Journal of Clinical Immunology (2019) 39:264–266 https://doi.org/10.1007/s10875-019-00626-3 LETTER TO EDITOR Hemorrhagic Pneumonia as the First Manifestation of Anhidrotic Ectodermal Dysplasia with Immunodeficiency Yuko Ichimiya1,2 & Motoshi Sonoda1 & Masataka Ishimura1 & Shunsuke Kanno1 & Shouichi Ohga1 Received: 16 November 2018 /Accepted: 7 April 2019 /Published online: 13 April 2019 # Springer Science+Business Media, LLC, part of Springer Nature 2019 Abbreviations immunodeficiency. Flow cytometric screening indicated the de- IL Interleukin fective production of tumor necrosis factor (TNF)-α.Molecular LPS Lipopolysaccharide autopsy determined the diagnosis of IKBKG deficiency in the NEMO Nuclear factor κB essential modulator family, which led to the neonatal diagnosis and preemptive care NF-κB Nuclear factor κB of a next-born sibling. TNF Tumor necrosis factor A 43-day-old male infant with hemoptysis and respiratory XL-EDA-ID X-linked anhidrotic ectodermal distress entered our emergency room. He was delivered via dysplasia with immunodeficiency cesarean section because of non-reassuring fetal status at full term, weighing 2682 g. The newborn had meconium aspira- tion syndrome but was discharged from hospital without com- To the Editor: plication 5 days after birth. Neonatal mass-screening and reg- X-linked anhidrotic ectodermal dysplasia with immunodefi- ular health check were normal. The umbilical cord was sepa- ciency (XL-EDA-ID) is a primary immunodeficiency disease rated over 21 days after birth. He was the first child of healthy (PID) arising from the mutation of IKBKG that encodes non-consanguineous parents (Supplementary Fig. 1a). Family NF-κB essential modulator (NEMO). Clinical expressions of history was unremarkable, but skin macules were noticed on the disease are characterized by abnormal teeth, hypohidrosis, the forearms of the mother, aunt, and grandmother in the ma- sparse hair, and the immunological defects of impaired anti- ternal side (Fig. 1a). body response to polysaccharides, hypogammaglobulinemia, On admission, the afebrile infant exhibited tachycardia and impaired natural killer cell cytotoxicity. Patients are sus- (165/min), tachypnea, retraction (60/min), and 69 mmHg of ceptible to infections with pyogenic bacteria, mycobacteria, systolic blood pressure. SpO2 was 97% on receiving 10 L/ parasites, viruses, and fungi [1]. Inflammatory bowel disease min of mask oxygen. Capillary refill time was over 2 s. The and autoimmunity are notable complications affecting the cold legs showed livedo reticularis and spotty pigmentations growth of pediatric patients. (Fig. 1b). Blood clots stained the mouth. He had eczema on the We herein report a young infant who suddenly died of hem- face, large pigmented nevi on the lower lip, sparse hair and orrhagic pneumonia. Isolated pathogens of Stenotrophomonas eyebrows, but no dysmorphisms. Auscultation revealed poor maltophilia (S. maltophilia), Klebsiella oxytoca (K. oxytoca), aeration but no heart murmur or adventitious breath sounds. 9 and cytomegalovirus suggested an underlying Blood tests showed a leukocyte count of 31.910 × 10 /L with 18% neutrophils, 67% lymphocytes, 5% monocytes, a hemo- Electronic supplementary material The online version of this article globin concentration of 8.1 g/dL, and a platelet count of 33 × (https://doi.org/10.1007/s10875-019-00626-3) contains supplementary 109/L. Aspartate aminotransferase (157 U/L, rr 24–43), lactate material, which is available to authorized users. dehydrogenase (2854 U/L, rr 190–365), creatine kinase (987 U/L, rr 43–270), and C-reactive protein (5.65 mg/dL, rr * Masataka Ishimura < 0.04) levels were increased. Slightly elevated D-dimer levels [email protected] (1.7 μg/mL, rr 0.15–1) heralded severe coagulopathy. Venous blood gas analysis showed respiratory acidosis (pH 7.229, 1 Department of Pediatrics, Graduate School of Medical Sciences, PCO2 59.6 mmHg) and elevated lactate levels (28 mg/dL, rr Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan < 18). Cefotaxime was immediately administrated. Positive pressure ventilation and transfusions led to a transient improve- 2 Emergency and Critical Care Center, Kyushu University, Fukuoka, Japan ment of desaturation, but pulmonary bleeding required J Clin Immunol (2019) 39:264–266 265 c a Isotype control TNFα 0.8% 70.8% CD14 Cont. b d 1.2% 3.7% Pt. e f 0.0% 4.9% Male sibling IgG1 Fig. 1 a Skin macules on the right forearm of the mother. b Skin as previously established. d Postmortem histopathology of the lung tissue pigmentation on the leg of the patient (white arrow). c Flow cytometric shows diffuse alveolar bleeding and frequently encountered Gram- analysis of intracellular TNF-α production of monocytes in response to negative rods (black arrow), but few infiltrations of inflammatory cells. LPS. Intracellular staining for TNF-α shows its expressing monocytes are e, f Cytomegalovirus-infected airway epithelial cells (black arrow) diminished to 3.7% compared with controls assessed by flow cytometry, extracorporeal membrane oxygenation 15 h after admission 1e, f). Delayed separation of the umbilical cord and skin pig- (Supplementary Fig. 2). S. maltophilia and K. oxytoca were mentations prompted us to complete the mutation analysis of isolated from blood, sputum, and stool cultures; IRAK4, MYD88,andIKBKG genes [1]. He had a reported trimethoprim/sulfadiazine and anti-mycotic agents were then pathogenic hemizygous mutation (c.1167dupC, exon 10, added with the introduction of polymyxin B-immobilized fiber p.Glu390ArgfsTer5) in IKBKG gene [2], but no mutation in column. Despite the intensive care, he died of massive bleeding IRAK4 or MYD88 gene that reached the diagnosis of XL- 36 h after admission. EDA-ID (Supplementary Fig. 1c). His healthy mother, aunt, During the intensive care, flow cytometric analyses indicat- and grandmother received the diagnosis of incontinentia ed defective TNF-α production from lipopolysaccharide pigmenti because of sharing the heterozygous mutation in (LPS)-stimulated monocytes with healthy controls (3.7% vs. IKBKG gene, pigmented macules, and normal monocytic 70.8%, Fig. 1c). CD14+ mononuclear cells did not release TNF-α production (Supplementary Figs. 1cand1d). A next- TNF-α after stimulation with LPS alone, or LPS plus 10 or born male received the neonatal diagnosis of XL-EDA-ID and 100 U/ml of interferon-γ (data not shown). Serum levels of has been carefully observed on antimicrobial prophylaxis and interleukin (IL)-6 and IL-8, but not TNF-α, were elevated dur- immunoglobulin replacement (Fig. 1c, Supplementary Fig. 1c). ing the treatment (Supplementary Fig. 2). Histopathology of the The early diagnosis and management of XL-EDA-ID are autopsied lungs showed diffuse alveolar bleeding and Gram- challenging because of a wide spectrum of phenotypes. Some negative rods, few unremarkable infiltrations of inflammatory patients with c.1167dupC, p.Glu390ArgfsTer5 resulted in fa- cells (Fig. 1d, Supplementary Fig. 1b). Cytomegalovirus infec- tal infections in infancy and others with the mutation received tion was determined in the immunohistochemical staining (Fig. successful bone marrow transplantations [2]. In the young 266 J Clin Immunol (2019) 39:264–266 infant with hemorrhagic pneumonia, delayed separation of the Hematopoietic stem cell transplantation is the curative treat- umbilical cord, skin pigmentation, and rapid screening for ment for the infection proneness of XL-EDA-ID [2]. This TNF-α production narrowed the diagnosis of innate immune family emphasizes the significance of newborn screening of defect. His mother’s female relatives shared the mutation and inborn errors of immunity to infection for the complete cure of a skin manifestation of incontinentia pigmenti. The basis of disease. aggressive pneumonia accounts for the genetic effect and mul- tiple infections. Acknowledgments We sincerely thank Dr. Noriyuki Kaku, Dr. Patients with XL-EDA-ID are prone to infections with var- Yoshitomo Motomura, Dr. Katsuhide Eguchi, Dr. Akira Shiraishi, Dr. Kanako Ishii, Prof. Hidetoshi Takada, and Prof. Tomoaki Taguchi for ious pathogens including encapsulated bacteria, nosocomial valuable advices. We are grateful to Dr. Yui Nozaki and Prof. Yoshinao microbes, and mycobacteria. Dysmorphism and recurrent in- Oda for pathological diagnosis. This work was supported in part by fections are not evident in early infancy. Hypomorphic muta- Practical Research Project for Rare/Intractable Diseases tions in IKBKG are associated with varied expressions in af- (JP16ek0109099) and Grant-in-Aids (JP16ek0109098h0002) from the IKBKG Japan Agency for Medical Research and Development (AMED) and fected boys [2]. Amorphic mutation of results in the the Research on Measures for Intractable Diseases Project and Health full expressions of female incontinentia pigmenti. Therefore, and Labor Sciences Research Grants (Research on Intractable Diseases) the recognition of incontinentia pigmenti in the mother is crit- from the Ministry of Health, Labour and Welfare. ical for the neonatal diagnosis of XL-EDA-ID. Numerous ’ stimuli via Toll-like receptor, IL-1 receptor, and TNF receptor Authors Contribution The contributions of each author are as follows. YI, MS, MI, and SO were the principal investigators, taking primary make use of common interacting and adaptor molecules to responsibility for the paper. MS completed the immunological studies induce the classical NF-κB pathway in mammals. Immune and genetic analysis. MI established the immunological