Poster Design & Printing by Genigraphics ® - 800.790.4001 Audiologic and Otologic Manifestations of Hutchinson-Gilford Progeria Syndrome Elizabeth Guardiani, MD 1 ; Christopher Zalewski, MA 2 ; Carmen Brewer,PhD 2 ; Melissa Merideth, MD MPH 3 ; Wendy Introne, MD 3 ; Leslie Gordon, MD PhD 3 ; William Gahl, MD Ph.D 3 ; H. Jeffrey Kim, MD 1,2 1 Georgetown University Hospital Dept. of Otolaryngology-HNS, Washington, DC 2 National Institute on Deafness and Other Communication Disorders, Bethesda, MD 3 National Human Genome Research Institute, Bethesda, MD INTRODUCTION DISCUSSION RESULTS Figure 4: Audiograms Table 2. Middle Ear Immitance Testing and acoustic reflexes. ABSTRACT Objectives: To define the audiologic and otologic phenotype of Hutchinson-Gilford Progeria syndrome (HGPS). Study Design: Prospective case series. Methods: Fifteen patients with HGPS were enrolled in a prospective natural history study; fourteen were evaluated in the neurotology clinic and eleven received audiologic evaluations. The physical exam and audiologic findings of these patients were reviewed to define an otologic and audiologic phenotype for HGPS in the largest series of subjects in the literature. Results: All patients were noted to have stiff auricular cartilages, small or absent lobules and hypoplasia of the lateral soft tissue portion of the external ear canal leading to a shortened canal. 10/14 patients (71%) had dry cerumen impaction and 4/14 patients (29%) reported a history of recurrent otitis media. 19/22 ears (86.4%) demonstrated low frequency conductive hearing loss in the 250 Hz to 500 Hz range. 16/22 ears (73%) had type A tympanograms. 3/22 ears (14%) displayed bimodal or "W" peaked tympanograms. 2/22 ears (9%) had type B tympanograms. 1/22 ears (4%) had a type C tympanogram. 9/10 patients had distortion product otoacoustic emissions consistent with normal peripheral hearing sensitivity. Conclusions: HGPS is caused by a mutation in the LMNA gene resulting in the production of an abnormal nuclear protein; this in turn affects nuclear structure and function. Patients with HGPS have characteristic otologic features due to cartilaginous and subcutaneous tissue abnormalities and typically demonstrate low frequency conductive hearing loss despite largely normal tympanometry. It is important to be aware of these conditions in managing these patients. Clinical features The median age of patients undergoing neurotologic evaluation was 7 years (range 1-12). Our patients all had very similar ears with characteristically stiff cartilages, small or shortened lobules and a shortened canal (Figure 2). Four of fourteen patients (29%) reported a history of recurrent otitis media. In addition to their characteristic otologic features, essentially all patients displayed lack of subcutaneous fat resulting in prominent scalp veins, narrowed nasal dorsa and stiffened nasal cartilages. The patients were also noted to have facies resembling that of an ‘inverted triangle’ due to a disproportionately hypoplastic midface and mandible, prominent eyes and thin lips (Figure 1 & 3). Pure tone audiometry The median age of patients who underwent comprehensive audiologic examination was 8 years (range 5-16 years). An air to bone gap for at least one frequency,), was observed in 20/22 ears (91%). This impairment involved 250-500 Hz in 20/22 ears (91%), 1000 Hz in 11/22 ears (50%), 2000 Hz in 5/22 ears (23%), and 4000 Hz in 4/22 ears (18%). High frequency hearing loss was seen in both ears of the two oldest patients ages 12 and 16. See Figure 4 for complete audiograms. Tympanometry, Acoustic Reflexes and Otoacoustic Emissions Normal peak compensated static compliance and middle ear pressure (type A tympanograms) were documented in 15/22 ears(68%). See Table 2 for tympanogram details. Five patients underwent acoustic reflex testing.. Three of five patients (60%) had absent acoustic reflexes, all of whom had normal tympanometry and exhibited significant conductive impairment on pure-tone audiometry. Distortion product otoacoustic emissions were performed in 10 patients, nine of which were consistent with normal peripheral hearing sensitivity in the mid to high frequencies. Our results represent the first and largest cohort describing the otologic and audiologic phenotype of Hutchinson-Gilford Progeria syndrome. The presence of a low frequency conductive hearing impairment in nearly all of our patients most likely represents the effect of a middle ear abnormality. Despite a small sample size of 11 patients and only 2 patients above the age of 10, high frequency hearing loss was observed in only those patients above 10 years of age suggesting that a neural hearing loss may also develop with age. Given the largely normal otoacoustic emissions and the tendency of many school-based hearing screens to focus on the mid and high frequencies, the hearing loss in HGPS may be missed by routine screening. Therefore it is important for children with this condition to undergo regular, formal audiologic testing as even mild hearing loss has been shown to affect word recognition in setting background noise such as a classroom. 4 29% of our patients reported a history of recurrent otitis media and ranged from 7 to 12 years old, slightly older than expected. This may be explained by stiffened elastic cartilage in the Eustachian tube or by the presence of a hypoplastic maxilla resulting in Eustachian tube dysfunction. As such, these patients should be monitored on a regular basis for the presence of middle ear disease. Fifteen patients were enrolled in a prospective natural history study approved by the institutional review board at the National Human Genome Research Institute. Of these patients, fourteen were evaluated in the neurotology clinic and eleven received comprehensive audiologic evaluations. Comprehensive assessment could not be completed on the remaining four patients due to young age. Audiometric evaluation of our patients consisted of speech and pure tone audiometry with air and bone conduction, 226 Hz tympanometry, acoustic reflexes when tolerated, and distortion product otoacoustic emissions (DPOAEs). When more than one audiogram was available, the more comprehensive of the two, or the one done in the absence of known pathology (e.g. otitis media) was included in the data analysis. Although HGPS is a rare condition, it is important for providers caring for these patients to be aware of the expected manifestations of this disease. Our study has demonstrated that abnormal lamin A leads to specific otologic and audiologic abnormalities and these patients should be monitored appropriately. Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare entity, occurring in approximately 1 in 4 million people, characterized by features that are often associated with advanced age. 1 Children afflicted by HGPS have many distinctive features including alopecia, failure to thrive, short stature, lipodystrophy, joint abnormalities and facial features resembling elderly persons (Figure 1). 1,2 Children are typically normal at birth, however a rapid progression of characteristic features appears soon after. Death occurs at an average age of 13 years, and is most often secondary to progressive cardiovascular disease. 3 HGPS is a sporadic autosomal dominant condition now known to be caused by de novo point mutations in the lamin A (LMNA) gene. 3 Lamin A plays an important role in the structural integrity and shape of the inner nuclear membrane, therefore accumulation of the mutant protein leads to defects in nuclear architecture and function. This is hypothesized to be the cause of the premature aging phenotype in HGPS patients. Audiologic findings in HGPS have been primarily described as isolated case reports in the literature. Some authors have reported normal hearing in HGPS. Given the pathogenesis of HGPS, however, some speculation has focused on whether or not presbycusis is part of the phenotype. METHODS AND MATERIALS 1. Hennekam RCM. Hutchinson-Gilford Progeria Syndrome: Review of the Phenotype. Am J Med Genet. 2006; 140A: 2603-624. 2. Merideth MA, Gordon LB, Clauss S, et al . "Phenotype and Course of Hutchinson-Gilford Progeria Syndrome.” NEJM. 2008; 358 : 592-604. 3. Eriksson M, Brown WT, Gordon L, et al. Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature. 2003 ; 423 :293-297. 4. Crandell C. Speech Recognition in Noise by Children with Minimal Sensorineural Hearing Loss. Ear & Hearing. 1993; 14 : 210-216. CONCLUSIONS SELECTED REFERENCES Elizabeth Guardiani, MD Georgetown University Hospital Department of Otolaryngology-Head and Neck Surgery Email: lizguardiani@gmailcom Figure 1. Typical Progeria Patients Absent/small lobule Stiff cartilage Shortened EAC Cerumen impaction Middle ear effusion Patient 1 yes yes yes yes no Patient 2 yes yes yes no yes, AD Patient 3 yes yes yes yes no Patient 4 yes yes yes yes no Patient 5 yes yes yes no no Patient 6 yes yes yes yes no Patient 7 yes yes yes yes no Patient 8 - - - - - Patient 9 yes yes yes yes yes, AS Patient 10 yes yes yes yes no Patient 11 yes yes yes yes yes, B Patient 12 yes yes yes no no Patient 13 yes yes yes yes no Patient 14 yes yes yes no no Patient 15 yes yes yes yes no Tympanogram AD Tympanogram AS Acoustic Reflexes Patient 1 W A absent Patient 2 C A NT Patient 3 A A NT Patient 4 A As NT Patient 5 A A NT Patient 6 A A present Patient 7 A W NT Patient 8 A A present Patient 9 B B NT Patient 10 A A absent Patient 11 A W absent Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 10 Patient 9 Patient 11 Composite of Right Ear MATERIALS AND METHODS . Table 1. Physical Exam Characteristics Figure 2. Ear with absent lobule and shortened canal Figure 3. Characteristic facial features CONCLUSIONS