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Characteristics of Hearing Loss in the Barakat Syndrome

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Characteristics of Hearing Loss in the Barakat Syndrome Review Article Annals of Pediatric Research Published: 15 Dec, 2020 Characteristics of Hearing Loss in the Barakat Syndrome Amin J Barakat1* and Habib Zalzal2 1Department of Pediatrics, Georgetown University Medical Center, Washington, DC, USA 2Department of Otolaryngology, Children’s National Medical Center, Washington, DC, USA Abstract Barakat syndrome, also known as HDR syndrome, is a clinically heterogeneous, rare genetic disorder characterized by the triad of hypoparathyroidism, sensorineural deafness, and renal disease. In most cases, the syndrome is caused by deletions or mutation in the zinc-finger transcription factor GATA3 on chromosome 10p14. Hearing loss is the most consistent feature of the syndrome, occurring in 96% of reported patients. Patients present with early onset, moderate to severe sensorineural hearing loss, usually bilateral and slightly worse at the higher end of the frequency spectrum. The outer hair cells play an important role in the etiology of the hearing loss. Using a next generation sequencing gene panels that included GATA3 in patients with apparently isolated deafness has allowed the early identification of GATA3 mutations in patients with previously unrecognized Barakat syndrome. Hearing treatment should be instituted as early as possible in children to help their speech, language, and social skills reach their full potential. We discuss here the characteristics and genetics of sensorineural hearing loss associated with the Barakat syndrome. Keywords: Barakat syndrome; GATA3 mutations; HDR; Sensorineural hearing loss Abbreviations ABI: Auditory Brain Stem Implants; ABR: Auditory Brainstem Evoked Response; CKD: Chronic Kidney Disease; EHDI: Early Hearing Detection and Intervention; HCs: Hair Cells; HDR: Hypoparathyroidism, Deafness, Renal disease; NGS: Next Generation Sequencing; OAE: Otoacoustic Emission; SNHL: Sensorineural Hearing Loss Introduction Barakat syndrome, also known as HDR syndrome, is a clinically heterogeneous, rare genetic OPEN ACCESS disorder characterized by the triad of Hypoparathyroidism (H), sensorineural Deafness (D), and Renal disease (R) [1]. The syndrome in most cases is caused by deletions or mutation in the zinc- *Correspondence: finger transcription factor GATA3 on chromosome 10p14 [2]. In the past, patients have presented Amin J Barakat, Department of mainly with signs and symptoms of hypocalcemia secondary to hypoparathyroidism. Since the Pediatrics, Georgetown University advent of routine newborn hearing screening and prenatal ultrasonography, hearing loss and renal Medical Center, Washington, DC, 107 disease have become the more common modes of presentation. Hearing loss is the most consistent North Virginia Ave, Falls Church, VA. feature of the syndrome, occurring in 96% of reported patients. The purpose of this paper is to 22046, USA, Tel: +703-568-0243; Fax: discuss the characteristics, etiology, genetics, and treatment of hearing loss associated with the +747-247-8787; Barakat syndrome. E-mail: [email protected] Barakat Syndrome Received Date: 02 Nov 2020 Accepted Date: 09 Dec 2020 Barakat syndrome, also known as HDR syndrome was first described by Barakat et al. [3] in Published Date: 15 Dec 2020 1977. The syndrome is usually caused by deletions or mutation in the zinc-finger transcription factor GATA3 on chromosome 10p14 [1]. The syndrome may present with variable clinical features Citation: even in the same family. So far, all carriers of GATA3 mutations have been found to have at least one Barakat AJ, Zalzal H. Characteristics of of the defects characterizing the syndrome [4]. To date, about 200 cases have been reported in the Hearing Loss in the Barakat Syndrome. literature; however, most likely many cases have been missed or underreported. Reported pedigrees Ann Pediatr Res. 2020; 4(5): 1051. seem to follow an autosomal dominant pattern with variable expression and incomplete penetrance. Copyright © 2020 Amin J Barakat. This The complete clinical triad (HDR) was found in 64% of reported patients [2]. Hearing loss is the most is an open access article distributed consistent feature of the syndrome, affecting 96% of reported patients, while hypoparathyroidism under the Creative Commons Attribution and renal disease affect 93% and 72% of patients, respectively. Patients with isolated Sensorineural License, which permits unrestricted Hearing Loss (SNHL) where other neurogenetic causes of deafness have been excluded should be use, distribution, and reproduction in suspected to have the syndrome, especially if there is history of hypoparathyroidism, deafness or any medium, provided the original work renal disease in any member of the family. In these instances, GATA3 testing should be performed is properly cited. to confirm the diagnosis. Remedy Publications LLC. 1 2020 | Volume 4 | Issue 5 | Article 1051 Amin J Barakat, et al., Annals of Pediatric Research Figure 1: Auditory pathway of sound through the ear to the brain (yellow arrows). Tiny middle ear bones initially amplify the sound from the external auditory canal towards the cochlea, which sorts the sound by frequency. The vestibulocochlear nerve passes signal from cochlea to brainstem. Signal travels through the brain getting decoded along the way until the auditory cortex processes the sound. Labels: 1: Tympanic membrane; 2: Ossicular bones; 3: Cochlea; 4: Vestibulocochlear nerve; 5: Cochlear nucleus; 6: Superior olivary nucleus; 7: Lateral lemniscus; 8: Inferior colliculus; 9: Medial geniculate body; 10: Temporal lobe; 11: Auditory receiving center Figure modified from “© www.gograph.com/[PATTER]”. The presence of hypoparathyroidism should suggest the Barakat prior to age 1 month. Infants who do not pass the initial screen would syndrome, and prompt audiometry and renal investigation, since have a comprehensive audiologic evaluation by age 3 months, and it is caused only by few other disorders. Patients have historically if needed treatment implemented by age 6 months. Otoacoustic presented with signs and symptoms of hypocalcemia (non-febrile Emissions (OAEs) are used for newborn hearing screening. Incoming seizures, tetany, myalgia, and irritability) and low serum Parathyroid sounds and reflections occurring naturally within the cochlea are Hormone (PTH). Since newborn hearing screening and prenatal amplified by the outer hair cells and propagated out of the ear and ultrasonography have become the standard of care, it is more detected by a microphone in the ear canal as an OAE [6]. OAE tests common now for the syndrome to present with deafness or renal cochlear function only and do not detect pathology in the auditory disease. Renal disease associated with the syndrome is variable nerve or auditory brainstem pathways. Auditory Brainstem Evoked and consists of Congenital Anomalies of the Kidney and Urinary Response (ABR) which detects hearing loss caused by outer hair cell Tract (CAKUT) in 40% of cases, hematuria, proteinuria, nephrotic dysfunction or problems in conveying the sound information to the syndrome renal tubular acidosis, CKD and others. Several additional brain provides another way to assess hearing in newborns. Passing features have been described in association with the syndrome, the ABR test requires a normal middle ear, cochlea, auditory nerve, including congenital heart disease, facial abnormalities, cerebral and auditory brainstem pathways (Figure 1) [6]. A newborn with infarctions, retinitis pigmentosa, basal ganglia calcifications, severe auditory neuropathy, will pass OAE, but fail ABR testing. cognitive disability, and several others [2,5]. This clinical diversity underscores the phenotypic heterogeneity and variable penetrance of Hearing Loss in Barakat Syndrome the syndrome [5]. Hearing loss affects 96% of patients affected with this syndrome. Patients may exhibit the full phenotypic triad of HDR or only a It is characterized by early onset, moderate to severe SNHL (56 dB subset of these. By age 50 years, nearly all patients will have the full to 70 dB) that is usually bilateral and slightly worse in the higher spectrum of the syndrome, as the chances to develop any component sound frequencies. This occurs when there is a problem translating of the syndrome increases with age [4]. In contrast, Barakat et al. [2] the sound vibrations in the cochlear HCs into electrical signals, or in reported that the three components of HDR occurred in 64% of 180 transmitting the information to the brain [8]. The higher frequency reported cases. The authors did remark that it is possible that some SNHL may progressively worsen with age [9]. The absence of clinical features might have been missed or may have appeared Distortion Product Otoacoustic Emissions (DPOAEs) and presence later in life in their study. Early diagnosis of Barakat syndrome of normal ABRs support a cochlear site for the lesion [10]. According provides an opportunity for early treatment and improved prognosis. to the authors, there is no evidence of vestibular dysfunction in these Management should follow a comprehensive approach, which patients. A decrease in the age of onset of deafness and increased includes treatment of hypocalcemia and early identification and severity in subsequent generations may indicate the presence of management of hearing loss. Since the prognosis usually depends on genetic anticipation [11]. Deafness may be associated with many other the severity of renal disease, early intervention is crucial in preventing hereditary kidney disorders; however, none of these is associated with or
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