International Journal of Pediatric Otorhinolaryngology 76 (2012) 443–446

Case report

Multiple branchial cleft anomalies in conjunction with a congenital dermal fistulaof the lower extremity: First report of the Guarisco–Winters syndrome§

Ryan Winters a,*, J. Lindhe Guarisco b

a Tulane University Department of Otolaryngology, 1430 Tulane Ave., SL-59, New Orleans, LA 70112, United Statesb Ochsner Clinic Foundation Department of Otolaryngology, 1514 Jefferson Highway, New Orleans, LA 70112, United States

A R T I C L E I N F O

Article history:

Received 28 August 2011

Received in revised form 29 November 2011

Accepted 1 December 2011

Available online 22 December 2011

Keywords:

Branchial cleft anomalies

Limb development

Embryology

A B S T R A C T

Branchial cleft anomalies are congenital remnants of the embryologic branchial clefts persisting past the

embryo stage. Most occur singly and sporadically, though syndromic associations are described.

Multiple branchial cleft anomalies coincident in the same patient are exceptionally rare, and rarer still

are peripheral dermal sinus tracts on the extremities, with one prior documented case. We report the

first case of multiple branchial cleft anomalies with a peripheral dermal sinus of the ipsilateral lower

extremity. Numerous concurrent congenital anomalies exist in the patient, representing the first

description of the Guarisco–Winters syndrome. The patient is intellectually and developmentally age-

appropriate in all other regards.

� 2011 Elsevier Ireland Ltd. All rights reserved.

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International Journal of Pediatric Otorhinolaryngology

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1. Case report

A 9-year-old Caucasian female presented for evaluation of adraining punctum of the skin of the right anterior neck. This lesionhad been present for her entire life, and had always had a scantmucoid discharge. For 3 days prior to her presentation she hadincreased foul-smelling purulent drainage accompanied by sorethroat and neck pain. Physical examination was remarkable for anenlarged, medialized right tonsil with peritonsillar abscess, as wellas a punctum of the right preauricular skin. This preauricularpunctum was non-tender, and scant mucoid fluid was expressiblewith palpation (Fig. 1). The parents noted that her preauriculararea would become tender and edematous with upper respiratoryinfections, occasionally developing a palpable, cordlike subcuta-neous lesion extending toward her external ear. Examination of theears revealed a 10% posterior superior perforation of the tympanicmembrane without effusion. No otorrhea was present, and thefamily denied a history of recurrent otitis or otorrhea. Audiologicevaluation revealed normal pure-tone and speech recognitionthresholds.

Examination of the extremities revealed a punctum on thedorsum of the right foot, with mucoid fluid expressed withpalpation (Fig. 2). The family reported she had a similar lesion on

§ The authors have no financial conflicts of interest to disclose. These data were

presented, in abstract form, at the Southern Section Meeting of the Triological

Society on January 28, 2011, in Scottsdale, Arizona.

* Corresponding author. Tel.: +1 504 988 5454; fax: +1 504 988 7846.

E-mail address: rwinters@tulane.edu (R. Winters).

0165-5876/$ – see front matter � 2011 Elsevier Ireland Ltd. All rights reserved.

doi:10.1016/j.ijporl.2011.12.001

the posterior right calf. These lesions had become periodicallyinfected in the past, with development of erythema and edemaextending down the lateral leg to the foot, accompanied bypurulent drainage. This calf lesion had been inscised and drained inthe past, but the infection had recurred since drainage. Develop-mentally, she reached all of her milestones appropriately, and wasconsistently in the 40th percentile in height, weight and headcircumference.

Her past medical history was remarkable for multiple othercongenital anomalies including atrial septal and ventricular septaldefects repaired in infancy, as well as congenital renal anomaliesrequiring right nephrectomy and bilateral ureteral implantation.She was born at 32 weeks gestation due to maternal preeclampsia,and she was noted to have a 2-vessel umbilical cord after delivery.

Computed tomography (CT) of the head and neck with contrastwas performed, which revealed an infected sinus tract consistentwith a 2nd branchial cleft fistula extending from the right tonsillarfossa to the right anterior neck (Fig. 3). A subcutaneous cysticlesion, 1 cm in greatest dimension, was noted in the rightpreauricular area, with no evidence of extension or sinus tractto the ear. The patient underwent successful abscess tonsillectomyand excision of the infected 2nd branchial cleft fistula. Intra-operative fistulogram with gastrograffin confirmed the path of the2nd branchial cleft fistula extending from the tonsillar fossa to theskin of the neck (Fig. 4). An abscess tonsillectomy was firstperformed transorally. The cervical component of the 2ndbranchial cleft fistula was then addressed. With the umbilicalcatheter (utilized for the intraoperative fistulogram) in place, afisuform skin incision was made around the catheter in the cervicalskin. The infected sinus tract was traced superiorly, after

Fig. 1. External appearance of 1st branchial cleft cyst (left) together with intra-operative fluoroscopic fistulogram (middle) and CT with contrast (right). Arrow denotes 1st

branchial cleft cyst in each image.

R. Winters, J.L. Guarisco / International Journal of Pediatric Otorhinolaryngology 76 (2012) 443–446444

identifying the carotid sheath deep to the dissection and peeling thesinus tract off of the sheath. Dissection was carried superiorlytoward the inferior border of the mandible, and at this point, asecond, stair-step skin incision was made in the skin to facilitatevisualization as dissection was carried toward the parapharyngealspace and tonsillar fossa, between the external and internal carotidarteries and superficial to cranial nerves IX and XII. Intraoperativefistulogram of the 1st branchial cleft cyst, first with methylene blue,then with gastrograffin, demonstrated no fistula to the middle ear.

The patient did well postoperatively and has had no recurrenceof the 2nd branchial cleft fistula, nor recurrent infections of eitherthe 1st branchial cleft cyst or the peripheral cutaneous fistula ofthe leg. An extensive medical genetics workup excluded branchio-oto-renal syndrome, and also yielded a normal chromosomalanalysis, acetylcarnitine and carnitine profiles, and no evidence ofmicrodeletion of chromosome 22q11.2. This genetic workupincluded known genetic anomalies causing branchio-oto-renalsyndrome, specifically EYA1, SIX1 and SIX5 genes did not displayabnormalities. The remainder of the genetics workup did notreveal any other recognized syndrome, thus the patient appears tohave multiple congenital anomalies in association with a singleumbilical artery. Orthopedic evaluation of the lower extremitieswas otherwise unremarkable, and the patient does not suffer anylimitations to the use of her right foot.

2. Discussion

Branchial cleft anomalies, including cysts, sinuses and fistulae,are congenital remnants of the embryologic branchial cleftspersisting past the embryo stage. There are various theories as

Fig. 2. Punctum of fistula on lateral dorsum of right foot (arrow). Mucoid fluid could

be expressed.

to the embryogenesis of these congenital anomalies, but perhapsthe most widely accepted are vestigial remnant theory and cell resttheory. Vestigial remnant theory proposes some portion of abranchial cleft or cervical sinus of His fails to completely obliterateduring embryologic development, and this results in a cyst, sinusor fistula persisting after birth. Cell rest theory proposes cellsbecome trapped within the branchial apparatus during embryo-genesis, and that the persistence of these cells into the fetal stageand after birth can lead to cyst, sinus or fistula formation [1]. Theseremnants typically present in the pediatric population, thoughmay go unnoticed into adulthood. The vast majority (97–98%) areunilateral, and only 2 cases of combined 1st and 2nd branchial cleftanomalies have been described, to our knowledge, in the Englishlanguage literature [2].

The 1st branchial cleft gives rise to the maxilla, mandible,Eustachian tube, external auditory canal (EAC), and somestructures of the middle ear in weeks 6–7, and if remnants ofthe 1st branchial cleft are present, they are already present at thistime. From weeks 6–8, the facial nerve and parotid gland aredeveloping from endoderm in the mouth and ear, and migratingtoward their adult positions. For this reason, the relationship of any1st branchial cleft remnants with the facial nerve and/or parotidgland is widely variable. Work categorized 1st branchial cleftremnants into two types: Type I remnants are characterized byduplication of the EAC and lie parallel to it and lateral to the facialnerve, with a preauricilar skin opening. Type II remnants open ontothe skin posterior or inferior to the angle of the mandible, with asinus tract intimately associated with the facial nerve or parotidgland, and a variable course [3]. Given the diverse structures of 1stbranchial cleft origin, it is not surprising that the anatomic locationis widely variable. They can open anywhere along the nasophar-ynx, EAC or into the middle ear, can lie anterior or posterior to thepinna, extend below the angle of the mandible, and involve theparotid gland, or lie completely superficial to it [1].

The 2nd branchial cleft gives rise to the facial muscles, styloidprocess, pinna, and certain middle ear structures. As withdevelopment of 1st branchial cleft structures, embryogenesis iscomplete by weeks 6–7, and any vestigial remnants are alreadypresent at this time. The classic course of a 2nd branchial cleftfistula begins with an opening onto the skin at the anterior borderof the sternocleidomastoid (SCM) muscle, typically at the junctionof the lower 1/3 of the muscle. From here, the fistula passes deep toplatysma, along the carotid sheath between the external (ECA) andinternal (ICA) carotid arteries, superficial to CN IX and XII, with apharyngeal opening in or around the faucial tonsil. Baileyattempted to categorize 2nd branchial cleft remnants into fourtypes: Type I is superficial. It courses deep to platysma, butsuperficial to SCM. Type II is the most common. It courses from thedermal opening, deep to platysma, and may intimately associate

Fig. 3. CT with contrast of infected 2nd branchial cleft fistula with peritonsillar

abscess (top, arrow) passing through neck (middle, arrow) opening onto skin of

neck anterior to right SCM (bottom, arrow).

Fig. 4. Intraoperative fistulogram demonstrating 2nd branchial cleft fistula from

right tonsillar fossa (arrow) to skin anterior to right sternocleidomastoid (double

arrow).

R. Winters, J.L. Guarisco / International Journal of Pediatric Otorhinolaryngology 76 (2012) 443–446 445

itself with the internal jugular vein. It is generally accepted thatthis represents persistence of the cervical sinus of His. Type IIIfollows the course of a Type II, coursing between the ICA and ECAand opens into the lateral pharyngeal wall. Rarely, a projection ofthis remnant may extend superiorly, nearing the skull base. TypeIV opens into and abuts the pharyngeal wall, and may represent aremnant of a pharyngeal pouch [1].

Embryogenesis of the lower limb is an active area of ongoingresearch. It begins in week 3, when the primordial lower limb budis first visible. Skeletogenesis and limb bud formation properbegins in week 5. Rapid changes of the malleoli and talus occur inweek 8, with the talus extracting itself from the malleoli, and all

adult foot structures are present by the end of week 8. Boehmdescribed four stages of foot development: Stage 1 (2nd gestationalmonth): the foot is 908 equinus and adducted. Stage 2 (early 3rdgestational month): The foot is 908 equinus, adducted andsupinated. Stage 3 (middle 3rd month): The foot dorsiflexes, mildequinus remains. Remains supinated and 1st metatarsal remainsadducted. Stage 4 (4th month): The foot begins to pronate andreaches midsupination. Slight metatarsus varus remains, butequinus is no longer present [4]. It is certainly possible tohypothesize that such a fistula could form around week 8, whenthe foot is undergoing rapid development as the talus extracts fromthe malleoli. If any aberrant cells were present during this time,they could lead to fistula formation, or failure of fusion ofdevelopmental planes could lead to persistent fistula, similar tocell rest theory and vestigial remnant theory. Unfortunately,development of such extremity fistulae remains an area ofspeculation, and this case, like the only prior documented casebefore it [5], cannot conclusively comment on the origin.

Branchio-oto-renal syndrome (BOR) is a spectrum of disordersmanifested by concomitant malformations of the ear, includinghearing loss, and kidneys. While diagnosis typically rests onclinical criteria, a significant proportion of cases have identifiedgenetic mutations, including the EYA1, SIX5, and SIX1 genes, whichwere not present in this patient. Additionally, the classical mode ofinheritance is autosomal dominant, and this patient’s family

R. Winters, J.L. Guarisco / International Journal of Pediatric Otorhinolaryngology 76 (2012) 443–446446

history was negative for renal or auditory problems. BOR has alsonot been described to involve malformations of the cardiovascularsystem or malformations of the extremities. Chang et al., analyzinga subset of families with known BOR, described a set of major andminor criteria for clinical diagnosis of BOR to be used in addition toa positive family history [6]. They proposed that the presence ofthree major criteria, or two major and two minor criteria,combined with genetic analysis and/or family history, yielded aspecificity of 40% for BOR. Major criteria are: second branchial cleftanomalies, deafness, preauricular pits, auricular deformities, andrenal anomalies. Minor criteria are: external auditory canalanomalies, middle ear anomalies, inner ear anomalies, preauri-cular tags, and facial or palate abnormalities. While this patientdoes have three ‘‘major’’ criteria (2nd branchial cleft anomalies,preauricular pit, renal anomaly), her family history and fullmedical genetic workup was negative for BOR. A definitive geneticmechanism for this patient’s syndrome has yet to be defined,though is an ongoing areas of investigation. Known geneticabnormalities of BOR and other syndromes have been excluded viagenetics workup, however, leading to this description of a novelsyndrome consisting of ipsilateral multiple branchial cleftanomalies, peripheral dermal sinus, renal and cardiac abnormali-ties, as well as a single umbilical artery.

3. Conclusion

Multiple anomalies of the branchial clefts can coexist in apatient, along with other congenital malformations, representingthe first report of a novel syndrome, the Guarisco–Winterssyndrome. The precise mechanisms of development of theseanomalies remain elusive, though plausible theories exist. Whilewe feel this represents a distinct syndrome, the possibility that thisis a variant of BOR stemming from a heretofore unrecognizedgenetic mechanism cannot be excluded based on our data.

References

[1] M.T. Benson, K. Dalen, A.A. Mancuso, H.H. Kerr, A.A. Cacciarelli, M.F. Mafee, et al.,Congenital anomalies of the branchial apparatus: embryology and pathologicanatomy, Radiographics 12 (1992) 943–960.

[2] A.K. Gupta, S. Kumar, A. Jain, Bilateral first and second branchial cleft fistulas: a casereport, Ear Nose Throat J. 87 (5) (2008) 291–293.

[3] G. Ankur, A.S. Bhalla, R. Sharma, First branchial cleft cyst (type II), Ear Nose Throat J.88 (11) (2009) 1194–1195.

[4] M. Boehm, The embryologic origin of club foot, J. Bone Joint Surg. 11 (1929) 229.[5] R. Lusskin, Serpentine sinus—a tract leading nowhere: congenital peripheral

dermal tract, J. Bone Joint Surg. Am. 43 (1961) 118–122.[6] E.H. Chang, M. Menezes, N.C. Meyer, R.A. Cucci, V.S. Vervoort, C.E. Schwartz, et al.,

Branchio-oto-renal syndrome: the mutation spectrum in EYA1 and its phenotypicconsequences, Hum. Mutat. 23 (2004) 582–589.