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Pendred syndrome

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Pendred syndrome is an autosomal recessive disorder that is classically defined by the combination of sensorineural deafness/hearing impairment, goiter, and an abnormal organification of iodide with or without hypothyroidism. The hallmark of the syndrome is the impaired hearing, which is associated with inner ear malformations such as an enlarged vestibular aqueduct (EVA). The thyroid phenotype is variable and may be modified by the nutritional iodine intake. Pendred syndrome is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes the multifunctional anion exchanger pendrin. Pendrin has affinity for chloride, iodide, and bicarbonate, among other anions. In the inner ear, pendrin functions as a chloride/bicarbonate exchanger that is essential for maintaining the composition and the potential of the endolymph. In the thyroid, pendrin is expressed at the apical membrane of thyroid cells facing the follicular lumen. Functional studies have demonstrated that pendrin can mediate iodide efflux in heterologous cells. This, together with the thyroid phenotype observed in humans (goiter, impaired iodine organification) suggests that pendrin could be involved in iodide efflux into the lumen, one of the steps required for thyroid hormone synthesis. Iodide efflux can, however, also occur in the absence of pendrin suggesting that other exchangers or channels are involved. It has been suggested that Anoctamin 1 (ANO1/TMEM16A), a calcium-activated anion channel, which is also expressed at the apical membrane of thyrocytes, could participate in mediating apical efflux.

In the kidney, pendrin is involved in bicarbonate secretion and chloride reabsorption. While there is no renal phenotype under basal conditions, severe metabolic alkalosis has been reported in Pendred syndrome patients exposed to an increased alkali load.

This review provides an overview on the clinical spectrum of Pendred syndrome, the functional data on pendrin with a focus on its potential role in the thyroid, as well as the controversy surrounding the relative physiological roles of pendrin and anoctamin.

Introduction

Vaughan Pendred, a British practitioner, was the first to report on the “the curious association of deaf-mutism and goitre occurring in two members of a large family“ [1]. The phenotype was present in two sisters of an Irish family with ten children. He emphasized that the findings could not be explained by iodine deficiency and that there was no evidence for hypothyroidism. He also expressed his hope that “perhaps some… may be able to throw some light on the cause of this combination of diseases” in the future. The description of twelve children from five families from the eastside of London in 1927 then stimulated the interest in this syndrome again [2]. None of the parents was affected, which was suggestive for an autosomal recessive disorder. In 1958, Morgans and Trotter studied the iodine organification with the so-called perchlorate test and demonstrated that it was decreased in the goitrous thyroid tissue of affected individuals [3]. A century after the first description of the syndrome, two groups established linkage of the phenotype to a region on chromosome 7q22-31.1 [4], [5] and shortly thereafter the SLC26A4 gene, originally named PDS gene, was cloned in 1997 [6]. The SLC26A family consists of multifunctional anion exchangers and channels and the motor protein prestin, which is found in outer hair cells (SLC26A5) [7], [8].

Section snippets

Clinical presentation

The classical clinical phenotype consists of the triad sensorineural deafness/hearing impairment, goiter, and an abnormal organification of iodide with or without hypothyroidism [9], [10]. The prevalence of Pendred syndrome has been estimated to be between 7.5 and 10 per 100,00 [11], [12]. Importantly, Pendred syndrome accounts for about 4–10% of all cases of hereditary deafness [11], [13]. Thus, it may be the most frequent cause of syndromic deafness.

Inner ear

Aside from formal auditory evaluation, thin-section high-resolution imaging of the inner ear with magnetic resonance imaging (MRI) using a T2 protocol in the axial and sagittal planes is considered the imaging modality of choice [37], [38]. In all patients studied by MRI, enlargement of the endolymphatic sac and duct, as well as an enlargement of the vestibular aqueduct can be identified [37]. EVA is defined as an antero-posterior diameter of the vestibular aqueduct of 1.5 mm or more [39]. A

Hearing impairment

Hearing loss can have serious and far-reaching consequences and comprehensive audiology support is essential. In subjects with modest and moderate hearing impairment, personal amplification devices or hearing aids can be beneficial. If this does not lead to acceptable improvements, or in patients with severe deafness, cochlear implants are recommended [51]. If a Mondini cochlea is present, an intraoperative leak (“gusher”) of cerebro-spinal fluid, can occur during the implantation procedure [52]

The role of pendrin and anoctamin 1 in thyroid cells

The controversies surrounding the role of pendrin in thyroid hormone synthesis have been the topic of several recent reviews [62], [63], [64], [65]. The synthesis of the thyroid hormones thyroxine (T4) and triiodothyronine (T3) requires the organification of iodide on selected tyrosyl residues of thyroglobulin within thyroid follicles [66]. Aside from active transport into thyroid cells at the basolateral membrane by the well characterized sodium-iodide symporter (NIS) [67], this requires an

Acknowledgment

The authors are grateful to Dr. Frédérique Dubrulle, Department of Radiology, Hôpital Claude Huriez, Centre Hospitalier et Universitaire de Lille, Lille, France, for providing imaging studies of the inner ear.

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