NEMO‐NDAS: Case Report and Review of the Literature

ABSTRACT

NEMO‐deleted exon 5 autoinflammatory syndrome (NEMO‐NDAS) is the result of a gain‐of‐function IKBKG pathogenic variant leading to dysregulated NF‐κB signaling and systemic inflammation. We present a case of NEMO‐NDAS in a 2‐year‐old female presenting with recurrent fevers, subcutaneous nodules, lymphadenopathy, and splenomegaly. This article highlights the symptoms that aid in diagnosis and how to differentiate it from other autoinflammatory diseases and reviews therapies for NEMO‐NDAS.

1. Introduction

NEMO‐deleted exon 5 autoinflammatory syndrome (NEMO‐NDAS) is a recently described X‐linked autoinflammatory syndrome caused by a gain‐of‐function pathogenic variant in the NEMO (IKBKG) gene, resulting in mRNA lacking exon 5 [1]. This pathogenic variant leads to dysregulated NF‐κB signaling, resulting in systemic manifestations such as fever, lymphadenopathy, hepatosplenomegaly, as well as cutaneous findings like ectodermal dysplasia and panniculitis [1]. It was first described in 2020 and represents one of four Mendelian phenotypes associated with pathogenic variants of the NEMO gene [2].

Unlike loss‐of‐function pathogenic variants leading to immunodeficiency, this gain‐of‐function pathogenic variant in NEMO‐NDAS drives systemic autoinflammation, making it a unique addition to the clinical spectrum of NEMO‐associated disorders [3, 4]. Increased awareness among pediatric dermatologists will help improve recognition and diagnosis. This article outlines the characteristic cutaneous and systemic findings of NEMO‐NDAS in our patient and from the literature.

2. Case Report

A 2‐year‐old girl, who immigrated from sub‐Saharan Africa 8 months prior, was admitted for evaluation of recurrent fevers and generalized subcutaneous nodules noted since 2 months of age. Her fevers occurred every 3–5 weeks, with temperatures up to 39.5°C for the first 3 days, before slowly returning to normal over the subsequent 2–4 days. Past medical history included significant developmental delay, failure to thrive, and one episode of generalized tonic–clonic seizures at 23 months of age. Family history revealed that her parents were third‐degree relatives. She had two healthy older siblings.

On physical examination she had generalized lymphadenopathy and numerous firm subcutaneous nodules over the chest, back, arms, and legs (Figures 1 and 2). She also had conical teeth and localized lipoatrophy of the limbs. Prior diagnostic studies revealed mild pancytopenia, increased transaminases, and markers of systemic inflammation, including an elevated C‐reactive protein (CRP) (59 mg/L; normal < 10.0 mg/L) and raised erythrocyte sedimentation rate (ESR) (34 mm/h; normal 0–15 mm/h). An extensive infectious work‐up was non‐contributory.

FIGURE 1.

Subcutaneous, firm, skin‐colored nodules on the upper and mid back.

FIGURE 2.

(A) Skin‐colored, firm subcutaneous nodules over the right forearm. (B) Right index finger, without joint swelling or overlying skin inflammation.

Abdominal ultrasound revealed splenomegaly. An incisional biopsy of a subcutaneous nodule revealed a mostly lobar panniculitis without vasculitis. The adipose lobules were infiltrated by a mixture of neutrophils, lymphocytes, and numerous histiocytes phagocytizing adipocytic fat (Figure 3).

FIGURE 3.

(A) Biopsy of a skin nodule demonstrating a mostly lobar panniculitis (asterisks), involving the subcutaneous adipose tissue (H&E stain, 40×). (B) On higher magnification, the lobar inflammatory infiltrate is composed of sparse neutrophils, lymphocytes and histiocytes; foamy histiocytes are the result of adipocytic fat phagocytosis (H&E, 100×).

As our patient's clinical features suggested an interferonopathy, it prompted targeted testing for NEMO‐NDAS which revealed a heterozygous pathogenic variant in the IKBKG gene (c.519‐19_519‐2del p? in intron 4) consistent with NEMO‐NDAS.

3. Discussion

Under normal conditions, NF‐κB activation is tightly regulated by NEMO and the IKK complex. However, in NEMO‐NDAS, uncontrolled NF‐κB signaling drives excessive cytokine production, leading to recurrent fevers, hepatosplenomegaly, lymphadenopathy, and persistently elevated inflammatory markers. Although NEMO‐NDAS is sometimes grouped with interferon‐mediated autoinflammatory diseases, it is not a classic type I interferonopathy [5]. Investigators have shown that many patients have markedly elevated IFN‐γ, and the inflammatory signature is not dominated by type I IFN, which the term “interferonopathy” usually implies. In NEMO‐NDAS, activated TCRγδ⁺ T cells appear to be a major cellular source of IFN‐γ, suggesting a type II IFN–skewed inflammatory environment, rather than a canonical type I IFN disorder.

Genetic confirmation of NEMO‐NDAS can be challenging because the IKBKG pseudogene (IKBKGP1) is highly homologous to the functional gene [5]. Standard next‐generation sequencing often cannot reliably distinguish variants in IKBKG from those in IKBKGP1, and pathogenic splice‐site variants may therefore be missed, incorrectly mapped, or misinterpreted. Recent work has shown that pathogenic variants may even originate in the pseudogene and be introduced into IKBKG through non‐allelic homologous recombination, further complicating diagnosis. Because of this, long‐range PCR targeting of both IKBKG and IKBKGP1 or long‐read sequencing of this locus is recommended when clinical suspicion is high, but routine NGS testing is negative or ambiguous. Other techniques, such as optical genome mapping, have also demonstrated an advantage in the identification of structural pathogenic variants and can be considered for genetic confirmation [6].

Known skin findings in patients with NEMO‐NDAS include neutrophilic and histiocyte‐rich lobular panniculitis, often presenting as erythematous nodules or areas of lipoatrophy and hyperpigmentation [7]. Additionally, dysregulated ubiquitination pathways contribute to chronic immune activation, further driving inflammation and tissue damage. The immune imbalance not only triggers autoinflammatory symptoms but also predisposes affected individuals to autoimmune‐like features and increased susceptibility to infections, making NEMO‐NDAS a severe disorder with systemic and cutaneous inflammatory findings [8].

Our literature review identified 8 affected children and demonstrated that hepatosplenomegaly and systemic inflammation were among the most common systemic features, while cutaneous manifestations often included panniculitis and ectodermal dysplasia, which was described only as conical teeth (Table 1). While the systemic symptoms, such as generalized lymphadenopathy, hepatosplenomegaly, joint contractures, and autoimmune hemolytic anemia, show significant overlap with other conditions, the cutaneous findings in NEMO‐NDAS are valuable for diagnosis and can help differentiate this from OTULIN‐related autoinflammatory syndrome (ORAS) and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome [9, 10].

TABLE 1.

Summary of features of NEMO‐NDAS cases in the literature.

References	Age of symptom onset (weeks)	Sex	Molecular IKBKG variant	Cutaneous findings	Systemic findings	Treatment and response
Carneiro, 2017	12	M	—	Erythema nodosum	Systemic inflammation, hepatosplenomegaly, hypogammaglobulinemia, fevers, anemia, thrombocytopenia, pneumonia, hemorrhage	Cyclosporine (not reported), combined oral corticosteroid therapy and intravenous immunoglobulin (IVIG) (not reported)
DeJesus, 2020 and Lee, 2022	6	M	c.597G>A (p.Val199=)	Panniculitis, subcutaneous nodules, conical teeth	Systemic inflammation, hepatosplenomegaly, lymphopenia, fevers, granulomatous hepatitis, leukocytosis, lymphadenopathy, osteomyelitis, CNS bleed, white matter abnormality, optic neuritis, granulomatous uveitis, panuveitis, chorioretinitis	Adalimumab (partial response), prednisone (partial response)
DeJesus, 2020 and Lee, 2022	4	M	c.671+5G>A (p.?)	Panniculitis, lipodystrophy, rash NYD, subcutaneous nodules	Systemic inflammation, hepatosplenomegaly, lymphopenia, hypergammaglobulinemia, fevers, dsDNA virus, CNS bleed, subdural hemorrhage, white matter abnormality, anterior uveitis, joint swelling and stiffness	Combined MTX, MMF, tocilizumab, anakinra, etanercept, and infliximab (partial response), adalimumab (partial response), chloroquine (not reported), infliximab (partial response)
DeJesus, 2020 and Lee, 2022	12	M	c.671+2T>G (p.?)	Panniculitis, lipodystrophy, rash NYD, subcutaneous nodules	Systemic inflammation, hepatosplenomegaly, lymphopenia, hypogammaglobulinemia, fevers, anemia, thrombocytopenia, lymphadenopathy, pneumonia, CNS bleed, subdural hemorrhage, optic nerve edema	Combined cyclosporine and tocilizumab (partial response), adalimumab (partial response), combined cyclosporine and high dose steroids (worsened), Prednisone (partial response), oral steroid pulse therapy (not reported)
DeJesus, 2020 and Lee, 2022	—	F	c.519‐2A>G (p.?)	Panniculitis, Lipodystrophy	Lymphopenia, Anemia, Myositis, Basal ganglia calcification	MMF (partial response), Tofacitinib (No response)
Hegazy, 2022	2	M	c.671+3G>C (p.?)	Panniculitis, Rash NYD	Systemic inflammation, Splenomegaly, Fevers, Leukocytosis, Hypercalcemia, Hypertriglyceridemia, Periorbital edema	—
Eigemann, 2024	48	F	c.613C>T (p.Gln205Ter)	Incontinentia pigmenti, Conical teeth	Fevers, Neutropenia	Etanercept (Not reported), Adlimumab (Partial response), Tofacitinib (No response)
Our case	8	F	c.519‐19_519‐2del (p.?)	Panniculitis, Lipoatrophy, Subcutaneous nodules, Conical teeth	Systemic inflammation, Splenomegaly, Fevers, Pancytopenia, Lymphadenopathy	—

Biallelic loss‐of‐function pathogenic variants in OTULIN, a linear ubiquitin‐specific deubiquitinating enzyme, leads to ORAS, which is characterized by neonatal‐onset fevers, neutrophilic dermatitis, panniculitis, arthritis, lymphadenopathy, hepatosplenomegaly, gastrointestinal inflammation, and failure to thrive [11]. Patients with ORAS have excessive linear ubiquitination of target proteins, such as NEMO, which leads to increased signaling of the NF‐κB pathway, similar to NEMO‐NDAS. While the presenting features are very similar and overlap, there are some distinguishing features. Patients with ORAS typically have earlier‐onset disease and lack the ectodermal dysplasia and central nervous system (CNS) disease seen in patients with NEMO‐NDAS [12, 13]. However, given the overlapping clinical features of ORAS and NEMO‐NDAS, genetic testing may be needed to differentiate one from the other.

CANDLE syndrome also presents with similar features, including recurrent fevers, purpuric annular plaques, acral pernio‐like lesions, periorbital violaceous edema, lipodystrophy, arthralgias, anemia, and elevated inflammatory markers. Patients with CANDLE syndrome exhibit a distinct rash, often beginning with acral pernio‐like lesions over the nose, ears, fingers and toes and annular erythematous and purpuric plaques in infancy or childhood with later development of solitary subcutaneous nodules and violaceous periorbital swelling [14, 15]. In contrast, patients with NEMO‐NDAS have transient erythematous subcutaneous nodules that spare the face that lead to lipoatrophy and hyperpigmentation [8]. Importantly, ectodermal dysplasia is not seen in patients with CANDLE syndrome and may serve as a differentiating clinical feature [16]. Histopathologically, patients with NEMO‐NDAS have a granulomatous panniculitis with histiocytic changes, whereas patients with CANDLE syndrome tend to have a lobular panniculitis with mixed inflammatory infiltrates, including neutrophils, without histiocytic proliferation or granulomas [8].

Treatment strategies for NEMO‐NDAS remain under investigation. Treatment with TNF‐α inhibitors, such as adalimumab, infliximab, and etanercept, reports partial responses in some patients, whereas Janus kinase (JAK) inhibitors, such as tofacitinib, report no response. However, the long‐term safety and efficacy of these therapies remain unclear, necessitating further research into NF‐κB and interferon blockade as potential treatment avenues [17].

NEMO‐NDAS is a rare condition, which inherently limits the available literature for comparison. There is a lack of consensus on the optimal treatment strategies for NEMO‐NDAS, and current management is largely empirical and based on clinical response. The role of targeted therapies, such as NF‐κB inhibitors or type I interferon blockers, remains to be fully explored. Additionally, heterogeneity in genetic testing protocols across published case reports complicates NEMO‐NDAS case classification. Increased clinical awareness and broader access to standardized genetic testing are likely to improve recognition and characterization of NEMO‐NDAS in patients.

4. Conclusion

This report contributes to the growing understanding of NEMO‐NDAS, a rare autoinflammatory condition characterized by systemic inflammation and cutaneous manifestations such as panniculitis and subcutaneous nodules. Our case report and literature review highlight previously reported features, such as fever, splenomegaly, and lipodystrophy, while emphasizing the significance of location and progression of subcutaneous nodules, histopathological features, and presence of ectodermal dysplasia as helpful diagnostic clues to differentiate this from CANDLE syndrome and OTULIN deficiency. Further research is needed to establish clear diagnostic criteria, evaluate treatment efficacy, and the role of targeted therapies. Given its clinical overlap with other conditions, early recognition of skin findings by pediatric dermatologists can aid timely diagnosis of NEMO‐NDAS.

Author Contributions

The authors made significant contributions to study conception and design, data collection, analysis and interpretation of results, and draft manuscript preparation. All authors read and approved the final version.

Conflicts of Interest

The authors declare no conflicts of interest.

Supporting information

Data S1: pde70199‐sup‐0001‐Supinfo.docx.

Data Availability Statement

The data that supports the findings of this study are available in the Supporting Information of this article.