To the Editor:

Clinical features of X-linked anhidrotic ectodermal dysplasia with immunodeficiency (XL-EDA-ID) include hypohidrosis, delayed eruption of teeth, coarse hair, and immunodeficiency associated with frequent bacterial infections [1]. XL-EDA-ID is caused by dysfunction of the IKBKG gene, which encodes NEMO, the NF-kB essential modulator. NEMO participates in activation of the IkB kinase complex, which enables nuclear translocation of NF-kB dimers. It is well known that patients with XL-EDA-ID are susceptible to inflammatory colitis [1]; however, there is no report of XL-EDA-ID presenting with congenital duodenal atresia or multiple intestinal perforations.

A male infant who was prenatally diagnosed as having duodenal obstruction was born at 39 weeks of gestation via elective cesarean section. His birth weight was 2300 g. There was no family history of ectodermal dysplasia or immunodeficiency. The patient had bilious nasogastric aspirates and abdominal distension. Plain radiographs showed a double-bubble sign, and a contrast study revealed complete duodenal obstruction (Fig. 1a). Laboratory studies revealed a white blood cell count of 15,900/μL, a hemoglobin level of 12.8 g/dL, and a serum C-reactive protein level of 0.0 mg/dL. On day 1, exploratory laparotomy showed hemorrhagic ascites, complete duodenal atresia, multiple perforations of the duodenum and proximal jejunum (Fig. 1b), annular pancreas, and intestinal malrotation. Subsequently, duodenojejunostomy was performed. There was no evidence of meconium peritonitis. Histological examination of the duodenum showed mild congestion, bleeding, focal mucosal atrophy, and a defect of the muscle layer (Fig. 1c, d). A few fibrinoid materials and inflammatory cells were also observed. The postoperative period was unremarkable until postoperative day 11, when the patient presented with prolonged fever that did not easily respond to antibiotics treatment and required 2 months of hospitalization. Despite repeated cultures of blood, urine, and stool, no pathogenic organisms were isolated. No cytomegalovirus DNA was detected in his dried umbilical cord by polymerase chain reaction (PCR).

Fig. 1
figure 1

Congenital duodenal atresia and multiple intestinal perforations. a Contrast study showing complete duodenal obstruction. b Intraoperative photograph showing duodenal atresia and multiple perforations of the duodenum and proximal jejunum. An asterisk indicates the dilated proximal duodenum. The collapsed intestine distal the atresia was inflamed and had multiple perforations with mucous membrane edges (arrows). c Resected small intestine. d Hematoxylin and eosin staining of the duodenum

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Shortly after discharge from the hospital, the patient had frequent episodes of fever, vomiting, and diarrhea. At 5 months of age, gastroduodenal anastomosis was performed because of frequent vomiting, poor weight gain, and stagnation of contrast medium at the anastomotic region. At 6 months, the patient was hospitalized again for gastrointestinal hemorrhage caused by anastomotic ulcer. Because he showed positive cytomegalovirus antigenemia and Pneumocystis jirovecii pneumonia, primary immunodeficiency was clinically suspected. Prophylactic use of antibiotics and antifungals was initiated. However, an immunological evaluation was largely normal. Serum immunoglobulin (Ig) levels were as follows: IgG, 767 mg/dL (normal, 290–950); IgA, 94 mg/dL (normal, 8–50); and IgM, 131 mg/dL (normal, 46–176). There was no lymphopenia, and immunophenotypic analysis of lymphocytes showed a normal percentage of CD3+ T (71.0%; normal, 67.5 ± 6.9%) and CD4+ T cells (41.0%; normal, 45.6 ± 9.3%), with a slight increase in the percentage of CD8+ T cells (26.2%; normal, 15.2 ± 4.2%) and CD20+ B cells (28.4%; normal, 16.7 ± 5.4%). Lymphocytes showed normal proliferation in response to phytohemagglutinin. Levels of T cell receptor excision circles and kappa-deleting recombination excision circles were normal. Whole exome sequencing failed to identify any pathogenic mutations in genes related to primary immunodeficiency. Mutations of duodenal atresia-related genes, such as NKX3–2, HNF1B, and RFX6, were also absent.

At 12 months of age, the patient was found to have ectodermal dysplasia, including sparse hair, hypohidrosis, and conical teeth. One month later, we identified a missense mutation (c.545G > C, p.Arg182Pro) in the IKBKG gene by cDNA sequencing analysis, and XL-EDA-ID was diagnosed. Thus, immunoglobulin replacement therapy was started, and the patient has had no episode of severe vomiting and fever until 30 months of age.

This report illustrates the first case of XL-EDA-ID presenting with congenital duodenal atresia and multiple intestinal perforations. Congenital duodenal atresia is an uncommon condition, with an estimated incidence of 1:4000 to 1:15,000 live births. Failure of duodenal recanalization during the 8th and 10th week of embryological development is thought to be the main cause of duodenal atresia. However, the patient had annular pancreas that could be an uncommon etiology for duodenal atresia. This form of obstruction is due to failure of duodenal development rather than intrinsic causes. Thus, the co-presence of XL-EDA-ID and duodenal atresia in the patient may be independent from the IKBKG mutation. Other malformations may exist in patients with congenital duodenal atresia. In fact, our patient also had intestinal malrotation. Simultaneous occurrence of congenital duodenal atresia and jejunal perforations is quite rare, and has only been reported in a single case, in which the underlying etiology is unknown [2]. Our case is peculiar in terms of the presence of multiple perforations at birth.

The mechanisms linking NEMO deficiency to multiple intestinal perforations in our case are presently unclear. NEMO-hypomorphic patients are at an increased risk of developing inflammatory colitis. It has been reported that IKBKG mutations cause diverse clinical and immunologic phenotypes, and that colitis phenotype is associated with mutations in two particular regions: the first coiled coil and α-helix domains and the zinc finger domain [3]. In fact, our patient’s mutation is located at the former region. In a murine model of intestinal epithelium-specific NEMO deficiency, intestinal epithelium cells exhibit increased sensitivity to tumor necrosis factor-α-induced apoptosis and cause disruption of the epithelial barrier, resulting in chronic intestinal inflammation [4]. The mice did not have any apparent developmental defects of stomach and gut. Therefore, it is possible that the multiple intestinal perforations distal the atresia were derived from susceptibility of the intestine to inflammation on the basis of NEMO deficiency.

Early diagnosis of XL-EDA-ID is difficult unless signs of ectodermal dysplasia are present. Most patients with XL-EDA-ID exhibit subtle immunological findings, and the presence of a pseudogene (IKBKGP1) makes genetic diagnosis difficult using short amplicon Sanger sequencing. To eliminate contamination of the pseudogene sequence, cDNA or a long-range PCR amplicon using primers that do not amplify the pseudogene should be used as PCR templates. Furthermore, our findings indicated that whole-exome sequencing may also give a false negative result in NEMO deficiency because of an inability to unambiguously map reads.

Hematopoietic stem cell transplantation (HSCT) can correct immunological phenotypes, but inflammatory signs, including colitis, may persist in XL-EDA-ID [5]. A recent international cohort study of NEMO-hypomorphic patients indicated that preexisting mycobacterial infection and colitis were associated with poor HSCT outcome, and that HSCT did not appear to correct susceptibility to colitis [6]. Because infections may trigger symptoms of inflammatory colitis in NEMO deficiency, appropriate use of antibiotic, antifungal, and antiviral agents to treat and prevent infections is also important for colitis, in addition to conventional treatment for inflammatory bowel syndrome.

In summary, this case showed congenital duodenal atresia and multiple intestinal perforations in a patient with XL-EDA-ID, the latter of which may be unique gastrointestinal symptoms related to NEMO deficiency. This suggests that NEMO deficiency may cause a broad spectrum of consequences of inflammation in the gastrointestinal system.