Association between Incontinentia Pigmenti and Systemic Lupus Erythematosus

Author: Sabatina Liuni
Date: 20/06/2014


Sabatina Liuni and Elisa Ingargiola


This is, to the best of the authors’ knowledge, the first report of an association of Systemic Lupus Erythematosus (SLE) and Incontinentia Pigmenti (IP; also called NEMO syndrome).

A 35-years-old female patient.

Personal physiological history
She was born post-term (41st week).
Dystocic birth.
Miscarriage at age 35.

Family history
Family history reveals that the patient’s mother had had multiple miscarriages (six miscarriages of male foetuses). She has two living children, a daughter (the patient described herein) and a son in good health who is 2 years younger. She also had dental malformations and reported skin blistering in infancy.
The patient’s grandmother had dental malformations and hypodontia, and had given birth to five children (two females with oligodontia and dental malformations).
Miscarriages were also reported in the great-grandmother (four miscarriages).

Past medical history
Birth trauma.
Pyramidal left hemi-syndrome with seizures and brachial palsy were evident shortly after birth.
She also presented dysmorphic hands and pes planovalgus, for which she later underwent surgery (left Achilles tendon extension and realignment of the left knee extensors).
As of the first weeks of life she presented with skin blistering and lesions that healed, although with hyperpigmentation, which progressively improved after the 6th month of life, and disappeared after the first year of life.
Mild growth delay, frequent infections and agenesis of permanent dentition were also present.
Partial agenesis of the corpus callosum and an arachnoid cyst were diagnosed at age 4, following severe seizures that occurred in the context of a febrile illness.
At age 24, SLE was diagnosed in the context of a clinical picture of pleuropericarditis, severe arthralgia, most likely worsened by the presence of the skeletal malformations mentioned above, fever and anemia. At diagnosis of SLE, photosensibilisation and dyschromic areas were evident.
The main biochemical data at diagnosis were:

  • anti-dsDNA 150–200 IU/ml (normal: <10 IU/ml), whose titres remained persistently elevated over the following 5 years;
  • high antinuclear antibodies (1/640 at diagnosis and during follow-up);
  • low complement levels (C3 60 mg/dl; normal: 80–185 mg/dl; C4 10 mg/dl; normal 15- 45 mg/dl at diagnosis);
  • serum electrophoresis was normal;
  • immunoglobulin levels were normal;
  • Coomb’s test was negative;
  • Lupus-Like AntiCoagulant (LLAC) was positive at diagnosis and was occasionally positive over the following years.

Clinical remission was obtained by administering oral steroids (1 mg/kg/day with rapid tapering to 0.5 mg/kg/day, and subsequently to 0.25 mg/kg/day), while all attempts to add immunosuppressive or immunomodulating drugs were unsuccessful, mainly because of various side effects (leukopenia with azathioprine; severe infections and neurological toxicity on cyclosporine A, including brucellosis and respiratory infections; gastrointestinal intolerance with hydroxychloroquine).
At age 34, the patient developed recurrent urinary tract infections, for which she underwent a first renal evaluation. Moderate renal functional impairment (serum creatine [sCr] 1 mg/dl with estimated glomerular filtration rate [eGFR] 60 ml/min) with microhematuria and low-grade proteinuria were found (proteinuria 0.3 g/day) in the context of clinical remission on prednisone 15 mg/day with negative anti-dsDNA antibodies.

Recent medical history
Upon referral to the Materno-foetal Medicine Unit dedicated to kidney diseases, in her 8th week of pregnancy:

  • proteinuria was 0.8–1 g/day;
  • sCr was 1 mg/dL ;
  • microhematuria was present;
  • creatinine clearance was 60 ml/min.

The patient was being treated with prednisone alone (15 mg/day).
Following miscarriage a month later, the patient underwent an extensive clinical re-evaluation.
On account of the clinical and family history, genetic consultation was carried out and a diagnosis of NEMO syndrome was suspected, which was later confirmed by genetic testing (NEMO gene (Xq28): deletion of exons 4–10 in heterozygosity).
The patient’s skin lesions were thus re-evaluated and typical hypopigmented striae, along with papular lesions were found. These lesions correspond to the adult phase of IP or NEMO syndrome.
Since the patient wanted to attempt another pregnancy, a kidney biopsy was performed in the context of the extensive re-evaluation. It revealed 18 glomeruli, including 5 with global ischaemic sclerosis, while the remainder were normal. Mild interstitial fibrosis with areas of tubular atrophy, as well as normal small vessels and intimal fibrosis in one medium sized arteriole were present. Immunohistochemistry staining was negative.
Owing to the histological picture and to the lack of major signs of immunological reactivity (negative anti-dsDNA antibodies, normal complement level, negative LLAC, no anaemia), the patient restarted low-dose hydroxychloroquine in order to progressively decrease the steroid dose.
She is presently in clinical and laboratory remission on prednisone 5–7.5 mg/day, and hydroxychloroquine 100–200 mg on alternate days.
NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012


Incontinentia Pigmenti (IP; also called NEMO syndrome, an acronym of the involved gene: NF-kB essential modulator) is an X-linked multisystemic disorder affecting the skin, teeth, nails, hair and the central nervous system. The disease has protean manifestations and variable expressivity.
Its predominant form is generally lethal to males in utero (80% of cases: deletion that removes exons 4 through 10 of the NEMO gene); thus adult patients are mainly females. A history of recurrent miscarriages is frequently observed.
Once considered a rare genodermatosis, associated with neurological impairment, NEMO syndrome has recently been defined as a primary immunodeficiency with immune and non-immune manifestations.
The immunodeficiency is particularly severe in surviving males who are usually affected by rare types of NEMO mutations that differ from the more common deletion.
NEMO syndrome is probably the best-characterised disease in the NF-kB pathway.
Indeed, recent clinical data have been published reporting the involvement of the NEMO syndrome in inflammatory and autoimmune diseases, including atypical enterocolitis, Behçet's syndrome and rheumatoid arthritis.
NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012

Systemic lupus erythematosus (SLE) is a multisystem chronic inflammatory autoimmune disorder whose etiology remains unknown, but genetic and environmental factors are both important in the development of the disease.
It can affect a variety of different organs including brain, skin and kidney, and it predominantly affects young women. Analysis of the functional NFKB1 promoter polymorphism in rheumatoid arthritis and systemic lupus erythematosus.,2005
It leads to the production of a plethora of autoantibodies which chiefly target nuclear antigens. Of those autoantibodies, the most common are antibodies to double-stranded DNA (dsDNA) which are specific for the disease. The production of these autoantibodies allows for formation of immune complexes which deposit in tissues, leading to local injury and inflammation.
NF-κB is constitutively activated in some rheumatic conditions such as systemic lupus erythematosus. NF-kappaB and rheumatic diseases.,2006
NF-kB plays a crucial role in the activation and development of normal lymphocytes and dendritic cells (DCs), including positive and negative selection of T and B cells. Problems with NF-κB can lead to the release of autoreactive T cells and B cells, which are critical in autoimmune diseases.
B-cell development occurs in the bone marrow when immature B cells express a B-cell receptor (BCR). Autoreactive BCRs arise in the bone marrow from random rearrangements of the immunoglobulin genes. Under regular conditions, these autoreactive BCR-expressing B cells are removed by the time the cells become mature. This process is under the control of NF-κB. If problems arise in NF-κB regulation of B cells in either the spleen or the bone marrow, autoreactive B cells can avoid negative selection and be released into the periphery.
B cells in SLE are often abnormal; this abnormality stems from a variety of different causes including NF-κB. Errors in NF-κB or constitutive activation or deregulation of it can lead to prolonged survival of B cells and autoimmune reactivity. Once these autoreactive B cells are released, NF-κB plays an integral role in B-cell homeostasis. One method by which this is accomplished is through B-cell activating factor, BAFF. In humans, overexpression of the BAFF protein is found in systemic lupus erythamatosus. BAFF signaling leads to weak stimulation of the classical NF-κB pathway as well as stimulation of the alternative NF-κB pathway. Activation of these pathways leads to enhanced B-cell survival, growth and avoidance of apoptosis.
Samples taken from patients with varying stages of SLE showed constitutive activation of NF-κB in peripheral B cells. This activation is mediated through different avenues including CD154 (also called CD40 ligand)/CD40 which are members of the TNF family. CD40 mediates NF-κB activation through the Tumor necrosis factor Receptor-Associated Factor (TRAF) proteins, while CD154 leads to phosphorylation of IκBα, leading to its degradation and to further activation of NF-κB. Circulating levels of CD154 in SLE patient blood samples correlate with anti-dsDNA autoantibodies and disease activity.
Patients suffering from SLE also have decreased expression of the Leukocyte-Associated Ig- like Receptor 1 (LAIR1) on CD20 B cells. LAIR1 binding with collagen allows for inactivation of immune cells such as B cells. The B cells with decreased LAIR1 can be fully stimulated by autoantigens which would allow them to proliferate and produce pathogenic Ig with no negative regulation.
T-cell development takes place in the thymus in the form of both positive and negative selection. T cells which weakly recognize the self-antigens are positively selected, while those that are autoreactive are eliminated via apoptosis.
Defects in NF-κB expression can lead to incorrect selection and allow for the release of autoreactive T cells.
NF-κB is a key player in T-cell activation and maturation.
NF-κB plays a critical role in the production of cytokines by Th cells and is found to be overexpressed in patients with SLE. Patient blood samples from those diagnosed with SLE have shown that Th1 cells are more active and lead to many of the manifestations of SLE.
Occasionally, T cells that recognize self-antigens are released into the periphery; the body uses regulatory T (Treg) cells to contain and remove these improper T cells, allowing the body to function normally. They can suppress B cells, DCs, macrophages and monocytes as well through cytokine release as well as modulation of antigen-presenting cell maturation and function.
NF-κB plays an important role in the development of Treg.
In SLE mouse models, Tregs are present in significantly lower levels, illustrating their important role in controlling autoimmune responses.
NF-κB and systemic lupus erythematosus: examining the link., 2013


The patient of the case reported here presented the main features both of NEMO syndrome and of SLE (serositis, arthritis, positive autoantibodies, including dsDNA antibodies, antinuclear factor and LLAC) when she became pregnant. The presence of skin lesions averted attention from the underlying genetic disease, while calling attention to SLE. However, in NEMO syndrome the lesions develop through four phases starting in early childhood: blistering, wart-like rash, swirling macular hyperpigmentation and linear hypopigmentation, while alopecia is typically at the vertex, unlike the typical ‘lupus hair’.
Likewise, a history of recurrent miscarriages may be shared by both diseases, even though miscarriages in patients with NEMO syndrome are typically of male foetuses. Furthermore, the patient’s dystocic birth averted attention from the genetic origin of the seizures and of the peripheral palsy since they were ascribed to hypoxia and birth trauma.
Frequent infections were present in the patient’s history prior to the development of SLE. Again, sensitivity to infections may be a sign of a predisposition to SLE and is common in NEMO patients in whom non-typical pathogens, including mycobacteria and other intracellular bacteria, are often observed (the patient had a history of Brucella infection).
The patient also presented with at least two elements that do not overlap with SLE, i.e. complex dental anomalies (present in up to 80% of patients with NEMO) and seizures in infancy (dysgenesis of the corpus callosum, typical of NEMO syndrome).
In IP the affected gene is the NEMO/IKKγ essential regulator, which is central to both innate and adaptive immune responses to a variety of pathogens; this should point towards immunodeficiency more than to an increase in immune response. Indeed, both common and rare infections are frequently observed in children.
The relationship with the development of autoimmune diseases has two main facets: the generic hypothesis which states that repeated infective challenges may trigger the immune response, a mechanism that has long been postulated in SLE, and the more specific hypothesis regarding the role of the NF-kB complex in starting and blunting the immune response. In fact, inhibition of NF-kB during the resolution of inflammation was found to prolong inflammatory response and to inhibit apoptosis.
NF-kB plays a role in cancer in maintaining the immunosuppressive phenotype of tumour-associated macrophages.
An apparently paradoxical anti-inflammatory role was described in sepsis, together with a pro-apoptotic effect of the NF-kB complex in neutrophils.
Prolonged pharmacological inhibition of IKKb augments IL-1b secretion upon endotoxin challenge. Thus, a note of caution was recently published regarding long-term IKKb inhibition that could, in contrast, induce persistence of inflammation. NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012
In patients suffering from systemic lupus erythematosus has been shown that there is a upregulation of BAFF and simultaneously a deficit of some subunit of NF-kB (in particular p65) that lead to an altered factor binding to DNA with repression of certain genes, such as that dell'IL2, which are activated in the healthy following antigenic stimulus exterior. Abnormal NF-kappa B activity in T lymphocytes from patients with systemic lupus erythematosus is associated with decreased p65-RelA protein expression.,1999
There have been a variety of studies which have discovered many different gene polymorphisms linked to SLE. Some polymorphisms which have been identified directly relate to NF-κB (_some polymorphisms of the component IkBalpha appear to be related to SLE_).
By inference then that alters the activity of IKK may predispose to SLE, and therefore the presence of alterations of NEMO found in the IP could do so.
The hypothesis that arises from experimental observations is that - in the patient with IP - the presence of congenital anomalies of the regulatory system of NF-kB for NEMO mutations can lead to a state of deregulation of the delicate balance between immunocompetence and responsiveness to the self that to develop, in conjunction with contingent epigenetic trigger factors, the development of autoimmune abnormalities and at the same time an increased susceptibility to infections with protracted inflammation, related to immunosuppression and the lack of an modulating effect "in negative", still partly not clear, on the immune response.
Thus, while no general law can be drawn by a single case, this report supports the importance of chronic NEMO inhibition in the development of complex immunological diseases, of which SLE is often considered the prototype, and calls for further attention to the risk of autoimmune diseases in patients with IP or NEMO syndrome.
NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012


Increased awareness of the importance of rare genetic diseases should encourage the search for a common origin and a genetic nature in the case of an association between malformations and immunological derangement in young patients, as in the case of uncommon infections in childhood. This case, which reports an association between NEMO syndrome and SLE, may highlight the importance of the NF-kB complex in down-regulating the immune response.
NEMO syndrome (incontinentia pigmenti) and systemic lupus erythematosus: a new disease association.,2012

2014-07-15T12:40:37 - Paolo Pescarmona

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