Nasal Mucosa Ulceration and Septal Perforation As Initial Presentation of a Patient

International Journal of Pediatric Otorhinolaryngology Extra 9 (2014) 56–59

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International Journal of Pediatric Otorhinolaryngology

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Case Report

Nasal mucosa ulceration and septal perforation as initial presentation of a patient

with probable Behcet’s disease

Annika Meyer, Mary Czerny, Jastin Antisdel *

Department of Otolaryngology, Saint Louis University School of Medicine, United States

A R T I C L E I N F O A B S T R A C T

Article history: Behcet’s disease is a vasculitis that affects multiple systems in the body, classically oral and genital

Received 3 September 2013

mucosa. Nasal mucosa involvement is a rare manifestation of the disease, reported in only a handful of

Accepted 7 January 2014

patients. We present an HLA-B51 positive, suspected Behcet’s patient with predominantly nasal

manifestations including epistaxis, nasal mucosa ulceration and septal perforation. Her nasal symptoms

Keywords:

have improved since being started on a daily regimen of colchicine. We believe this case supports the

Behcet’s disease

wide clinical heterogeneity of the disorder, and serves as a reminder to consider Behcet’s disease when a

Behcet syndrome

patient presents with an atypical head and neck manifestation.

HLA-B5

HLA-B51

Nasal septum perforation

Nasal ulcer

1. Report of a case room and showed evidence of ulceration, acute and chronic

inﬂammation, squamous metaplasia, and ﬁbrosis.

A 14-year-old girl presented to an academic pediatric Nasal irrigation and topical antibiotics were prescribed. Over

otolaryngology clinic with a 2-year history of recurrent epistaxis. the next three months the nasal ulcer decreased in size by

She described the episodes as typical nosebleeds, usually from the approximately 40% by endoscopic visualization, though she was

right nostril; they would last for about 10 min and could be still having regular epistaxis. She also complained of chronic

stopped with pressure. No further intervention had been neces- headaches and recurrent small oral ulcers. The patient’s other

sary. Rigid nasal endoscopy performed bilaterally revealed an medical problems include nodular acne vulgaris, hyperhidrosis of

inﬂamed, abnormal-appearing mucosa with an ulcerated lesion the axillae, and attention deﬁcit hyperactivity disorder, for which

over her right septum covered with a thin crust (Figs. 1 and 2). The she is receiving treatment with norgestimate-ethinyl estradiol,

etiology of the lesion was unclear. There was no history of trauma, axillary botulinum injections, and a combination of aripiprazole

illicit drug abuse, or application of nasal sprays. The patient and methylphenidate, respectively. Her acne vulgaris has been

appeared to be Caucasian with fair skin, but information on her resistant to oral contraceptive treatment, with failure to improve

ethnic background was not available as she was adopted. on two prior formulations. She has also been noted to have

Granulomatosis with polyangiitis (GPA, formerly Wegner’s gran- persistent livedo reticularis on physical exam.

ulomatosis), Churg Strauss syndrome, and sarcoidosis were The following month she began to bleed from the left nostril.

considered but C-ANCA, P-ANCA, and glomerular basement She was found to have a small ulceration and a hypervascular area

membrane antibodies were negative, and an angiotensin convert- on the left septum (Fig. 3), which was cauterized and packed with

ing enzyme (ACE) level was normal. A chest radiograph showed no Gelfoam. This lesion was biopsied and found to have pathology

evidence of hilar adenopathy. The patient denied symptoms very similar to the previous biopsy. She continued to have near-

suggestive of other sinonasal, lung, or kidney problems. A daily epistaxis. Lab results at this time showed elevated total

laboratory evaluation including ESR, LDH, CK, TSH, and T4 was complement, with normal levels of C3 and C4. She had

normal, and anti-thyroglobulin and anti-TPO antibodies were indeterminate test results for lupus anticoagulant. Her IgM and

negative. A septal mucosal biopsy was performed in the operating IgG anticardiolipin, histone, and beta-2 glycoprotein antibodies

were negative. The remaining autoimmune workup was negative,

including rheumatoid factor, ANA, chromatin, dsDNA, SS-A, SS-B,

* Corresponding author. Tel.: +1 314 577 8884; fax: +1 314 268 5111.

E-mail address: [email protected] (J. Antisdel). as well as Smith, RNP, and cyclic citrullin peptide antibodies.

A. Meyer et al. / International Journal of Pediatric Otorhinolaryngology Extra 9 (2014) 56–59 57

Fig. 1. Right nasal lesion. Endoscopic view of the crusted, ulcerated lesion of the

Fig. 3. Left nasal lesion. Endoscopic view of small ulceration and more anterior

mucosa of the right nasal septum.

hypervascular region of the left nasal septum.

Several weeks later, the patient presented to the emergency gynecologic exam showed normal vaginal mucosa with no

room with epistaxis. The ulceration had eroded through the nasal ulceration. She has, however, complained of persistent joint pain,

septum, resulting in a septal perforation. A septal button was burning with urination, and recurrent right eye blurriness. Given

placed at that time (Fig. 4). The patient was referred to positivity for HLA-B51 in the setting of oral and nasal ulceration

rheumatology for further evaluation. Her Factor V Leiden, and myriad nonspeciﬁc (but potentially rheumatologic) com-

prothrombin, antithrombin III, protein C and protein S were plaints, the patient was started on colchicine 0.6 mg daily for

normal. She was found to have a heterozygous A1298C mutation presumed Behcet’s disease. Her epistaxis has decreased from 3–4

for methylenetetrahydrofolate reductase (MTHFR). Anti-Saccha- to 1–2 episodes per week since starting the colchicine. She

romyces cerevisiae antibodies IgG and IgA were negative. She continues to have a septal perforation with septal button in place

was found to be a carrier of HLA-B51, which is found in greater and is followed by rheumatology.

than 60% of patients with Behcet’s disease. She was noted to

develop a red bump at the needle stick site immediately

2. Discussion

following lab draws, but true pathergy should occur 24–48 h

later. An ophthalmologic exam was negative for uveitis and a

Behcet’s disease is a systemic leukocytoclastic vasculitis

characterized by recurrent episodes of mucosal apthae, classically

of the oral and genital mucosa, and inﬂammatory ocular

involvement such as uveitis. However, any system may be

affected, with multiple other manifestations involving the skin,

joints, vessels, as well as the CNS and gastrointestinal tract [1].

Involvement of the nasal mucosa in Behcet’s disease is rare and

Fig. 2. Right nasal lesion, another view. Intraoperative endoscopic view of the lesion

on the right nasal septum after crust removal. Fig. 4. Septal button. Endoscopic view of the septal button from the left nasal cavity.

58 A. Meyer et al. / International Journal of Pediatric Otorhinolaryngology Extra 9 (2014) 56–59

only a few cases have been reported in the literature. In a cross- Other explanations for the contributory relationship include

sectional study of nasal involvement in Behcet’s patients, only 2 cross-reactivity between self-antigens and HLA-B51 itself [9], or

out of 400 patients reviewed had nasal ulcers [2]. More common the presence of a linkage disequilibrium with a nearby and truly

examples of nasal involvement included dysosmia in 15 patients causal gene such as the nearby alleles for tumor necrosis factor

and nasal obstruction in 10 patients. No patients reported a history and MHC class I-related (MIC-A and MIC-B) genes, which are

of epistaxis or septal perforation. involved in the immune response [9,10]. However, the contribu-

Perforations of the nasal septum occur when the blood supply tion of HLA-B51 to the overall genetic susceptibility is estimated

to the avascular cartilage is interrupted bilaterally at the same to be only 20%, implying that genes outside the MHC complex are

location. The most common cause is iatrogenic injury from prior involved in the pathogenesis of Behcet’s disease [10]. Recently,

nasal surgery, followed by trauma, nasal spray use, inhaled drug two large genome-wide association studies reported a correlation

use, autoimmune disease, neoplasia, and inﬂammatory or infec- between single nucleotide polymorphisms (SNP) of interleukin

tious origins [3]. A literature search revealed only one published (IL)-10 and IL-23R/IL-12RB2 genes and Behcet’s disease [10].

case report of a Behcet’s patient presenting with a destructive Evidently the pathogenesis of Behcet’s disease is complicated, and

sinusopathy, including septal perforation and amputation of without a clear etiology it has been difﬁcult to delineate effective

conchae [4]. That patient had severe widespread disease with pharmacotherapy.

middle ear involvement and hearing loss, dysphonic laryngitis, The mainstays of treatment of Behcet’s disease rely on

severe oral and genital ulcerations, and skin manifestations. The immunosuppression and anti-inﬂammation. Topical and systemic

currently presented case is the ﬁrst to our knowledge of a patient corticosteroids may be used to control the inﬂammatory process.

with suspected Behcet’s disease presenting predominantly with Many immunosuppressant agents are used, including colchicine,

nasal manifestations with relative sparing of other organs, save cyclophosphamide, chlorambucil, methotrexate, azathioprine,

occasional minor oral ulceration and acneiform nodules. Diagnosis cyclosporine, tacrolimus, dapsone, and thalidomide. Though there

of Behcet’s disease is determined clinically with criteria including is variable success with each of these drugs and disease recurrence

various combinations of oral and genital aphthosis, with lesions of is common, the most popular agents prescribed are azathioprine,

the eyes, skin, and vessels [5]. Though our patient lacks classic cyclosporine, colchicine, and corticosteroids, either as single

ﬁndings such as genital ulcers and uveitis that are usually required agents or in combination [11]. Biologic agents including the

for diagnosis, we believe her HLA-B51 positive status paired with TNF-alpha monoclonal antibodies inﬂiximab and etanercept have

nasal and oral ulcers, in the absence of lab ﬁndings to suggest other shown some promise in cases that have failed standard therapy

conditions, designate Behcet’s disease as the most likely etiology. [11]. Recombinant human interferon alpha-2a has been used with

Nasal mucosa ulceration and septal perforation is more commonly favorable results in some cases of refractory ocular disease. A

a manifestation of GPA, lupus, primary antiphospholipid syn- number of physicians include antibiotics and antivirals to augment

drome, or sarcoidosis [6], all of which were ruled out in this patient. treatment to control the presence of pathogens that may be

This patient was found to have a heterozygous A1298C MTHFR inciting the disease process. Choosing the most appropriate

mutation, which, though not associated with mucosal ulceration or pharmacotherapy regimen is patient-dependent and may require

coagulopathy, has been associated with thrombosis and increased several attempts before medical remission is achieved, if at all.

risk for spontaneous abortion when patients are homozygous for When Behcet’s is suspected, patients must also undergo extensive

the mutation [7]. surveillance for other serious manifestations of the disease.

Behcet’s is originally a disease of countries along the ancient Treatment of nasal septal perforation depends on the size and

Silk Road with a high prevalence in the Mediterranean basin, location of the lesion, as well as the degree of discomfort

Turkey, Middle East countries, Japan, Korea, and China, though experienced by the patient. Most asymptomatic patients require

Behcet’s disease can be found globally due to migration [1]. In no treatment [3]. Conservative treatment includes symptomatic

contrast, the prevalence of Behcet’s disease in North America is control to decrease pain, epistaxis, and crusting with nasal

comparably low. No single gene has been identiﬁed as the cause of irrigation and emollients, or the non-surgical option of septal

Behcet’s disease, though there is a strong association with class I button placement [3], as in our patient. Septal buttons are placed

major histocompatibility complex (MHC) allele HLA-B5, particu- under local anesthesia to ﬁll the septal defect in order to prevent

larly the B51 portion of the broad allele. Meta-analysis of 4800 bleeding, obstruction, and whistling of air through the perforation.

cases and 16,289 controls showed an increased risk of developing Complicated or large perforations can be challenging to close and

Behcet’s disease by a factor of 5.78 (95% CI 5.00–6.67) in B5/B51 typically rely on the surgical grafting of well-vascularized mucosal

carriers, which increased to 5.90 (95% CI 4.87–7.16) when ﬂaps, sometimes also requiring cartilage or bone transplants [3].

considering HLA-B51 carriers alone [8]. Before rhinosurgery is considered in a patient with a systemic

Many etiologies have been postulated to explain how this gene disease that caused the initial perforation, the patient should

promotes the inﬂammatory changes characteristic of the disease. ideally be in remission with adequate control of inﬂammation to

HLA-B51 is thought to genetically predispose carriers to develop ensure optimal postsurgical outcomes.

Behcet’s disease via a T cell-mediated response. HLA-B51 may

selectively bind to and present certain microbial antigens that then Contributions

act as pathogenic peptides, possibly by cross-reacting with self-

antigens or by inducing a dysregulated immune response [9,10]. Annika Meyer: manuscript writing and preparation; Mary

Antigens from microbes such as streptococcus species and from Scaduto: manuscript editing and preparation; Jastin Antisdel: case

heat shock proteins have been shown to induce ﬁndings identiﬁcation, input and guidance, and manuscript editing.

characteristic of the disease, such as uveitis, in lab animals [9].

Behcet’s disease has recently been found to have clinical features of Conﬂicts of interest

an autoinﬂammatory disease as well, with increased activity of

neutrophils, natural killer (NK) cells, and cytotoxic T cells, as well The authors have no conﬂicts of interest to disclose.

as elevated levels of proinﬂammatory cytokines [9]. This non-

speciﬁc hyperactive inﬂammatory response is evidenced by the Acknowledgement

skin pathergy reaction, in which a small aseptic needle prick to the

skin results in an exaggerated papule or pustule. We received no ﬁnancial or material support for this report.

A. Meyer et al. / International Journal of Pediatric Otorhinolaryngology Extra 9 (2014) 56–59 59

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