X-Linked Ectodermal Dysplasia with Immunodeficiency Caused by NEMO Mutation Early Recognition and Diagnosis

Home , Ectodermal dysplasia, Genodermatosis, Incontinentia pigmenti

OBSERVATION X-Linked Ectodermal Dysplasia With Immunodeficiency Caused by NEMO Mutation Early Recognition and Diagnosis

Anthony J. Mancini, MD; Leslie P. Lawley, MD; Gulbu Uzel, MD

ϩ ϩ Background: X-linked ectodermal dysplasia with im- revealed lymphocytosis with elevated CD3 and CD4 munodeficiency (XL-EDA-ID) is described in patients with counts and low levels of natural killer cells. Amplifica- hypomorphic mutations in IKBKG (the inhibitory ␬B ki- tion and sequencing of IKBKG revealed insertion of cy- nase ␥ gene), which encodes nuclear factor ␬B essential tosine at nucleotide 1167 (1167-1168insC) in exon 10, modulator (NEMO). Features include hypohidrosis, den- with frameshift mutation in the zinc-finger domain. Pe- tal anomalies, alopecia, and immunodeficiency. Boys with ripheral blood stem cell transplantation led to initial en- NEMO mutations often present with serious infections, graftment and improvement in his skin findings, but his but the NEMO mutations are rarely diagnosed early in engrafted cell counts diminished, and a second stem cell infancy. Cutaneous features in these patients are poorly transplantation was planned. elucidated. Conclusions: Mutations in NEMO should be consid- Observations: A 12-week-old male infant presented with ered in male infants with recalcitrant seborrheic or atopic a recalcitrant skin eruption, intertrigo, atopiclike der- dermatitislike eruptions and intertrigo, especially when matitis, and erythroderma. Alopecia, frontal bossing, and features of ectodermal dysplasia are present. Early rec- periorbital wrinkling were present, and family history re- ognition and diagnosis are desirable, prior to the onset vealed incontinentia pigmenti in his mother. Labora- of manifestations of immunodeficiency. tory evaluation revealed leukocytosis with eosinophilia, low IgG and IgM levels, and absent IgA. Flow cytometry Arch Dermatol. 2008;144(3):342-346

CTODERMAL DYSPLASIA (ED) unit of the IKK (I␬B kinase) complex. The refers to a group of inher- NEMO complex is essential for NF-␬B sig- ited disorders involving ab- naling,2 and NF-␬B is a heterogeneous col- sence or dysplasia of the ec- lection of cytoplasmic dimers that, once free todermal appendages. of its regulatory subunit, enters the nucleus Clinically,E it is characterized by absence, ab- to initiate transcription of a variety of genes normality, or deficient function of ectoder- involved in immunity, inflammation, apop- mal derivatives, including skin, teeth, hair, tosis, adhesion, and cell growth.3 eccrine glands, or nails. The hypohidrotic/ Mutations of NEMO are difficult to di- anhidrotic form of ED (HED/EDA) has been agnose early in infancy for male patients, attributed to at least 4 genes (EDA1 [ecto- most presenting with manifestations of im- dysplasin]; EDA3; EDAR [the EDA-A1 iso- munodeficiency.4 Herein, we describe a form receptor]; and EDARADD [EDAR- male infant with XL-EDA-ID caused by associated death domain]), with at least 3 NEMO mutation diagnosed at age 12 modes of inheritance1: X-linked recessive weeks and subsequently treated with al- (OMIM 305100), autosomal dominant logeneic stem cell transplantation. Author Affiliations: Division of Dermatology, Children’s For editorial comment REPORT OF A CASE Memorial Hospital and Departments of Pediatrics and see page 387 Dermatology, Northwestern PATIENT MEDICAL HISTORY University Feinberg School of (OMIM 129490), and autosomal recessive Medicine, Chicago, Illinois (OMIM 224900). Recently, the syndrome of A 12-week-old male infant presented to the (Drs Mancini and Lawley); and X-linked EDA with immunodeficiency (XL- pediatric dermatology clinic for a persistent Laboratory of Clinical Infectious Diseases, National EDA-ID) (OMIM 300291) was described in skineruptionsinceage1month.Hewasborn Institutes of Health, National patients with hypomorphic mutations in after a 39-week uncomplicated pregnancy, Institute of Allergy and IKBKG (inhibitory ␬B kinase ␥ gene), which delivered via elective cesarean section to a Infectious Diseases, Bethesda, encodes NEMO (nuclear factor ␬B[NF-␬B] 40-year-oldgravida2,para2woman.Exami- Maryland (Dr Uzel). essential modulator), the regulatory sub- nation revealed a well-developed male infant

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Figure 1. Diffuse alopecia, erythema, and scaling of the scalp.

Figure 4. Erythroderma with patches of sparing. The patient also had persistent intertrigo.

He was initially diagnosed with severe intertrigo and seborrheic dermatitis and treated with oxiconazole ni- trate, 1%, and alclometasone diproprionate, 0.05%, creams, oral cephalexin, and oral fluconazole. A prior culture had revealed heavy growth of Staphylococcus aureus that was pansensitive. Findings from fungal and repeated bacterial cultures from affected skin fold areas were negative. Given the severity of involvement, a laboratory evaluation for immunodeficiency was performed. Subsequently, his mother reported having been diagnosed with incontinentia pigmenti as a child, with ap- Figure 2. Frontal bossing, periorbital wrinkling, and a thickened, everted parent mild expressivity. She recalled her history of blis- lower lip. ters with eventual spontaneous involution. She denied any history of dental or musculoskeletal defects, oph- thalmic abnormalities (aside from myopia), and devel- with the following growth parameters: weight at the 10th opmental abnormalities or seizures. Her hair and nails to 25th percentile for age, length at the 10th to 25th percen- were normal, and findings of her most recent skin ex- tile for age, and head circumference at the 50th percentile amination were notable only for faintly hyperpig- for age. His scalp revealed diffuse alopecia and diffuse, yel- mented linear and whorled streaks following the lines of low, greasy scales superimposed on erythema (Figure 1). Blaschko on the posterior aspects of her legs and flanks. He was noted to have mild frontal bossing, periorbital wrin- Throughout his early course, the patient’s skin in- kling, and an everted lower lip (Figure 2). His axillary and volvement varied. He developed intermittent erythro- inguinal folds and perianal region revealed erosive erythema derma with patchy clearing (Figure 4), yet the inter- (Figure 3), and his umbilicus was erythematous and moist. trigo was a fairly persistent finding. He had occasional His oral mucosa was clear, and he had no lymphadenopa- atopic dermatitislike, erythematous, scaly plaques su- thy or hepatosplenomegaly. perimposed on a background of faint erythroderma. Dur-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 results of chemical analysis were normal. Findings of a A chronic granulomatous disease flow study were normal, as were the expression of CD11b integrin (ruling out leukocyte adhesion deficiency) and mitogen stimulation assays (phytohemagglutinin, concanavalin A, and pokeweed mitogen). Tetanus titer showed undetectable levels, and a quantitative assay for immunoglobulins revealed a normal level of IgE, no detectable IgA, and diminished levels of IgG (128 mg/dL; normal range, 169- 558 mg/dL) and IgM (11.5 mg/dL; normal range, 23-85 mg/dL). Flow cytometry revealed overall lymphocytosis (lym- phocyte count, 12 672/µL; normal range, 3886/µL-10 750/ µL)withsignificantlyincreasednumbersofCD3ϩ andCD4ϩ T lymphocytes (7476/µL; normal range, 1392/µL-5210/µL) expressing activation markers and increased numbers of ϩ − − B double-negative T lymphocytes (CD3 CD4 CD8 ) but very few natural killer cells (CD3−CD16ϩCD56ϩ). His T-cell receptor V␤ repertoire suggested polyclonal T cells, which made maternal transplacental T-cell engraftment unlikely. Review of peripheral blood smear findings revealed no features suggestive of hematologic malignancy. The recom- bination activating genes RAG1 and RAG2 as well as inter- leukin 7 (IL-7) receptor sequences revealed no mutations, ruling out Omenn syndrome and a severe combined immunodeficiency (SCID) with maternally engrafted cells. To convert leukocytes and lymphocytes to number of cellsϫ109/L, multiply by 0.001; platelets to number of plateletsϫ103/µL, multiply by 1.0; hemoglobin to grams per liter, multiply by 10.0; and IgA and IgM to milligrams per liter, multiply by 10.0. Sequencing of the coding region of IKBKG revealed Figure 5. Histologic features of skin biopsy specimens taken at age 4 months. A, The epidermis shows slight acanthosis and spongiosis with a superficial insertion of cytosine at nucleotide 1167 (1167- interface and perivascular lymphohistiocytic infiltrate and focal satellite cell 1168insC) in exon 10, resulting in a predicted frame- necrosis (hematoxylin-eosin, original magnification ϫ10). B, Necrotic shift at codon 390 (E390fsX394), and a short protein with- keratinocytes are visible in the epidermis and pigment-laden macrophages in the upper dermis (hematoxylin-eosin, original magnification ϫ20). out the zinc-finger domain. Molecular testing of his mother revealed heterozygosity for the same mutation. ing his pretransplantation hospitalization and condition- Both sisters were tested and found to be homozygous for ing, he developed increasing erythroderma with crusted the wild-type gene. fissures of the abdomen and lateral aspects of the legs. Skin culture yielded methicillin-resistant S aureus, and HISTOPATHOLOGIC FINDINGS he was treated with intravenous vancomycin with clear- ance. Also during the pretransplantation course, he dis- Skin biopsy was performed during a follow-up visit at age played poor weight gain, diarrhea, and vomiting with feed- 4 months (prior to confirmation of the NEMO muta- ing. Gastrointestinal evaluation and endoscopy were tion) to assess for possible graft-vs-host disease (GVHD). performed, revealing normal-appearing mucosa. Biopsy Hematoxylin-eosin staining revealed acanthosis and spon- specimens of the duodenum and sigmoid colon showed giosis of the epidermis and a superficial interface and peri- nonspecific findings without viral inclusion bodies or vascular lymphohistiocytic infiltrate with focal satellite granulomas. Of note, he had no radiologic evidence of cell necrosis (Figure 5). Numerous necrotic keratino- osteopetrosis and no lymphedema of the limbs. cytes were noted as were pigment-laden macrophages. The changes were considered to be consistent with GVHD LABORATORY FINDINGS with a superimposed eczematous process. Interestingly, the findings from his variable number of tandem re- Complete blood cell count revealed leukocytes at peats (VNTR) studies for maternal engraftment in both 22 710/µL (normal range, 5000/µL-19 500/µL) and plate- peripheral blood and skin biopsy specimens were re- lets at 597 000/µL (normal range, 150 000/µL-450 000/ ported as negative, ruling out the possibility of GVHD. µL). Hemoglobin level was 11.3 g/dL (normal range, 9.0- 14.0 g/dL). The differential analysis revealed 6% THERAPY monocytes (normal range, 3%-10%), 55.8% lymphocytes (normal range, 44%-74%), 30.4% neutrophils (nor- The patient was initially treated with intravenous im- mal range, 14%-34%), 6.4% eosinophils (normal range, munoglobulin, trimethoprim-sulfamethoxazole (Pneu- 0%-6%), and 1.4% basophils (normal range, 0%-2%). The mocystis prophylaxis), azithromycin (mycobacterial pro-

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 phylaxis), cyclosporine A, and prednisone. He tosomal dominant form of EDA-ID has been described, subsequently had peripheral blood stem cell transplan- associated with a gain-of-function mutation of I␬B␣ (an tation with donor cells from his HLA-matched sister. Chi- inhibitor of the IKK complex), thereby impairing NF-␬B merism studies revealed initial engraftment, and 1 month activation.13 This form is distinguished by a severe T- after transplantation, some initial improvement in his skin cell immunodeficiency. Immunodeficiency without EDA was noted. Subsequently, he developed vomiting and di- has also been recognized with IKBKG mutations, sug- arrhea, and repeated endoscopy with bowel biopsies re- gesting that different mutations in this gene may result vealed acute GVHD. His clinical course was also com- in distinct clinical and immunologic phenotypes.14,15 While plicated by pseudotumor cerebri, which was believed to mutations in the coding region of IKBKG are associated be medication induced and eventually resolved. with EDA-ID, stop codon mutations cause a more se- Three months after transplantation, his skin was im- vere syndrome with associated osteopetrosis and lymph- proved with only mild erythema and xerosis, and his alo- edema (OL-EDA-ID).1,7 Hence, hypomorphic muta- pecia resolved with growth of scalp, eyelash, and eye- tions in this gene cause 2 allelic conditions.1 brow hair. Subsequently, results of his VNTR studies The type of immunodeficiency seen in patients with XL- continued to reveal diminished numbers of engrafted my- EDA-ID varies. The most consistent finding is impair- eloid cells, and a second stem cell transplantation (using ment of antibody response to polysaccharides.12,16,17 Other a modified reduced-intensity conditioning protocol for reported defects include defective natural killer cell activ- nonmalignant disorders5) was recommended. ity, impairments in CD40-mediated B-cell activation and isotype class switching, impaired response to lipopolysac- charide stimulation, and decreased production of tumor COMMENT necrosis factor and IL-12.3,4,12,18-20 Patients with XL- EDA-ID are predisposed to infections with pyogenic bac- Defects in the NF-␬B pathway have been linked to sev- teria during early infancy, including Streptococcus pneu- eral human diseases, including incontinentia pigmenti, moniae, because they are unable to mount a specific antibody ED, EDA-ID, osteopetrosis and/or lymphedema with EDA response against the polysaccharide antigens.2,21 Other com- and ID (OL-EDA-ID), familial cylindromatosis, von Hip- mon pathogens include Haemophilus influenzae, S aureus, pel-Lindau disease, primary lymphedema, a variety of os- Klebsiella, Salmonella, and Pseudomonas species, as well as teoclast diseases, inflammatory bowel disease, Blau syn- mycobacteria (including Mycobacterium avium intracellu- drome, familial cold autoinflammatory syndrome, and lare), cytomegalovirus, herpes simplex virus and Pneumo- Muckle-Wells syndrome.6 Nuclear factor ␬B dimers are cystis carinii.2,3,15,22 Infections may present as sepsis, pneu- involved in the development and function of the im- monia, otitis media, sinusitis, lymphadenitis, bronchiectasis mune system, with activation affecting a diverse array of (secondary to recurrent pyogenic pulmonary infections), immunity- and inflammation-associated genes, includ- skin and soft tissue infections, and infections of the bones ing acute-phase reactants, cytokines, chemokines, growth and gastrointestinal tract.3,22 factors and receptors, adhesion molecules, and regula- The skin abnormalities in patients with XL-EDA-ID tors of apoptosis and cellular proliferation.7 Nuclear fac- (aside from the classic features associated with ED) largely tor ␬B also plays an essential role in ectoderm develop- lack mention in the existing literature. Dry, pale, wrinkled, ment through its association with (and activation through) and/or hyperpigmented skin are all noted. In 1 cohort, the EDAR/ectodysplasin A pathway.8 Nuclear factor ␬B prominence of superficial veins was present in 3 of 7 af- essential modulator, or NEMO, has been the topic of fre- fected siblings.23 A chronic, atopiclike dermatitis with quent scientific and clinical interest in recent years. Large- prominent involvement of the neck and intertriginous scale deletions of IKBKG, the gene encoding NEMO, re- areas has been described.4 sult in incontinentia pigmenti, an X-linked dominant Our patient presented with extensive and recalcitrant genodermatosis. Around 80% of new mutations are caused intertrigo and seborrheic dermatitis, with progression to by deletions in exons 4 to 10, with truncation and loss erythroderma, a cutaneous phenotype reminiscent of that of protein function.9,10 The effects of this mutation lead described in patients with other congenital immunodefi- to death for most affected male fetuses, while female fe- ciencies such as severe combined immunodeficiency and tuses survive because of the moderating effects of skewed Omenn syndrome. The possibility of cutaneous GVHD was X-inactivation, with selective elimination of cells ex- considered before his immune defect was known, and while pressing the mutation.11 the skin biopsy findings were consistent, the demonstrated Hypomorphic mutations in IKBKG, which result in lack of maternal engraftment did not support this diagno- some preservation of NEMO function, are well de- sis. Other potential explanations include a GVHD-like clini- scribed as a cause of XL-EDA-ID. The exact incidence of cal presentation from autoreactive T lymphocytes or a XL-EDA-ID caused by NEMO mutation is unknown, and GVHD-like histologic mimic resulting from keratinocyte clinical features vary in severity based on the residual func- apoptosis related to the NEMO mutation. Our patient’s fa- tion of the mutated protein. Hypohidrosis, delayed tooth cial appearance evolved over time, with a gradually increas- eruption, coarse hair, and immunodeficiency with fre- ing prominence of periorbital wrinkling, inferior periorbital quent bacterial infections may be present.12 Hair may be duskiness,flatteningofthemalarridges,athickevertedlower absent (atrichosis) or minimally present (hypotricho- lip, and frontal bossing, all consistent with the facial fea- sis), and hypohidrosis may result in heat intolerance or tures noted in HED/EDA. heat stroke. Other dental findings include hypodontia or The mutation noted in our patient (1167-1168insC) anodontia with conical incisors and gapped teeth. An au- has been described in several patients.18,21 A trend noted

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©2008 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/24/2021 in several of these patients includes decreased serum lev- technical, and material support: Mancini. Study supervi- els of IgA (noted in our patient) and elevation of IgM lev- sion: Mancini and Uzel. els. Infectious complications varied, but bacterial sepsis Financial Disclosure: Dr Mancini has served as a paid was common, and 3 of the reported patients with this mu- consultant and/or received honoraria from Astellas, Novar- tation developed disseminated mycobacterial (M avium tis, Connetics, Galderma, and Ranbaxy. intracellulare) infection. In 1 series of 7 patients with Additional Contributions: Ronald Berne, MD, initially NEMO mutation and ID, the 2 with this mutation were referred the patient. noted to have the most severe clinical courses.18 Clarifi- cation of genotype-phenotype correlations is desirable and REFERENCES will likely evolve with further observations and reports of patients with XL-EDA-ID. 1. Smahi A, Courtois G, Rabia SH, et al. The NF-kappaB signaling pathway in human The optimal therapy and prognosis for patients with diseases: from incontinentia pigmenti to ectodermal dysplasias and immune- XL-EDA-ID are unclear. Ectodermal dysplasia is man- deficiency syndromes. Hum Mol Genet. 2002;11(20):2371-2375. 2. Do¨ffinger R, Smahi A, Bessia C, et al. X-linked anhidrotic ectodermal dysplasia with aged supportively, with the goals of minimizing over- immunodeficiency is caused by impaired NF-kappaB signaling. Nat Genet. 2001; heating and preventing long-term preventable sequelae 27(3):277-285. such as impaired speech development and cosmetic dis- 3. Uzel G. The range of defects associated with nuclear factor kappaB essential modulator. figurement. Early dental intervention with use of dental Curr Opin Allergy Clin Immunol. 2005;5(6):513-518. 4. Schmid JM, Junge SA, Hossle JP, et al. Transient hemophagocytosis with deficient prostheses and/or implants is indicated, and referral to cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell the National Foundation for Ectodermal Dysplasias (www numbers, and hypomorphic NEMO mutation. Pediatrics. 2006;117(5):e1049-e1056. .nfed.org) is important for patients and families. Treat- 5. Shenoy S, Grossman WJ, DiPersio J, et al. A novel reduced-intensity stem cell transplant regimen for nonmalignant disorders. Bone Marrow Transplant. 2005;35(4): ment for the immunodeficiency may include immune- 345-352. based therapies (such as intravenous immunoglobulin) 6. Orange JS, Levy O, Geha RS. Human disease resulting from gene mutations that in- and aggressive management of infections, including pro- terfere with appropriate nuclear factor-kappaB activation. Immunol Rev. 2005;203: phylaxis against (and/or treatment for) gram-positive and 21-37. 7. Puel A, Picard C, Ku CL, Smahi A, Casanova JL. Inherited disorders of NF-kappaB- gram-negative bacteria, mycobacteria, cytomegalovi- mediated immunity in man. Curr Opin Immunol. 2004;16(1):34-41. rus, herpes simplex virus, and P carinii.14,18,19 Hemato- 8. Orange JS, Geha RS. Finding NEMO: genetic disorders of NF-[kappa]B activation. poietic stem cell transplantation offers the potential ad- J Clin Invest. 2003;112(7):983-985. 9. Steffann J, Raclin V, Smahi A, et al. A novel PCR approach for prenatal detection of vantage of immune reconstitution but bears the risks of the common NEMO rearrangement in incontinentia pigmenti. Prenat Diagn. 2004; obligatory immunosuppression, including dissemi- 24(5):384-388. nated infection (especially mycobacterial) and organ toxic 10. Pauly E, Linderkamp O, Poschl J. Incontinentia pigmenti in combination with de- effects.19,24 Following peripheral blood stem cell trans- creased IgG subclass concentrations in a female newborn. Biol Neonate. 2005;88 (3):172-174. plantation, our patient showed improvement in his skin 11. Mansour S, Woffendin H, Mitton S, et al. Incontinentia pigmenti in a surviving male is appearance and evidence of initial engraftment from his accompanied by hypohidrotic ectodermal dysplasia and recurrent infection. Am J Med sister’s donor cells, but eventually the good effect waned. Genet. 2001;99(2):172-177. 12. Nishikomori R, Akutagawa H, Maruyama K, et al. X-linked ectodermal dysplasia and im- Because of the immunologic dysregulation and infec- munodeficiency caused by reversion mosaicism of NEMO reveals a critical role for NEMO tious risks associated with NEMO mutations, a second in human T-cell development and/or survival. Blood. 2004;103(12):4565-4572. stem cell transplantation is planned. 13. Courtois G, Smahi A, Reichenbach J, et al. A hypermorphic IkappaBalpha mutation is In summary, we describe a patient with XL-EDA-ID due associated with autosomal dominant anhidrotic ectodermal dysplasia and T cell immunodeficiency. J Clin Invest. 2003;112(7):1108-1115. to a hypomorphic mutation in NEMO diagnosed at age 5 14. Niehues T, Reichenbach J, Neubert J, et al. Nuclear factor kappaB essential modulator- months. Subsequent to his diagnosis, the patient’s mother deficient child with immunodeficiency yet without anhidrotic ectodermal dysplasia. recalled her prior diagnosis of incontinentia pigmenti (with J Allergy Clin Immunol. 2004;114(6):1456-1462. very mild expressivity), and molecular testing revealed her 15. Orange JS, Levy O, Brodeur SR, et al. Human nuclear factor kappa B essential modulator mutation can result in immunodeficiency without ectodermal dysplasia. J Al- heterozygosity for the same mutation. The NEMO muta- lergy Clin Immunol. 2004;114(3):650-656. tion should be considered in male infants presenting with 16. Ku CL, Dupuis-Girod S, Dittrich AM, et al. NEMO mutations in 2 unrelated boys with extensive or recalcitrant seborrheic or atopic dermatitis- severe infections and conical teeth. Pediatrics. 2005;115(5):e615-e619. 17. Schweizer P, Kalhoff H, Horneff G, Wahn V, Diekmann L. Polysaccharide specific hu- like skin eruptions and intertrigo, especially when facial moral immunodeficiency in ectodermal dysplasia: case report of a boy with two af- features of ED or maternal history of incontinentia pig- fected brothers. Klin Padiatr. 1999;211(6):459-461. menti are present. 18. Orange JS, Jain A, Ballas ZK, Schneider LC, Geha RS, Bonilla FA. The presentation and natural history of immunodeficiency caused by nuclear factor kappaB essential modulator mutation. J Allergy Clin Immunol. 2004;113(4):725-733. Accepted for Publication: April 6, 2007. 19. Orange JS, Brodeur SR, Jain A, et al. Deficient natural killer cell cytotoxicity in pa- Correspondence: Anthony J. Mancini, MD, Division of tients with IKK-gamma/NEMO mutations. J Clin Invest. 2002;109(11):1501-1509. Dermatology, Children’s Memorial Hospital, 2300 Chil- 20. Jain A, Ma CA, Liu S, Brown M, Cohen J, Strober W. Specific missense mutations in NEMO result in hyper-IgM syndrome with hypohydrotic ectodermal dysplasia. Nat dren’s Plaza No. 107, Chicago, IL 60614 (amancini Immunol. 2001;2(3):223-228. @northwestern.edu). 21. Zonana J, Elder ME, Schneider LC, et al. A novel X-linked disorder of immune defi- Author Contributions: Dr Mancini had full access to all ciency and hypohidrotic ectodermal dysplasia is allelic to incontinentia pigmenti and of the data in the study and takes responsibility for the due to mutations in IKK-gamma (NEMO). Am J Hum Genet. 2000;67(6):1555-1562. 22. Carrol ED, Gennery AR, Flood TJ, Spickett GP, Abinun M. Anhidrotic ectodermal dyspla- integrity of the data and the accuracy of the data analy- sia and immunodeficiency: the role of NEMO. Arch Dis Child. 2003;88(4):340-341. sis. Study concept and design: Mancini. Acquisition of data: 23. Ørstavik KH, Kristiansen M, Knudsen GP, et al. Novel splicing mutation in the NEMO Mancini and Lawley. Analysis and interpretation of data: (IKK-gamma) gene with severe immunodeficiency and heterogeneity of X-chromosome Mancini and Uzel. Drafting of the manuscript: Mancini. inactivation. Am J Med Genet A. 2006;140(1):31-39. 24. Dupuis-Girod S, Corradini N, Hadj-Rabia S, et al. Osteopetrosis, lymphedema, anhi- Critical revision of the manuscript for important intellec- drotic ectodermal dysplasia, and immunodeficiency in a boy and incontinentia pig- tual content: Mancini, Lawley, and Uzel. Administrative, menti in his mother. Pediatrics. 2002;109(6):e97.

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