Voice Characteristics in Adults With Neurofibromatosis Type 1

Voice Characteristics in Adults With Neurofibromatosis Type 1 *Marjan Cosyns, †,§Geert Mortier, *,‡Paul Corthals, †Sandra Janssens, and *John Van Borsel, *yzGhent and xAntwerp, Belgium

Summary: Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by mutations in the NF1 gene, which is located at the long arm of chromosome 17. Major characteristics include multiple cafe´-au-lait spots and neurofibromas. Voice abnormalities have been reported to occur in this patient group. However, most studies relied on subjective measurements only. The present study reports the results of an objective voice assessment based on a multiparameter approach in 22 adults with NF1. Aerodynamic measurements, voice range profiles, acoustic voice quality and intonation measurements, and dysphonia severity indices were obtained and compared with data from a control group, consisting of 22 healthy adults. It was found that NF1 patients show a poorer overall voice quality compared with controls. Particularly, a reduction of vital capacity and limitations in laryngeal possibilities with respect to frequency and intensity were observed in the NF1 group. Key Words: Neurofibromatosis type 1–Voice–Aerodynamic measurement–Voice range profile–Acoustic analysis– Dysphonia severity index. INTRODUCTION Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that mainly affects nerve sheath cells in the peripheral nervous system. Its hallmark features include multiple cafe´au-lait spots and neurofibromas, which may grow anywhere on or in the body.1 Estimates of the prevalence of NF1 range from one in 29962 to one in 4560.3 NF1 occurs without regard to sex, race, or ethnic origin. In about half of the cases, the disorder is inherited or familial in nature. The other half are sporadic cases.1 The NF1 gene is located at chromosome 17q11.2 and encodes the protein neurofibromin. Neurofibromin is most abundant in the nervous system4 and is thought to function as a tumor suppressor or negative growth regulator.5 Mutations can occur anywhere within the NF1 gene and range from single nucleotide substitution to large genomic rearrangements.6 Most of the mutations result in gross truncation of neurofibromin.1 Although genetic testing is available, diagnosis of NF1 is based on clinical criteria (Table 1) originally established by the National Institutes of Health.7 Other clinical manifestations include learning problems, macrocephaly, attention deficit hyperactivity disorder, short stature, and scoliosis.8 It is well known that certain genetic syndromes are associated with communication disorders.9 Change or loss of voice in patients with NF1 has been associated with laryngeal and hypopharyngeal neurofibromas.10–13 However, laryngeal involvement in NF1 is rare, and voice abnormalities have also been reported in absence of such tumors (Table 2). Hence, it is expected that NF1 patients (or at least some of them) will demonstrate dysphonic characteristics. However, it is shown that most studies based their results on perceptual evaluations only. ActuAccepted for publication July 20, 2010. From the *Department of Otorhinolaryngology and Logopaedic & Audiologic Sciences, Ghent University, Ghent, Belgium; yDepartment of Medical Genetics, Ghent University Hospital, Ghent, Belgium; zDepartment of Health Care Vesalius, University College Ghent, Ghent, Belgium; and the xDepartment of Medical Genetics, Antwerp University Hospital, Antwerp, Belgium. Address correspondence and reprint requests to Marjan Cosyns, Department of Otorhinolaryngology and Logopaedic & Audiologic Sciences, Ghent University, UZ Gent 2P1, De Pintelaan 185, B-9000 Ghent, Belgium. E-mail: [email protected] Journal of Voice, Vol. 25, No. 6, pp. 759-764 0892-1997/$36.00 Ó 2011 The Voice Foundation doi:10.1016/j.jvoice.2010.07.007

ally, there is only one study20 in which analyses by ear were completed with a few acoustic measurements. To the best of our knowledge, no studies examined the voice characteristics of NF1 patients objectively by means of a multiparameter approach. Therefore, the aim of the present study was to objectify the voice characteristics in adult NF1 patients in terms of aerodynamic measurements, voice range profiles, acoustic voice quality and intonation measurements, and dysphonia severity indices (DSI). METHODS Participants The participants of this study involved a patient group and a control group. The patient group consisted of 22 adults with NF1 recruited from a database registered at the Center for Medical Genetics of the Ghent University Hospital and through NF Kontakt, a Flemish organization for individuals with NF. They were nine men ranging in age from 18 to 64 years (mean age, 39.4 years) and 13 women ranging in age from 17 to 48 years (mean age, 32.8 years). All fulfilled the diagnostic criteria for NF1. Clinical diagnosis of NF1 was not confirmed by genetic testing in one patient. However, because the clinical diagnosis was beyond doubt, this individual was not excluded from the patient group. The NF1 patients were all native Dutch speakers and reportedly nonsmokers. None of them was diagnosed with a laryngeal or pharyngeal neurofibroma and none reported the occurrence of a voice problem within 5 years before this study. The control group consisted of 22 healthy adults: 12 men and 10 women. The age range of the men was 18–67 years (mean age, 38.0 years), and the age range of the women was 22–43 years (mean age, 32.11 years). They were reportedly nonsmokers and were all native Dutch speakers. None of them reported a history of voice problems. Age distribution did not differ significantly in male NF1 patients compared with male controls (independentsample t test, P ¼ 0.840) nor in NF1 females compared with female controls (independent-sample t test, P ¼ 0.951). Aerodynamic measurements Aerodynamic measurements comprised the determination of maximum phonation time (MPT), vital capacity (VC), and

760 TABLE 1. The Diagnostic Criteria for NF17 The diagnostic criteria for NF1 are met in an individual if two or more of the following are found: Six or more cafe´-au-lait macules greater than 5 mm in greatest diameter in prepubertal individuals and greater than 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or one plexiform neurofibroma Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion, such as sphenoid dysplasia or thinning of long-bone cortex, with or without pseudoarthrosis A first-degree relative (parent, sibling, or offspring) with NF1 by the aforementioned criteria

phonation quotient (PQ). For MPT, individuals were instructed to inhale as deeply as possible, start sustaining the vowel /a:/ at normal pitch and loudness without any previous exhalation and continue sustaining it until completely running out of breath. MPT was defined as the length in seconds (s) of the sustained phonation and was measured in a sitting position using a stopwatch (C510-B; Oregon Scientific, Berkshire, UK). The best of three test trials was retained for further analysis. During the vowel prolongation, individuals were both verbally and visually encouraged by the researcher. Whenever the researcher felt that an individual did not inhale completely before starting the vowel prolongation, terminated it before the end of the exhalation, or phonated at an abnormal pitch and/or loudness, the test was repeated. VC (in mL) was measured in a sitting position using a dry spirometer (Riester, Jungingen, Germany). Individuals were asked to inhale as deeply as possible and exhale completely into the mouthpiece of the spirometer. Verbal coaching was provided by the researcher throughout the blowing. Whenever the researcher felt that an individual did not inhale maximally before blowing, lost air near the mouthpiece, or did not exhale completely, the test was repeated. PQ (in mL/s) was determined by dividing the VC value by the MPT value. Voice range profile Phonetogram recordings were performed according to the recommendations by the Union of European Phoniatricians21 using the Voice Range Profile from the Computerized Speech Lab (model 4500; Kay Elemetrics Corporation, Lincoln Park, NJ). Individuals were instructed to sustain the vowel /a:/ successively at habitual pitch and loudness, maximal pitch (Fhigh, in Hz), minimal pitch (Flow, in Hz), minimal intensity (Ilow, in dB sound pressure level), and maximal intensity (Ihigh, in dB sound pressure level). Acoustic analysis Individuals were asked to count to 3 and then immediately afterward to sustain the vowel /a:/ at habitual pitch and loudness

Journal of Voice, Vol. 25, No. 6, 2011

for at least 4 seconds. This speech sample was recorded using the Main Program from the Computerized Speech Lab, and subsequently, a midvowel segment of 2 seconds was extracted for further analysis. The following acoustic voice quality parameters were determined using the Multi-Dimensional Voice Program from the Computerized Speech Lab: jitter (in %), shimmer (in %), and noise-to-harmonic ratio (NHR). Acoustic analyses regarding voice pitch were based on the video-recorded readings of a standardized text (a Dutch version of ‘‘The North Wind and the Sun’’22). The video-recordings were made with a hard-disk drive high-definition camcorder (Sony HDR-SR1E, Sony Corporation, Tokyo, Japan) in a sound-treated room by the first author (M.C.), yielding digital samples. From these video-recordings, the audio signal was extracted (Adobe Audition 3.0; Adobe Systems Incorporated, San Jose, CA) and converted into WAV format (AoA Audio Extractor 1.2.5; AoA media.com). The mean fundamental frequency (F0, in Hz) and standard deviation of that frequency (STD, in Hz) were determined using the Main Program from the Computerized Speech Lab. Additionally, an index of pitch variation was obtained using Praat software (Boersma & Weenink, University of Amsterdam, The Netherlands)23 by means of a Praat script developed for that purpose by the third author (P.C.). This index is the sum of the absolute value of all F0 changes between the fifth and 95th percentile, cumulated from the start to the end and divided by the total duration of the utterances. The extreme F0 values were not taken into account to avoid the influence of possible artifacts in the recordings or the pitch detection algorithm. The pitch variation index, expressed in Hz/s, reflects both extent and speed of the intonation maneuvers in the speech samples. Dysphonia severity index For each participant, we also calculated the DSI. The DSI, developed by Wuyts et al,24 quantifies perceived voice quality objectively and numerically. It consists of a specific weighted combination of MPT, highest fundamental frequency, lowest intensity, and jitter, that is, DSI ¼ 0.13 3 MPT + 0.0053 3 Fhigh  0.26 3 Ilow  1.18 3 jitter + 12.4. The DSI equals +5 and 5 for normal and severely dysphonic voices, respectively. The lower a patient’s index, the worse is his or her voice quality. Statistics Statistical analyses were performed using SPSS 15.0 for Windows (SPSS Inc., Chicago, IL). Data collected from the NF1 patients were compared with those from the controls for males and females separately. If the distribution of observations approximated a normal distribution, an independent-sample t test was used. If not, a Mann-Whitney rank sum test was executed. The significance level was set at a ¼ 0.05. The distribution of a variable was considered deviated from a normal distribution when either the difference between the mean and median is larger than 0.3 times the standard deviation, the skewness or kurtosis values exceed four times their standard error, the P value in the Kolmogorov-Smirnov test or the Shapiro-Wilk’s test is smaller than 0.01, or an outlier with a large impact on the mean was present.

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Voice Characteristics in Adults With NF1

TABLE 2. Literature Review on Voice Abnormalities in NF1 Patients Authors

Participants

Assessment Techniques

Riccardi14

5 NF1 patients and 5 controls

Blind analysis of recordings of a standardized protocol

White et al15

257 NF1 patients (newborn to 60 y) 23 children with NF1 and 10 healthy siblings

Retrospective study

Solot et al16

Speech, language, and hearing were examined by a speechlanguage pathologist and an audiologist Recordings were reviewed and rated by a neurolinguist, a neurologist, and a speech therapist

Lorch et al17

30 adults with NF1 (17–73 y)

Cosyns et al18

60 NF1 patients (4.5–61.3 y)

Questionnaire study among the patients themselves

Thompson et al19

19 preschool children with NF1 (3–5 y)

Alivuotila et al20

62 NF1 patients (7–66 y) and 24 controls (7–62 y)

Speech samples were evaluated by 3 speech-language pathologists Data were analyzed by both ear and acoustic measurements, but analysis by listening was the primary method used

RESULTS The results of the different voice assessments are presented in Table 3. Aerodynamic measurements Of the aerodynamic measurements, only VC revealed significant differences between NF1 patients and controls, namely, VC was significantly reduced in male (Mann-Whitney rank sum test, P ¼ 0.042) and female (independent-sample t test, P ¼ 0.004) NF1 patients compared with that of controls. Voice range profile In female NF1 patients, both frequency and intensity ranges showed to be significantly narrower compared with those in

Outcome Relating to Voice The 5 NF1 patients (and 12 others with NF1) had speech abnormalities characterized by breathiness, hoarseness, monotone, tremor, and unvarying loudness The speech of a patient with NF1 is characterized by poor strength Hoarseness was found in 5 children with NF1 but did not occur in the control group 12 adults (40%) were rated as having atypically loud volume and eight (27%) as having harshness or creak present in voice quality 24.6% of the respondents indicated having a remarkably loud or soft voice, 15.8% having hoarseness or harshness, 7% having weakness of the voice, and another 7% having a remarkably high or low voice 3 children (16%) had a voice disorder with the most salient feature being hoarseness Strained, creaky, hoarse, or breathy voice qualities were found in 24% of NF1 patients, an inability to maintain a steady pitch in 3%, and problems with speech respiration in 5% 13 patients had distorted harmonic structure The NF1 patients operated on a narrower pitch range than the healthy controls, and regulating pitch was difficult for 53% of patients with NF1

female controls (Mann-Whitney rank sum test, P < 0.001; and independent-sample t test, P ¼ 0.010, respectively). This is because of a significantly lower Fhigh (Mann-Whitney rank sum test, P < 0.001) and a significantly lower Ihigh (independentsample t test, P ¼ 0.002) in female NF1 patients compared with female controls, respectively. Similarly, frequency and intensity ranges were significantly narrower in male NF1 patients compared with those in male controls (independent-sample t test, P ¼ 0.011 and P < 0.001, respectively). Besides a significantly lower Fhigh (Mann-Whitney rank sum test, P ¼ 0.015) and a significantly lower Ihigh (Mann-Whitney rank sum test, P ¼ 0.027), a significantly higher Ilow (Mann-Whitney rank sum test, P ¼ 0.001) in male NF1 patients accounted for these significant differences. Furthermore, we observed a trend

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TABLE 3. Results of the Aerodynamic Measurements, Voice Range Profiles, Acoustic Measurements, and Dysphonia Severity Indices in NF1 Patients and Controls Presented for the Male and Female Participants Males

Females

NF1 Patients (n ¼ 9) Controls (n ¼ 12)

NF1 Patients (n ¼ 13) Controls (n ¼ 10)

SD

Mean

SD

P Value

Mean

SD

Mean

SD

P Value

Aerodynamic measurements MPT (s) 20.93 VC (mL) 3988.89 PQ (mL/s) 232.32

7.51 697.22 149.18

24.75 4583.33 202.29

9.34 557.32 53.53

0.887 0.042 0.776

21.98 2746.15 158.23

10.57 569.53 88.18

27.53 3530.00 139.84

10.49 563.82 41.29

0.224 0.004 0.852

Voice range profile Flow (Hz) Fhigh (Hz) Frange (Hz) Ilow (dB SPL) Ihigh (dB SPL) Irange (dB SPL)

100.50 440.18 339.67 71.11 107.44 36.33

23.08 140.78 146.84 6.17 5.81 9.31

84.09 600.25 516.16 61.67 113.33 51.67

13.21 135.19 138.45 4.23 5.09 7.04

0.053 0.015 0.011 0.001 0.027 <0.001

145.22 706.56 561.35 63.31 104.08 40.77

22.60 204.82 215.97 3.43 5.71 7.69

135.35 1081.34 946.00 62.90 112.40 49.50

20.95 103.48 101.70 2.81 5.34 6.79

0.296 <0.001 <0.001 0.763 0.002 0.010

Acoustic analysis Jitter (%) Shimmer (%) NHR Mean F0 (Hz) STD (Hz) Pitch variation (Hz/s)

0.91 2.20 0.12 133.85 15.65 85.00

0.39 0.83 0.05 19.63 3.58 18.76

1.26 3.05 0.13 131.64 19.47 103.50

0.87 1.09 0.04 14.76 4.76 28.80

0.267 0.068 0.563 0.771 0.059 0.111

1.43 2.47 0.11 210.18 24.13 224.69

0.91 1.08 0.04 24.56 7.01 57.38

1.10 2.51 0.13 197.37 31.95 222.00

0.48 0.59 0.04 18.20 7.63 49.44

0.385 0.925 0.556 0.182 0.019 0.926

2.10

2.38

1.28

2.50

0.006

0.85

2.08

4.06

2.00

0.001

Voice Assessment

DSI

Mean

Abbreviations: SD, standard deviation; SPL, sound pressure level.

toward a higher Flow (independent-sample t test, P ¼ 0.053) in male NF1 patients compared with that in male controls.

Acoustic analysis Acoustic analysis of the sustained vowel /a:/ revealed no significant differences between NF1 patients and the control group for any of the parameters obtained. During reading, however, female NF1 patients exhibited a smaller STD compared with female controls (independent-sample t test, P ¼ 0.019). This trend was also observed in the male NF1 patients, but the difference with the controls was only marginally significant (independent-sample t test, P ¼ 0.059). For both sexes of the patient group, no significant differences were found for mean F0 and pitch variation when compared with controls. As the mean is sensitive to extreme values (for instance, caused by possible artifacts in the recordings), it was verified that the mean and median F0 values did not differ significantly from each other (independent-sample t test, P ¼ 0.984 for the male participants and P ¼ 0.945 for the female participants).

Dysphonia severity index The DSI scores were significantly lower in male (independentsample t test, P ¼ 0.006) and female (independent-sample t test, P ¼ 0.001) NF1 patients compared with those of the controls.

DISCUSSION The purpose of the present study was to examine the voice characteristics in adult NF1 patients. Several studies have mentioned the occurrence of voice disorders in this patient group. However, all but one relied on subjective measurement only. Therefore, we used a multiparameter approach based on aerodynamic, voice range, and acoustic measurements to document the voice characteristics of adult NF1 patients objectively. This allowed us to determine the DSI, a measure of voice quality. The results of this study indicate that the overall voice quality, as measured by the DSI, is worse in NF1 patients compared with controls. The finding of a narrower voice range profile in NF1 patients compared with controls contributes greatly to this poorer voice quality observed. Alivuotila et al20 already stated that patients with NF1 operate on a narrower pitch range than healthy controls. Our study confirms their observation and adds the finding of a reduced intensity range in NF1 patients compared with controls. Furthermore, it seems that female NF1 patients experience limitations in the high frequencies and intensities, whereas male NF1 patients exhibit difficulties in both high and low frequencies and intensities. This suggests that male NF1 patients show an even narrower voice range profile than women with NF1. The reduced laryngeal possibilities of NF1 patients with respect to frequency are also reflected in the results of the acoustic analysis of the reading text. During reading, NF1 patients demonstrated a smaller STD compared

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with the controls. However, the pitch variation did not differ significantly between both groups. In contrast with Riccardi,14 who mentioned monotony as a feature of speech in NF1 patients, it appears that NF1 patients do intonate, but that the extent of their pitch variations is not as large as in controls. In addition, the reduced laryngeal possibilities with respect to intensity could be related to VC, which was significantly reduced in NF1 patients in comparison with controls. Each of the aerodynamic voice parameters MPT, VC, and PQ, approach voice production from a different angle. MPT is considered a measure of phonatory ability, VC of pulmonary function, and PQ of air usage during phonation.25 As only VC showed significant differences between NF1 patients and controls, we cannot corroborate the occurrence of poor strength, weakness of the voice, and speech respiration problems as suggested by some authors.15,18,20 Generally, the respiration in function of phonation seems to be sufficient in NF1 patients. Another term often used in literature when characterizing the speech of NF1 patients is hoarseness or harshness of the voice.14,16–20 However, no significant differences were found between NF1 patients and controls for the acoustic parameters jitter, shimmer, and NHR, which are known to correlate with the perception of hoarseness in sustained vowels.26 Apparently, hoarseness of the voice is as prevalent in NF1 patients as in healthy individuals. It can be concluded that NF1 patients exhibit a poorer overall voice quality in comparison with controls. Particularly, a reduced VC and limitations in laryngeal possibilities were observed in the NF1 group. The etiology of these voice deviations is yet to be established. Neurofibromas, a hallmark sign of NF1, are benign peripheral nerve sheath tumors and may grow anywhere on or in the body.1 Paraspinal nerve root neurofibromas or neurofibromas occurring along the brachial, cervical, or lumbosacral plexus are commonly reported locations of neurofibromas in the NF1 literature.27 In the study of Van Meerbeeck et al,27 one-third (eight of 24) of the NF1 patients presented with neurofibromas occurring along paraspinal nerve plexus or intercostal or lumbar nerves. Especially, paraspinal nerve root or cervical plexus involvement could interfere with the innervation of the respiratory muscles and give cause to the voice abnormalities observed. As detailed information on the location of the neurofibromas occurring in our patient group is not known, we were not able to test this hypothesis. Further research implementing whole-body magnetic resonance imaging (MRI) could help clarify this issue. Some authors have suggested a neurological basis for the speech problems noted in NF1 patients.14,15,20 A reduction of VC28 and a decreased frequency variability29 can also be found in patients with Parkinson’s disease. Therefore, the results of the present study remind of extrapyramidal involvement. Actually, studies with NF1 knockout mice revealed an increase in g-amino butyric acid (GABA)-mediated inhibition30 and a relationship between neurofibromin, the protein encoded by the NF1 gene, and a dopamine receptor.31 Both GABA and dopamine are inhibiting neurotransmitters, which play an important role in the extrapyramidal circuits. Furthermore, Zamboni et al32 found micro-

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structural changes of brain tissue in the basal ganglia, thalamus, parietooccipital and frontal white matter, pons, and corpus callosum of adults with NF1. If the extrapyramidal system is involved, one expects some kind of a movement disorder. We did find a case report on a 13-year-old girl with NF1 presenting with a right-hand action dystonia associated with left subthalamic and thalamic MRI abnormalities.33 However, as far as we know, studies reporting on akathisia, muscular rigidity, bradykinesia/akinesia, resting tremor, or postural instability in NF1 are nonexistent. Further research in this area is needed. Acknowledgment Marjan Cosyns is funded through an aspirant scholarship by the Flanders Research Foundation, Belgium. REFERENCES 1. Korf BR, Rubenstein AE. Neurofibromatosis. A Handbook for Patients, Families, and Health Care Professionals. 2nd ed. New York, NY: Thieme Medical Publishers; 2005. 2. Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005;141:71–74. 3. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A: 327–332. 4. Daston MM, Scrable H, Nordlund M, Sturbaum AK, Nissen LM, Ratner N. The protein product of the neurofibromatosis type 1 gene is expressed at highest abundance in neurons, Schwann cells, and oligodendrocytes. Neuron. 1992;8:415–428. 5. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124–133. 6. Lee M, Stephenson DA. Recent developments in neurofibromatosis type 1. Curr Opin Neurol. 2007;20:135–141. 7. National Institutes of Health Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol. 1988;45:575–578. 8. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007;6:340–351. 9. Van Borsel J, Tetnowski JA. Fluency disorders in genetic syndromes. J Fluency Disord. 2007;32:279–296. 10. Dave SP, Farooq U, Civantos FJ. Management of advanced laryngeal and hypopharyngeal plexiform neurofibroma in adults. Am J Otolaryngol. 2008;29:279–283. 11. Rahbar R, Litrovnik BG, Vargas SO, et al. The biology and management of laryngeal neurofibroma. Arch Otolaryngol Head Neck Surg. 2004;130: 1400–1406. 12. Chen Y, Lee K, Yang C, Chang K. Laryngeal neurofibroma: case report of a child. Int J Pediatr Otorhinolaryngol. 2002;65:167–170. 13. Yucel EA, Guldiken Y, Ozdemir M, Ozturk AS. Plexiform neurofibroma of the larynx in a child. J Laryngol Otol. 2002;116:49–51. 14. Riccardi VM. Von Recklinghausen neurofibromatosis. N Engl J Med. 1981; 305:1617–1627. 15. White AK, Smith RJH, Bigler CR, Brooke WF, Schauer PR. Head and neck manifestations of neurofibromatosis. Laryngoscope. 1986;96:732–737. 16. Solot CB, Zackai EH, Obringer AC, Konkle DF, Handler S, Meadows AT. Communication disorders in children with neurofibromatosis type 1. In: Rubenstein, Korf, eds. Neurofibromatosis. A Handbook for Patients, Families, and Health Care Professionals. Garant: Leuven-Apeldoorn; 1998: 83–95. 17. Lorch M, Ferner R, Golding J, Whurr R. The nature of speech and language impairment in adults with neurofibromatosis 1. J Neurolinguistics. 1999; 12:157–165.

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Journal of Voice, Vol. 25, No. 6, 2011 26. Halberstam B. Acoustic and perceptual parameters relating to connected speech are more reliable measures of hoarseness than parameters relating to sustained vowels. J Otorhinolaryngol Relat Spec. 2004;66:70–73. 27. Van Meerbeeck SFL, Verstraete KL, Janssens S, Mortier G. Whole body MR imaging in neurofibromatosis type 1. Eur J Radiol. 2009;69:236–242. 28. Metter EJ. Speech Disorders: Clinical Evaluation and Diagnosis. New York, NY: Spectrum Publications; 1985. 29. Gamboa J, Jime´nez-Jime´nez FJ, Nieto A, et al. Acoustic voice analysis in patients with Parkinson’s disease treated with dopaminergic drugs. J Voice. 1997;11:314–320. 30. Costa RM, Federov NB, Kogan JH, et al. Mechanism for the learning deficits in a mouse model of neurofibromatosis type 1. Nature. 2002;415: 526–530. 31. Donarum EA, Halperin RF, Stephan DA, Narayanan V. Cognitive dysfunction in NF1 knock-out mice may result from altered vesicular trafficking of APP/DRD3 complex. BMC Neurosci. 2006;7:22. 32. Zamboni SL, Loenneker T, Boltshauser E, Martin E, Il’yason KA. Contribution of diffusion tensor MR imaging in detecting cerebral microstructural changes in adults with neurofibromatosis type 1. Am J Neuroradiol. 2007; 28:773–776. 33. Di Capua M, Lispi ML, Gianotti A, Longo D, Fariello G. Neurofibromatosis type 1 presenting with hand dystonia. J Child Neurol. 2001;16:606–608.