Case Report: X-linked recessive anhidrotic ectodermal dysplasia with immunodeficiency and an unusual Aspergillus infection

Introduction

X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) is a rare congenital disease, characterized by susceptibility to infectious diseases and abnormal development of ectoderm-derived skin appendages^1–5.

XL-EDA-ID clinical and immunological phenotypes are highly mutation dependent. Previous reports showed the associations of specific mutations with particular phenotypes including susceptibility to poorly virulent mycobacteria, invasive pyogenic bacterial fungal and severe viral infections, due to the essential role of NEMO (nuclear factor-kappa B (NF-κB) essential modulator) in both innate and adaptive immunity^3,6–14. Both cellular and humoral abnormalities were recorded in XL-EDA-ID cases^15,16. Most patients bearing NEMO gene mutations (also called IKBKG, encoder of NEMO protein) have an impaired antibody response, in particular to glycans¹⁷. However, impairments in CD40-mediated B cell activation, isotype class switching, NK cell cytotoxicity, response to LPS stimulation, and production of TNF and IL-12 have been verified by in vitro studies for some NEMO-deficient patients¹⁴. In this report, we present a 7-year-old boy with XL-EDA-ID suffering from disseminated BCGitis and fungal infection with specific antibody deficiency against glycan antigens.

Case presentation

This report describes a male child born to a non-consanguineous parents with no history of immunodeficiency in the family. The mother had a history of Behçet's disease. Birth growth parameters and mental development were in normal range. Vaccinations were up-to-date without any complication except diffuse lymphadenopathy following Bacillus Calmette-Guérin (BCG) vaccination at the age of 3 days. At 1 month of age, he was admitted to hospital with low fever, dry cough and respiratory distress and was diagnosed with pneumonia. During admission, abnormal signs such as tremor of upper and lower extremities and upward gaze were inspected. Cerebrospinal fluid analysis was normal (sugar: 36mg/dl; protein: 26mg/dl; no cells). He was diagnosed with suspected febrile convulsion due to a viral infection. During the first 9 months, he developed recurrent episodes of respiratory tract infections. Later on, another episode of disseminated BCGitis was detected while he was under continuous phase of isoniazid (INH) and rifampin (RIF) (10 mg/kg daily) for one month. Physical examination found multiple cervical lymphadenopathies, which later revealed caseating granulomatous lymphadenitis on biopsy. Spiral CT-scan of the abdomen illustrated hepatomegaly with inflammatory parenchyma and multiple para-aortic lymphadenopaties. Bone marrow study was normal. Continuation of antimycobacterial therapy at maximum dose of INH (15 mg/kg/day) and RIF (20 mg/kg/day) significantly improved disseminated BCGitis after 18 months.

Two other episodes of pneumococcal pneumonia were reported at the age of 3.5 and 4 years. At the age of 5, the patient experienced severe Aspergillus nidulans pneumonia and was started on Voriconazole (8mg/kg) followed by Itraconazole (5 mg/kg) twice a day for 1 year with a favorable outcome.

At the age of 6, the patient was referred to our center for the evaluation of immunodeficiency. Further examination revealed additional features of ectodermal dysplasia including conical lacteal teeth without agenesia, ridged nails, sparse hair and skin abnormalities. In terms of problems associated with recurrent opportunistic and unusual infections, laboratory evaluation of the immune system was performed and reported normal immunoglobulin levels, impaired response to pneumococcal vaccine and defective reaction to PPD (<5mm induration) (Table 1). Gene sequencing revealed a homozygous NEMO missense mutation in exon 8, c.932 A>G which led to the substitution of asparagine by glycine at residue 311 (designated D311G). Molecular testing of the pateint’s mother, grandmother and second aunt revealed heterozygous NEMO mutations in the corresponding locus. The patient has been administered monthly courses of intravenous immunoglobulin (800 mg/kg) and a prophylactic dose of Itraconazole (5mg/kg/day). Currently, patient is symptom free.

Discussion

Hypomorphic mutations in NEMO are associated with XL-EDA-ID^6–8. Patients with hypomorphic hemizygous IKBKG mutation appear to possess some variety of immunodeficiency, regardless of presence or absence of EDA^2–5. This could be due to an abnormal NF-κB which results in defective lymphocytic receptor signaling^18,19. Here we describe the first patient with NEMO deficiency who presents a classical EDA phenotype, disseminated BCGitis and pulmonary Aspergillosis. This patient carries a hemizygous NEMO mutation, D311G, which has also been reported previously in a patient with recurrent mycobacterial infections (M. avium and M. abscessus) without any history of fungal infections¹⁹. The mycobacterial susceptibility in both patients can be explained by the impairment of CD40-dependent IL-12 production²⁰. Defective PPD of our patient is the only document which revealed cellular immune system failure leading to disseminated BCGitis.

The immunological phenotypes of these two cases are comparable, because both patients displayed the same impaired antibody response to glycans as the only detected immunologic abnormality¹⁹. Almost all patients bearing mutations in NEMO have an impaired antibody response to glycans, including pneumococcal capsules in particular^3,4. Half of them have also hypogammaglobulinemia, probably secondary to CD40 signaling impairment³. Some mutations in the IKBKG gene are associated with T-cell defects, because NEMO is an essential component of the inhibitor of NF-κB (IκB)-kinase (IKK) complex, affecting the phosphorylation of IκB which is necessary for nuclear translocation of NF-κB²⁴. Signaling through the IKK complex has been shown to be essential for production of mature/memory T- cells, which may be an explanation for the low memory T-cell phenotype observed in these patients^25,26.

Lastly, regarding the developmental phenotype, the patient reported here displays a more severe EDA phenotype (dysmorphic conical lacteal) compared to the patient with the same hemizygous NEMO mutation who has only teeth agenesis of maxillary lateral incisors and premolars¹⁹. Hence, appropriate genetic diagnosis and genetic counseling looks essential and testing for NEMO carriers should be considered (if applicable) as performed in our case for the patient’s mother and maternal aunts. Intravenous immunoglobulins is the treatment of choice in NEMO-deficient patients with evidence of impaired antibody production^5,6. High incidence of atypical mycobacterial disease infection in these cases emphasize the need of prophylaxis. Prophylaxis against pneumocystis pneumonia should also be considered, specifically in males with low T-cell counts or severely impaired lymphocyte proliferation^27–29. Conclusively, attention to gender, pattern of infections, and skin involvements helped us to diagnose and appropriately manage this case.

Consent

Written informed consent for publication of the patient’s details was obtained from the patient’s parents.