1

Introduction

Chronic rhinosinusitis (CRS) is a chronic inflammatory condition of the sinonasal mucosa symptomatically characterized by purulent rhinorrhea, nasal obstruction, facial pain and pressure . Various mechanisms, such as overly exuberant inflammation or aberrant functioning of the sinonasal mucosa, may predispose to or underlie the pathogenesis of CRS. Moreover, CRS itself is associated with a complex mucosal milieu consisting of inflammatory cytokines and cells as well as abnormal cyto-architecture of the sinonasal mucosa . In this context, it is impossible to predict the inciting factor for the development of CRS in any given patient by physical examination of the sinonasal mucosa at the time of presentation.

Increasing evidence has pointed to the important role of the sinonasal epithelium in modulating the immune response, driving mucociliary clearance, and serving as barrier to inhaled antigens . These functions are carried out in a carefully coordinated manner through not only a dynamic interaction with the sinonasal environment but also a complex communication network between the epithelial cells of the sinonasal mucosa. Communication between epithelial cells can be mediated through paracrine signaling as well as cell-to-cell ion currents. These cell-to-cell ion currents are carried by gap junctions . Gap junctions consist of transmembrane proteins that aggregate to form ion channels, which allow ion current to flow directly from one epithelial cell to the next. In vertebrates, the transmembrane proteins comprising most of these gap junctions are a part of a family of genes called connexins . Communication through gap junctions allows for the synchronized beating of cilia on the respiratory epithelium that underlies mucociliary clearance . Connexins are also involved in the maintenance of tight junctions which establish cellular barriers between sinonasal epithelial cells . As such, connexin proteins may be critical to maintaining the normal function of the sinonasal epithelium.

Connexin proteins 26, 30, 32 and 43 are commonly implicated in human disease. Mutations in some of these proteins have been associated with sensorineural hearing loss through disruption of ion currents necessary for proper functioning of supportive non-sensory epithelial cells in the inner ear . Decreased connexin function has been suspected in allergic rhinitis as well . Although no clear connections between connexin 32 and sinonasal pathophysiology have been reported, connexin 32 mutations have been associated with specific disease processes . Connexin 43 has been previously shown to be expressed in sinonasal epithelial cells and olfactory neurons . Expression of connexin 43 in sinonasal epithelial cells has also been shown to decrease in the presence of the inflammatory mediator LPS . This inflammatory regulation of connexin 43 suggests one possible mechanism for connexin-mediated dysfunction in the setting of sinonasal inflammation. We have previously reported that mutations in connexin 26 and connexin 30 do not appear to be particularly enriched in patients with chronic recurrent sinusitis (CRS) including those with recurrent acute rhinosinusitis (RARS) . In this study, we assess for the presence of mutations in connexin 32 and connexin 43, which may lead to dysfunction of these proteins in vivo , in patients with CRS including RARS.

2

Methods

This study was approved by the institutional review board at the Massachusetts Eye and Ear Infirmary.

This is a prospective case series of 19 pediatric and adult patients who presented with CRS including RARS at a single tertiary care facility. CRS and RARS were defined according to previous guideline-established criteria . Disease confirmation by nasal endoscopy and/or computed tomography (CT) was required. Exclusion criteria included known disorders of mucociliary clearance such as Kartagener’s syndrome and cystic fibrosis. The following data were collected in addition to the defining diagnosis: age; gender; duration of symptoms; history of sensorineural hearing loss (SNHL); history of otitis media and whether tympanostomy tube placement had been required; and family history of SNHL, otitis media or rhinosinusitis. Two buccal mucosal swabs using cytology brushes were obtained in standard fashion. The buccal swab samples were processed at the Partners Healthcare Center for Personalized Genetic Medicine ( http://pcpgm.partners.org/ ). Genomic DNA was extracted using the Puregene kit (Gentra Systems, Minneapolis, MN) according to the manufacturer’s instructions. Eighteen out of nineteen patients had extractable DNA which was processed initially for connexin gene 32 and subsequently for connexin gene 43.

2

Methods

This study was approved by the institutional review board at the Massachusetts Eye and Ear Infirmary.

This is a prospective case series of 19 pediatric and adult patients who presented with CRS including RARS at a single tertiary care facility. CRS and RARS were defined according to previous guideline-established criteria . Disease confirmation by nasal endoscopy and/or computed tomography (CT) was required. Exclusion criteria included known disorders of mucociliary clearance such as Kartagener’s syndrome and cystic fibrosis. The following data were collected in addition to the defining diagnosis: age; gender; duration of symptoms; history of sensorineural hearing loss (SNHL); history of otitis media and whether tympanostomy tube placement had been required; and family history of SNHL, otitis media or rhinosinusitis. Two buccal mucosal swabs using cytology brushes were obtained in standard fashion. The buccal swab samples were processed at the Partners Healthcare Center for Personalized Genetic Medicine ( http://pcpgm.partners.org/ ). Genomic DNA was extracted using the Puregene kit (Gentra Systems, Minneapolis, MN) according to the manufacturer’s instructions. Eighteen out of nineteen patients had extractable DNA which was processed initially for connexin gene 32 and subsequently for connexin gene 43.

3

Results

Our cohort consisted of 19 individuals with an average age of 20.4 years (range 6–33 years) [ Table 1 ]. These four men and fifteen women with CRS including RARS were drawn from a previously described cohort that was utilized to study connexin 26 and 30 mutations. These particular patients were chosen because they were the youngest of the larger cohort and therefore the most likely to have a genetic etiology (i.e. connexin mutation) for their RARS or CRS. In these patients the average duration of paranasal sinus disease prior to presentation was 5.7 years (rage 1–19 years).

Table 1

Patient characteristics. * .

Patient	Age (yrs)	Gen	Dura (yrs)	Hx OM	M + T	SNHL	Fm Hx	# Fm Mem	Diagnosis	Connexin 32	Connexin 43
1	26	F	3	No	No	No	No	0	CRS	Normal	Het R239R
4	8	F	3	No	No	No	Yes	2	RARS	Het V193I	Normal
5	6	M	4	No	No	No	Yes	1	RARS	Normal	Normal
6	15	F	3	Yes	No	No	Yes	1	CRS	Normal	Normal
11	28	F	4	No	No	No	No	0	RARS	Normal	Het 3′UTR
12	8	F	3	Yes	No	No	Yes	2	RARS	Normal	Normal
16	26	F	6	Yes	Yes	No	Yes	2	RARS	Normal	Normal
17	23	F	3	Yes	Yes	No	Yes	2	RARS	Normal	Normal
23	8	M	6	Yes	No	No	Yes	2	RARS	Normal	Normal
24	16	F	4	No	No	No	Yes	4	RARS	Normal	Normal
26	8	F	5	No	No	No	Yes	1	CRS	Normal	Normal
28	27	M	13	No	No	No	Yes	1	CRS	Normal	Normal
29	27	F	19	Yes	No	No	Yes	2	RARS	Normal	Normal
31	30	M	5	No	No	No	No	0	RARS	⁎⁎	⁎⁎
32	30	F	1	No	No	No	Yes	1	CRS	Normal	Normal
34	10	F	3	No	No	No	No	0	RARS	Normal	Normal
37	28	F	10	Yes	No	No	No	0	RARS	Normal	Normal
39	31	F	10	No	No	No	Yes	2	RARS	Normal	Normal
40	33	F	3	No	No	No	No	0	RARS	Normal	Normal

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