Association of Hearing Loss with PHACE Syndrome

OBSERVATION

ONLINE FIRST Association of Hearing Loss With PHACE Syndrome

Kelly J. Duffy, PhD; Christina Runge-Samuelson, PhD; Michelle L. Bayer, BS; David Friedland, MD, PhD; Cecille Sulman, MD; Robert Chun, MD; Joseph E. Kerschner, MD; Denise Metry, MD; Denise Adams, MD; Beth A. Drolet, MD

Background: PHACE syndrome describes a spectrum nance imaging features of lesions consistent with of anomalies associated with large facial infantile hem- intracranial hemangiomas involving auditory struc- angiomas and characterized by posterior fossa malfor- tures. All 6 patients had facial hemangiomas in a nearly mations, hemangiomas, arterial anomalies, coarctation identical distribution ipsilateral to the ear with the hear- of the aorta and cardiac defects, and eye abnormalities. ing loss, with involvement of the proposed facial seg- With improved recognition and imaging practices of ments S1 and S3, the affected ear, the periauricular re- infants with PHACE syndrome, additional associations gion, and the midoccipital area of the scalp. have been identified. To our knowledge, the potential association of ipsilateral hearing loss and PHACE syn- Conclusions: There is an underrecognized risk of hear- drome has not been previously emphasized. ing loss in patients with PHACE syndrome, although the exact nature of such deficiencies can vary. Patients with Observations: We describe 6 patients, 4 with definite PHACE syndrome who have cutaneous hemangiomas in- and 2 with probable PHACE syndrome, according to the volving the ear should be evaluated for intracranial hem- new diagnostic criteria, and associated auditory deficien- angiomas and monitored for hearing loss. Early detec- cies. One patient had isolated conductive hearing loss; tion and therapy of intracranial hemangiomas may slow 2 patients had isolated sensorineural hearing loss; 1 pa- or stop tumor growth, resultant hearing loss, and struc- tient had mixed hearing loss (both conductive and sen- tural damage. sorineural components); and 1 patient had hearing loss that was inconclusive at the time. Also, 1 patient had con- Arch Dermatol. 2010;146(12):1391-1396. ductive loss and auditory neuropathy and auditory dys- Published online August 16, 2010. synchrony. Four of the 6 patients had magnetic reso- doi:10.1001/archdermatol.2010.201

HACE SYNDROME (ONLINE REPORT OF CASES Mendelian Inheritance in Man [OMIM] 606519) describes a CASE 1 spectrum of anomalies associated with large facial infan- A female infant presented with a large seg- tile hemangiomas (IHs): posterior fossa P mental IH involving the right side of the malformations, hemangiomas, arterial forehead, the right cheek, and the bottom anomalies, coarctation of the aorta and car- lip, with extension to the right ear, the pa- diac defects, and eye abnormalities. With in- rietal and occipital scalp area, and the an- creased awareness of the syndrome and terior aspect of the chest (Figure 1A). She more comprehensive evaluations, addi- met diagnostic criteria for definite PHACE tional associations, including otolaryngo- syndrome according to magnetic reso- logical, have been reported. While recent nance imaging (MRI) findings of a hypo- case reports have suggested a potential link plastic right cerebellum and magnetic between PHACE syndrome and hearing resonance angiographic findings of a hy- loss,1,2 this association has not been de- poplastic distal right internal carotid ar- scribed in detail (to our knowledge). We de- tery and a hypoplastic left posterior com- scribe 6 patients, 4 with definite and 2 with municating artery. Magnetic resonance probable PHACE syndrome, according to imaging of the nasopharynx showed con- the new diagnostic criteria, and auditory im- siderable impingement of the right eusta- Author Affiliations are listed at pairments and review prior reports with chian tube by a lesion that showed imaging the end of this article. similar features. features consistent with an IH (Figure 2).

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Figure 1. Segmental distribution of hemangiomas in patients 1 (A) and 4 (B) involving proposed facial segments S1 and S3. There is also involvement of the entire ear and the periauricular region as well as extension to the midoccipital area of the scalp.

Figure 2. Magnetic resonance images revealing a lesion consistent with an intracranial hemangioma infringing on the right eustachian tube in patient 1 (circled portions).

Repeated otoacoustic emissions testing from newborn carotid artery stenosis. An echocardiogram also showed screening through 6 months of age showed no otoacous- a small, muscular ventricular septal defect and patent tic emissions from the right ear. Tympanometry per- foramen ovale. formed at 6 months showed a right-sided reduction in tym- The patient passed a neonatal hearing screen in her panic membrane mobility with negative middle ear right ear but was referred for further audiometric test- pressure. Air and bone conduction auditory brainstem re- ing owing to abnormal results in her left ear. At 3 months sponse testing using click stimuli at 10 months of age in- of age, otoacoustic emissions results showed normal coch- dicated a right-sided, conductive hearing loss. These re- lear function in the right ear and absent cochlear func- sults were consistent with right middle ear dysfunction. tion in the left ear; middle ear function was normal in both ears. Auditory brainstem response testing was con- CASE 2 ducted at this time, and responses to click stimuli and 250- and 1000-Hz tone-burst stimuli revealed moderate A female infant presented for evaluation of a large IH hearing loss in the left ear. Magnetic resonance imaging that extended over the left side of her face and involved at 3 months of age did not show intracranial extension the upper and lower eyelids, the lateral aspect of the of the IH or involvement of internal auditory structures, upper lip, the preauricular skin, the left ear, and the although computed tomography at 11 months of age dem- parietal region of the scalp. She met diagnostic criteria onstrated a prominent enhancing region within an ex- for definite PHACE syndrome according to MRI find- panded left internal auditory canal, a large cochlear ap- ings of a Dandy-Walker malformation and magnetic erture, and prominence of the labyrinthine facial canal resonance angiographic findings of right internal proximally. A dedicated internal auditory canal MRI has

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 not been performed to evaluate the enhancing region; served in 3 patients. In 2 of these 3 patients, the conduc- however, the combined results of tympanometry, oto- tive hearing loss was unilateral and could be directly at- acoustic emissions testing, and auditory brainstem re- tributable to occlusion of the eustachian tube by the IH. sponse testing suggested sensorineural hearing loss in the In the third patient (case 6), the conductive hearing loss left ear. was thought to be attributable to a middle ear effusion because (1) the conductive hearing loss was bilateral, (2) there was no occlusion of the external ear canal, and COMMENT (3) MRI did not reveal occlusion of the eustacian tube. Sensorineural hearing loss was definitively observed in In 1996, Frieden et al3 introduced the PHACE acronym another 3 patients, 2 of whom had unilateral hearing loss. to describe the association of a large, cervicofacial he- The etiology of unilateral sensorineural hearing loss in mangioma with the following extracutaneous complica- children is multifactorial and includes genetic defects that tions: posterior fossa brain malformations, hemangio- affect sensory and neural function and anatomical and mas, arterial cerebrovascular anomalies, cardiovascular developmental abnormalities. Defects may manifest at any anomalies, and eye anomalies. PHACE syndrome is un- point along the auditory pathway, from the cochlea to common but not rare, with well over 300 cases reported the central nervous system. Two of our patients (cases 4 in the literature. While the exact prevalence of the syn- and 5) had unilateral sensorineural hearing loss that could drome is unknown, a recent prospective study using stan- be directly attributable to the IH affecting cranial nerve dardizing screening protocols and strict diagnostic cri- VIII in the internal auditory canal (Figure 3). The other teria for the syndrome demonstrated a 31% incidence patient (case 2) did not have any quality images at 3 among infants with facial IHs larger than 22 cm2..4 Such months of age to definitively address involvement of the efforts will positively affect future PHACE studies be- IH or its association with any internal auditory struc- cause more complete evaluations of at-risk patients are tures, and computed tomograms at 11 months of age were being performed and extracutaneous anomalies other- only suggestive of a possible intracranial IH; therefore, wise common to the normal population (so-called nor- the exact cause of her sensorineural hearing loss could mal variants) are now excluded from the criteria for de- not be verified. finitive diagnosis. One of our patients (case 6) was uniquely diagnosed We describe 6 patients, 4 with definite and 2 with prob- as having bilateral auditory neuropathy and auditory able PHACE syndrome, according to the new diagnostic dyssynchrony, which is characterized by the presence criteria, with associated hearing loss (Table). The hear- of cochlear microphonics and absent or asynchronized ing loss was ipsilateral to the cutaneous IH in all cases. neural response during auditory brainstem response The IH distribution was nearly identical in all cases, in- testing. There are multiple potential localized and sys- volving the proposed facial segments S1 and S3, as de- temic causes of auditory neuropathy/auditory dyssyn- scribed by Haggstrom et al,5 with additional extension chrony. Localized causes, including absent or deficient to most of the ear and the periauricular and midoccipi- auditory nerves, auditory nerve myelinopathy, and tal region in a circular pattern on the scalp (Figure 1). abnormal labyrinthine structures, are usually unilateral This latter region is not a previously characterized seg- and were excluded in our patient after careful review of ment according to the original description by Haggstrom MRIs of the auditory pathways showed normal struc- and colleagues, nor does it correspond to any known tures and myelination. The bilateral nature of our representative embryologic fields. Infantile hemangio- patient’s auditory neuropathy/auditory dyssynchrony mas occurring in this distribution with ear involvement suggests a systemic pathogenesis, and the 2 greatest risk are particularly vulnerable to ulceration of the superior factors known for this type of auditory deficiency are helical rim, as was observed in our group and others,6,7 perinatal hypoxia and hyperbilirubinemia. Review of although the exact reason for such susceptibility is our patient’s birth records indicated that she was unknown. exposed to both factors. While this may be independent In at least 4 of these 6 patients, enhancing intracra- from her PHACE syndrome, it is also plausible that a nial lesions that were consistent with IHs involving combination of congenital PHACE anomalies with auditory structures were seen on MRI and were present maternal preeclampsia (per birth records) contributed on the same side as the hearing loss. A 2002 review by to an environment of global hypoxia resulting in audi- Poetke et al8 showed a 12% incidence of intracranial IHs tory neuropathy/auditory dyssynchrony. among patients with PHACE syndrome. Viswanathan et While prior case reports of PHACE syndrome have al9 later emphasized the need for careful identification suggested a potential link with hearing loss, to our of true intracranial IHs, which can be distinguished by knowledge this association has not been examined in their unique natural history, response to therapy, and pat- detail nor previously emphasized. Two recent, indepen- tern of central nervous system involvement, to avoid mis- dent reviews by Hartemink et al2 and Rudnick et al6 rec- classification and improper management. Their study also ognized the potential impact of otologic abnormalities supported observations by other authors that intracra- and vascular anomalies of the head and neck on oto- nial IHs tend to localize in or adjacent to the internal au- logic development, suggesting that such findings may ditory canal and cerebellopontine angle ipsilateral to the be more prevalent in patients with PHACE syndrome. cervicofacial IHs. Three previously reported cases of PHACE syndrome The nature of hearing loss observed in our patients noted the presence of conductive hearing loss,1,6 and 2 varied. Conductive hearing loss was definitively ob- other reports mentioned the presence of sensorineural

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Patient PHACE Diagnosis Facial IH Auditory-Related Newborn Hearing Audiologic Type of No./Sex and Criteria Met Distribution MRI Findings Screen Results Assessment Hearing Loss 1/F Definite PHACE: S1 and S3 Significant Passed (left) Birth to 6 mo: Absent Conductive hearing Large facial IH (right) impingement of the Failed (right) OAEs (right) loss (right) Hypoplastic right right eustachian 6 mo: Reduced tympanic cerebellum tube by a lesion membrane mobility Hypoplastic distal right with imaging with negative middle internal carotid artery features consistent ear pressure (right) Hypoplastic left posterior with IH 10 mo: Air and bone communicating artery conduction ABR MRI enhancement indicative of middle ear consistent with dysfunction (right) intracranial IH

2/F Definite PHACE: S1, S2, and None to date Referred (left) 3 mo: Absent OAEs (left); Sensorineural Large facial IH S3 (left) Passed (right) middle ear function hearing loss (left) Dandy-Walker normal (left) malformation 3 mo: ABR revealed Right internal carotid artery moderate hearing stenosis loss (left) Ventricular septal defect

3/F Definite PHACE: S1 and S2 (left) Lesion consistent Passed (left) 12 mo: Absent OAEs (left) Conductive and/or Large facial IH S3 (bilateral) with IH within the Passed (right) 12 mo: Moderately reduced sensorineural Cerebellar hypoplasia left mastoid air tympanic membrane hearing loss (left) Small left internal carotid cells and left mobility (right) and artery internal auditory severely reduced MRI enhancement canal compliance (left) consistent with 12 mo: Air conduction intracranial IH audiometric testing showed normal hearing (right) and moderate to moderately severe hearing loss (left)

4/M Probable PHACE: S1, S2, and Extensive involvement Passed (left) 3 mo: OAEs could not be Sensorineural Large facial IH S3 (left) of IH with external Passed (right) measured because IH hearing loss (left) Small posterior fossa ear, left cranial completely occluded Multiple extra-axial nerve VIII within external auditory enhancing lesions cerebellopontine canal (left) consistent with angle and internal 3 mo: Auditory steady-state intracranial IH auditory canal response testing showed mild, bone conducted sensitivity loss at 4000 Hz (left)

5/F Probable PHACE: S1, S2, and Lesion consistent Passed (left) 21 mo: Tympanometry Conductive and Large facial IH S3 (left) with separate IH Passed (right) showed severely reduced sensorineural MRI enhancement present in the left mobility (left) hearing loss (left) consistent with internal auditory 26 mo: Pure-tone intracranial IH canal audiometric testing showed moderate to severe conductive and sensorineural hearing loss (left)

6/F Definite PHACE: S1 and S3 None to date Passed (left) 24 mo: Reduced tympanic Bilateral conductive Large facial IH (right) Passed (right) membrane mobility hearing loss and Bilateral optic nerve (right) bilateral auditory hypoplasia 33 mo: Present OAEs and neuropathy and Narrowing of right internal absent middle ear muscle auditory carotid artery reflexes (bilateral) dyssynchrony Left-sided aortic arch 33 mo: Normal ABR Aberrant origin of right subclavian artery Tortuosity of both vertebral arteries with a dominant left vertebral artery

Abbreviations: ABR, auditory brainstem response; IH, infantile hemangioma; MRI, magnetic resonance imaging; OAEs, otoacoustic emissions.

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 should be counseled, and the pediatrician vigilant, in look- ing for delays or plateaus in language development over the first several years of life. Any delays should prompt referral for speech-language, audiological, and otolaryn- gological evaluation. In conclusion, with the involvement of multidisci- plinary clinical teams in the diagnosis, management, and study of PHACE syndrome, previously unrecog- nized manifestations of PHACE syndrome continue to be elucidated. Our cases show that hearing loss is a true potential association, which has probably been underdi- agnosed previously but is likely to become more appar- ent with improved recognition of at-risk patients and screening practices. Hearing loss in association with PHACE syndrome can be conductive or sensorineural in nature and affect various auditory structures but is often directly attributable to an intracranial IH involving auditory structures. Infants at particular risk for PHACE syndrome–associated hearing impairments tend to have large IHs that extend over the head and neck in an S1 and S3 distribution, with additional ipsilateral ear and scalp involvement. Although many children with PHACE syndrome pass their initial newborn hearing screen, it is important that complete audiological assessment and testing be completed routinely for all at-risk children. Early evaluation and diagnosis can pro- vide opportunity for more timely intervention and Figure 3. Magnetic resonance image revealing a lesion consistent with an intracranial hemangioma associated with the left cranial nerve VIII within the treatment of potential intracranial IH-associated hearing cerebellopontine angle and internal auditory canal in patient 4. deficits.

Accepted for Publication: June 8, 2010. hearing loss.10,11 Other case reports of PHACE syn- Published Online: August 16, 2010. doi:10.1001 drome have described patients with clinical presenta- /archdermatol.2010.201 tions similar to ours: one with a large facial IH in asso- Author Affiliations: Departments of Pediatric Derma- ciation with “hemangiomatous” tympanic membrane tology (Dr Duffy), Otolaryngology and Communication involvement and conductive hearing loss,6 and another Sciences (Dr Runge-Samuelson), and Otolaryngology and with an intracranial IH involving the internal auditory Communication Sciences (Dr Friedland), Medical Col- canal and/or cerebellopontine angle but without men- lege of Wisconsin (Ms Bayer), and Division of Pediatric tion of auditory status.8,12,13 Otolaryngology, Department of Otolaryngology and Com- These prior and current cases indicate a likely under- munication Sciences (Drs Sulman, Chun, and Kersch- recognized role for intracranial IH in hearing loss among ner), and Department of Dermatology and Pediatric Der- patients with PHACE syndrome, given their proximity matology (Dr Drolet), Medical College of Wisconsin, to and involvement with auditory structures. Impor- Children’s Hospital of Wisconsin, Milwaukee; Depart- tantly, because IHs are generally subtle or nonevident at ments of Dermatology and Pediatrics, Texas Children’s birth and proliferate during the first 6 to 18 months of Hospital and Baylor College of Medicine, Houston (Dr life, patients at risk for hearing loss may pass their ini- Metry); and Departments of Pediatrics and Oncology, Cin- tial newborn hearing screen but go on to develop prob- cinnati Children’s Hospital Medical Center and Univer- lems later in infancy. In contrast to conductive hearing sity of Cincinnati, Cincinnati, Ohio (Dr Adams). loss, sensorineural hearing loss is generally irreversible; Correspondence: Beth A. Drolet, MD, Department of although in cases of a space-occupying mass such as an Dermatology, Medical College of Wisconsin, 9000 W IH, it may still be possible to preserve function or to pre- Wisconsin Ave, Milwaukee, WI 53226 (drolet@mcw vent further damage with early lesion detection and thera- .edu). peutic intervention. We therefore recommend that pa- Author Contributions: All authors had full access to all tients with PHACE syndrome with large, at-risk IHs of the data in the study and take responsibility for the in- the face, scalp, and ears be closely monitored for poten- tegrity of the data and the accuracy of the data analysis. tial auditory deficiencies, including audiological objec- Study concept and design: Duffy, Runge-Samuelson, Bayer, tive testing with tympanometry and auditory brainstem Kerschner, Adams, and Drolet. Acquisition of data: Duffy, response, even if they pass their newborn hearing screen. Runge-Samuelson, Bayer, Kerschner, Metry, Adams, and These patients should undergo additional audiometric Drolet. Analysis and interpretation of data: Duffy, Runge- evaluation at 6 to 9 months of age and again at 12 to 18 Samuelson, Bayer, Friedland, Sulman, Chun, Kersch- months of age, depending on the progression of the IH ner, Adams, and Drolet. Drafting of the manuscript: Duffy, and the child’s development. Furthermore, the family Runge-Samuelson, Bayer, Kerschner, and Drolet. Criti-

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©2010 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 cal revision of the manuscript for important intellectual con- 3. Frieden IJ, Reese V, Cohen D. PHACE syndrome: the association of posterior fossa tent: Duffy, Runge-Samuelson, Bayer, Friedland, Chun, brain malformations, hemangiomas, arterial anomalies, coarctation of the aorta and cardiac defects, and eye abnormalities. Arch Dermatol. 1996;132(3):307- Sulman, Kerschner, Metry, Adams, and Drolet. Admin- 311. istrative, technical, or material support: Duffy, Runge- 4. Haggstrom AN, Garzon MC, Adams D, et al. A prospective study examining the Samuelson, Friedland, Kerschner, and Drolet. Study su- risk for PHACE syndrome in infants with large facial hemangiomas. Pediatrics. pervision: Duffy, Kerschner, Adams, and Drolet. Specialty In press. knowledge: Sulman. 5. Haggstrom AN, Lammer EJ, Schneider RA, Marcucio R, Frieden IJ. Patterns of Financial Disclosure: None reported. infantile hemangiomas: new clues to hemangioma pathogenesis and embryonic facial development. Pediatrics. 2006;117(3):698-703. Funding/Support: This work was supported in part 6. Rudnick EF, Chen EY, Manning SC, Perkins JA. PHACES syndrome: otolaryngic by National Institutes of Health grant K23DC008837 considerations in recognition and management. Int J Pediatr Otorhinolaryngol. (Dr Runge-Samuelson). 2009;73(2):281-288. Additional Contributions: The audiologists at the Mas- 7. Durusoy C, Mihci E, Tacoy S, Ozaydin E, Alpsoy E. PHACES syndrome present- ters Family Speech and Hearing Clinic at the Children’s ing as hemangiomas, sternal clefting and congenital ulcerations on the helices. Hospital of Wisconsin, the Koss Cochlear Implant Pro- J Dermatol. 2006;33(3):219-222. 8. Poetke M, Frommeld T, Berlien HP. PHACE syndrome: new views on diagnostic gram at the Medical College of Wisconsin, and the Uni- criteria. Eur J Pediatr Surg. 2002;12(6):366-374. versity of Illinois at Chicago provided the audiometric 9. Viswanathan V, Smith ER, Mulliken JB, et al. Infantile hemangiomas involving test results. Carol Chute, CPN, of the Hemangioma and the neuraxis: clinical and imaging findings. AJNR Am J Neuroradiol. 2009; Vascular Malformation Center at Cincinnati Children’s 30(5):1005-1013. Hospital assisted with patient histories. 10. Poindexter G, Metry DW, Barkovich AJ, Frieden IJ. PHACE syndrome with intra- cerebral hemangiomas, heterotopia, and endocrine dysfunction. Pediatr Neurol. 2007;36(6):402-406. REFERENCES 11. James PA, McGaughran J. Complete overlap of PHACE syndrome and sternal malformation–vascular dysplasia association. Am J Med Genet. 2002;110(1): 1. Badi A, Kerschner J, North P, Messner A, Perkins J, Drolet B. Histopathological 78-84. and immunophenotypic profile of subglottic hemangioma: multi-center study with 12. Metry DW, Hawrot A, Altman C, Frieden IJ. Association of solitary, segmental literature review. Paper presented at: SENTAC Annual Meeting; December 2, 2007; hemangiomas of the skin with visceral hemangiomatosis. Arch Dermatol. 2004; Milwaukee, WI. 140(5):591-596. 2. Hartemink DA, Chiu YE, Drolet BA, Kerschner JE. PHACES syndrome: a review. 13. Heyer GL, Garzon MC. An infant with a facial hemangioma and more. Semin Pe- Int J Pediatr Otorhinolaryngol. 2009;73(2):181-187. diatr Neurol. 2008;15(4):160-163.

Correction

Error in Text. In the Practice Gap by Stratman titled “Overscreening and Underscreening for Melanoma,” published in the October issue of the Archives (2010;146[10]: 1102), the second sentence of the first paragraph, “This occurs not just in free skin cancer screenings, as described in the article by Andrulonis et al, but also in dermatologist offices for patients seeking or being encour- aged to seek full-body screening,” should have read: “This occurs not just in free skin cancer screenings, but also in dermatologist offices for patients seeking or being en- courged to seek full-body screening, as described in the article by Andrulonis et al.”

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