Pendred syndrome: Advances in diagnostics and unresolved therapeutic challenges

INTRODUCTION

Currently, the global prevalence of hearing loss exceeds 0.5 billion individuals, with the latest projections from the World Health Organisation (WHO) indicating a rise to approximately 2.5 billion by 2050 [1, 2]. Among children, the estimated prevalence of permanent bilateral hearing loss stands at 1.7 per 1000 live births, escalating to 5 per 1000 adolescents [3].
Pendred syndrome, initially characterised in 1896, exemplifies a congenital condition contributing to hearing impairment. This syndrome constitutes a rare disorder manifesting with congenital primary hypothyroidism, non-endemic goitre, and deafness attributed primarily to inner ear abnormalities, especially Mondini dysplasia [4]. Notably, pathogenic variants in the SLC26A4 gene represent a prominent aetiological factor in non-syndromic sensorineural hearing loss globally [5]. Pendred syndrome is inherited in an autosomal recessive disorder and is closely associated with pathogenic alterations in the SLC26A4 gene. Expression of the pendrin protein, primarily localised in the inner ear, thyroid, and kidneys, underscores its pivotal role in maintaining normal physiological functions. Mutations in SLC26A4 result in dysfunctional transmembrane protein synthesis, precipitating disturbances in ion transport mechanisms [6]. Frequently, Pendred syndrome presents in concurrence with enlarged vestibular aqueduct (EVA) and/or inner ear malformations, necessitating meticulous evaluation during diagnostic assessments [7].
Advancements in newborn screening protocols facilitate expedited identification of hearing impairments, thereby expediting subsequent genetic evaluations. Consequently, prompt diagnosis enables timely initiation of interventions aimed at mitigating the heightened risks of speech-language delays and academic challenges among affected individuals [8]. The objective of this review is to systematically consolidate existing knowledge regarding the genetic disorder known as Pendred syndrome. This comprehensive publication encompasses epidemiological insights, elucidation of pathogenetic mechanisms, exploration of clinical ramifications, diagnostic methods, and therapeutic modalities.

MATERIAL AND METHODS

All relevant publications were retrieved from PubMed databases using the keywords “Pendred syndrome”. During the initial review, 131 items were selected to represent the current state of knowledge regarding Pendred syndrome. Some articles were rejected due to poor quality or because they were outdated. Ultimately, 32 studies were selected. All publications are from the years 2015-2024, with the reviewed literature focusing on the last 4 years. The key results of the review are presented and discussed in the text of the review.

STATE OF KNOWLEDGE

EPIDEMIOLOGY

Pendred syndrome, characterised by its autosomal recessive inheritance pattern, wherein carriers harbour one mutated gene without exhibiting clinical manifestations. The likelihood of both carrier parents transmitting the pathogenic mutation to their offspring, thereby resulting in the full-blown disease, stands at 25% per pregnancy, a risk consistent across genders [9]. Epidemiologically, Pendred syndrome manifests with an approximate incidence of 2-3 cases per 1000 children. Notably, no discernible correlation has been established between disease prevalence and racial or ethnic origins, as shown by data compiled by the National Organisation for Rare Disorders (NORD). Furthermore, data from the WHO indicate that hearing loss afflicts over 5% of the global population, with 3-5% of these cases attributed to mutations in the SLC26A4 gene [10].

PATHOGENESIS

Pendred syndrome arises from genetic alterations, predominantly mutations affecting three key genes – SLC26A4, FOXI1, or KCNJ10 – in approximately 50% of afflicted individuals. However, in the remaining 50%, the aetiology remains elusive. Notably, pathogenic variants in the SLC26A4 gene predominate, accounting for the majority of Pendred syndrome cases. These mutations engender dysfunctional pendrin, a transmembrane protein pivotal for chloride (Cl–), iodide (I–), or bicarbonate (HCO3–) transport [11]. The breadth of genetic diversity underlying Pendred syndrome is exemplified by the identification of over 8000 mutation variants of the SLC26A4 gene, with approximately 810 characterised as missense mutations. A study analysing 761 such missense mutations, excluding intronic and coding regions, revealed their pervasive distribution across various genetic loci, with notable exceptions within the CL6 loop of pendrin. Moreover, investigations substantiate the significant pathogenic contribution of mutations localised within the CL1-TM3 and EL5TM10 regions [10].
Emerging evidence supports the notion that the recurrence of specific mutations within distinct populations stems from the founder effect. This hypothesis finds corroboration in the conservation of haplotypes defined by closely linked genetic markers, such as short tandem repeats (STRs) or single nucleotide polymorphisms (SNPs). Table 1 illustrates the most prevalent pathogenic mutations documented depending on the geographical region [6].

INNER EAR

Within the inner ear, pendrin protein expression is localised predominantly within the epithelial cells lining the cochlear spiral prominence, endolymphatic sac, saccule, utricle, and ampulla. Pathogenic mutations disrupt the regulation of endolymph composition and pH stability, particularly impeding bicarbonate (HCO₃–) secretion [10]. Consequently, the resultant acidification of the endolymph precipitates cascading alterations within the cochlea, ultimately contributing to auditory dysfunction and the onset of deafness [12].

THYROID GLAND

In the thyroid gland, pendrin facilitates the transport of chloride (Cl–) and iodide (I–) across the apical membrane of thyrocytes. Mutation-induced perturbations in this transport mechanism impede cellular iodide transport into the follicular lumen, thereby disrupting thyroid hormone synthesis and homeostasis [13].

KIDNEY

In the kidney, pendrin localises to type B and non-A, non-B intercalated cells within the connecting tubule and cortical collecting duct. Here, it orchestrates renal chloride (Cl–) absorption and bicarbonate (HCO₃–) secretion, thereby modulating acid-base balance and electrolyte homeostasis. It was noted that in some patients with Pendred syndrome, excessive alkali load may cause acid-base disturbances [14].

CLINICAL MANIFESTATIONS

Pendred syndrome is characterised by multi-organ dysfunction, presenting with a spectrum of clinical manifestations. Key symptoms typically encompass congenital hearing loss, thyroid goitre with or without hypothyroidism, hypotension, and metabolic alkalosis resulting from renal involvement [15]. SLC26A4 mutation is one of the common syndromic forms of hereditary sensorineural hearing loss, which is diagnosed even in the youngest patients and may worsen over time or due to causative factors (e.g. head injury). Thyroid goitre is present in approximately 30-75% of patients with Pendred syndrome, which most often appears after the age of 10 years [7].

HEARING LOSS

Approximately 20% of congenital hearing impairments stem from inner ear anomalies, with profound bilateral sensorineural hearing loss representing the predominant phenotype [16]. The onset is typically congenital or prelingual, often progressing gradually or triggered by specific factors such as head trauma. Symmetric hearing loss is prevalent, although asymmetry may manifest in select cases. Early indicators include absent responses to auditory stimuli or delays in language acquisition, potentially culminating in speech and cognitive developmental disorders [4].

VESTIBULAR DISORDERS

Unfortunately, the vestibular characteristics in Pendred syndrome remain poorly described [17]. However, bilateral vestibular areflexia may be present in patients with Pendred syndrome [16]. Recent investigations on murine models with SLC26A4 mutations suggest that otolithic dysfunction underpins vestibular impairments, primarily involving otoconia development, formation, and maintenance [18].

THYROID DISORDERS

Thyroid abnormalities are hallmark features of Pendred syndrome, typified by thyroid goitre with or without concurrent hypothyroidism [4]. Thyroid function is phenotypically variable, and not all affected individuals develop goitre [15]. Goitres usually grow gradually and do not obstruct the respiratory airways, but it is possible [19]. Emerging evidence implicates SLC26A4 mutations in the pathogenesis of thyroid follicular nodular disease and potential malignant transformations within the thyroid architecture [13].

KIDNEY DISORDERS

Mutations affecting the pendrin protein precipitate alterations in blood pressure regulation, characterised by bicarbonate retention within renal tissues and ensuing metabolic alkalosis [20]. Furthermore, pendrin modulates vascular volume and blood pressure, with angiotensin II and aldosterone acting as pivotal stimulators of pendrin activity [21]. Is important to know that angiotensin II and aldosterone are stimulators of pendrin activity. Corrective measures targeting alkalosis and preserving NaCl homeostasis are imperative for maintaining physiological blood pressure levels.

RESPIRATORY DISORDERS

In patients with Pendred syndrome, attention should be paid to the presence of bronchiectasis. An in vitro study showed that mutations of SLC26A4 cause acidification of airway surface fluid (ASL), reduce airway defence, and increase the thickness of ASL. Chronic inflammation ensuing from recurrent infections exacerbates airway remodeling, ultimately culminating in respiratory dysfunction characterised by structural alterations within the airway walls and the development of bronchiectasis [11].

DIAGNOSIS

GENETIC TESTS

Whole exome sequencing (WES) and XON-array analysis have emerged as indispensable tools in the diagnostic armamentarium for individuals with sensorineural hearing loss (SNHL), offering substantial diagnostic efficacy. These modalities play a pivotal role in confirming the diagnosis of Pendred syndrome and guiding subsequent clinical investigations and interventions. Given the complexity of Pendred syndrome, a confirmed diagnosis necessitates the coordinated efforts of a multidisciplinary team comprising various specialists [21]. Predominantly, mutations in the SLC26A4 gene underpin the pathogenesis of Pendred syndrome. Nonetheless, it is imperative to recognise that mutations in the FOXI1, KCNJ10, or EPHA2 genes may also precipitate the syndrome, albeit infrequently, occurring in less than 1% of affected individuals. Notably, investigations have unveiled a shared haplotype, denoted as CEVA (Caucasian EVA), distinctive to individuals of Caucasian descent [23]. In recent years, the advent of novel genotyping methodologies has expanded diagnostic capabilities. The STH-PAS genotyping harnesses allele-specific polymerase chain reaction (PCR) coupled with single-stranded tag hybridisation chromatographic printed-array strips, facilitating rapid and precise genetic profiling within a remarkably short timeframe [24]. Proactive engagement in preconception or prenatal genetic carrier screening is paramount, offering profound implications for clinical management and outcomes. Early identification of mutation carriers through comprehensive screening initiatives ensures timely implementation of multidisciplinary care strategies, thereby optimising clinical trajectories and enhancing patient prognosis [25].

IMAGING TESTS

Individuals with Pendred syndrome frequently present with temporal bone anomalies, notably an enlarged vestibular aqueduct (EVA), and occasionally a “Mondini deformity”, now recognised as an incomplete partition type II malformation (IP-II). It is essential to underscore that while radiological evidence of EVA, with or without cochlear involvement, may be discernible, it does not invariably signify a clinical diagnosis of Pendred syndrome [26]. In patients harbouring biallelic mutations in the SLC26A4 gene, imaging studies such as computed tomography (CT) scans or magnetic resonance imaging (MRI) often reveal bilateral enlargement of the vestibular aqueduct. Additionally, the examination may occasionally detect the presence of Mondini dysplasia, characterised by cochlear incomplete partition type II morphology [17].

DIAGNOSIS OF HEARING LOSS AND VESTIBULAR DISORDERS

In individuals with Pendred syndrome, low-frequency auditory bone gaps may be evident, primarily attributed to the third window effect. However, in some cases, diminished stapes mobility may also contribute to this phenomenon. Hearing impairment tends to progressively deteriorate, typically plateauing within the range of 50 to 70 dB [17].
In patients with Pendred syndrome, vestibular function was assessed using the video head impulse test (VHIT) and the cervical vestibular evoked myogenic potential (cVEMP) test, assessing the high frequency vestibulo-ocular reflex (VOR) and the saccular function. Intriguingly, despite underlying anatomical aberrations within the vestibular system and profound hearing loss, VHIT often reveals normal VOR function. Notably, saccular function appears to exhibit abnormal sensitivity, characterised by low cVEMP thresholds and heightened amplitudes. The presence of an enlarged vestibular aqueduct (EVA) precipitates a secondary “third window” effect, further complicating auditory and vestibular manifestations in affected individuals [27].

DIAGNOSIS OF THYROID DISORDERS

Neonatal screening tests may detect congenital hypothyroidism in some individuals with Pendred syndrome [15]. It is believed that every patient with deafness should have thyroid function tests (TSH, FT4), and patients with Pendred syndrome should be tested regularly. Ultrasound examination of the thyroid gland provides information about the volume of the thyroid gland and the presence and location of nodules. In patients with thyroid nodules, follow-up ultrasound examinations are recommended [14].
Histopathological examination of the thyroid gland often reveals distinct features, such as diffuse follicular hyperplasia, nodularity, scant colloid, and potential nuclear atypia. Immunohistochemical profiling utilising specific markers such as thyroglobulin (Tg), thyroid peroxidase (TPO), and thyroid transcription factor-1 (TTF-1) aids in discerning cancerous transformations within thyroid cells. Altered ciliogenesis further underscores the malignant potential of thyroid lesions [13]. Notably, there exists a 1% probability of developing non-medullary thyroid carcinoma in individuals with Pendred syndrome. C-cell hyperplasia, when present, warrants classification as either reactive or neoplastic, necessitating meticulous histopathological evaluation for accurate prognostication and management [28].

DIAGNOSIS OF KIDNEY DISORDERS

Disruptions in bicarbonate resorption within the kidneys can precipitate disturbances in acid-base equilibrium, culminating in potentially life-threatening metabolic alkalosis [20]. In cases where metabolic alkalosis is suspected, continuous monitoring of acid-base balance through gasometry is imperative to guide appropriate therapeutic interventions. A series of studies in mice showed that the deletion of pendrin and the sodium-chloride cotransporter (NCC) leads to salt loss, hypovolaemia, and renal failure. It important to now that pendrin affects the release of catecholamines, which may result in changes in blood pressure [14]. It is worth paying attention to these pathomechanisms when diagnosing kidney function.

TREATMENT

SYMPTOMATIC TREATMENT

Unfortunately, no causal treatment has been identified for Pendred syndrome to date. Consequently, treatment primarily focuses on managing symptomatic manifestations. It is imperative that patients suspected of having Pendred syndrome receive comprehensive care from a multidisciplinary team comprising specialists such as otorhinolaryngologists, endocrinologists, geneticists, and surgeons. Additionally, genetic testing should be extended to family members under the guidance of a geneticist to facilitate early detection and intervention [4].
Levothyroxine treatment is used in patients with congenital hypothyroidism. Thyroidectomy is performed in patients with goitre causing airway obstruction or suspicion/presence of cancer. Sometimes the thyroid gland is removed for cosmetic reasons [14].
Upon confirmation of a diagnosis of Pendred syndrome, patients and their families must be educated about the potential for progressive hearing loss. Furthermore, particular attention should be directed towards mitigating factors that may exacerbate hearing impairment, including avoiding head injuries, refraining from the Valsalva manoeuvre, and abstaining from diving activities, as these practices have been associated with accelerated hearing loss progression [16].

TREATMENT AS IN MENIERE’S DISEASE

In a comparative study, researchers examined the similarities and distinctions between Meniere’s syndrome and Pendred syndrome. These 2 different diseases have 2 main features in common: endolymphatic oedema and variable and progressive hearing loss. Drawing from their findings, the scientists arrived at several key conclusions. Firstly, in cases where individuals exhibit residual or normal hearing, consideration should be given to implementing repositioning manoeuvres as part of the hydrops treatment protocol, akin to approaches utilised in managing Meniere’s syndrome. These manoeuvres aim to alleviate fluctuating episodes of symptoms associated with endolymphatic hydrops, potentially offering symptomatic relief and improving overall quality of life. Secondly, for individuals presenting with advanced foetal hydrops accompanied by congenital bilateral cochlear obliteration, auditory rehabilitation strategies such as cochlear implantation warrant consideration. Cochlear implantation offers a viable solution for restoring auditory function and facilitating language development in individuals with profound hearing loss, ensuring optimal communication outcomes. These insights underscore the importance of tailoring treatment approaches to the specific clinical manifestations and needs of therapeutic outcomes and enhancing patient well-being [17].

COCHLEAR IMPLANT

In SLC26A4-biallelic patients, inner ear anomalies may encompass a spectrum ranging from normal cochlear morphology to incomplete partition of the cochlea (IP-1 or IP-2). Among these anomalies, the most frequently encountered type is IP-2 + EVA. Notably, this finding holds particular significance for cochlear implant surgeons, as individuals with IP-2 anomaly do not exhibit an elevated risk of complications such as “gushers” or recurrent meningitis [29]. A comparative study investigated the outcomes of cochlear implantation in 2 distinct cohorts: individuals with Pendred syndrome and cochlear implants versus individuals with deafness stemming from other aetiologies who underwent cochlear implantation. Remarkably, the study revealed comparable results in speech perception between the 2 groups. This underscores the efficacy of cochlear implantation as a viable intervention for restoring auditory function in individuals with Pendred syndrome, mirroring outcomes observed in individuals with other causes of deafness [26].

INNOVATIVE METHODS

Several innovative methods have emerged in recent research endeavours aimed at elucidating the pathomechanisms underlying Pendred syndrome and exploring potential therapeutic interventions:
• TMED Protein Connection: A groundbreaking study identified a connection between TMED proteins and the pathogenesis of Pendred syndrome. Upregulation of TMED proteins was found to potentiate pendrin expression, offering a promising avenue for the development of targeted treatments for Pendred syndrome [30];
• scRNA-seq Analysis of Cochlear Stria Vascularis Cells: In a recent study, cells expressing SLC26A4 and KCNJ10 were isolated from the cochlear stria vascularis. Using single-cell RNA sequencing (scRNA-seq), researchers identified pH-regulating genes in spindle cells responsible for maintaining endolymphatic pH homeostasis. This discovery sheds light on the intricate mechanisms governing pH regulation in stria vascularis cells, potentially paving the way for novel therapeutic strategies targeting this pathway [31];
• Pendrin Corrector (PC2-1): Another study investigated the efficacy of a pendrin corrector (PC2-1) in increasing the surface expression and anion exchange activity of p.H723R pendrin, a common mutation associated with Pendred syndrome. Notably, high concentrations of PC2-1 did not inhibit the activity of Kv11.1 or exhibit cytotoxic effects, suggesting its potential as an innovative treatment for Pendred syndrome [32].
These innovative approaches hold promise for advancing our understanding of Pendred syndrome and may ultimately lead to the development of targeted therapies aimed at improving patient outcomes and quality of life.

CONCLUSIONS

Pendred syndrome, characterised by mutations in the pendrin protein, manifests primarily as sensorineural hearing loss, hypothyroid goitre, and potentially reduced blood pressure, with vestibular disorders occasionally present.
Notably, individuals with SLC26A4 mutations are at increased risk of developing thyroid cancer, underscoring the importance of vigilant monitoring and management strategies.
The definitive diagnosis of Pendred syndrome necessitates confirmation through genetic testing, highlighting the critical role of molecular analysis in establishing a conclusive diagnosis.
Given the genetic nature of Pendred syndrome, consultation with a genetic counsellor is imperative for affected individuals and their families. It is recommended that mutation carriers seek guidance from a geneticist when contemplating pregnancy to assess potential risks and inform reproductive decision-making.
While effective treatments for Pendred syndrome remain elusive, recent research has introduced innovative treatment models that warrant further investigation and clinical evaluation. These advancements offer hope for the development of targeted therapies in the future, underscoring the importance of ongoing research efforts in the field.

Disclosures

This research received no external funding.
Institutional review board statement: Not applicable.
The authors declare no conflict of interest.

References