Indian Journal of Otology

ORIGINAL ARTICLE
Year
: 2019  |  Volume : 25  |  Issue : 3  |  Page : 109--113

Ear, nose, and throat manifestations of alkaptonuria patients from Jordan


Hani Mosleh Al-Shagahin1, Nesrin Mwafi2, Mahmoud Khasawneh3, Khalid Al Zubi1, Mohammad Alsbou4,  
1 Department of Special Surgery, Faculty of Medicine, Mutah University, Al-Karak, Jordan
2 Department of Biochemistry and Molecular Biology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
3 Department of Radiology, Faculty of Medicine, Mutah University, Al-Karak, Jordan
4 Department of Pharmacology, Faculty of Medicine, Mutah University, Al-Karak, Jordan

Correspondence Address:
Dr. Hani Mosleh Al-Shagahin
Department of Special Surgery-Otorhinolaryngology, Faculty of Medicine, Mutah University, Al-Karak
Jordan

Abstract

Objective: Alkaptonuria (AKU) is a rare inborn error of metabolism that is characterized as a multisystem disease with specific ear, nose, and throat (ENT) manifestations. The present study reports ENT findings in pediatric and adult AKU patients from Jordan. Materials and Methods: A full ENT examination and audiological assessment were conducted among the patients attending the AKU Research Office in our University. Results: The results showed that 88% of both pediatrics and adult patients had ENT signs or symptoms; while, the pediatric age group had only one sign that is the discoloration of the cerumen. The adult group had more than one sign, including the discoloration of cerumen and pinna, hearing loss, and discoloration of the gum and teeth. Conclusion: Discoloration of the cerumen is a common sign in pediatric patients; therefore, it is considered as an important early clinical sign for the diagnosis of AKU. Annual follow-up of pediatric patients with audiological assessment is needed to clarify the association between AKU and hearing loss. Otolaryngologist should be aware of these signs for early diagnosis and provide patients early treatment with nitisinone.



How to cite this article:
Al-Shagahin HM, Mwafi N, Khasawneh M, Al Zubi K, Alsbou M. Ear, nose, and throat manifestations of alkaptonuria patients from Jordan.Indian J Otol 2019;25:109-113


How to cite this URL:
Al-Shagahin HM, Mwafi N, Khasawneh M, Al Zubi K, Alsbou M. Ear, nose, and throat manifestations of alkaptonuria patients from Jordan. Indian J Otol [serial online] 2019 [cited 2019 Nov 13 ];25:109-113
Available from: http://www.indianjotol.org/text.asp?2019/25/3/109/269551


Full Text



 Introduction



Alkaptonuria (AKU) is a rare metabolic disease that is inherited as autosomal recessive trait. The worldwide prevalence of AKU is 1 case in 250,000–1,000,000 births. So far, 950 AKU sufferers have been identified in 40 different countries.[1] It is a condition that is reported to be more prevalent in Slovakia, the Dominican Republic, India, and Jordan.[2] The highest prevalence is in Slovakia, where up to 1 in 19,000 individuals are affected.[3] AKU is characterized by increased homogentisic acid (HGA), which is caused by the lack of enzyme, known as homogentisate dioxygenase. Excess HGA is oxidized to a melanin like polymer involving a process known as ochronosis. The excess of HGA or the resultant ochronosis is characterized as a clinical manifestation of AKU.[4]

AKU can be recognized at birth by the dark urine characteristic and nappies discoloration due to HGA uria. However, patients grow in early adulthood and manifest the full multisystem involvement with irreversible marked morbidity affecting virtually all connective tissues, if the disease is not diagnosed timely.[5] All opportunities for early diagnosis are important and worthwhile, especially concerned with the potential disease-modifying therapy, nitisinone, and the availability of new drugs.[6]

AKU has three distinct clinical features that include; homogentisic aciduria, ochronosis, and ochronotic osteoarthropathy.[7] Each feature is presented at various stages in life, the earliest being detected as HGA in the urine.[8] The process of black urine passing is the only the condition known in pediatrics, leading to 21% of patients being diagnosed with AKU before the age of 1 year.[9] Otological symptoms such as discoloration of the pinna and cerumen are well documented and considered as cardinal features.[7],[10] Some of the previous case reports have shown the discoloration of the tympanic membrane among AKU patients.[11],[12] Another study has a high percentage of patients with AKU presented with ear, nose, and throat (ENT) signs and symptoms and hearing loss identified in some cases.[13] Nose and throat symptoms are less commonly documented; however, they include discoloration of nasal and laryngeal cartilage.[7]

Systematic investigation and reporting are difficult in rare diseases such as AKU due to the lack of national centers to have a database for those patients that make the clinical studies difficult. Studying a series of patients enables better description of clinical manifestations. In the similar context, the present study aims to determine the ENT manifestations of AKU among the Jordanians at different age groups. The study also discusses the ENT manifestations and the potential causes of hearing the loss in terms of AKU.

 Materials And Methods



Study design and setting

This study was undertaken in cooperation with the Ministry of Health as well as AKU society for Jordanian patients after the establishment of AKU Research Office in 2009 at our university. In addition, the targeted population of this study was otolaryngology clinic in a governmental teaching hospital in the South of Jordan.

Study participants

The patients were assessed by otorhinolaryngologist and a range of other specialists including ophthalmology, orthopedics, and genetics on a yearly basis. All patients were confirmed with the diagnosis of AKU by means of homogentisic aciduria and genetic testing.

Ethical approval

All patients who accepted to participate in this study signed informed consent. The study was approved by the local research ethics committee.

Data collection

The patients completed a detailed questionnaire regarding their visit. General demographic details were also collected, including gender and age. Patients were asked specific questions related to ENT manifestations addressing the signs and symptoms of otological diseases such as discolorations of the pinna, otalgia, hearing loss, rhinological, and laryngological symptoms.

All the patients underwent a full ENT examination, including otoscopy and flexible nasolaryngoscopy. Pure tone audiometry was performed along with tympanometry, where appropriate. Pure tone audiometry results were averaged for right and left ears using 0.5, 1, 2, 4, 6, and 8 kHz frequencies to ensure that low and high frequency loses were not missed. Hearing loss of 20 dB was accepted as the cutoff for normal hearing. Individual audiograms were reviewed to establish the type of hearing loss. A preprinted pro forma was used to record data. Pediatric patients were assessed for hearing using tympanometry in combination with otoacoustic emission test for preschool children. However, schoolchildren were assessed using play audiometry, and the older children were assessed using pure tone audiogram.

 Results



A total of 24 patients' data sets were analyzed. Patients were divided into two major groups, one for pediatric age group including 8 patients and adult age group including 16 patients. In the adult age group, there were 13 males and 3 females, with mean age of 46 years. In the pediatric age groups, 6 patients were male and 2 patients were female, with mean age of 8 years [Table 1]. The average age at the time of diagnosis was 30 years for adult patients, with a range of 0–62 years; while, most of the pediatric patients diagnosed immediately after birth. ENT signs and symptoms were presented by 88% of the studied patients in both the age groups.{Table 1}

Otological signs and symptoms

Majority of the adult patients (75%) had pinna discoloration followed by cerumen discoloration (63%) and tinnitus (44%). Majority of these findings in adult patients were discoloration of the pinna or cerumen. Other sings included discoloration of the tympanic membrane [Table 2].{Table 2}

Audiological findings

Pure tone audiometry average demonstrated hearing loss in 7 of the 16 adult patients. The types and patterns of hearing loss are shown in [Table 3]. All patients were cases of mild-to-moderate hearing impairments. The average age of those patients with hearing loss was 54 years (range, 46–62 years). All tympanograms performed were Type A (normal) and temporal bone imaging conducted for the patient with mixed hearing loss and showed normal study. In the pediatric age group, none of them complain the hearing loss. The screening for hearing in the preschool ages was done using the combination of tympanometry and oto-acoustic emissions. The hearing ability of school age children was assessed by playing audiometry; while, older children were assessed by pure tone audiometric testing.{Table 3}

The present study has reported the ENT findings in 24 patients with AKU from Jordan. This study differs from other studies as it includes adults and children. There is a difference in the findings between the two age groups. In adult patients, it presents discoloration of the cerumen and the discoloration of the ear cartilage, which can be localized or diffuse [Figure 1] and [Figure 2], tympanic membrane discoloration [Figure 3], tinnitus, and hearing loss. Whereas, the pediatric age group was presented with discoloration of cerumen [Figure 4].{Figure 1}{Figure 2}{Figure 3}{Figure 4}

Nasal signs and symptoms

One patient had discoloration of the nasal septum on examination. Four patients reported nasal symptoms; including nasal obstruction and rhinorrhea. Moreover, two of them were diagnosed to have deviated nasal septum and the other two had allergic rhinitis.

Throat signs and symptoms

One patient had black discoloration, which affected the gum and the teeth [Figure 5]. Throat symptom in the form of occasional dysphagia was reported by one of the patients; however, it was not confirmed during the examination.{Figure 5}

 Discussion



The cardinal features of AKU, including discoloration of sclera and the external ear, were described by Garrod in his first published manuscript in 1899. The study outlined the key features of the disease.[14] The condition was described extensively in his subsequent seminal work inborn errors of metabolism published in 1909.[15] Previous studies have documented the discoloration of the pinna.[7],[15] A study demonstrating the natural history of the condition describes this discoloration as a development in patients over the age of 30 years.[9] In contrast, the present study documented the discoloration of the ear cartilage in four patients before the age of 30 that is nearly at an average age of 27 years. Nodules on the pinna have been described as a presenting feature; although, none were observed in the present study. Previous case reports have also been referred to discoloration of the tympanic membrane, along with the hearing loss and tinnitus.[11],[12] This was a case of bilateral, mixed, and high frequency hearing loss, which proposed that the conductive element of the hearing loss was due to altered tympanic membrane elasticity or ochronotic impairment of the interossicular joints.

Another study demonstrated the darkening of the tympanic membrane with high frequency hearing loss.[12] However, in the present study, one patient had discoloration of the tympanic membrane on both sides, which was described as a dark rim around the tympanic membrane. No patient had dark discoloration of the middle ear. These findings did not seem to correlate with hearing loss in all cases. The patient with the dark rim around the right tympanic membrane displayed a mild bilateral high frequency hearing loss, but reported no symptoms. A search of previous report of hearing loss associated with AKU revealed two cases of mixed high frequency hearing loss.[12]

In the present study, only one of the patients demonstrated a similar pattern of mixed hearing loss with a high frequency. These findings were in agreement to a study conducted in the UK.[13] It has been proposed that stiffening of the tympanic membrane is one of the potential causes for the conductive element. Despite this, Type A tympanograms was recorded in the two previous reported causes. Interossicular joint ochronosis is another proposed theory for a conductive hearing loss.[12] These synovial joints have not undergone any direction histological study; however, they share similarities with the elbow joint, as they are nonweight bearing joints, where histological examination has shown marked pigmentation of the cartilage.[7]

In the present study, all the patients in both age groups had a Type A tympanogram whereas loss of compliance of the tympanic membrane would also be unlikely to give a solely high frequency loss. Another proposed theory for a conductive hearing loss was interossicular joint ochronosis.[12] Therefore, a potential mechanism could be ossicular discontinuity, if the cause of the conductive element is within the middle ear. In the present study, when hearing loss was analyzed in more detail, 7 of the 16 adult patients were presented with hearing loss that was of sensorineural type of high frequency. Whereas, one of the cases was presented with mixed type; while, in the pediatric group none of them had a hearing loss. Due to the inclusion of small number of patients with a display of hearing loss, majority of patients portrayed a sensorineural type of hearing loss, which is present in the general population. These factors concluded unclear association between AKU and hearing loss and; therefore, require further studies to clarify this association.

Dark pigmentations of the cerumen are also commonly observed in AKU patients and it is the only finding in pediatric age groups as discoloration of ear cartilage and hearing loss uncommon in these patients. It may occur early in asymptomatic individuals. In the present study, 63% of the adult patients had discoloration of the cerumen; while, 88% in the pediatric age group had discoloration of cerumen [Figure 4]. The average age of these patients was 8 years, indicating that cerumen discoloration is an early symptom that could have important diagnostic potential; although, majority of symptoms develop after the age of 30 years.

Nose and throat signs and symptoms are not as well documented. In the case report of the patient presenting with pinna nodules, examination revealed pigmentation of the nasal end of the eustachian tube, and discoloration of the valleculae and pyriform fossae.[11] However, in the present study, one patient of 31-year-old had severe black discoloration of the gum and the teeth that was a new finding reported among the studied patients [Figure 5]. AKU is a rare inborn error of metabolism with multisystem involvement. In the present study, the most common associated diseases include discoloration of the sclera, degenerative changes in the spine, arthropathy, spontaneous rupture of the tendon Achilles, and renal stones. Majority of the patients in this study presented ENT manifestations whereas, pinna and cerumen discoloration were the most common clinical signs in adult patients and cerumen discoloration was the only early sign found in those pediatric patients. In Jordan, these two factors together help to reach for early diagnosis of the cases of AKU and offer the patients treatment and follow up by the group of different specialists working in cooperation with AKU office. This is because of the establishment of the AKU research office in our university, which is the only referral center in the country to AKU cases and the increase awareness of the disease.

Early diagnosis allows patients to be offered potentially disease-modifying therapy, otological presentation, and recognition that can lead to early diagnosis. Treatment in the past was supportive and palliative. However, nitisinone has the potential to modify the disease by decreasing homogentisic aciduria. A recent study in the United Kingdom National AKU Centre concluded that ear ochronosis progression was arrested by nitinosine therapy.[6] Therefore, it is important to recognize AKU early so that patients may be offered proper treatment.

 Conclusion



The present study has reported ENT findings in pediatric and adult AKU patients from Jordan. The results depicted that early ENT manifestations are presented with discoloration of the cerumen, which can be an early sign of the disease. The increase awareness of these signs can lead to early diagnosis as this allows appropriate investigation and management of the ENT aspects of AKU and offer early treatment with nitisinone as a drug that can arrest the progression of ear ochronosis. It is difficult to conclude that there is an association between hearing loss and AKU as the majority of patients in this study had normal hearing thresholds, while those with hearing loss are more likely to have a sensor-neural hearing loss. Further audiological examination of patients particularly those in pediatric age group during annual reviews will help to clarify whether any association exists. Specialist centers, such as the UK National Centre of AKU, have the expertise and knowledge to manage AKU optimally. Annual follow-up of pediatric patients with AKU can be helpful to detect early otological problems and to offer early treatment for those patients and to give true statements regarding the association between AKU and hearing loss as a possible etiology in the future studies.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Acknowledgment

The authors are very thankful to all the associated personnel in any reference that contributed in/for the purpose of this research.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Ranganath L, Taylor AM, Shenkin A, Fraser WD, Jarvis J, Gallagher JA, et al. Identification of alkaptonuria in the general population: A United Kingdom experience describing the challenges, possible solutions and persistent barriers. J Inherit Metab Dis 2011;34:723-30.
2Mistry JB, Bukhari M, Taylor AM. Alkaptonuria. Rare Dis 2013;1:e27475.
3Develop AKUre 950 AKU Patients. Cambridge (UK): The AKU Society and the Develop AKUre Consortium; C2014. Available from: http://www.developakure.eu/950-aku-patients. [Last accessed on 2013 May 15].
4Ranganath LR, Cox TF. Natural history of alkaptonuria revisited: Analyses based on scoring systems. J Inherit Metab Dis 2011;34:1141-51.
5Ranganath LR, Jarvis JC, Gallagher JA. Recent advances in management of alkaptonuria (invited review; best practice article). J Clin Pathol 2013;66:367-73.
6Ranganath LR, Khedr M, Milan AM, Davison AS, Hughes AT, Usher JL, et al. Nitisinone arrests ochronosis and decreases rate of progression of alkaptonuria: Evaluation of the effect of nitisinone in the United Kingdom national alkaptonuria centre. Mol Genet Metab 2018;125:127-34.
7Helliwell TR, Gallagher JA, Ranganath L. Alkaptonuria – A review of surgical and autopsy pathology. Histopathology 2008;53:503-12.
8Peker E, Yonden Z, Sogut S. From darkening urine to early diagnosis of alkaptonuria. Indian J Dermatol Venereol Leprol 2008;74:700.
9Rovenský J, Imrich R, Urbánek T, Bošák V. Alkaptonuria and ochronosis. In: Gerontorheumatology. Cham: Springer; 2017. p. 233-43.
10Arora S, Sodhi N, Harith AK, Kapoor U. A case of 'blue skin' and 'dark urine'. Med J Armed Forces India 2018;74:300-3.
11Sanji RR, Reddy KE, Channegowda C. Alkaptonuria: otolaryngologic clues to diagnosis. Indian J Otol 2011;17:22-5.
12Sagit M, Uludag M, San I. An unusual dark pigmentation on the tympanic membrane. J Laryngol Otol 2011;125:1059-61.
13Steven RA, Kinshuck AJ, McCormick MS, Ranganath LR. ENT manifestations of alkaptonuria: Report on a case series. J Laryngol Otol 2015;129:1004-8.
14Garrod AE. A contribution to the study of alkaptonuria. Med Chir Trans 1899;82:367-94.
15Garrod AE. Inborn Errors of Metabolism. London: Henry Frowde;