Inherited Immunodeficiency: Brigitte Bader-Meunier, MD,a,b Frédéric Rieux-Laucat, PhD,b Fabien Touzot, MD, PhD,c Marie-Louise Frémond, MD,a, b AIsabelle New André-Schmutz, Association PhD,b Sylvie Fraitag, MD,d Christine With Bodemer, MD, PhDEarly-b,e,f Onset Childhood Panniculitis abstract
We report on 4 children who presented with asepticTRNT1 panniculitisNF- κb2 associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the and genes aDépartements d'Immunologie, Hématologie, et LCK Rhumatologie Pédiatrique, dd'Anatomie Pathologique, (no mutation was found in the third patient), and 1 had a T-cell deficiency and ede Dermatologie Pédiatrique, Hôpital Necker-Enfants (mutation in the gene). Panniculitis occurred before the age of 2 years Malades, Assistance Publique-Hôpitaux de Paris, Paris, b f in the 4 patients and preceded the onset of recurrent infections because France; Institut Imagine, INSERM U1163; Université Paris Descartes, Sorbonne Cité, Paris, France; and cDépartement of immunodeficiency in 2. It presented either as nodules, which resolved d’Immunologie et Rhumatologie Pédiatrique, Centre spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions Hospitalier Universitaire Sainte-Justine, Université de Montréal, Quebec, Canada (1 patient) associated with unexplained fever and elevated acute phase Drs Bodemer, Fraitag, and Bader-Meunier reactants, without evidence of infection or high-titer autoantibodies. Febrile conceptualized and designed the study, supervised nodules relapsed in 2 patients, and recurrent attacks of unexplained fever the data collection, and drafted the initial (without relapse of panniculitis) occurred in the third. Skin biopsy revealed manuscript; Drs Touzot and Frémond conducted predominantly lympho-histiocytic or septal neutrophilic panniculitis in the initial analyses and reviewed and revised the manuscript; Dr Fraitag was involved in the 1 and 3 patients, respectively. Panniculitis was associated with dermal pathologic analysis; Drs André-Schmutz and involvement in the 4 patients. Patients with B-cell deficiency received Rieux-Laucat were involved in the genetic studies; monthly intravenous immunoglobulin replacement. Two patients who and all authors approved the final manuscript as submitted. underwent bone marrow transplant died of bone marrow transplant- DOI: https://doi.org/10.1542/peds.2017-0213 related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In Accepted for publication Aug 28, 2017 these cases, the need for careful immunologic evaluation of patients who Address correspondence to Brigitte Bader-Meunier, present with unexplained panniculitis, especially early-onset panniculitis MD, Hémato-Immunologie Pédiatrique, Hôpital Necker APHP, 149 rue de Sèvres, 75015 Paris, before the age of 2 years, is highlighted. France. E-mail: [email protected] PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275). Pediatric panniculitis occurs in a group disorders. Some types of panniculitis Copyright © 2018 by the American Academy of Pediatrics of rare disorders characterized by 1,2 are specific to children, including inflammation of the subcutaneous fat. those only seen in neonates such FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships Histopathological analysis is required as subcutaneous fat necrosis of relevant to this article to disclose. to confirm the diagnosis because the newborn, or occur in a specific FUNDING: No external funding. the lesions may present differently, context such as postcorticosteroid1, 2 often consisting of erythematous panniculitis and cold panniculitis. POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of nodules or large infiltrated plaques. Other recognized etiologies described interest to disclose. Panniculitis cases are classified as in adults may be observed in children mostly lobular, mostly septal, or but are less frequent or rare in this – mixed, depending on the distribution population, including: infectious, To cite: Bader-Meunier B, Rieux-Laucat F, Touzot F, – et al. Inherited Immunodeficiency: A New Association of the dominant subcutaneous3 connective tissue disease related, With Early-Onset Childhood Panniculitis. Pediatrics. inflammatory infiltrates. Panniculitis subcutaneous lymphoma like, 2018;141(s5):e20170213 can be a primary disease but is metabolic (alpha1-antitrypsin most often a secondary process deficiency, pancreatitis), and drug- related to many different underlying or trauma-induced panniculitis. In Downloaded from www.aappublications.org/news by guest on September 23, 2021 CASE REPORT PEDIATRICS Volume 141, number s5, April 2018:e20170213 Patient 1 + many pediatric patients, no classic, low levels of CD27 B cells and specific cause can be identified. Such switch memory B cells. IVIg was A 2-month-old girl was referred cases are designated as idiopathic started (400 mg/kg per day). He because of fever and an erythematous panniculitis. Here, we describe the developed further chronic fever, nodule on 1 toe lasting 2 weeks (Fig 1). cases of 4 patients who presented diarrhea, arthritis, failure to thrive, C-reactive protein (CRP) was with early-onset panniculitis and multiple ulcerative plaques (Fig 1) 42 mg/L. A skin biopsy revealed associated with inherited B- or T-cell that did not undergo biopsy. At predominantly septal lympho- immunodeficiency. We propose that onset, he responded to treatment histiocytic panniculitis (Fig 1). The inherited immunodeficiency is a new with high doses of prednisone (2 symptoms resolved spontaneously β cause of panniculitis, underlying mg/kg per day) and treatment with within 4 weeks. During the course of – the need for careful immunologic interleukin-1 inhibitors (anakinra, the disease, the patient presented with evaluation for cases of unexplained canakinumab), anti tumor necrosis relapsing noninfectious panniculitis pediatric panniculitis, particularly factor inhibitors (infliximab), and coinciding with febrile attacks with onset before the age of 2 years. cyclophosphamide were not steroid- without any other manifestations sparing. He underwent a bone marrow CASE REPORTS and elevated acute-phase reactants transplant but died of treatment- without any other manifestations. related complications within the first Two to 4 episodes per year occurred NF-κB2 days of the procedure. WES identified We identified 4 patients and resolved spontaneously within 1 who displayed inherited a mutation in the gene. to 2 weeks. Other findings included Patient 3 immunodeficiency associated with recurrent otitis and ataxia, and we panniculitis among 18 cases of performed immunologic tests that pediatric idiopathic panniculitis revealed hypogammaglobulinemia+ (onset before the age of 16 years) and CD27 memory B-cell deficiency A 12-month-old girl was referred recorded in the database of the (Table 1). Replacement intravenous because of recurrent attacks of Department of Dermatological immunoglobulin (IVIg) therapy was fever from the age of 2 months, Pathology of the Necker-Enfants started (400 mg/kg per day). At 8 with or without documented Malades hospital from January 2004 years of age, she was normal-sized infections, and failure to thrive. to December 2014. Specific infectious for her age, and no more infections CRP levels were elevated during causes for the panniculitis lesions – had occurred. Relapsing panniculitis each episode. Infections consisted were excluded by specific stains and a mild ataxia persisted. WES of recurrent septicemias. Aseptic (periodic acid Schiff, Grocott, Ziehl, was performed but did not allow febrile manifestations were vulvitis, and Gram) in cases of neutrophilic identification of the underlying parotitis, adenitis, and the occurrence and/or macrophagic infiltrates, Patientgenetic defect2 . of 1 noninfectious erythematous and Epstein-Barr encoding region nodule of the limb (at 10 months). staining was used for those A skin biopsy of the nodule revealed composed of lymphocytes. Blood A 20-month-old boy was referred lobular and septal neutrophilic cultures and serological tests because of undocumented lower panniculitis. Other features included for Epstein-Barr virus, human Salmonella respiratory tract infections, chronic microcytic anemia (from the herpesvirus 6, and cytomegalovirus infections, and failure to age of 2 months), low levels of serum were performed if an infection was thrive. From the age of 10 months, IgG, IgA, and IgM, and low levels of suspected. Specific gene sequencing + he had a history of noninfectious, CD27 B cells and memory B cells. or whole exome sequencing (WES) relapsing episodes of fever associated IVIg was started (400 mg/kg per was performed on DNA of the 4 ’ with multiple erythematous nodules day). At 6 years of age, her height patients after obtaining informed (hands, feet, bottom) (Fig 1) and was normal, and no infections had consent from the patients parents. undocumented diarrhea. CRP levels occurred. She continued to have 3 The 4 patients were referred to the rose substantially during these to 4 febrile attacks (lasting for 1 to Department of Pediatric Immunology attacks (Table 1). A skin biopsy of 1 2 days) each month, associated with and Rheumatology of the Necker- nodule revealed septal and lobular elevated CRP levels. There were no Enfants Malades hospital at the neutrophilic panniculitis (Fig 1). further episodes of panniculitis or onset of disease. All were born to Immunologic investigation revealed a other inflammatory manifestations healthy, nonconsanguineous parents. deficiency of serum immunoglobulin associated with fever, and the Their demographic, biochemical, G (IgG), immunoglobulin A (IgA), anemia resolvedTRNT1 spontaneously. WES immunologic, pathologic, and genetic and immunoglobulin M (IgM); poor identified a compound heterozygous features are shown in Table 1. vaccine responses; and abnormally mutation in the gene. Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number s5, April 2018 S497 TABLE 1 Demographic, Clinical, Biological, and Pathologic Features in 4 Patients With Panniculitis Associated With Immunodeficiency Patient 1 Patient 2 Patient 3 Patient 4 Sex, ethnicity Female, white Male, white Female, white Female, white Age at onset of panniculitis, 2 (36) 10 (20) 10 (2) 22 (15) mo (No. of infections) Clinical characteristics of Relapsing erythematous Relapsing erythematous Unique episode of 1 aseptic Chronic multiple ulcerating panniculitis nodules coinciding with nodules coinciding with erythematous nodule of skin nodules (PIP joints) febrile attacks (toes, febrile attacks (hands, feet, the limb coinciding with associated with fever abdomen, limb) bottom) fever CRP at onset of panniculitis, 42 60 90 77 mg/L (N: <6 mg/L) Serum immunoglobulin (37) (32) (4) (23) (age, mo) IgG, g/L 3.5 (5.4–10.2) 3.26 (5.5–10.2) 1.14 (2.9–5.5) 8.7 (4.8–8.9) IgA, g/L 0.16 (0.4–1.4) <0.06 (0.4–1.4) <0.04 (0.1–0.4) 1.21 (0.3–1.2) IgM, g/L 0.16 (0.5–1.5) 0.18 (0.5–1.5) 0.07 (0.3–0.8) 3.06 (0.5–1.5) Lymphocytes/μL (age, mo) 2200 (90) 4200 (90) 5600 (15) 1300 (3600–8900) (29) T cells/μL CD3+ 1738 (1200–2600) 3822 (1200–2600) 2800 (1400–3700) 520 (2100–6200) CD4+ 1100 (650–1500) 3444 (650–1500) 1792 (700–2200) 156 (1300–3400) CD8+ 418 (370–1100) 380 (370–1100) 640 (490–1300) 338 (620–2000) B cells/μL CD19+ 286 (273–860) 250 (350–1100) 0 (390–1400) 559 (720–2600) CD27+/CD19+ (memory 11 (23–185) 42 (200–420) 0 (330–500) ND B cells) Other immunologic tests Decrease of specific antibody Decrease of specific antibody Decrease of specific antibody Low levels of CD4 and CD8 responses to vaccines responses to vaccines responses to vaccines expression at the cell surface, lack of response to T-cell receptor activation ANA — — — 1 out of 600 without specificity Pathologic findings (age at Lobular and septal Lobular and septal Lobular and septal Lobular and septal neutrophilic skin biopsy, mo) lymphohistiocytic neutrophilic panniculitis; neutrophilic panniculitis; panniculitis; (24); N+++, panniculitis (2); CD3+ T (80); N+++, CD3+ T cells+ (10); N+++, CD3+ T cells++ M++, CD3+ T cells, fat cells++ (CD8+), CD20 ±, (CD8+), M+, CD20−, (CD8+), CD20−, M+, dermis necrosis +, dermis M++, N±, Eo±, dermis fat necrosis, dermis involvement ± involvement +++ involvement + involvement + Genetic analysis No mutation Mutation in NF-κB2 Compound heterozygous Homozygous mutations in LCK (c.2593/2594 del AG) mutations in TRNT1 (c.1022T > C) (c.1213G > A/c.1057–7C > G)
For immunoglobulin levels and T and B cells, normal values according to age are given in parentheses. Each cellular infiltrate was quantified as absent −( ), weak (±), mild (+), moderate (++), or high (+++). ANA, antinuclear antibodies; Eo, eosinophils; PIP, proximal interphalangeal; M, macrophages; N, neutrophils; ND, not done; —, not applicable.
Patient 4
thrive. A skin biopsy of a lesion panniculitis. Classic causes of revealed lobular neutrophilic panniculitis in children include α A 22-month-old girl was referred panniculitis without granuloma (Fig 1). infection, inflammatory rheumatic 1 because of daily spiking fever, She had elevated CRP levels, and + disorders, -antitrypsin deficiency, accompanied by multiple ulcerative immunologic studiesLCK revealed CD4 T-cell cytotoxic lymphoma, trauma- skin nodules and inflammation T-cell lymphopenia and low CD4 and and cold-induced panniculitis, of the interphalangeal joints (Fig 1). CD8 expression. A gene defect subcutaneous fat necrosis of the No infection was found, and was identified. Given the severe T-cell newborn, corticosteroid use, and these manifestations persisted deficiency, the patient underwent erythema nodosum. Inherited despite intravenous antibiotic bone marrow transplant but died immunodeficiency has not previously therapy (ceftriaxone, gentamycin, shortly after the procedure from been considered as1,2 being associated vancomycin, clarithromycin, treatment-relatedDISCUSSION complications. with panniculitis. Indeed, the ciprofloxacin, rifampicin, isoniazid). association of aseptic panniculitisGATA2 From the age of 15 months, she had CECR1with inherited immunodeficiencyGATA2 has undocumented protracted diarrhea been reported only for and and recurrent undocumented We report on 4 patients with an mutations. mutations upper and lower respiratory tract inherited B- or T-cell deficiency result in a broad phenotype that infections, resulting in failure to that was associated with aseptic encompasses immunodeficiency, Downloaded from www.aappublications.org/news by guest on September 23, 2021 S498 BADER-MEUNIER et al FIGURE 1 Clinical presentation and biopsy specimens from skin lesions stained with hematoxylin eosin saffron of panniculitis. A1, Erythematous plaque of the toe (patient 1). A2, Erythematous nodules and ulcerative plaque of the leg (patient 2). A3, Ulcerating skin nodules of the fingers (patient 4). B1, Lobular lymphocytic panniculitis with a slight lymphocytic infiltrate localized around the adipocytes (original magnification× 25) (patient 1). B2, Inflammation of the deep dermis and the subcutis, located in the septa and the lobules and composed of mixed cells with a predominance of neutrophils (original magnification ×200) (patient 2). B3, Lobular panniculitis with dense neutrophilic infiltrate replacing part of the subcutis (original magnification× 200) (patient 4).
myelodysplastic syndrome, deficiency and as chronic ulcerative (1) chronic atypical neutrophilic CECR1pulmonary disease, and vascular3 plaques associated with fever in the dermatosis with lipodystrophy and/or lymphatic dysfunction. patient with a T-cell deficiency. In and elevated temperature, mutations result in adenosine the fourth patient, a single episode characterized by early-onset, deaminase 2 deficiency associated of febrile aseptic neutrophilic recurrent fever, skin lesions, with a spectrum of vascular and panniculitis occurred in addition lipodystrophy, and multisystemic inflammatory phenotypes, ranging to recurrent noninfectious febrile inflammatory manifestations, from early-onset recurrent stroke attacks associated with systemic resulting from autosomal recessive5 to systemic vasculopathy or inflammation. These episodes of mutations in proteasome genes ; vasculitis, and is associated with panniculitis that are associated with (2) familial Mediterranean fever, hypogammaglobulinemia4 in some an unexplained fever and systemic which classically consists of patients. inflammation, without evidence short, recurrent febrile episodes, of high-titer autoantibodies or serositis, and arthritis resulting
Panniculitis occurred before 2 autoantigen-specific T cells, are from mutations in marenostrin-6 years of age in the 4 patients and suggestive of autoinflammatory encoding fever gene ; (3) otulipenia, preceded the manifestation of manifestations. Until now, early- which presents as neonatal-onset immunodeficiency (infections) onset panniculitis associated with fever, neutrophilic dermatitisOTULIN and/ in 2. At the onset of the disease, systemic inflammation had been or panniculitis, and failure to thrive panniculitis presented as relapsing reported only in 4 autoinflammatory because of mutations in 7 , nodules that coincided with febrile diseases that did not display an encoding a deubiquitinase ; and (4) attacks in 2 patients who had a B-cell immunodeficiency phenotype: granulomatous panniculitis in infants Downloaded from www.aappublications.org/news by guest on September 23, 2021 PEDIATRICS Volume 141, number s5, April 2018 S499 NF-κB2 of hematopoiesis, lymphatics, and immunity. Blood. 2014;123(6):809–821 who present with infantile-onset the gene cause the recently 4. Zhou Q, Yang D, Ombrello AK, et al. of widespread lobular panniculitis, defined clinical syndrome, common Early-onset stroke and vasculopathy panuveitis, arthropathy,8 and severe variable immunodeficiency, with11 associated with mutations in ADA2. systemic illness. central adrenal insufficiency. Thus, N Engl J Med. 2014;370(10):911–920 Skin biopsy revealed predominantly the occurrence of autoinflammatoryTRNT1 5. Liu Y, Ramot Y, Torrelo A, et lympho-histiocytic or septal panniculitisNF-κB2 expands the phenotypes al. Mutations in proteasome neutrophilic panniculitis in 1 associated with mutations in subunit β type 8 cause chronic and 3 patients, respectively. and . atypical neutrophilic dermatosis A histologic classification scheme CONCLUSIONS with lipodystrophy and elevated has been proposed, dividing the temperature with evidence of genetic and phenotypic heterogeneity. Arthritis cases into mostly lobular, septal, or Rheum. 2012;64(3):895–907 mixed panniculitis, depending on In these cases, we demonstrate the distribution of the dominant that early-onset childhood 6. Leiva-Salinas M, Betlloch I, Arribas MP, subcutaneous inflammatory infiltrate, panniculitis may reveal inherited Francés L, Pascual JC. Neutrophilic 2 lobular panniculitis as an expression with or without vasculitis. This immunodeficiency, and we highlight the need for careful immunologic of a widened spectrum of familial classification is helpful to guide the Mediterranean fever. JAMA Dermatol. etiological investigation in most of evaluation of patients who present “ ” 2014;150(2):213–214 the cases. In our series, none of the 4 with unexplained panniculitis, even 7. Zhou Q, Yu X, Demirkaya E, et al. patients displayed a pure panniculitis before clinical manifestations of Biallelic hypomorphic mutations in a without dermal involvement, and we immunodeficiency have emerged. ACKNOWLEDGMENT linear deubiquitinase define otulipenia, could not identify a clear correlation an early-onset autoinflammatory between the nature of inflammatory disease. Proc Natl Acad Sci USA. infiltrate and the diagnosis of 2016;113(36):10127–10132 We thank Pr Capucine Picard for primary immunodeficiency because 8. Wouters CH, Martin TM, Stichweh D, studying immunophenotyping of the the panniculitis was either mostly et al. Infantile onset panniculitis with patients. neutrophilic or mostly lymphocytic in uveitis and systemic granulomatosis: a the 3 patients who presented with a ABBREVIATIONS new clinicopathologic entity. J Pediatr. B-cell deficiency. 2007;151(6):707–709 Mutations were identified in 3 9. Hauck F, Randriamampita C, Martin E, CRP: C-reactive protein patients, whereas we failed to et al. Primary T-cell immunodeficiency IgA: immunoglobulin A identify any mutation in the fourth with immunodysregulation caused LCK TRNT1 IgG: immunoglobulin G patient using WES. 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Downloaded from www.aappublications.org/news by guest on September 23, 2021 Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis Brigitte Bader-Meunier, Frédéric Rieux-Laucat, Fabien Touzot, Marie-Louise Frémond, Isabelle André-Schmutz, Sylvie Fraitag and Christine Bodemer Pediatrics 2018;141;S496 DOI: 10.1542/peds.2017-0213
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