The skin in primary immunodeficiency disorders

J Henk Sillevis Smitt; Nico M Wulffraat; Taco W Kuijpers

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The skin in primary immunodeficiency disorders

European Journal of Dermatology. Volume 15, Number 6, 425-32, November-December 2005, Review article

Summary

Author(s) : J Henk Sillevis Smitt, Nico M Wulffraat, Taco W Kuijpers , Dept of Dermatology, A0-228, Academic Medical Center, University of Amsterdam Postbox 22660, 1100 DD Amsterdam, The NetherlandsFax: +(31) 20 6960076., Dept of Pediatrics, University Medical Center of Utrecht, Utrecht, the Netherlands, Dept of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.

Summary : Primary immunodeficiency disorders comprise serious and rare diseases, predominantly in children. The skin may be involved in a primary immunodeficiency and the cutaneous alterations such as infections, eczematous dermatitis, erythroderma, autoimmune dermatoses and vasculitis may be the basis for the ultimate diagnosis. Dermatologists may realize something is wrong with the immunity of their patient and prompt diagnosis of the defect can lead to lifesaving treatment. Since atypical presentations of well known dermatoses are common in immunodeficiency disorders, histopathology and bacterial, fungal or viral tests of the skin lesions are often indispensable. The knowledge of skin findings in primary immunodeficiency diseases may help dermatologists to play a role in the early detection of these diseases. Key findings constitute specific skin symptoms combined with unusual or severe infections.

Keywords : autoimmune diseases, eczematous dermatitis, erythroderma, granuloma, immunodeficiency disorders, skin infections, vasculitis

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ARTICLE

Auteur(s) : J Henk Sillevis Smitt¹, Nico M Wulffraat², Taco W Kuijpers³

¹Dept of Dermatology, A0-228, Academic Medical Center, University of Amsterdam Postbox 22660, 1100 DD Amsterdam, The NetherlandsFax: +(31) 20 6960076.
²Dept of Pediatrics, University Medical Center of Utrecht, Utrecht, the Netherlands
³Dept of Pediatrics, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands

accepté le 13 Juillet 2005

Primary immunodeficiency disorders comprise a number of serious and rare diseases, predominantly in children, which result from mutations in one or more genes that encode components of the immune system [1]. Based on the defect involved, immunodeficiency disorders may be classified (table 1)[2].For details concerning the diseases belonging to each group, refer to reviews in the literature [1-3]. In a growing number of primary immunodeficiency diseases the gene which corresponds to the particular deficiency has been identified. In recent years, long term survival of patients with primary immunodeficiency disorders has been described after haematopoietic stem cell transplantation [4].The skin may be one of the organs involved in a primary immunodeficiency and cutaneous alterations such as infections, eczematous dermatitis or erythroderma may be the basis for the ultimate diagnosis. Dermatologists may be the first to realize something is wrong with immunity in their patient and prompt diagnosis of the defect can lead to lifesaving treatment. Since atypical presentations of well known dermatoses are common in immunodeficiency disorders, histopathology and bacterial, fungal or viral tests of the skin lesions are often indispensable. Knowledge of specific clinical warning signs is of help in diagnosing a primary immunodeficiency (table 2)[5, 6] The focus of this review will be on skin symptoms in primary immunodeficiency diseases (table 3).

Skin infections

Fungal

( Table 1 )( Table 2 )( Table 3 )Candida infection of the skin and/or mucous membranes may be the first sign of an immunodeficiency. It presents as oral candidiasis, mucocutaneous candidiasis, candida paronychia, granuloma formation or erythroderma. The presentation of a candida infection is often related to the immunodeficiency involved (table 4)( Table 4 ).

Apart from candida, other fungi may cause serious skin problems in immunodeficiency. Especially, Aspergillus species may be pathogenic [7]. In particular, patients with chronic granulomatous disease (CGD) [8, 9] and patients with severe bone marrow depression and – more rarely – T cell defects as observed in SCID or AIDS, are at risk.

Aspergillus infections have an often life-threatening impact; the involved skin may show erythemato-violaceous and sometimes purulent-to-necrotic nodular lesions [9]. Other “superficial” fungal infections may be caused by blastomycosis, coccidioidomycosis, cryptococcosis, histoplasmosis, paracoccidioidomycosis, mucormycosis or sporotrichosis. Light microscopic examination after routine staining with hematoxylin-eosin and/or special staining for fungi with either periodic acid-Schiff or Gomorri methenamine silver is recommended in diagnosing a systemic fungal infection, possibly extended by culture and/or PCR techniques of biopsies or blood.
Table 1 Main classes of primary immunodeficiency disorders [2]

• Combined ID (B and T cells)
• Antibody deficiencies (B cells)
• Cellular deficiencies (T cells, NK cells)
• Defects of phagocytic function (granulocytes, macrophages)
• Complement defects (all soluble complement components except factor B)
• Primary immunodeficiency disorders associated with unknown genetic or molecular mechanisms or part of well-characterised syndromes.

Table 2 Warning signs for a primary immunodeficiency (PID) [5, 6]

• Infections with atypical presentation, opportunistic organisms, or serious chronic course
• ≥ 6-8 episodes of otitis media within 1 year
• ≥ 2 months of antibiotic treatment for bacterial infections without effect
• ≥ 2 episodes of pneumonia in 1 year
• Failure to thrive, chronic diarrhoea
• Persistent oral thrush after 6-12 months of age
• Recurrent deep organ or skin abscesses
• Recurrent serious infections (e.g. meningitis, cellulitis, osteomyelitis, sepsis)
• Family history of PID

Table 3 Skin symptoms which may be related to immunodeficiency

• Skin infections (fungal, bacterial, viral)
• Eczematous dermatitis
• Erythroderma
• Skin symptoms of autoimmune diseases (e.g. SLE, scleroderma) and vasculitis
• Granuloma formation
• Skin problems characteristic of specific immunodeficiency syndromes (for example teleangiectasias, grey hair and depigmentation)

Table 4 Presentation of Candida infection in relation to immunodeficiency type

Skin symptoms	Immunodeficiency syndrome
Persistent mucocutaneous candidiasis	Severe Combined Immunodeficiency (SCID), Congenital thymus hypo/aplasia (DiGeorge syndrome), Hyper-IgE-syndrome (Job’s syndrome, HIES), Autoimmune polyendrocrinopathy-candidiasis ectodermal dysplasia (APECED), HIV-infection
Nail dystrophy, disseminated granulomatous plaques	APECED
Erythroderma	T-cell immunodeficiency disorders

Bacterial

Pyogenic infections of the skin, mainly caused by Staphylococcus aureus, occur frequently in the immunocompromised patient. Abscesses may arise, often causing only slight erythema (cold abscesses) due to the hampered influx or impaired function of granulocytes in, for example, the Hyper-IgE-syndrome and CGD. Pyoderma is the presenting sign in 15% of patients suffering from CGD [10] and in the Hyper-IgE-syndrome, 87% of the patients show furuncles [11]. In agammaglobulinemia around 40% of cases develop a constellation of skin infections (with either staphylococcus or pseudomonas), sepsis and neutropenia [12]. Pseudomonas skin infections may present as ecthyma gangraenosum [12, 13]. Recurrent cellulitis has been described caused by unusual bacteria such as Campylobacter coli [14] and Helicobacter species [15].

In the Wiskott-Aldrich syndrome (WAS), pyogenic infections are common too. In this syndrome abnormalities of the WAS protein (WASP)-gene (located on chromosome Xp11.23) [16], lead to defective interaction of T-lymphocytes and antigen-presenting cells such as dendritic cells and macrophages. The WASP related proteins are involved in the conformational change of white blood cells, necessary for the interaction of these cells with other cells and microbial agents [17].

Leukocyte adhesion deficiency (LAD) causes a failure of neutrophil migration and the dermatological findings include delayed umbilical cord separation and impaired wound healing, ulcerative stomatitis, recurrent cutaneous abscesses and pyoderma gangraenosum-like skin lesions, infected with Staphylococcus aureus and Pseudomonas aeruginosa [18].

Congenital complement deficiencies regularly present with pyogenic infections. Complement-deficient patients are, in particular, vulnerable for infections with encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenza type b [19]. In C3 deficiency, the clinical picture of these infections resembles that occurring in agammaglobulinemia [19]. In the case of deficiency of complement factors C5-C9, recurrent Neisseria infections are relatively common and may give rise to severe skin symptoms such as meningococcal necrotising vasculitis.

Weakly pathogenic atypical mycobacteria species may give rise to severe infections, not only in SCID patients [20] but also in patients with cytokine deficiencies or defects of the cytokine-receptors [21]. In these patients well organized granulomata, effective to clear mycobacteria, are not formed and their cells can not produce or respond to gamma interferon or IL-12 [21, 22]. BCG vaccination may be a life-threatening hazard in these children as well as in SCID patients ( (figure 1) ).

Viral

Herpes viruses (cytomegalovirus, Epstein-Barr virus, Herpes simplex virus and Varicella-Zoster virus) are among the most common viral skin infections encountered in T-cell deficient patients [23] or patients with dysfunctional T cells [24]. The symptoms are often impressive and severe. Aciclovir-resistant herpes strains may occur [25], but are very rare.

Molluscum contagiosum infections may be severe, widespread and disfiguring [26, 27]( (figure 2) ).

Papilloma viruses (PV) may cause warts and condylomata [1]. Epidermodysplasia verruciformis associated with mutations in the EVER1 and EVER2 gene predisposes to PV infections in a so far unknown way. A general immunodeficiency is not present. These warts constitute a pre-malignant condition. In a rare autosomal-dominant syndrome, designated Warts-Hypoimmunoglobulinaemia-Myelokathexis (WHIM), the warts coincide with recurrent bacterial infections due to a B-cell defect and concomitant neutropenia with abnormal hypersegmented nuclei in the granulocytes in bone marrow smears. The defect is localised in the CXCR4 gene [28].

Eczematous skin problems

Eczematous eruptions occur rather frequently in primary immunodeficiency diseases, in table 5( Table 5 )[29-32] those which most frequently show eczema are shown. In the general population eczematous dermatitis is very common in children: atopic dermatitis occurs in approximately 10% of infants. Primary immunodeficiency diseases, on the other hand, are very rare in children, around 1 in 100,000 neonates is born with a symptomatic primary immunodeficiency disease. In general practice, the problem is how to recognize the few children in whom eczematous dermatitis is part of an immunodeficiency.

Symptomatic IgA deficiency accounts for 10-15% of the immunodeficient patients with clinical symptoms [33]. IgA deficiency shares an MHC-linked genetic defect with the more rare common variable immunodeficiency (CVID), an acquired and more severe disorder of Ig production characterized by, in the course of life, a progressive decrease in IgG, IgA and often IgM. Dermatitis resembling atopic eczema is one of the most notable skin symptoms in IgA-deficient patients. It is not known whether the dermatitis in patients with IgA-deficiency fulfils atopic dermatitis criteria such as those defined by Hanifin and Rajka [29] or the UK Working Party’s Diagnostic Criteria for Atopic Dermatitis [30-32]. Differences between IgA deficient patients with atopic eczema-like eruptions and atopic dermatitis have never been looked for. The atopic-like dermatitis can be accompanied by asthma. Multiple allergies, particularly to bovine serum and milk proteins, are present rather often. In healthy children in particular, high levels of secretory IgA (sIgA) seem to protect against developing allergic symptoms during the first 2 years of life, supporting a possible protective role of sIgA against development of allergy [34]. In IgA-deficient patients the protection of sIgA is lacking. Of note is that specific IgE serum levels in IgA deficiency are most often normal.

In hypo- or agammaglobulinaemia, atopic dermatitis-like eruptions may occur. Furthermore, the hypo- or agammaglobulinaemia favours the susceptibility to secondary infections in the vulnerable eczematous skin. Laboratory difficulties arise in the diagnosis of atopy in children with agammaglobulinaemia since IgE biosynthesis in these patients is also blocked.

The diagnosis of WAS is based on three major clinical features: dermatitis, thrombocytopenia and recurrent pyogenic infections. The dermatitis is hardly discernable from atopic dermatitis and fulfils the diagnostic criteria for atopic dermatitis of Hanifin and Rajka [29, 35]. The eczema in WAS may be recognized because of its haemorrhagic component and its combination with nose bleeds, both caused by the thrombocytopenia. A complete clearance of the eczema is reported after successful bone marrow transplantation [36], suggesting a causal relationship between the immunodeficiency and atopic eczema.

The hyperimmunoglobulin E syndrome, probably autosomal-dominant with variable expression, is in some families linked to chromosome 4q [37]. It is a multisystem disorder with immune, skeletal, and dental abnormalities. It includes recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum IgE, and hypereosinophilia, pneumatocoeles, reduced neutrophil chemotaxis, and variable impaired T cell function. It is best diagnosed with the help of a scoring system of clinical and laboratory tests, in which the old triad of recurrent infection in the skin (abscesses) and sinopulmonary tract from childhood on, and an IgE level of at least 2,000 IU/ml is included [37]. In the neonatal period, a vesiculo-pustular skin eruption is present in around 80% of hyper-IgE-syndrome patients [38], often starting in the face, which may be confused with neonatal acne. It develops in due time into eczema. In a group of 43 patients, this eczema has been scored according to the validated UK Working Party’s Diagnostic Criteria for Atopic Dermatitis [30-32] and it was shown that 65% of cases fulfilled these criteria [38]( (figure 3) ). The eczematous eruption may be distinguished from atopic dermatitis because of the presence of intertriginous and retroauricular lesions, external otitis, folliculitis of the upper back and shoulders, cutaneous abscesses, mucocutaneous candidiasis and in some patients, a face with pitted scarring [38].

SCID is a heterogeneous group of disorders characterized by defective T cell and B cell function. Eczematous and morbilliform eruptions are common, and graft-versus-host disease (GVHD) due to maternal engraftment has been documented. Skin symptoms, including scaling erythematous maculo-papular eruptions, spread widely over the trunk and extremities, leading to near-erythroderma in some patients. The eruption is not easily confused with localised atopic eczema in general, but it may be hard to distinguish from near-erythrodermic eczema.
Table 5 Primary immunodeficiency diseases possibly presenting with eczematous dermatitis, their resemblance to atopic dermatitis, and their frequency

Immunodeficiency	Frequency	Fulfils diagnostic AD- criteria[29-32]
Selective IgA deficiency	1: 600	NT
Common variable Immunodeficiency	1:10,000-100,000	NT
Wiskott-Aldrich syndrome	1:250,000 males	Yes
X-linked agammaglobulinaemia	1:200,000	NT
Hyper IgE syndrome	1:100,000-500,000	Yes
Omenn’s syndrome	1:500,000	NT

Erythroderma

Congenital erythroderma is a rare skin symptom in neonates and often the cause is hard to determine [39]. In a retrospective study, in a department of paediatric dermatology of a university hospital, fifty-one patients who presented with exfoliative erythroderma during their first year of life were studied. On average, the etiological diagnosis was established 11 months after the onset of erythroderma. The underlying causes observed included immunodeficiency (30%) (see also table 6( Table 6 )[39-41]), simple or complex ichthyosis (24%), Netherton syndrome (18%), and eczematous or papulosquamous dermatitis (20%). Five patients (10%) had erythroderma of unknown origin [40]. Erythroderma may even be the presenting sign of immunodeficiency. In almost all children studied, the cutaneous symptoms were itch and skin induration. Alopecia often occurs and lymphadenopathy is seen in, for example, Omenn’s syndrome ( (figure 4) ). Most cases are treatment-resistant, but healing occurred after bone marrow transplantation [40], whether or not this is because of the effect of concomitant systemic immunosuppression is not clear. In Omenn’s syndrome cyclosporin A treatment has been reported to heal the erythroderma [42].

The cause of the erythroderma, may be infectious (see also fungal infections), may be due to graft versus host disease (GVHD) (by maternal engraftment in 25% of SCID patients [43] or by transfusions of non-irradiated blood), due to drug eruptions, or remains unknown.

The cutaneous manifestations of GVHD associated with maternal engraftment in SCID patients has been thoroughly studied. The symptoms may vary from a transient morbilliform eruption to erythroderma with alopecia [43]. The first sites of involvement are the face, the neck and the palms and soles. Later generalisation occurs. Histopathology shows psoriasiform hyperplasia with parakeratosis, variable spongiosis and necrotic keratinocytes [43]. To differentiate erythroderma in GVHD from erythroderma caused by Omenn’s syndrome, additional clinical findings such as eosinophilia and pronounced lymphadenopathy, or genetic markers to distinguish nonautologous from autologous cells may be used.

The so called Leiner’s disease appears to represent a clinical picture in children showing failure to thrive, diarrhoea and erythroderma, but varying specific immunodeficiencies underlie the disease entity.
Table 6 The primary immunodeficiency syndromes possibly presenting with erythroderma [39, 40]

• Severe Combined Immune Deficiency (SCID)
• Omenn’s syndrome
• DiGeorge syndrome (T-cell deficiency) [41]
• Wiskott-Aldrich syndrome
• Selective IgA deficiency
• Common Variable Immune Deficiency (CVID)

Vasculitis and auto-immune diseases of the skin

In WAS, cutaneous vasculitis occurs in around 20% of patients within the first 15 years of life [44], in a number of cases presenting as Henoch-Schönlein purpura with arthritis and renal involvement [45].

Why auto-immune diseases occur regularly in primary immunodeficiency disorders is not clear, but it may be hypothesized that insufficiently cleared persistent antigens, and defects in apoptosis routes, such as FAS, FAS-ligand or caspases, may lead to neo-antigens, thus inducing auto-immune processes. The balance of subpopulations of T-lymphocytes may be disturbed by above the mentioned situations.

Systemic lupus erythematosus is found in several immunodeficiency disorders. IgA-deficiency is detected in around 2-5% of SLE patients [46, 47]. Sporadic SLE cases have been reported in hyper-IgE-syndrome [48, 19]. In CGD, both systemic lupus erythematosus (SLE) [50-52] and discoid lupus erythematosus (DLE) are seen [53, 54]. The latter occurs in patients as well as in the carriers of the X-linked variants. The DLE is comparable with DLE or subacute LE in non-CGD patients, and direct immunofluorescence tests may be negative [54].

Patients with deficiency of one of the early components of the classical complement cascade (C1, C4, C2) are at risk for SLE. The incidence of SLE in patients with C1q, C2 or C4 deficiency is respectively 90%, around 15% and 75% [19, 55]. Characteristic features of SLE patients with complement deficiencies are early age of onset, prominent photosensitivity, lower frequency of renal disease and variable antinuclear antibody titres. In C2 deficiency a high prevalence of SLE, subacute LE and DLE with photosensitivity and frequent presence of anti-Ro (SSA) antibodies is seen [56]. It appears that the prognosis for SLE patients with C2 deficiency is comparable to that for SLE patients in general [56]. Other autoimmune diseases with skin symptoms e.g. systemic onset juvenile idiopathic arthritis, dermatomyositis, vasculitis, Henoch Schönlein purpura, atrophoderma, cold urticaria and linear scleroderma may be associated with complement deficiency too, but to date mostly isolated observations have been reported.

Recently the defects in autoimmune polyendrocrinopathy-candidiasis ectodermal dysplasia (APECED) and immune dysregulation polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) have been discovered and have received much attention in the literature [1]. APECED is associated with mutations of a single gene, designated autoimmune regulator (AIRE), while IPEX is characterized by a FOXP3 deficiency, causing a loss of regulatory T cells. In both instances, auto-immune diseases of several endocrine organs as well as skin problems (deep panniculitis, dermatitis, alopecia, candidiasis and bullous pemphigoid) have been described [57, 58].

Granuloma formation

The presence of non-infectious granulomata in the skin of immunodeficient children has been described as long ago as 1970 [59]. In particular, in ataxia telangiectasia patients, these granulomata have regularly been seen, even as a presenting sign [60, 61] and in CVID these lesions are also frequently reported [62]. They are hard to differentiate clinically from granuloma annulare ( (figure 5) ), or other granulomatous skin diseases, including granulomatous infections. Histopathology is helpful in making a definite diagnosis and bacterial as well as fungal tests (e.g. culture, staining, PCR) from skin biopsies are mandatory to exclude infectious causes.

Skin problems characteristic of specific immunodeficiency syndromes

In a number of primary immunodeficiency syndromes the skin is one of the main clues to the diagnosis.

In ataxia telangiectasia, the telangiectasias are one of the key symptoms of the disease [63, 64]. They usually appear first in the eyes and later also on the skin, in particular on sun-exposed areas ( (figure 6) ), sometimes after the presence of unexplained ataxia for several years. In this syndrome the immunodeficiency is humoral (hypogammaglobulinaemia) as well as cellular, and of variable severity [3]. Apart from the characteristic telangiectasias, vitiligo and poliosis may occur and progeroid skin findings have been described [64]. Moreover a propensity for lymphatic malignancy occurs.

In Chediak-Higashi syndrome, patients show hypopigmented skin, silvery hair and ocular albinism [65]( (figure 7) ). A diminished neutrophil chemotaxis and natural killer cell function leads to severe pyogenic or viral infections.

In the Griscelli syndrome, silvery hair is also a feature, but these patients show an irregular melanin pattern in the hairs, there is a pigment dilution on the skin and immunologically variable cellular and humoral immunodeficiency is found [66]. In both these syndromes a fatal “accelerated phase” of haemophagocytosis may occur upon viral infection. Allogeneic bone marrow transplantation is the only life-saving measure.

The cartilage hair hypoplasia syndrome is rare and patients demonstrate thin and hypopigmented, sparse hair, sometimes in combination with impaired cellular immunity.

Conclusion

Knowledge of skin findings in primary immunodeficiency diseases may help dermatologists to play a role in the early detection of these diseases. Key findings constitute skin symptoms combined with unusual or severe infections.

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