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CME ARTICLE
Year : 2017  |  Volume : 18  |  Issue : 3  |  Page : 155-159

Cutaneous manifestations of primary immunodeficiency


Department of Pediatrics, Stony Brook University Hospital, Stony Brook, New York, USA

Date of Web Publication7-Jun-2017

Correspondence Address:
Ratna B Basak
Department of Pediatrics, Stony Brook University Hospital, Stony Brook, New York
USA
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpd.IJPD_10_17

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  Abstract 

Primary immunodeficiency diseases (PIDs) are a group of rare, chronic disorders with deficient or malfunctioning immune system. It commonly affects the hematopoietic system, with skin the second most affected organ. Skin involvement is observed in half of pediatric PID cases and often precedes the final diagnosis. Skin infections and eczemas are the two most common manifestations in PID.[1] Skin manifestations associated with PIDs can be of infectious and noninfectious causes. Common noninfectious causes are eczema, erythroderma, cutaneous granulomas, dysplasia, vasculitis, and telangiectasia. It is important to be aware of skin manifestations in pediatric patients as early detection of PID may aid in the management of serious immunologic conditions and prevent associated morbidity and mortality.

Keywords: Ataxia telangiectasia, chronic granulomatous disease, common variable immunodeficiency, leukocyte adhesion defects, primary immunodeficiency, severe combined immunodeficiency, Wiskott–Aldrich syndrome


How to cite this article:
Abdelhakim S, Cafone J, Basak RB. Cutaneous manifestations of primary immunodeficiency. Indian J Paediatr Dermatol 2017;18:155-9

How to cite this URL:
Abdelhakim S, Cafone J, Basak RB. Cutaneous manifestations of primary immunodeficiency. Indian J Paediatr Dermatol [serial online] 2017 [cited 2017 Oct 22];18:155-9. Available from: http://www.ijpd.in/text.asp?2017/18/3/155/206046


  Introduction Top


Primary immunodeficiency diseases (PIDs) are an inherited defect in innate and adaptive immunity that predisposes to infection with both common and uncommon organisms. The overall incidence is 1:10,000 live births with a prevalence of 1 in 1200.[1] IgA deficiency is the most common, followed by common variable immunodeficiency (CVID), and Agammaglobulinemia. Skin infections are seen in the third of the PID cases, followed by eczemas.[2] The incidence of humoral immunodeficiency is higher in Arabs, likely due to higher rate of consanguinity.[3] Secondary immunodeficiency is caused by external noninherited factors affecting the immunity such as malnutrition, chemotherapeutic agents, and specific viral infections.

This paper will focus mainly on PID and their skin manifestations. While cutaneous infections are more frequently associated with PIDs, noninfectious cutaneous conditions could also signal PID.[4]


  Infections Top


Bacterial

Pyogenic infections of the skin are the first and most common skin manifestation in PID.[5] This is due to congenital defects in phagocytes as in hyper IgE syndromes or antibody deficiencies.[1],[6] Chronic granulomatous disease (CGD), leukocyte adhesion defect (LAD), and hyper IgE Syndrome most commonly present with bacterial infections. It may manifest as folliculitis, abscesses, furuncles, or impetigo.[5] Patients with CGD are prone to catalase-positive bacteria.[6] The most common organism is Staphylococcus followed by Haemophilus, Serratia, Klebsiella, Escherichia coli, and Pseudomonas.[6],[7] The most common presentation is with frequent infections and chronic skin abscesses. It is due to a defect in the expression of NADPH-oxidase complex in phagocytes responsible for generating O2-radical necessary for intracellular killing of ingested microorganisms.[8] LAD is an autosomal recessive disorder due to mutations in integrin affecting CD18 which prevents neutrophils to aggregate or bind to intercellular adhesion molecules on endothelial cells and to migrate to sites of infection.[9] Recurrent infection of the skin, generally due to Staphylococcus aureus or Gram-negative bacilli is typical which tend to necrotize and ulcerate without pus at the wound site.[10] Other features include delayed umbilical cord separation, omphalitis, persistent leukocytosis, and severe destructive gingivitis.[9] Hyper IgE syndrome is a phagocytic defect resulting in recurrent bacterial infections which are difficult to control.[7] The cold abscess-like lesions typically lack the usual redness, warmth, or pain which may delay diagnosis.[9],[11]

Fungal

Fungal infections are another major manifestation of primary immunodeficiency typically seen in patients with combined T- and B-cell immunodeficiencies.[1] Pathology related to fungal infections are generally secondary to defects in Th17mediated immunity, DOCK8 mutation (IgE), CARD9 deficiency, and the autoimmune regulator (AIRE) gene.

Severe combined immunodeficiency (SCID) is a primary immunodeficiency with combined B- and T-cell deficiency that may present with failure to thrive in addition to bacterial, fungal, and viral infections. Persistent mucocutaneous candidiasis of the mouth and anus during infancy may be a presenting feature of SCID.[5],[6]

Candidiasis associated with eczema is a common feature of Hyper IgE syndrome.[5] When presents with mucocutaneous candidiasis, autoimmune endocrinopathies and dystrophy of the dental enamel and nails, it is important to recall autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED) caused by mutations in the AIRE, resulting in autoreactive T-cells which develop autoantibodies.[12] Complete DiGeorge Syndrome represents a form of SCID due to complete absence of thymic tissue leading to profound immunodeficiency. Patient presents with a triad of cardiac defect, hypocalcemia, and facial dysmorphism.[13]

Viral

Viral infections are due to deficiency or defects in CD4+ T-cells and NK Cells resulting in neutropenia and hypogammaglobulinemia. Typical infections are caused by herpes zoster, herpes simplex, and human papillomavirus.[10] Molluscum contagiosum, condylomata, and viral warts have a much higher prevalence in acquired immunodeficiencies than in PID.[6]


  Noninfection Top


Eczema

The second most common skin condition in patients with PIDs is Eczema, occurring in 19% of patients.[1] A number of genes have been associated with eczema, one of which is filaggrin. This disease manifest as inflammation of the skin associated with itchiness, swelling, and redness. Areas typically affected include neck, wrist, forearm, thighs, and ankles. It is important to recall that uncontrolled dermatitis may lead to further bacterial infections.[7] Timing of diagnosis is also important as many children with humoral immunodeficiencies generally present with severe eczema shortly after birth.[5] Some PIDs afflicted with eczema include Hyper IgE syndrome, Wiskott–Aldrich syndrome (WAS), and IgA deficiency.

Hyper IgE is caused by a mutation in STAT3, DOCK8, and TYK2 which alters downstream signaling pathway for cytokine receptors, resulting in a complex array of altered immune responses favoring inflammation.[11] Patients with Hyper IgE often present with a newborn rash consisting of eosinophilic pustules.[11] Others may present with pruritic dermatitis with cutaneous lesions resembling lichenified skin which increasing risk for further infection. WAS is an X-linked disease defined by a triad of eczema, thrombocytopenia, and immunodeficiency.[2] Mutation of the WAS protein gene results in abnormal cell polarization, migration, and phagocytosis.[9] Eczema in WAS is described as atopic dermatitis in most of the cases.[14]

People with selective IgA deficiency lack IgA antibody that protects against infections in mucous membranes. Patients with IgA deficiency may be asymptomatic although they may suffer from recurrent sinopulmonary infections, gastrointestinal conditions, and allergic disorders. Reviewing skin conditions with these diseases are may identify the disease.[15] Dermatitis resembling atopic dermatitis occurs in IgA deficient patients.[14],[16]

Erythroderma

Erythroderma is a condition with severe skin irritation causing erythema and/or scaling involving >90% of the total body surface.[17] Almost half of erythroderma in infancy is due to PID.[1] Erythroderma with diffuse alopecia is the third most common skin condition in patients with PID. Exfoliative erythroderma has also been described as the initial skin abnormality in infants with Comèl-Netherton syndrome characterized by atopic diathesis, eczema, atopic dermatitis, recurrent infections, congenital ichthyosis, failure to thrive, and bamboo hair with high fatality rate in early childhood.[17],[18],[19] Although not generally listed as an immunodeficiency, the recurrent infections in patients with this syndrome typically are a result of immune defects which improve with intravenous immunoglobulin.[19]

Exfoliative erythroderma in neonatal period is also common in patients with Omenn syndrome, a rare inherited combined immunodeficiency caused by mutations in various SCID genes. These patients show hypereosinophilia, associated with T-cell infiltration of gut, liver, spleen, and skin leading to erythroderma, diarrhea, hepatosplenomegaly, alopecia, recurrent infection, and failure to thrive.[20],[21] This clinical picture in Omenn syndrome involving alopecia and erythroderma is similar to that in SCID patients who develop graft-versus-host disease.[22],[23]

Cutaneous Granulomas

Granulomas are well-formed, noncaseating, pigmented macrophages.[8] Granulomas are most common in CGD although may be seen in other PIDs.[10] They can be commonly of infectious etiology or noninfectious etiologies. Noninfectious granulomas are rare well-established feature of PIDs.[24]

Although skin granulomas are less common than granulomas in visceral organs, they are still present in a majority of patients. CVID is a heterogeneous group of primary immunodeficiency leading to a defect in B-cell differentiation.[25] Multisystem granulomatous disease is an established complication of CVID, occurring in 8%–22% of CVID patients, with 7%–19% of these cases manifesting with skin involvement alone or in combination with granulomas at other body organs.[24],[25] Studies showed a correlation between low percentage of switched memory B-cells in CVID patients and a higher frequency of granulomatous disease in addition to a higher morbidity and early mortality compared with the general CVID population.[26],[27],[28] Moreover, there is an association between CVID patients with granulomatous disease and an increased susceptibility to autoimmune complications, especially immune cytopenias. Although lung is the most affected organ in CVID, cutaneous granulomas on the extremities, face, and buttocks are also common.[27],[28]

Cutaneous granulomas are also present in patients with ataxia telangiectasia (AT) which is a multisystem disease, caused by alterations in the ATM gene leading to telangiectasia, immunodeficiency, and severe neurological affectation.[29],[30] Immune dysregulations is a suggested cause to the development of granulomas since there is a noted reduction in peripheral CD19fi B-cells, a low number of CD3fi CD4fi and CD45RAfi naive T-cells in the presence of normal NK cells.[31] In few reported patients with AT, the onset of the granulomatous skin lesions preceded the diagnosis and other symptoms of the condition.

Dysplasia

PID may present with dysplasia of skin, nails, or hair. Alopecia areata and vitiligo are diseases associated with APECED complex.[12] Hypomorphic mutations in IKBG (NEMO gene) causes X-linked ectodermal dysplasia with immunodeficiency (XL-EDA-ID) which leads to variable T- and B-cell defects, impaired NK cytotoxicity, abnormal immunoglobulin production and increased susceptibility to mycobacterial infection, and encapsulated bacterial infections.[12] Clinically, it presents with hypohidrosis or anhydrosis and hair abnormalities such as hypotrichosis, or atrichosis.

Cartilage-hair hypoplasia is an autosomal recessive form of metaphysical chondrodysplasia presents with a variable degree of cellular immune impairment, bone marrow dysplasia, short-limbed dwarfism, Hirschsprung disease, and predisposition to malignancies and light-colored hypoplastic hair.[32]

Dyskeratosis congenita is a multisystem inherited syndrome, with mutations in several genes important in telomere maintenance. It is genetically heterogeneous condition with a classic triad of leukoplakia of oral mucosa, nail dystrophy, and abnormal skin pigmentation such as a lacy, reticular pigmentation of the neck and chest, and dysplastic fingernails and toenails. Some patients may present with hyperhidrosis and abnormal eyelash growth, ectropion or entropion of eyelids.[33],[34]

Papillon–lefevre syndrome is a rare autosomal recessive disorder caused by a mutation in the gene encoding cathepsin C, leading to impaired chemotaxis. It presents with ectodermal dysplasia, palmar, and plantar hyperkeratosis. Patients present with severe periodontal disease, loss of teeth, and increased susceptibility to pyogenic infections including staphylococcal skin abscesses.[12]

Vasculitis

It is well established that patients with PID are more susceptible to developing autoimmune disease due to immune dysregulation. Immunodeficiency may result in an inability to get rid of microbial antigens, leading to chronic activation of the immune system. Patients with humoral immunodeficiencies, especially CVID, IgA deficiency, and APECED, are more likely to develop vitiligo and alopecia compared with the rest of the general population.[35] In addition, autoimmunity has a significant prevalence in WAS patients and as vasculitis in Henoch-Schonlein purpura and AT.[36] It may present with café-au-lait macules, hypopigmented macules, melanocytic nevi, facial papulose-squamous rashes, and hypertrichosis. Last, patients with deficiency in complement components such as C1, C4, and C2 tend to develop photosensitive malar rash and mucocutaneous vasculitis, characteristic of systemic lupus erythematosus.[37]

Telangiectasia

A PID commonly associated with telangiectasia is Chediak-Higashi syndrome which is an autosomal recessive disorder due to a defect in a lysosomal regulation leading to decreased phagocytosis. Patients present with telangiectasias and partial albinism with silver gray hair.[1] This population is affected by infections of the mucous membranes, skin, and respiratory track due to bacteria and fungi.


  Conclusion Top


Skin manifestation in PID is common. Pediatricians and dermatologists should be attentive to skin conditions and recognize their association with PID. Prompt immunologic workup should be done if a pediatric patient presents with failure to thrive, multisystem involvement, and recurrent refractory infectious or noninfectious cutaneous conditions.

Financial Support and Sponsorship

Nil.

Conflicts of Interest

There are no conflicts of interest.

 
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