1 Pediatric Immunohematology Department, Bone Marrow Transplantation Center Tunis, Tunisia.
2 Laboratory of Transmission, Control and Immunobiology of Infections (LR11IPT02), Institut Pasteur de Tunis, 1002 Tunis, Belvédère, Tunisia.
Received: August 27, 2018
Accepted: October 15, 2018
Mediterr J Hematol Infect Dis 2018, 10(1): e2018065 DOI 10.4084/MJHID.2018.065
| This is an Open Access article distributed
under the terms of the Creative Commons Attribution License
(https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Skin manifestations are frequent among patients with primary immunodeficiency diseases (PIDs). Their prevalence varies according to the type of immunodeficiency. This review provides the reader with an up-to-date summary of the common dermatologic manifestations of PIDs among Tunisian children. We conducted a prospective study on two hundred and ninety children with immune deficiency. Demographic details (including age, sex, and consanguinity) with personal and family history were recorded. Special attention was paid to cutaneous manifestations. Dermatological involvements were grouped according to the etiology of their most prominent sign. Cutaneous manifestations were found in 164 patients (56.5%). They revealed the diagnosis of PIDs in 71 patients (24.5 %). The mean age at presentation was 21 months. Overall the most prominent cutaneous alterations were infectious. They accounted for 106 cases (36.55%). The most prevalent causes of cutaneous infections were bacterial: 93 cases (32.06%). Immuno-allergic skin diseases were among the common findings in our study. These include eczematous dermatitis found in 62 cases (21.38%). Malignancy related PIDs was seen in a boy with Wiskott Aldrich syndrome. He developed Kaposi’s sarcoma at the age of 14 months. Cutaneous changes are common among children with PIDs. In pediatric patients with failure to thrive, chronic refractory systemic manifestations often present in other family members, recurrent cutaneous infections unresponsive to adequate therapy, atypical forms of eczematous dermatitis or unusual features should arouse the suspicion of PIDs and prompt specialized immunologic consultation should be made.
Materials and Methods
|Table 1. Distribution of PIDs in the studied population|
Staphylococcus aureus represented by far the most common pathogen (32 cases), and Pseudomonas was responsible for one other case. Unfortunately bacterial culture was not done in all infections. BCG infections were common among patients with combined immunodeficiency (CID) and septic granulomatous disease while anal margin abscesses were frequently seen in phagocytic disorders (Table 2). The next type of skin infection consisted of viral infections seen in 11 (3.8%) of the studied patients. Most of them had warts. Recurrent oral papillomatous lesions related to human papillomavirus were seen in 2 sisters with major histocompatibility complex class II deficiency (Figure 1). The third type was fungal skin infection (Table 2).
|Table 2. Groups of PIDs: Associated skin infections.|
|Figure 1. Disseminated warts on oral cavity in a patient with MHC class II deficiency.|
In this study, oral candidiasis was the most common infection in patients with CID, frequently associated with broncho-pulmonary infections (61 cases, 66.30%), digestive infections (56 cases, 60.9%), ear, nose, and throat infections (23 cases, 25%) and persistent diarrhea resulting in failure to thrive (39 cases, 42.4%). Mucocutaneous lesions due to candida were more frequently oral, whitish, adherent plaques and paronychia (Figure 2). Immuno-allergic skin diseases were among the common findings in our study. These include eczematous dermatitis found in 62 cases (21.38%), (Table 3). Severely generalized erythroderma with alopecia revealed Omenn syndrome in 17 cases (Figure 3 and 4). Mean patient age at the onset of these cutaneous manifestations was 6.4 months (1 day to 48 months). Other extracutaneous manifestations led to the diagnosis including recurrent infections observed in 11 patients with failure to thrive, as well as infiltration of lymphoid organs with hepatosplenomegaly. Lymphopenia was found in 15 patients (88 %) and eosinophilia in 16 cases (94%). Specific muco-cutaneous manifestations of PIDs were seen in 22 cases (7.6%) among them telangiectasia (Figure 5) revealed ataxia telangiectasia syndrome in 14 cases (100%). Among these patients, three had hypopigmented and café-au-lait macules. Cutaneous albinism was noted in 8 other cases with Chediack Higashi syndrome (five cases), Griscelli syndrome (one case) or Hermanski pudlak type 2 syndrome (two cases). Malignancy related PIDs was seen in a boy with Wiskott Aldrich syndrome. He developed Kaposi’s sarcoma at the age of 14 months (Figure 6).
|Figure 2. Oral candidiasis in a patient with SCID.|
|Table 3. Groups of PIDs: Associated immunoallergic skin disorders.|
|Figures 3 and 4. Erythroderma with alopecia in a patient with Omenn syndrome..|
|Figure 5. Conjunctival telangiectasias in a patient with ataxia telangiectasia syndrome.|
|Figure 6. Kaposi’s sarcoma in a patient with Wiskott-Aldrich syndrome.|
Although widely present in PIDs, eczema was a consistent feature in patients with Wiskott- Aldrich syndrome(WAS), a complex and severe X-linked disorder characterized by microthrombocytopenia, eczema, increased susceptibility to infection, and increased risk in developing autoimmunity and lymphomas. Other cutaneous and mucosal manifestations and hemorrhages are frequent in WAS patients ranging from non-life-threatening (epistaxis, petechiae, purpura, oral bleeding) to severe manifestations. This heterogeneous syndrome may be complicated by autoimmune mucocutaneous manifestations including Henoch–Schönlein-like purpura, dermatomyositis and recurrent angioedema. In a clinical series conducted by Ouederni, eczema was observed in four patients among 35 MHC Class II Deficiency patients. An underlying primary immunodeficiency should also be suspected when a patient shows severe early-onset, atypical, eczematous dermatitis, refractory to therapy with a tendency to become extensive and flaring up with systemic infections chronic diarrhea and failure to thrive or family history suggestive of immunodeficiency in patients with severe atopic dermatitis. These features underscore the importance of eliciting a history of recurrent infections or family history suggestive of immunodeficiency in patients with severe atopic dermatitis.
A cutaneous granuloma is a histopathological diagnosis on a tissue that is usually taken for the evaluation of the cause of an unexplained nodular swelling in the skin. Aghamohammadi reported a 27-year-old patient with CVID who presented with multiple skin granulomas on both hands. The patient had been well until the age of 20 years when she developed these skin lesions with frequent upper respiratory infections and recurrent diarrhea. Intravenous immunoglobulin therapy improved skin lesions. In our study, one patient with CVID developed annular granuloma of the right leg.
Erythroderma with diffuse alopecia was the third most common skin manifestation in children with SCID and a consistent presenting feature in infants with Omenn syndrome, a rare inherited combined immunodeficiency caused by mutations in various SCID genes. Erythroderma can occur from birth or develop during the first weeks of life. It is evocative by its infiltrated character. 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.
Our findings support the results of other studies that most PIDs have cutaneous features.
These features, being their aspects typical, are highly suggestive for the diagnosis of PIDs. One of the specific cutaneous manifestations of PIDs is telangiectasia. This PID is caused by alterations in the ATM gene leading to telangiectasia, immunodeficiency with progressive ataxia and oculomotor apraxia often accompanied by extrapyramidal movement disorders.[21,22] In most cases, telangiectasias first appear when the child reaches three to five years of age. Conjunctival telangiectasias are first noted in the interpalpebral bulbar conjunctiva away from the limbus. Cutaneous telangiectasias are seen on the ears, palate, bridge of the nose and later extend to the neck, the dorsum of the hands and feet. In our study all patients with ataxia telangiectasia had telangiectasia. Other skin manifestations were reported including abnormalities of pigmentation (hypopigmented and café-au-lait macules), poikiloderma, seborrheic dermatitis, and less common findings including acanthosis nigricans and hirsutism. Hypopigmented macules were found in 2 other patients mainly on the face, trunk, and hands. In our study, hypopigmented and café- au-lait macules were seen in three cases. Another specific feature of PIDs is partial albinism with silvery gray hair. This association is an evocative or even pathognomonic cutaneous sign of complex PIDs including Chediak Higashi, Griscelli, Hermansky-Pudlak, and MAPBP-interacting protein deficiency syndromes.
An association of PIDs and cancers has been known for many years and confirmed from data collected in established registries. The overall risk for cancer developing in children with PIDs is estimated to range from 4 to 25%. In a recent study from the United States Immune Deficiency Network conducted among 3658 patients, 171 separate cancers were diagnosed 25 (15%) of them were skin cancers. There were 119 cancers (70%) in subjects with CVID. Thirteen cancers (9%) were observed in subjects with hypogammaglobulinema and agammaglobulinemia, and eight cancers (4.6%) were observed in subjects with WAS. Despite the relatively high number of chronic granulomatous disease patients in the registry (483), none were diagnosed with cancer. One of the studied patients with Wiskott Aldrich syndrome developed a Kaposi’s sarcoma at the age of 14 months.To our knowledge, this patient is the first case described in the literature.
- Picard C, Al-Herz W, Bousfiha A, Casanova JL,
Chatila T, Conley ME, Cunningham-Rundles C, Etzioni A, Holland SM,
Klein C, Nonoyama S, Ochs HD, Oksenhendler E, Puck JM, Sullivan KE,
Tang ML, Franco JL, Gaspar HB. Primary Immunodeficiency Diseases: an
Update on the Classification from the International Union of
Immunological Societies Expert Committee for Primary Immunodeficiency
2015. J Clin Immunol. 2015 Nov; 35(8):696-726 http://dx.doi.org/10.1007/s10875-015-0201-1 PMID:26482257
- Lehman H. Skin manifestations of primary immune deficiency. Clin Rev Allergy Immunol 2014;46:112 119 http://dx.doi.org/10.1007/s12016-013-8377-8 PMID:23760761
JHS, Wulffraat NM, Kuijpers TW. The skin in primary immunodeficiency
disorders. Eur J Dermatol 2005;15: 425- 432. PMID:16280293
A , Farhoudi A, Moin M, Pourpak Z, Bazargan N. Cutaneous Manifestations
of Primary Immunodeficiency Diseases in Children. Iran J Allergy Asthma
Immunol 2006;5:121-126. http://dx.doi.org/05.03/ijaai.121126 PMID:17237563
- Al Herz W, Nanda A. Skin manifestations in primary immunodeficient children. Pediatr Dermatol 2011; 28:494 501. http://dx.doi.org/10.1111/j.1525-1470.2011.01409.x PMID:21453308
Elfaituri S, Matoug I .Cutaneous Manifestations of Primary
Immunodeficiency Diseases in Libyan Children. J Clin Dermatol Ther
2017;4: 025. http://dx.doi.org/10.24966/CDT-8771/100025
JE, Azar AE, Chong HJ, Jongco AM 3rd, Prince BT. Considerations in the
Diagnosis of Chronic Granulomatous Disease. J Pediatric Infect Dis Soc
2018; 7(suppl 1):S6-S11. http://dx.doi.org/10.1093/jpids/piy007 PMID:29746674
S L. Clinical Immunology Review Series: An approach to the patient with
recurrent superficial abscesses. Clin Exp Immunol 2008; 152(3):397–405.
Z, Norouzi S, Mamishi S, Rezaei N. BCGiosis as a presenting feature of
a child with chronic granulomatous disease. Braz J Infect Dis 2011;15:
- Galal N , Boutros J,
Marsafy A, Kong XF, Feinberg J, Casanova JL, Boisson-Dupuis S,
Bustamante J. Mendelian susceptibility to mycobacterial disease in
egyptian children. Mediterr J Hematol Infect Dis 2012. http://dx.doi.org/10.4084/MJHID.2012.033 PMID:22708048
S, Aghamohammadi A, Mamishi S, et al. Bacillus Calmette-Guérin (BCG)
complications associated with primary immunodeficiency diseases. J
Infect 2012;64:543–54. http://dx.doi.org/10.1016/j.jinf.2012.03.012 PMID:22430715
Beaucoudrey L, Samarina A, Bustamante J, Cobat A, Boisson-Dupuis S, et
al. Revisiting human IL-12Rβ1 deficiency: a survey of 141 patients from
30 countries. Medicine (Baltimore) 2010; 89: 381-402. http://dx.doi.org/10.1097/MD.0b013e3181fdd832 PMID:21057261
N , Baccar Y, Mustapha IB, Ouederni M, Chouaibi S, El Fekih N,
Barbouche MR, Fezaa B, Kouki R, Hmida S, Mellouli F, Bejaoui M. Oral
HPV infection and MHC class II deficiency (A study of two cases
with atypical outcome). Clin Mol Allergy. 2012 Apr 23;10(1):6. http://dx.doi.org/10.1186/1476-7961-10-6 PMID:22524894
SM, Dominguez M, Ilmarinen T, Costigan C, Irvine D. Dermatological
manifestations of autoimmune polyendocrinopathy candidiasis ectodermal
dystrophy syndrome. Br J Dermatol 2006;154:1088 - 1093. http://dx.doi.org/10.1111/j.1365-2133.2006.07166.x PMID:16704638
A, Berron-Perez R, Ruiz-Maldonado R. Cutaneous markers of primary
immunodeficiency diseases in children. Pediatr Dermatol. 2000
- Imai K, Morio T, Zhu Y, et al. Clinical course of patients with WASP gene mutations. Blood 2004;103:456-464. http://dx.doi.org/10.1182/blood-2003-05-1480 PMID:12969986
M, Castiello MC, Pala F, Bosticardo M, Villa A. Autoimmunity in
wiskott-Aldrich syndrome: an unsolved enigma. Front
Immunol.2012;3:209. http://dx.doi.org/10.3389/fimmu.2012.00209 PMID:2282671
M, Vincent QB, Frange P, et al: Major histocompatibility complex class
II expression deficiency caused by a RFXANK founder mutation: a survey
of 35 patients Blood 2011;118(19):5108-5118. http://dx.doi.org/10.1182/blood-2011-05-352716 PMID:21908431
A, Kycler Z, Pietrucha B, Heropolitanska-Pliszka E, Breborowicz A, et
al. The hyperimmunoglobulin E syndrome - clinical manifestation
diversity in primary immune deficiency. J Rare Dis 2011 ;6:76. http://dx.doi.org/10.1186/1750-1172-6-76 PMID:22085750
A, Moghaddam ZG, Abolhassani H, Hallaji Z, Mortazavi H, Pourhamdi S, et
al. Investigation of underlying primary immunodeficiencies in patients
with severe atopic dermatitis. Allergol Immunopathol (Madr) 2014;
42(4):336- 341. http://dx.doi.org/10.1016/j.aller.2013.02.004 PMID:23735167
LY, Verhagen MM, Haraldsson A, Wulffraat N, Driessen GJ, Netea MG,
Weemaes CM, Seyger MM, van Deuren M. Cutaneous granulomas in ataxia
telangiectasia and other primary immunodeficiencies: Reflection of
inappropriate immune regulation? Dermatology 2011;223(1):13-19. http://dx.doi.org/10.1159/000330335 PMID:21876338
D, Vega AK, Torres Rusillo S, Montero E, Martinez LJ, Santamaría M, et
al. Molecular and functional characterization of a cohort of Spanish
patients with ataxia telangiectasia. Neuromolecular Med 2017;
19(1):161-174. http://dx.doi.org/10.1007/s12017-016-8440 PMID:27664052
S , Berkun Y, Ben-Zeev B, Levi YB, Barziliai A, Nissenkorn A.
Dermatologic manifestations of ataxia- telangiectasia syndrome. J Am
Acad Dermatol 2013;68(6):932-6. http://dx.doi.org/10.1016/j.jaad.2012.12.950 PMID:23360865
L, Parolini S, Prandini A, Tabellini G, Antolini M, Kingsmore SF,
Badolato R . Clinical, laboratory and molecular signs of
immunodeficiency in patients with partial oculo- cutaneous albinism.
Orphanet J Rare Dis 2013; 17(8):168. http://dx.doi.org/10.1186/1750-1172-8-168 PMID:24134793
- Notarangelo LD .PIDs and cancer: an evolving story. Blood 2010;116(8):1189-1190. http://dx.doi.org/10.1182/blood-2010-06-286179 PMID:20798238
E, Tabarsi P, Mansouri D, Khosravi A, Garssen J, Velayati A, Adcock IM.
Cancers Related to Immunodeficiencies: Update and Perspectives. Front
Immunol 2016;7:365.e Collection 2016. http://dx.doi.org/10.3389/fimmu.2016.00365 PMID: 27703456
PC, Eng KH, Singel KL, Abrams SI, Odunsi K, Moysich KB, Fuleihan R,
Garabedian E , Lugar P, Ochs HD, Bonilla FA, Buckley RH, Sullivan KE,
Ballas ZK, Cunningham-Rundles C, Segal BH. Cancer in primary
immunodeficiency diseases: Cancer incidence in the United States Immune
Deficiency Network Registry. J Allergy Clin Immunol.
2018;141(3):1028-1035. http://dx.doi.org/10.1016/j.jaci.2017.05.024 PMID:28606585
C , Mellouli F, Duprez R, Chédeville G, Neven B, Fraitag S, Delaunay J,
Le Deist F, Fischer A, Blanche S, Bodemer C, Gessain A, Casanova JL,
Bejaoui M. Kaposi's sarcoma in a child with Wiskott-Aldrich syndrome.
Eur J Pediatr.2006;165(7):453-457. http://dx.doi.org/10.1007/s00431-006-0107-2 PMID:16602009