[4]. Sam et al . [5] described three generations of a single

family that presented autosomal dominant CMC without

endocrinopathy. In fact, CMC could be considered a syn-

drome that presents different clinical forms, probably

involving different genetic defects. A cellular immune

defect has been suggested as the central factor of CMC.

The disturbance could be located in effector cells (mac-

rophages, natural killer or cytotoxic lymphocytes) or at the

regulatory level, involving T cell cytokines or possibly

antigen presenting cells (APCs), as these are infl uenced by

regulatory cytokines [6 – 8]. The underlying defect is poorly

understood and further studies are required to elucidate the

pathophysiology of CMC.

Case report

NRSP, a 39-year-old Caucasian woman born in 1971

to non-consanguineous parents, was two years old when

she fi rst presented with recurrent severe oral candidiasis

that led to a growth defi cit. When she was three years

old, ungueal and cutaneous candidiasis (Fig. 1) appeared

on her face, extremities and scalp, associated with alopecia

(Fig. 2). It is important to stress that these pictures were

taken when the patient was 26 years old.

At 21 years of age in 1992, she developed arthralgias

and arthritis in large joints, associated with high titers of

Received 26 March 2011 ; Received in fi nal revised form 31 August 2011;

Accepted 7 September 2011

Correspondence: Dewton de Moraes-Vasconcelos, University of S ã o

Paulo School of Medicine, Dermatology, Av. Dr. Eneas de Carval-

ho Aguiar, 470, Building 2, 3rd fl oor, Sao Paulo, 05403-000 Brazil.

E-mail: dmvascon@usp.br

Chronic mucocutaneous candidiasis and systemic

lupus erythematosus: a new variant of chronic

mucocutaneous candidiasis?

DEWTON DE MORAES-VASCONCELOS * , MAURICIO DOMINGUES-FERREIRA * , PATRICIA DE CAMPOS PIERI † &

ALBERTO JOSE DA SILVA DUARTE ‡

Departments of * Dermatology , † Pediatrics and ‡ Pathology , University of S ã o Paulo School of Medicine , S ã o Paulo , Brazil

Chronic mucocutaneous candidiasis (CMC) is characterized by susceptibility to Candida infection of skin, nails, and mucous membranes. Autoimmune endocrin-opathies are common in CMC patients, but there are no reports of the involvement of systemic autoimmune disorders. We present here the fi rst case of this kind of associa-tion in a patient with an autosomal dominant variant of CMC. The individual had had this disorder since childhood and systemic lupus erythematosus with secondary antiphospholipid syndrome, as well as renal, articular and hepatic manifestations with-out thymoma.

Keywords Candida , chronic mucocutaneous candidiasis , autoimmune diseases , systemic lupus erythematosus , autosomal dominant inheritance

Introduction

Chronic mucocutaneous candidiasis (CMC) refers to a

heterogeneous group of rare disorders characterized by

recurrent or persistent superfi cial infections of the skin,

mucous membranes, and nails by Candida spp., usually

Candida albicans [1] . Very occasionally these patients

present with systemic candidiasis, with symptoms starting

in infancy and childhood, or even adulthood, with familial

or sporadic occurrence. In relation to the association of

CMC with autoimmunity, there have been two other asso-

ciations that have been described. The fi rst one involves

patients who present with autoimmune polyendocrinopa-

thy and candidiasis with ectodermal dysplasia (APECED),

showing an autosomal recessive inheritance. In this group,

mutations in the autoimmune regulator gene ( AIRE ) have

been identifi ed [2 – 4]. The second relates to an autosomal

dominant form of CMC that occurs with hypothyroidism

[3]. It is believed that the association with autoimmune

endocrinopathy represents at least 50% of cases of CMC

© 2012 ISHAM DOI: 10.3109/13693786.2011.622305

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400 de Moraes-Vasconcelos et al .

anti-double stranded DNA antibodies (1/600), chronic

lymphadenitis with extensive necrosis secondary to vascu-

litis and reactive hepatitis, leading to a diagnosis of

systemic lupus erythematosus (SLE). She was treated

with high doses of corticosteroids (methylprednisolone

500 mg/day pulses followed by prednisone 80 mg/day) and

azathioprine (100 mg/day), which led to worsening of

her infectious manifestations and eventually to bone mar-

row hypoplasia. In spite of the Candida infections since

childhood, it was only when she was 21 that CMC was

Fig. 1 Left foot showing scaly skin lesions and keratotic nail associated with paronychia. Picture taken when the patient was 26 years old.

Fig. 2 Scalp showed scarring alopecia. It is possible to observe the presence of collateral circulation in left shoulder, secondary to deep vein thrombosis

of the subclavian and jugular veins, when the patient was 26 years old.

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CMC and systemic lupus erythematosus 401

She was treated and recovered satisfactorily without

sequelae. The patient was submitted to several endosco-

pies involving biopsies due to the esophageal candidi-

asis (Fig. 3). She required anterograde esophageal

dilation in 2004 because of an esophageal stenosis, with

good results.

Today she is stable and continues treatment with itra-

conazole 400 mg/day, prednisone 5 mg/day and sodium

alendronate 10 mg/day. The patient has no history of CMC

in her family, although both her daughters (born in 1994

and 1997) have been diagnosed with CMC. In one, the

CMC was associated with hypothyroidism, with her symp-

toms beginning when she was 19 months old with oral

candidiasis. She is currently 16 years old and has buccal

and ungueal lesions due to C. albicans . The younger

daughter, now 13 years old, started prolonged episodes of

oral candidiasis and onychomycosis when she was two

years old. She was also found to have mycotic cutaneous

lesions that eventually disappeared and had two episodes

of Norwegian scabies at the ages of three and fi ve years

old. The mucocutaneous manifestations of candidiasis are

similar between the patient and her two daughters. On the

diagnosed leading to the withdrawal of corticosteroid and

azathioprine treatment and the initiation of G-CSF therapy

(300 μ g every other day). She required fi ve doses to recover

normal granulocyte counts. Her clinical features improved

and ketoconazole treatment (400 mg/day) was started to

control candidiasis, but one year later she was found

to have acute hepatitis, probably due to the use of this

antifungal. Therefore, it was replaced by fl uconazole,

300 mg/day and the patient recovered. In 1997, when she

was 26 years old and pregnant with her second daughter,

she was diagnosed as having nephrotic syndrome associ-

ated with focal segmental glomerulonephritis. She was

initially treated with an immunosuppressive dose of pred-

nisone (80 mg/day) until the remission of renal and articu-

lar manifestations, with subsequent tapering of the drug.

In the same year she again presented with hepatitis

and as a result, fl uconazole was substituted by itracon-

azole 400 mg/day. The clinical course was satisfactory

with control of the symptoms, but she continued to pres-

ent oral and esophageal candidiasis due to azole sensi-

tive C. albicans . In 1998 she had jugular and subclavian

thrombosis secondary to antiphospholipid antibodies.

Fig. 3 Upper digestive endoscopy: Esophagus covered by a fungal whitish layer due to Candida superfi cial infection. It is also possible to observe the

esophageal stenosis in the lower third of the organ.

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other hand, the patient presents only systemic manifesta-

tions of autoimmunity, without any endocrine organ

affected.

The diagnosis of mucocutaneous candidiasis was con-

fi rmed by identifi cation of C. albicans in cultures inocu-

lated with samples from oral and esophageal lesions, as

well as skin and ungueal specimens. Species identifi cation

was performed at the Laboratory of Mycology (LIM-53)

of the Instituto de Medicina Tropical de S ã o Paulo. Iso-

lated species were subcultured in ChromAgar Candida,

followed by micromorphological observations and bio-

chemical tests.

The patient has always presented normal levels of

plasma cortisol, serum calcium, thyroxin, thyroid-stimulat-

ing hormones and immunoglobulins IgG, IgM, IgA and

IgE. She has had numerous negative HIV tests. She has

shown no alteration in complement proteins C3 and C4,

and APH50 and CH50.

She presented severe proteinuria, up to 23 g of protein

per liter, only when the glomerulonephritis was active. At

that time she presented with ANA (1/1280) and anti-DNA

(104 IU/ml). Her peripheral blood lymphocyte prolifera-

tion test showed a normal response to phytohemagglutinin

(PHA), OKT3 and pokeweed (PWM) and a normal response

to Candida metabolic antigen (CMA), tested by tritiated

thymidine incorporation. Lymphocytes counts of CD3 � ,

CD4 � , CD8 � , CD19 � , CD3-CD16 � CD56 � were all

normal. Her Natural Killer Activity was decreased, as mea-

sured by the K562 lytic assay. The quantifi cation of cytok-

ines by ELISA in culture supernatants of PBMC stimulated

by CMA showed signifi cantly reduced levels of IL-2 and

IFN-gamma, but normal IL-4 and IL-10. The genetic anal-

ysis did not detect any mutation in the AIRE gene, exclud-

ing the possibility of an atypical presentation of

APECED.

Discussion

The diagnosis of CMC in this patient was characterized by

her history of persistent oral, esophageal and ungueal can-

didiasis and the absence of other causes of immunodefi -

ciencies, such as diabetes mellitus, cancer, AIDS, Di

George syndrome and severe combined immune defi cien-

cies. Her symptoms of chronic candidiasis began when she

was two years old, but no autoimmune manifestation

occurred until she was 21 years old. At that time, systemic

autoimmune manifestations were observed, such as arth-

ralgias and arthritis in large joints, chronic lymphadenitis

with extensive necrosis secondary to vasculitis and reactive

hepatitis, followed by nephrotic syndrome at the age of 26,

due to SLE. This diagnosis was established by the high

levels of anti-DNA (104 IU/ml) and ANA (1/1280) titers,

associated with clinical features, such as arthralgias and

arthritis; later on glomerulonephritis and eventually jugular

and subclavian thrombosis secondary to anti-phospholipid

antibodies.

Organ-specifi c endocrine autoimmunity is common

in patients with CMC, but systemic manifestations are

very rare events. In the medical literature, only one case

report of sporadic CMC associated with systemic auto-

immune manifestation (SLE), hypergammaglobulinemia

and thymoma has been described [6]. In this case, thy-

moma could explain the presence of the systemic auto-

immune manifestation. Moreover, the autoimmune

manifestations preceded the onset of candidiasis by

two years, which was followed three years later by thy-

moma. Recently, it was shown that CMC with thymoma

present autoantibodies to several cytokines of the IL-17

family [7,8].

The disorder seems to be different in our patient in

that she had manifestations of candidiasis since child-

hood, followed by autoimmune manifestations after

nearly 20 years. Her case demonstrates CMC associated

with SLE without thymoma. She has two daughters, both

of whom present CMC, characterizing a hereditary dis-

ease. One of them has CMC associated with hypothyroid-

ism, an organ-specifi c autoimmune manifestation, and

the other has only shown CMC up to now. This genetic

transmission characterizes an autosomal dominant inher-

itance, different from the variants previously described

[5,7]. This unique case is probably a new form of CMC

that is characterized by systemic autoimune manifesta-

tion associated with an autosomal dominant inheritance.

Follow-up on this family will continue, in an attempt to

extend our evaluation involving the genetic aspects of

this disorder.

To our knowledge this is the fi rst described case of auto-

somal dominant CMC with Systemic Lupus erythematosus.

Acknowledgements

This work was partially supported by Funda ç ã o de Amparo

a Pesquisa de S ã o Paulo (FAPESP) grant number,

02/00024-2 and 99/07399-7.

Declaration of interest : The authors report no confl icts of

interest. The authors alone are responsible for the content

and writing of the paper.

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This paper was fi rst published online on Early Online on 10 October 2011.

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