓, CD8+ T cell proportion↓, NK cells↓ | Death |
| 21 (18) | c.1250G>T (p.Cys417Phe, C417F) | – | + | + | IgA↑, IgM↑, IgG↓, production of polysaccharide-specific antibodies↓ | IVIG |
| 22 (22) | c.1171G>A (p.Arg352SerfsTer373, R352Sfs*373) | – | + | + | IgG↓, IgM↑ | HSCT |
| 23 (23) | c.1027 + 5G>A | + | + | + | IgG↑, IgA↓, IgM↓, T cells↑, B cells↓ | Unknown |
| 24 (24) | c.944A>C (p.Glu315Ala, E315A) | – | + | + | IgG↑, T cells↑ | Death |
| 25 (25) | c.916G>A (p.Asp306Asn, D306N) | + | + | + | IgA↑ | Death |
| 26 (26) | c.1249T>C (p.Cys417Arg, C417R) | – | + | + | IgG↓ | IVIG |
| 27 (18) | c.1249T>C (p.Cys417Arg, C417R) | – | + | + | IgG↓, IgA↓, IgM↑ | Death |
| 28 (18) | c.1249T>C (p.Cys417Arg, C417R) | – | + | + | IgG↓, NK cells↓ | IVIG |
| 29 (27) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | T cells↓, B cells↑ | IVIG |
| 30 (27) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | T cells↓, B cells↑ | IVIG |
| 31 (27) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | T cells↓, B cells↑ | IVIG |
| 32 (24) | c.761G>A(p.Arg254Gln, R254Q) | – | – | + | IgA↓, IgG↓, B cells↓, CD4+ T cells↓ | Death |
| 33 (28) | c.1117 + 1G>A | – | – | + | IgA↑, IgM↓, memory B cells↓ | Death |
| 34 (27) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | T cells↓, B cells↑ | IVIG |
| 35 (18) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | IgA↓, IgG↓, IgM↑ | Death |
| 36 (29) | c.458T>G (p.Leu153Arg, L153R) | – | + | + | NK cell cytotoxicity deficiency | HSCT |
| 37 (18) | c.1171G>T (p.Glu391Ter, E391X) | – | + | + | IgA↓, IgG↓, IgM↑ | Death |
| 38 (30) | c.399 + 850_674dup (Dupfrom intron 3 to exon 6) | + | + | + | IgG↑, IgA↑, IgM↓, CD4+ T cells↓ | Death |
| 39 (30) | c.399 + 850_674dup (Dupfrom intron 3 to exon 6) | + | + | + | T cell proliferation↓ | Death |
| 40 (24) | Rearrangement from Intron 4-8 | – | + | + | All Ig subclasses↓ | Unknown |
| 41 (24) | c.597G>A (A174_K224del) | – | + | + | IgA↓, IgG↓, IgM↑ | Unknown |
| 42 (31) | c.74_77delACGT(p.His25ArgfsTer14) | – | – | + | IgA↓, IgG↓, IgM↑ | Unknown |
| 43 (32) | c.613C>T (p.Gln205Ter, Q205X) | + | + | + | IgG↑, CD3+ T cells↓, CD4+ T cells↓, T cell proliferation↓ | HSCT |
| 44 (33) | c.505G>C (p.Ala169Pro, A169P) | – | + | + | T cells↓, B cells↑ | Fusiximab |
| 45 (24) | c.936C>G (p.Phe312Leu, F312L) | – | + | + | T and B cell ↓ | Death |
| 46 (34) | c.811_828del (p.Glu271_Ala276del) | – | + | + | IgG↑ | Unknown |
| 47 (34) | c.239T>C (p.Leu80Pro, L80P) | – | + | + | IgG↓, T cell proliferation↓ | IVIG |
| 48 (35) | c.518 + 866C>T | – | + | + | HLA-DR and CD4+ T cell ratio↑ | Death |
| 49 (36) | c.437T>G (p.Val146Gly, V146G) | – | + | + | IgG↓, IgM↓, IgA↑, CD8+ T cells↓, NK cells↓, B cells↓ | Unknown |
| 50 (37) | c.262_264delGAG(p.Glu88del, E88del) | + | + | + | IgG↓ | Unknown |
| 51 (38) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | IgM↑, IgE absent, IgA↓, T cells↑, TREC↓, NK cytotoxicity↓ | Unknown |
| 52 (39) | c.1056-1G>A(p.353-373) | – | – | + | B cell proliferation↓ | Unknown |
| 53 (40) | c.470A>C (p.Gln157Pro, Q157P) | – | + | + | IgG↓, T and B cell dysfunction | HSCT |
| 54 (41) | c.1249T>C (p.Cys417Arg, C417R) | – | + | + | IgG↓ | IVIG |
| 55 (42) | c.769-1G>C | – | + | + | CD19+ B cells↓ | Unknown |
| 56 (43) | c.931G>A(p.Asp311Asn, D311N) | – | + | + | IgG↓, IgA↑ | Unknown |
| 57 (44) | c.337G>A (p.Asp113Asn, D113N) | – | + | + | IgE↑ | Alive |
| 58 (22) | c.337G>A (p.Asp113Asn, D113N) | – | + | + | production of polysaccharide-specific antibodies↓ | IVIG |
| 59 (6) | c.458T>G (p.Leu153Arg, L153R) | + | + | + | IgG↓, NK cells↓ | IVIG |
| 60 (45) | c.545G>C (p.Arg182Pro) | – | + | + | B cells↑ | Unknown |
| 61 (46) | c.490A>C (p.Thr164Pro, T164P) | + | + | + | IgM↑, T cells↓, B cells↓, NK cells↓ | Death |
| 62 (47) | c.667_669del(p.Glu223del) | – | + | + | IgM↓, IgG↑, NK cytotoxicity↓ | IVIG |
| 63 (47) | c.667G>A | – | + | + | IgM↓, B cell ↓ | IVIG |
| 64 (48) | c.932A>G (p.Asp311Gly, D311G) | – | + | + | anti-B heterologous hemagglutinin↓ | Unknown |
| 65 (49) | c.519-23A>T | – | + | + | IgG↓, IgM↓, IgA↑, CD4+ T cells↓ | Death |
| 66 (44) | c.169G>A (p.Glu57Lys, E57K) | – | + | + | IgG↓, IgA↓, CD4+ T cells↓ | IVIG |
| 67 (50) | c.768 + 5G>A | – | + | + | IgG↓, IgM↑ | HSCT |
| 68 (51) | c.520_523dupCAGG | + | + | + | IgM↓, CD3+ T cells↓, T cell proliferation↓ | Death |
| 69 (52) | c.445T>G (p.Cys149Gly) | – | + | + | Ig subclasses↓, CD4+/CD8+ ratio↑ | Unknown |
| 70 (4) | c.1241T>A | – | + | + | IgA↓, IgM↓ | Death |
| 71 (53) | c.1249T>G (p.Cys417Gly, C417G) | – | + | + | IgG↓, CD8+ T cells↓, B cells↓ | IVIG |
| 72 (54) | c.1167dupC (p.Glu390fs, E390fs) | – | + | + | IgG↓ | HSCT |
| 73 (49) | c.519-23A>T | – | + | + | IgG↓, IgM↓, IgA↑, CD4+ T cells↓ | Death |
| 74 (6) | c.1207C>T (p.Gln403Ter, Q403X) | – | + | + | IgG↓, CD3+ T cells↓, CD4+ T cells↓, NK cells↓ | IVIG |
| 75 (6) | c.1250G>A (p.Cys417Tyr, C417Y) | – | + | + | IgG↓, NK cells↓ | IVIG |
| 76 (55) | c.943G>C (p.Glu315Gln, E315Q) | – | – | + | CD4+/CD8+ ratio↑, NK cell activity↓ | HSCT |
| 77 (56) | c.517C>G (p.Arg173Gly, R173G) | – | + | + | Impaired vaccine antibody response | IVIG |
| 78 (9) | c.944A>C (p.Glu315Ala, E315A) | + | + | + | CD40-dependent IL-12-induced selective injury | Death |
| 79 (57) | c.1238A>C (p.His413Pro, H413P) | + | + | + | IgM↑, no pneumococcal antibodies | Death |
| 80 (58) | c.1182_1183delTT(p.Phe394HisfsTer18) | + | + | + | IgM↑, IgG↓, B cells↑ | IVIG |
| 81 (44) | c.518 + 5G>A | + | + | + | IgG↓, IgM↑, memory B cells↓ | Death |
| 82 (59) | c.1167dupC (p.Glu390fs, E390fs) | – | + | + | IgA↓, IgM↓ | Death |
| 83 (60) | c.1167dupC (p.Glu390fs, E390fs) | + | + | + | – | Death |
| 84 (9) | c.956G>A (p.Arg319Gln, R319Q) | – | + | + | CD40-dependent IL-12-induced selective injury | Treatment for tuberculosis |
Cases 1–11 are classified as ID, cases 12–19 as OL-EDA-ID (OMIM:300301), and cases 20–84 as EDA-ID (OMIM:300291).
IVIG, intravenous injection Intravenous Immunoglobulin.
HSCT, Hematopoietic Stem Cell Transplantation.
↑ indicates an increase, while ↓ indicates a decrease.
The distribution of mutation types is summarized in Table 6. Frameshift or nonsense mutations were observed in the majority of cases, with common mutation sites including c.74-77delACGT, c.111dupC, c.1167dupC, c.1171G>T, c.1182-1183delTT, and c.520-523dupCAGG. Splicing site mutations were identified in cases with mutations such as c.1117 + 1G>A, c.1056-1G>A, c.1027 + 5G>A, c.769-1G>C, and c.768 + 5G>A. Missense mutations were frequently reported, involving amino acid substitutions including E57K, D311E, E315Q, R319Q, H413R, C417F, D306N, R254Q, A169P, V146G, D113N, L153R, F312L, L80P, R182P, T164P, D311G, D311N, C417R, C417Y, C417G, H413P, and R173G. Large-scale gene duplications or rearrangements, such as intron 3–exon 6 repeat and intron 4–8 rearrangement, were also documented.
Table 6.
Distribution of mutation types.
| Mutation type | Case number | Main mutation sites |
|---|---|---|
| Frameshift/Nonsense mutation | 2, 5, 11, 14, 16, 24, 31–36, 40–47, 55, 60–62, 80 | c.74_77delACGT; c.111dupC; c.601C>T; c.1182_1183delTT; c.1167dupC; c.1171G>A; c.613C>T; c.1171G>T; c.520_523dupCAGG; c.1207C>T |
| Splicing site mutation | 6, 7, 9, 12, 25, 54, 68, 70, 77–79 | c.1117 + 1G>A; c.1056-1G>A; c.1117 + 5G>C; c.518 + 5G>A; c.1027 + 5G>A; c.518 + 866C>T; c.769-1G>C; c.519-23A>T; c.768 + 5G>A |
| missense mutation | 1, 3, 8, 10, 13, 15, 17–23, 26, 27, 37–39, 53, 54, 57, 63, 67, 69, 71–73, 75, 76, 81–84 | E57K; D311E; E315Q; R319Q; H413R; Q157P; C417F; E315A; D306N; R254Q; A169P; V146G; C417R; D113N; L153R; F312L; L80P; D311N; R182P; T164P; c.667G>A; D311G; C149G; c.1241T>A; C417G; H413P; C417Y; R173G |
| Large-scale gene duplications/rearrangements | 51, 64, 65 | c.399 + 850_674dup (duplication from intron 3 to exon 6); rearrangement from intron 4 to intron 8 |
| In-frame deletion | 52, 58, 66, 74 | c.262_264delGAG; c.597G>A (p.Ala174_Lys224del); c.811_828del; c.667_669del |
| Loss-of-stop variant | 4, 28–30 | c.1259A>G |
The common immunological phenotypes are presented in Table 7. Decreased IgG levels were the most frequent finding, occurring in 40.5% of cases. Decreased IgA and elevated IgM were observed in 16.7% and 14.3% of patients, respectively. Reduced B-cell counts were noted in 10.7% of cases, while decreased NK cell counts or activity was reported in 15.5%. T-cell depletion or abnormal T-cell proportions were present in 20.2% of patients. A defect in specific polysaccharide antibody response was observed in 6.0% of cases, and an elevated CD4+/CD8+ ratio was identified in 2.4%.
Table 7.
Common manifestations of immunological phenotypes.
| Immunological phenotypes | Frequency | Case number |
|---|---|---|
| Decreased IgG | 46.4% | 1, 2, 5, 8–11, 13–15, 23–25, 27–29, 33, 34, 37–41, 43–47, 50, 52, 67, 69, 71, 77–79, 82 |
| Decreased IgA | 15.5% | 5, 9–11, 27, 31, 38, 40–42, 48, 50, 52 |
| Elevated IgM | 16.7% | 2, 5, 11, 24, 25, 37, 40–42, 52, 73, 79, 83 |
| Decreased B-cell | 15.5% | 6, 7, 22, 25, 48, 50, 53, 57, 70, 73, 75, 82 |
| Decreased NK cells/reduced activity | 13.1% | 12–15, 22, 33, 39, 46, 47, 57 |
| T-cell depletion or abnormal proportion | 29.8% | 14, 27, 28, 33, 42, 47–50, 55–57, 59–62, 64, 65, 67, 68, 73, 77, 78, 80–82 |
| Defect in the specific polysaccharide antibody response | 6.0% | 3, 8, 29, 36, 37 |
| Elevated CD4+/CD8+ ratio | 2.4% | 18, 81 |
4. Discussion
X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is caused by mutations in the IKBKG gene, which encodes the NF-κB essential modulator(NEMO) (1). Due to variations in gene mutation sites and their impact on different signaling pathways, the relationship between genotype and phenotype remains unclear. Only 77% of cases present as EDA-ID; the remainder present as immunodeficiency without ectodermal dysplasia (ID), or as more severe phenotypes (OL-EDA-ID) (2).
The IKBKG gene encodes NEMO (IKKγ), the regulatory subunit of the IKK complex, which is essential for the activation of NF-κB. The NEMO function is subject to regulation by phosphorylation and ubiquitination. Upon upstream signaling, IKK-mediated phosphorylation of IκBα promotes the translocation of NF-κB into the cell nucleus, thereby regulating biological processes such as immune responses, inflammatory processes, and cell survival (3). In addition, it is negatively regulated by three main classes of deubiquitinating enzyme: CyLD, A20 and OTULIN. CyLD has been shown to hydrolyze both linear and K63-linked ubiquitin chains, and by deubiquitinating NEMO, it inhibits TCR, BCR, and TLR-mediated canonical NF-κB activation, thereby regulating immune responses (61). A20 is involved in the negative regulation of various pro-inflammatory signals (such as TNF, IL-1, LPS, and the activation of T-cell and B-cell receptors). Typically, these signals activate NF-κB, and A20 acts to inhibit the excessive activation of NF-κB. A20 removes K63-linked polyubiquitin chains from proteins in NF-κB signaling pathways, preventing signal transmission and NF-κB activation (62, 63). OTULIN is a deubiquitinating enzyme which specifically cleaves linear polyubiquitin chains that are linked by N-terminal methionine residues and which are generated by the LUBAC complex. In patient cells, reduced levels of OTULIN protein and deubiquitinase activity lead to impaired deubiquitination of NEMO following TNF stimulation. This results in sustained IKK activity and IκBα phosphorylation, thereby negatively regulating NF-κB signaling (64, 65). A schematic diagram of the proposed mechanisms is presented in Figure 3.
Figure 3.
Activation and negative regulation of NEMO: Phosphorylation, Ubiquitination, and the Roles of Three Deubiquitinating Enzymes (CyLD, A20, OTULIN). Normally, NEMO (IKKγ) enables IKK-mediated IκBα phosphorylation and NF-κB activation, which drives expression of survival and immune genes. Deubiquitinases (CYLD, A20, OTULIN) remove ubiquitin chains from NEMO to terminate signaling. In our patient with the IKBKG c.1167dup (ZF-truncating) mutation, NEMO cannot bind linear ubiquitin chains, leading to defective IKK activation and reduced NF-κB-dependent transcription. This impairs B-cell differentiation and class-switching (explaining low IgG) and alters T-cell homeostasis (contributing to decreased CD8+ T cells and increased B-cell proportion). Moreover, loss of NEMO disrupts the deubiquitination feedback loop, further aggravating immune dysregulation and promoting intestinal epithelial necroptosis, which underlies the patient’s early-onset colitis.
The patient presented at two months of age with chronic diarrhea, mucoid bloody stools and fluctuating leukocytosis. Physical examination revealed sparse hair, reduced sweating, and a non-pruritic rash-findings consistent with ectodermal dysplasia. Most patients with mutations in the NEMO gene subtype typically present with infections caused by pyogenic bacteria or mycobacteria (66), but the patient described in this report was infected with Pneumocystis. This pattern of infection is associated with the pathological effects that zinc finger (ZF) domain mutations may induce; such mutations disrupt the CD40L-mediated degradation of the NF-κB inhibitor IκB-α, leading to defects in immunoglobulin class switching, and are also associated with T-cell defects (26, 67). Most patients with NEMO deficiency exhibit reduced IgG and impaired polysaccharide antibody responses (22), These manifestations, together with hypogammaglobulinaemia, decreased CD8+T cells, increased B cells and elevated IL-17, indicate immune dysregulation. Elevated IL-17 levels may indicate Th17 pathway activation, contributing to mucosal inflammation and increased susceptibility to fungal infections (68). The global survival rate for NEMO patients following allogeneic hematopoetic cell transplantation in children is 74% (69). For patients with NEMO deficiency and severely impaired T-cell function, early HSCT can be life-saving. Therefore, the child underwent HSCT (22). The c.1167dup (p.Glu390ArgfsTer5) frameshift mutation identified in this patient results in a truncated NEMO protein lacking the C-terminal zinc finger (ZF) domain, thereby causing loss of function. This variant has been documented as one of the most prevalent pathogenic IKBKG mutations. Mutations affecting the ZF domain have been demonstrated to contribute to phenotypic diversity, with a wide range of variants having been identified as causative agents of various diseases. For instance, severe mutations such as X420W have been shown to lead to OL-EDA-ID, a condition that can be life-threatening in severe cases (11). As demonstrated in Table 2, a comprehensive review of the extant literature reveals a total of 12 previously reported cases (references in Table 2, plus the present case) that carry the identical c.1167dup frameshift mutation. Among these, all 12 exhibited immunodeficiency, 11 had ectodermal dysplasia features, and 7 presented with gastrointestinal involvement (chronic diarrhea, colitis, or bloody stools). It is noteworthy that the onset of colitis in the present case occurred at 2 months of age, which is earlier than most reported cases. Immunological phenotypes were identified, encompassing decreased IgG, variable T-cell subset abnormalities, and elevated B-cell counts in a number of patients. This comparison highlights the presence of phenotypic heterogeneity, i.e. the occurrence of different manifestations of the same disease, even among patients carrying the same IKBKG null mutation (2). This genotype-Phenotype Mismatch may result from a number of different mechanisms. Firstly, it is important to note that NF-κB signaling is pleiotropic. This indicates that the same loss-of-function mutation can yield significantly divergent consequences, contingent on the specific cell type and the inflammatory context (70). However, it is also relevant to the mosaic expression of IKBG as a consequence of random X inactivation in heterozygous females (71). Furthermore, the modulation of environmental factors (such as differences in microbial exposure, gut microbiota composition, or concurrent infections) is likely to regulate the final clinical outcome (72).
Relevant mouse models have demonstrated that the activation of tumor necrosis factor (TNF) receptor 1 inhibits cell death downstream of the NEMO/IKKα/IKKβ complex, resulting in increased apoptosis in epithelial cells. The intestinal epithelium plays a key role in maintaining intestinal immune homeostasis. This leads to reduced expression of antimicrobial peptides, allowing bacteria to translocate into the mucosa. These bacteria then activate the innate immune response through pathways such as Toll-like receptors, which exacerbates intestinal damage and ultimately causes inflammatory bowel disease(IBD) (73, 74). Indeed, approximately 20% of male patients with NEMO deficiency develop intestinal inflammation, frequently accompanied by refractory diarrhea and/or growth failure (2). Gastrointestinal involvement is a salient yet often overlooked feature of NEMO deficiency. In the patient described here, the early onset of bloody stools and persistent occult blood suggest intestinal inflammation. Therefore, clinicians should consider X-linked ectodermal dysplasia with immunodeficiency in infants presenting with chronic diarrhea or colitis that is unexplained, especially if it is accompanied by ectodermal features or recurrent infections. This case further expands the clinical phenotype associated with this recurrent variant, emphasizing that early-onset colitis can be prominent features.
Treatment options include HSCT, antimicrobials and immunoglobulin replacement. HSCT is curative for the immunodeficiency, but not all manifestations are reverse, despecially in children with inflammatory bowel disease. Early HSCT improves prognosis, but mortality remains high without transplantation (69). Many untreated patients die from infections before one year of age, but early diagnosis and HSCT offer a chance for survival (10). There is still no cure, highlighting the urgent need for new treatments.
The study reports an EDA-ID case in a child caused by the c.1167dup variant in the IKBKG gene. It summarizes the clinical features, genetic diagnosis, and treatment process, while also analyzing the genotype-phenotype relationship. This case expands the clinical spectrum of the IKBKG c.1167dup mutation, particularly regarding severe gastrointestinal inflammation. Clinicians should remain vigilant for signs of ectodermal dysplasia and immunological abnormalities in early childhood.
Funding Statement
The author(s) declared that financial support was not received for this work and/or its publication.
Footnotes
Edited by: Attila Kumanovics, Mayo Clinic, United States
Reviewed by: Francisco Cammarata-Scalisi, Regional Hospital of Antofagasta, Chile
Roukaya Yaakoubi, University of Rochester, United States
Data availability statement
All relevant data is contained within the article: The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.
Ethics statement
The studies involving humans were approved by Shanxi Bethune Hospital Ethics Committee. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation in this study was provided by the participants’ legal guardians/next of kin. Written informed consent was obtained from the individual(s), and minor(s)’ legal guardian/next of kin, for the publication of any potentially identifiable images or data included in this article.
Author contributions
YX: Writing – original draft. XC: Writing – original draft. YY: Writing – review & editing. YW: Writing – review & editing.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
- 1. Kawai T, Nishikomori R, Heike T. Diagnosis and treatment in anhidrotic ectodermal dysplasia with immunodeficiency. Allergol Int. (2012) 61:207–17. doi: 10.2332/allergolint.12-rai-0446 [DOI] [PubMed] [Google Scholar]
- 2. Hanson EP, Monaco-Shawver L, Solt LA, Madge LA, Banerjee PP, May MJ, et al. Hypomorphic nuclear factor-kappaB essential modulator mutation database and reconstitution system identifies phenotypic and immunologic diversity. J Allergy Clin Immunol. (2008) 122:1169–1177.e16. doi: 10.1016/j.jaci.2008.08.018 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Zhang Q, Lenardo MJ, Baltimore D. 30 years of NF-κB: A blossoming of relevance to human pathobiology. Cell. (2017) 168:37–57. doi: 10.1016/j.cell.2016.12.012 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Johnston AM, Niemela J, Rosenzweig SD, Fried AJ, Delmonte OM, Fleisher TA, et al. A novel mutation in IKBKG/NEMO leads to ectodermal dysplasia with severe immunodeficiency (EDA-ID). J ClinImmunol. (2016) 36:541–3. doi: 10.1007/s10875-016-0309-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Niehues T, Reichenbach J, Neubert J, Gudowius S, Puel A, Horneff G, et al. Nuclear factor kappaB essential modulator-deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. J Allergy Clin Immunol. (2004) 114:1456–62. doi: 10.1016/j.jaci.2004.08.047 [DOI] [PubMed] [Google Scholar]
- 6. Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA, et al. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. (2004) 113:725–33. doi: 10.1016/j.jaci.2004.01.762 [DOI] [PubMed] [Google Scholar]
- 7. Rosenthal A, Goyal A, Chen SF, Lewis DB, Shah A. A patient with NEMO deficiency, disseminated M. szulgai, and post-HSCT inflammatory disease. Pediatr Transplant. (2025) 29:e70020. doi: 10.1111/petr.70020 [DOI] [PubMed] [Google Scholar]
- 8. Imamura M, Kawai T, Okada S, Izawa K, Takachi T, Iwabuchi H, et al. Disseminated BCG infection mimicking metastatic nasopharyngeal carcinoma in an immunodeficient child with a novel hypomorphic NEMO mutation. J ClinImmunol. (2011) 31:802–10. doi: 10.1007/s10875-011-9568-9 [DOI] [PubMed] [Google Scholar]
- 9. Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. (2006) 203:1745–59. doi: 10.1084/jem.20060085 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Ricci S, Romano F, Nieddu F, Picard C, Azzari C. OL-EDA-ID syndrome: a novel hypomorphic NEMO mutation associated with a severe clinical presentation and transient HLH. J ClinImmunol. (2017) 37:7–11. doi: 10.1007/s10875-016-0350-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Döffinger R, Smahi A, Bessia C, Geissmann F, Feinberg J, Durandy A, et al. X-linked anhidrotic ectodermal dysplasia with immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. (2001) 27:277–85. doi: 10.1038/85837 [DOI] [PubMed] [Google Scholar]
- 12. Mansour S, Woffendin H, Mitton S, Jeffery I, Jakins T, Kenwrick S, et al. Incontinentia pigmenti in a surviving male is accompanied by hypohidrotic ectodermal dysplasia and recurrent infection. Am J Med Genet. (2001) 99:172–7. doi: 10.1002/1096-8628(2001)9999:9999<::aid-ajmg1155>3.0.co;2-y [DOI] [PubMed] [Google Scholar]
- 13. Dupuis-Girod S, Corradini N, Hadj-Rabia S, Fournet JC, Faivre L, Le Deist F, et al. Osteopetrosis, lymphedema, anhidrotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pigmenti in his mother. Pediatrics. (2002) 109:e97. doi: 10.1542/peds.109.6.e97 [DOI] [PubMed] [Google Scholar]
- 14. Smahi A, Courtois G, Vabres P, Yamaoka S, Heuertz S, Munnich A, et al. Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium. Nature. (2000) 405:466–72. doi: 10.1038/35013114 [DOI] [PubMed] [Google Scholar]
- 15. Mancini AJ, Lawley LP, Uzel G. X-linked ectodermal dysplasia with immunodeficiency caused by NEMO mutation: early recognition and diagnosis. Arch Dermatol. (2008) 144:342–6. doi: 10.1001/archderm.144.3.342 [DOI] [PubMed] [Google Scholar]
- 16. Tono C, Takahashi Y, Terui K, Sasaki S, Kamio T, Tandai S, et al. Correction of immunodeficiency associated with NEMO mutation by umbilical cord blood transplantation using a reduced-intensity conditioning regimen. Bone Marrow Transplant. (2007) 39:801–4. doi: 10.1038/sj.bmt.1705658 [DOI] [PubMed] [Google Scholar]
- 17. Chang TT, Behshad R, Brodell RT, Gilliam AC. A male infant with anhidrotic ectodermal dysplasia/immunodeficiency accompanied by incontinentia pigmenti and a mutation in the NEMO pathway. J Am Acad Dermatol. (2008) 58:316–20. doi: 10.1016/j.jaad.2007.02.024 [DOI] [PubMed] [Google Scholar]
- 18. Zonana J, Elder ME, Schneider LC, Orlow SJ, Moss C, Golabi M, et al. A novel X-linked disorder of immune deficiency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and due to mutations in IKK-gamma (NEMO). Am J Hum Genet. (2000) 67:1555–62. doi: 10.1086/316914 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Frans G, van der Werff Ten Bosch J, Moens L, Gijsbers R, Changi-Ashtiani M, Rokni-Zadeh H, et al. Functional evaluation of an IKBKG variant suspected to cause immunodeficiency without ectodermal dysplasia. J ClinImmunol. (2017) 37:801–10. doi: 10.1007/s10875-017-0448-9 [DOI] [PubMed] [Google Scholar]
- 20. Permaul P, Narla A, Hornick JL, Pai SY. Allogeneic hematopoietic stem cell transplantation for X-linked ectodermal dysplasia and immunodeficiency: case report and review of outcomes. Immunol Res. (2009) 44:89–98. doi: 10.1007/s12026-008-8085-2 [DOI] [PubMed] [Google Scholar]
- 21. Artac H, Emsen A, Ucaryilmaz H, Emiroglu HH, Uygun V, Stray-Pedersen A, et al. Infliximab therapy for inflammatory colitis in an infant with NEMO deficiency. Immunol Res. (2019) 67:450–3. doi: 10.1007/s12026-019-09100-z [DOI] [PubMed] [Google Scholar]
- 22. Heller S, Kölsch U, Magg T, Krüger R, Scheuern A, Schneider H, et al. T cell impairment is predictive for a severe clinical course in NEMO deficiency. J ClinImmunol. (2020) 40:421–34. doi: 10.1007/s10875-019-00728-y [DOI] [PubMed] [Google Scholar]
- 23. Ørstavik KH, Kristiansen M, Knudsen GP, Storhaug K, Vege A, Eiklid K, et al. Novel splicing mutation in the NEMO (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome inactivation. Am J Med Genet A. (2006) 140:31–9. doi: 10.1002/ajmga.31026 [DOI] [PubMed] [Google Scholar]
- 24. Huppmann AR, Leiding JW, Hsu AP, Raffeld M, Uzel G, Pittaluga S, et al. Pathologic findings in NEMO deficiency: a surgical and autopsy survey. Pediatr Dev Pathol. (2015) 18:387–400. doi: 10.2350/15-05-1631-oa.1 [DOI] [PubMed] [Google Scholar]
- 25. Ramírez-Alejo N, Alcántara-Montiel JC, Yamazaki-Nakashimada M, Duran-McKinster C, Valenzuela-León P, Rivas-Larrauri F, et al. Novel hypomorphic mutation in IKBKG impairs NEMO-ubiquitylation causing ectodermal dysplasia, immunodeficiency, incontinentia pigmenti, and immune thrombocytopenic purpura. Clin Immunol. (2015) 160:163–71. doi: 10.1016/j.clim.2015.06.007 [DOI] [PubMed] [Google Scholar]
- 26. Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W, et al. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat Immunol. (2001) 2:223–8. doi: 10.1038/85277 [DOI] [PubMed] [Google Scholar]
- 27. Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M, Heyman MB, et al. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin Immunol. (2009) 132:124–31. doi: 10.1016/j.clim.2009.03.514 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28. Mooster JL, Cancrini C, Simonetti A, Rossi P, Di Matteo G, Romiti ML, et al. Immune deficiency caused by impaired expression of nuclear factor-kappaB essential modifier (NEMO) because of a mutation in the 5' untranslated region of the NEMO gene. J Allergy Clin Immunol. (2010) 126:127–132.e7. doi: 10.1016/j.jaci.2010.04.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Pai SY, Levy O, Jabara HH, Glickman JN, Stoler-Barak L, Sachs J, et al. Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-kappaB essential modulator deficiency. J Allergy Clin Immunol. (2008) 122:1113–8:e1. doi: 10.1016/j.jaci.2008.08.026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30. Nishikomori R, Akutagawa H, Maruyama K, Nakata-Hizume M, Ohmori K, Mizuno K, et al. X-linked ectodermal dysplasia and immunodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO in human T-cell development and/or survival. Blood. (2004) 103:4565–72. doi: 10.1182/blood-2003-10-3655 [DOI] [PubMed] [Google Scholar]
- 31. Ne K, G A, E U, C C, C OQ, A NP, et al. Disseminated BCG infectious disease and hyperferritinemia in a patient with a novel NEMO mutation. J Investig Allergol Clin Immunol. (2016) 26:268–71. doi: 10.18176/jiaci.0068 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32. Surucu Yilmaz N, Bilgic Eltan S, Kayaoglu B, Geckin B, Heredia RJ, Sefer AP, et al. Low density granulocytes and dysregulated neutrophils driving autoinflammatory manifestations in NEMO deficiency. J ClinImmunol. (2022) 42:582–96. doi: 10.1007/s10875-021-01176-3 [DOI] [PubMed] [Google Scholar]
- 33. Mizukami T, Obara M, Nishikomori R, Kawai T, Tahara Y, Sameshima N, et al. Successful treatment with infliximab for inflammatory colitis in a patient with X-linked anhidrotic ectodermal dysplasia with immunodeficiency. J ClinImmunol. (2012) 32:39–49. doi: 10.1007/s10875-011-9600-0 [DOI] [PubMed] [Google Scholar]
- 34. Ku CL, Dupuis-Girod S, Dittrich AM, Bustamante J, Santos OF, Schulze I, et al. NEMO mutations in 2 unrelated boys with severe infections and conical teeth. Pediatrics. (2005) 115:e615–9. doi: 10.1542/peds.2004-1754 [DOI] [PubMed] [Google Scholar]
- 35. Ueki M, Hirabayashi S, Honda Y, Takezaki S, Ohata H, Abdrabou S, et al. Increased response to granulocyte-macrophage colony-stimulating factor in peripheral blood cells and transient manifestations mimicking juvenile myelomonocytic leukemia in a male patient with NEMO deficiency caused by a deep intronic pathogenic variant of IKBKG. Immunol Med. (2025) 48:94–101. doi: 10.1080/25785826.2024.2422639 [DOI] [PubMed] [Google Scholar]
- 36. Devora GA, Sun L, Chen Z, van Oers NS, Hanson EP, Orange JS, et al. A novel missense mutation in the nuclear factor-κB essential modulator (NEMO) gene resulting in impaired activation of the NF-κB pathway and a unique clinical phenotype presenting as MRSA subdural empyema. J ClinImmunol. (2010) 30:881–5. doi: 10.1007/s10875-010-9445-y [DOI] [PMC free article] [PubMed] [Google Scholar]
- 37. Inaba S, Aizawa Y, Miwa Y, Imai C, Ohnishi H, Kanegane H, et al. Case report: Analysis of preserved umbilical cord clarified X-linked anhidrotic ectodermal dysplasia with immunodeficiency in deceased, undiagnosed uncles. Front Immunol. (2021) 12:786164. doi: 10.3389/fimmu.2021.786164 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38. Pachlopnik Schmid JM, Junge SA, Hossle JP, Schneider EM, Roosnek E, Seger RA, et al. Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation. Pediatrics. (2006) 117:e1049-56. doi: 10.1542/peds.2005-2062 [DOI] [PubMed] [Google Scholar]
- 39. Orange JS, Levy O, Brodeur SR, Krzewski K, Roy RM, Niemela JE, et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Allergy Clin Immunol. (2004) 114:650–6. doi: 10.1016/j.jaci.2004.06.052 [DOI] [PubMed] [Google Scholar]
- 40. Carlberg VM, Lofgren SM, Mann JA, Austin JP, Nolt D, Shereck EB, et al. Hypohidrotic ectodermal dysplasia, osteopetrosis, lymphedema, and immunodeficiency in an infant with multiple opportunistic infections. Pediatr Dermatol. (2014) 31:716–21. doi: 10.1111/pde.12103 [DOI] [PubMed] [Google Scholar]
- 41. Darbinyan A, Major EO, Morgello S, Holland S, Ryschkewitsch C, Monaco MC, et al. BK virus encephalopathy and sclerosing vasculopathy in a patient with hypohidrotic ectodermal dysplasia and immunodeficiency. Acta Neuropathol Commun. (2016) 4:73. doi: 10.1186/s40478-016-0342-3 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42. Karakawa S, Okada S, Tsumura M, Mizoguchi Y, Ohno N, Yasunaga S, et al. Decreased expression in nuclear factor-κB essential modulator due to a novel splice-site mutation causes X-linked ectodermal dysplasia with immunodeficiency. J ClinImmunol. (2011) 31:762–72. doi: 10.1007/s10875-011-9560-4 [DOI] [PubMed] [Google Scholar]
- 43. Haverkamp MH, Marciano BE, Frucht DM, Jain A, van de Vosse E, Holland SM, et al. Correlating interleukin-12 stimulated interferon-γ production and the absence of ectodermal dysplasia and anhidrosis (EDA) in patients with mutations in NF-κB essential modulator (NEMO). J ClinImmunol. (2014) 34:436–43. doi: 10.1007/s10875-014-9998-2 [DOI] [PubMed] [Google Scholar]
- 44. Keller MD, Petersen M, Ong P, Church J, Risma K, Burham J, et al. Hypohidrotic ectodermal dysplasia and immunodeficiency with coincident NEMO and EDA mutations. Front Immunol. (2011) 2:61. doi: 10.3389/fimmu.2011.00061 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 45. Mitani Y, Wada T, Matsuda Y, Sakai S, Yachie A. XL-EDA-ID presenting with congenital duodenal atresia and perforations. J ClinImmunol. (2018) 38:733–5. doi: 10.1007/s10875-018-0544-5 [DOI] [PubMed] [Google Scholar]
- 46. Bret Puvilland C, Boisson B, Fusaro M, Bustamante J, Bertrand Y, Ceraulo A, et al. EDA-ID: a severe clinical presentation associated with a new IKBKG mutation. J ClinImmunol. (2021) 41:1099–102. doi: 10.1007/s10875-021-00992-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 47. Karamchandani-Patel G, Hanson EP, Saltzman R, Kimball CE, Sorensen RU, Orange JS, et al. Congenital alterations of NEMO glutamic acid 223 result in hypohidrotic ectodermal dysplasia and immunodeficiency with normal serum IgG levels. Ann Allergy Asthma Immunol. (2011) 107:50–6. doi: 10.1016/j.anai.2011.03.009 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48. Hubeau M, Ngadjeua F, Puel A, Israel L, Feinberg J, Chrabieh M, et al. New mechanism of X-linked anhidrotic ectodermal dysplasia with immunodeficiency: impairment of ubiquitin binding despite normal folding of NEMO protein. Blood. (2011) 118:926–35. doi: 10.1182/blood-2010-10-315234 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 49. Jørgensen SE, Bøttger P, Kofod-Olsen E, Holm M, Mørk N, Ørntoft TF, et al. Ectodermal dysplasia with immunodeficiency caused by a branch-point mutation in IKBKG/NEMO. J Allergy Clin Immunol. (2016) 138:1706–9:e4. doi: 10.1016/j.jaci.2016.05.030 [DOI] [PubMed] [Google Scholar]
- 50. Toyohara M, Kajiho Y, Toyofuku E, Takahashi C, Owada K, Kanda S, et al. An infant with X-linked anhidrotic ectodermal dysplasia with immunodeficiency presenting with Pneumocystis pneumonia: A case report. Clin Case Rep. (2021) 9:e05093. doi: 10.1002/ccr3.5093 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 51. Yu HH, Hu TC, Lee NC, Chien YH, Yang YH, Hwu WL, et al. Mycobacterium abscessus infection in a boy with X-linked anhidrotic ectodermal dysplasia, immunodeficiency. J Microbiol Immunol Infect. (2019) 52:504–6. doi: 10.1016/j.jmii.2018.04.009 [DOI] [PubMed] [Google Scholar]
- 52. Wang W, Qiu ZQ, Ru Y, Wang CY, Song HM. (2014). “ A case of anhidrotic ectodermal dysplasia with immunodeficiency caused by a de novo mutation in the IKBKGgene”, in: Proceedings of the 12th National Conference on Medical Genetics (Zhengzhou, Henan, China, F: ). [Google Scholar]
- 53. Huang XM, Luo Y, He TY, Xu YB, Xia Y, Yang Z, et al. Clinical features analysis of a case of ectodermal dysplasia with immunodeficiency caused by a novel mutation in the IKBKGgene. Rare Dis Res. (2024) 3:492–500. [Google Scholar]
- 54. Martuszewski A, Paluszkiewicz P, Sierżęga-Staykov K, Wawrzyniak-Dzierżek E, Salamonowicz-Bodzioch M, Frączkiewicz J, et al. Successful allogeneic stem cell transplantation in nuclear factor-kappa B essential modulator deficiency syndrome after treosulfan-based conditioning: a case report. Transplant Proc. (2020) 52:647–52. doi: 10.1016/j.transproceed.2019.11.033 [DOI] [PubMed] [Google Scholar]
- 55. Inoue Y, Shimizu A, Suto M, Kishi C, Takahashi A, Yasuda M, et al. Cutaneous squamous cell carcinoma, thyroid cancer and Langerhans cell histiocytosis in a patient with X-linked recessive Mendelian susceptibility to mycobacterial diseases with a nuclear factor-κB essential modifier mutation. J Dermatol. (2018) 45:1017–9. doi: 10.1111/1346-8138.14482 [DOI] [PubMed] [Google Scholar]
- 56. Ku CL, Picard C, Erdös M, Jeurissen A, Bustamante J, Puel A, et al. IRAK4 and NEMO mutations in otherwise healthy children with recurrent invasive pneumococcal disease. J Med Genet. (2007) 44:16–23. doi: 10.1136/jmg.2006.044446 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 57. Khan TA, Schimke LF, Amaral EP, Ishfaq M, Barbosa Bonfim CC, Rahman H, et al. Interferon-gamma reduces the proliferation of M. tuberculosis within macrophages from a patient with a novel hypomorphic NEMO mutation. Pediatr Blood Cancer. (2016) 63:1863–6. doi: 10.1002/pbc.26098 [DOI] [PubMed] [Google Scholar]
- 58. Roberts CM, Angus JE, Leach IH, McDermott EM, Walker DA, Ravenscroft JC, et al. A novel NEMO gene mutation causing osteopetrosis, lymphoedema, hypohidrotic ectodermal dysplasia and immunodeficiency (OL-HED-ID). Eur J Pediatr. (2010) 169:1403–7. doi: 10.1007/s00431-010-1206-7 [DOI] [PubMed] [Google Scholar]
- 59. Lin WH, He YY, Shen J. Ectodermal dysplasia with immunodeficiency caused by IKBKG frameshift mutation. Zhonghua Er Ke Za Zhi. (2019) 57:638–40. [DOI] [PubMed] [Google Scholar]
- 60. Ichimiya Y, Sonoda M, Ishimura M, Kanno S, Ohga S. Hemorrhagic pneumonia as the first manifestation of anhidrotic ectodermal dysplasia with immunodeficiency. J ClinImmunol. (2019) 39:264–6. doi: 10.1007/s10875-019-00626-3 [DOI] [PubMed] [Google Scholar]
- 61. Mathis BJ, Lai Y, Qu C, Janicki JS, Cui T. CYLD-mediated signaling and diseases. Curr Drug Targets. (2015) 16:284–94. doi: 10.2174/1389450115666141024152421 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 62. Ma A, Malynn BA. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol. (2012) 12:774–85. doi: 10.1038/nri3313 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 63. Duong BH, Onizawa M, Oses-Prieto JA, Advincula R, Burlingame A, Malynn BA, et al. A20 restricts ubiquitination of pro-interleukin-1β protein complexes and suppresses NLRP3 inflammasome activity. Immunity. (2015) 42:55–67. doi: 10.1016/j.immuni.2014.12.031 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 64. Keusekotten K, Elliott PR, Glockner L, Fiil BK, Damgaard RB, Kulathu Y, et al. OTULIN antagonizes LUBAC signaling by specifically hydrolyzing Met1-linked polyubiquitin. Cell. (2013) 153:1312–26. doi: 10.1016/j.cell.2013.05.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 65. Lork M, Verhelst K, Beyaert R. CYLD, A20 and OTULIN deubiquitinases in NF-κB signaling and cell death: so similar, yet so different. Cell Death Differ. (2017) 24:1172–83. doi: 10.1038/cdd.2017.46 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 66. Wang J, Shen K, Lou H, Zhou L, An Y, Zhao X, et al. Clinical relevance of loss-of-function mutations of NEMO/IKBKG. Genes Dis. (2025) 12:101531. doi: 10.1016/j.gendis.2025.101531 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 67. Salt BH, Niemela JE, Pandey R, Hanson EP, Deering RP, Quinones R, et al. IKBKG (nuclear factor-kappa B essential modulator) mutation can be associated with opportunistic infection without impairing Toll-like receptor function. J Allergy Clin Immunol. (2008) 121:976–82. doi: 10.1016/j.jaci.2007.11.014 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 68. Draberova H, Janusova S, Knizkova D, Semberova T, Pribikova M, Ujevic A, et al. Systematic analysis of the IL-17 receptor signalosome reveals a robust regulatory feedback loop. EMBO J. (2020) 39:e104202. doi: 10.15252/embj.2019104202 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 69. Miot C, Imai K, Imai C, Mancini AJ, Kucuk ZY, Kawai T, et al. Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations. Blood. (2017) 130:1456–67. doi: 10.1182/blood-2017-03-771600 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 70. Lee Y, Wessel AW, Xu J, Reinke JG, Lee E, Kim SM, et al. Genetically programmed alternative splicing of NEMO mediates an autoinflammatory disease phenotype. J Clin Invest. (2022) 132(6):e128808. doi: 10.1172/jci128808 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 71. Sebban H, Courtois G. NF-kappaB and inflammation in genetic disease. Biochem Pharmacol. (2006) 72:1153–60. doi: 10.1016/j.bcp.2006.08.006 [DOI] [PubMed] [Google Scholar]
- 72. Klemann C, Pannicke U, Morris-Rosendahl DJ, Vlantis K, Rizzi M, Uhlig H, et al. Transplantation from a symptomatic carrier sister restores host defenses but does not prevent colitis in NEMO deficiency. Clin Immunol. (2016) 164:52–6. doi: 10.1016/j.clim.2016.01.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 73. Mikuda N, Schmidt-Ullrich R, Kärgel E, Golusda L, Wolf J, Höpken UE, et al. Deficiency in IκBα in the intestinal epithelium leads to spontaneous inflammation and mediates apoptosis in the gut. J Pathol. (2020) 251:160–74. doi: 10.1002/path.5437 [DOI] [PubMed] [Google Scholar]
- 74. Nenci A, Becker C, Wullaert A, Gareus R, van Loo G, Danese S, et al. Epithelial NEMO links innate immunity to chronic intestinal inflammation. Nature. (2007) 446:557–61. doi: 10.1038/nature05698 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
All relevant data is contained within the article: The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.