Pendred Syndrome

Etiology

The most common identifiable cause of Pendred syndrome is a mutation in the SLC26A4 gene, which encodes the pendrin protein.[6] The gene, located on chromosome 7q22.3, is expressed in multiple organs, including the inner ear, kidneys, thyroid, and bronchial epithelial cells.[1][6] Pendrin is a multifunctional anion exchanger with an affinity for chloride, iodide, bicarbonate, and other anions.[1] This function is critical for maintaining ion balance and proper physiological activity in affected tissues. Less common genetic causes of Pendred syndrome include mutations in the FOXI1 and KCNJ10 genes. Together, mutations in these genes, along with SLC26A4, account for approximately 50% of all Pendred syndrome cases.[7] The remaining 50% of cases currently lack a definitive genetic cause.

Epidemiology

The prevalence of Pendred syndrome is estimated to be between 7.5 and 10 per 100,000 live births.[1][7] This condition accounts for 7.5% to 15% of cases of congenital deafness,[6][3] potentially making it the most frequent cause of syndromic deafness.[1][8] Given its autosomal recessive mode of inheritance, children of 2 heterozygous carrier parents have a 25% risk of inheriting the condition.[1] This underscores the importance of genetic counseling, especially in families with a known history of hearing loss or thyroid abnormalities.

Pathophysiology

Pendred syndrome is an autosomal recessive disorder caused by biallelic mutations in the SLC26A4 gene, which encodes the anion exchanger pendrin. Pendrin is primarily expressed in the thyroid, inner ear, and kidney and facilitates the transport of chloride, iodide, and bicarbonate ions.

Inner Ear

Pendrin is expressed in the cochlea and vestibule of the inner ear, functioning as a chloride/bicarbonate exchanger, and plays a vital role in endolymphatic fluid resorption, acid-base balance, and the proper functioning of the inner ear.[6]

Thyroid Gland

In the thyroid, pendrin is expressed on the thyrocyte apical membrane, where its activity is postulated to involve chloride/iodide (Cl-/I-) exchange, which is essential for cellular iodide efflux into the follicular lumen. A defect in the SLC26A4 gene may lead to the partial impairment of thyroid organification. However, most patients with Pendred syndrome present with a euthyroid goiter.[1][6]

Kidneys

Pendrin protein is located at or near the apical membrane of type B and non-A non-B intercalated cells of the cortical collecting ducts.[6] Pendrin acts as a chloride/anion exchanger, facilitating bicarbonate secretion into the tubular lumen and chloride reabsorption.[1] As a result, it plays a crucial role in regulating blood pressure and maintaining fluid balance.[6][9] Defects in pendrin function can also lead to metabolic alkalosis.[10]

Bronchial Epithelium

Pendrin is also expressed at the apical membrane of bronchial epithelial cells in the airway and regulates airway surface liquid thickness through chloride/bicarbonate exchange activity. Dysfunction of the SLC26A4 gene can affect mucus production and contribute to conditions such as asthma and chronic obstructive pulmonary disease. Additionally, pendrin functions as a thiocyanate/chloride (SCN−/Cl−) exchanger, playing a role in the innate mucosal defense by secreting the antioxidant SCN− into the airway lumen.[6]

History and Physical

Patients with Pendred syndrome often present with unremarkable personal and family histories and a normal physical examination. However, a family history of early or congenital hearing loss may be identified with careful questioning. Due to the autosomal recessive inheritance pattern, such a history may be absent in many cases. The most common clinical presentation is early-onset or congenital hearing loss, which may be detected through failed newborn hearing screening.[11] A goiter may be observed on physical examination, although it typically develops later in childhood. 

Hearing Impairment 

Patients with Pendred syndrome experience a wide range of sensorineural hearing loss, ranging from mild to profound.[8] Hearing impairment is typically congenital or prelingual and is often profound. This condition can also develop later in infancy with progressive worsening, which may be aggravated by exposure to acoustic traumas, barotraumas, or head injury.[1][8] The hearing impairment is usually bilateral, although asymmetry may be present. Early signs include the absence of a reaction to sound or delayed language development.

Vestibular manifestations are usually subtle but may present during childhood as frequent falls, clumsiness, or other signs of imbalance.[1] Temporal bone abnormalities, particularly enlarged vestibular aqueduct and Mondini malformation, are commonly associated with the condition.[12] However, these cannot be detected through physical examination and require confirmation via temporal bone imaging.[7]

Thyroid

A euthyroid goiter is a typical feature of Pendred syndrome.[13] However, it may also be a multinodular goiter during late childhood or early puberty.[1] In some cases, thyroid enlargement develops later in adulthood. The goiter arises due to defects in iodide organification. Approximately 75% of patients with Pendred syndrome have a goiter detectable on physical examination.[13] While many present with congenital goiter,[8] others may have a normal-sized thyroid gland, especially if they have adequate iodine intake.[1][8][13] Since iodide organification is not solely dependent on pendrin, patients usually exhibit only partial organification defects.[13] About 50% of patients maintain normal thyroid function, while others may develop subclinical hypothyroidism, which can be congenital.[1]

Renal System

Patients with Pendred syndrome may develop life-threatening metabolic alkalosis due to acid-base balance abnormalities caused by pendrin dysfunction.[10] This condition results from impaired bicarbonate secretion and chloride reabsorption in the kidneys, highlighting the importance of monitoring electrolyte and acid-base status in affected individuals.

Evaluation

The evaluation of Pendred syndrome involves a combination of audiologic, laboratory, radiographic, and genetic tests to confirm the diagnosis and assess the extent of the disease. These evaluations help establish the diagnosis, guide management, and inform genetic counseling.

Audiologic Assessment

Patients with Pendred syndrome may fail the newborn hearing screening, bringing an otherwise asymptomatic infant to medical attention. Screening is most commonly performed using otoacoustic emissions, which have a low specificity, as they are designed only to detect potential hearing loss.[14] Therefore, confirmatory audiological testing is required to determine the type and severity of the hearing impairment.

In newborns and infants, this testing is typically performed using auditory brainstem response testing, which evaluates the presence and function of the cochlear nerve in each ear.[14] Other tests may be used in older children, such as visual reinforced audiometry or formal audiogram testing, depending on the child's developmental stage and ability to cooperate.[15] Formal balance testing is not routinely performed in pediatric patients undergoing workup for Pendred syndrome, but can be considered in older children when vestibular symptoms are present.[16] If Pendred syndrome is confirmed or strongly suspected, a computed tomography (CT) scan of the temporal bone is the initial imaging modality to assess the vestibular aqueducts.[13]

Genetic Testing 

Molecular genetic testing is the definitive confirmatory test for Pendred syndrome.[1] The SLC26A4 gene is the most commonly affected, with mutations identified in approximately 50% of patients.[1][7][13] Genetic testing involves direct sequencing of the coding region of the SLC26A4 gene to identify either a biallelic pathogenic variant in the gene or the presence of double heterozygosity for 1 pathogenic variant.[1][13]

Mutations in the FOXII and KCNJI0 genes account for fewer than 2% of cases.[7][13] Due to the genetic heterogeneity of the SLC26A4 gene, approximately 200 sequence variants have been identified.[1] As such, clinical suspicion should be guided by a thorough understanding of the variable phenotypic presentation of Pendred syndrome. Careful clinical evaluation based on established diagnostic criteria can help target appropriate candidates for molecular testing, improving diagnostic accuracy and cost-effectiveness.

Inner Ear Imaging

Individuals with Pendred syndrome may exhibit temporal bone abnormalities that can be identified through high-resolution, thin-cut CT imaging, which focuses on detailed cochlear anatomy. These structural changes are often not apparent on physical examination and require imaging for accurate diagnosis and classification. Enlargement of the vestibular aqueduct is the most common radiological finding and is best visualized on high-resolution CT scans of the temporal bone, with coronal and axial sections. Enlargement of the vestibular aqueduct is confirmed when the width of the middle portion of the descending limb of the vestibular aqueduct exceeds 1.5 mm (Valvassori criteria), or when the midpoint width is greater than 1 mm and the operculum width exceeds 2 mm, surpassing the 95th percentile for age (Cincinnati criteria).[13][17][18]

Additional abnormalities may include cochlear hypoplasia, where the cochlea exhibits only 1.5 turns instead of the normal 2.5 turns. When cochlear hypoplasia co-occurs with vestibular aqueduct enlargement, the condition is referred to as a Mondini malformation.[6][13] These findings are critical for diagnosing Pendred syndrome.[19]

Thyroid Evaluation

A euthyroid goiter is the most common thyroid abnormality seen in Pendred syndrome, and can be evaluated using volumetric imaging to assess gland size. Thyroid ultrasound is the preferred modality for measuring thyroid volume and characterizing the size, number, and structure of any nodules present.[1][13] Once the diagnosis of Pendred syndrome is confirmed, regular monitoring of thyroid function through laboratory testing is recommended. Pendred syndrome can coexist with autoimmune thyroiditis, which may further complicate thyroid function.[1]

The perchlorate discharge test is a screening test for iodide organification defects, involving the administration of radioactive iodine and measuring the retention of intrathyroidal radioactivity. A discharge of more than 10% suggests an organification defect. However, a negative test does not exclude the diagnosis of Pendred syndrome, as several factors, including recent high-dose iodine intake, can influence the accuracy of results.[1][13]

Guideline Recommendations

The American College of Medical Genetics and Genomics recommends a comprehensive diagnostic approach for hearing loss associated with Pendred syndrome, including genetic testing, thyroid function evaluation, and imaging studies.[19] Similarly, GeneReviews emphasizes the importance of these assessments in determining the extent of organ involvement in individuals with confirmed Pendred syndrome, guiding diagnosis and ongoing management.[13]

Treatment / Management

The recommended treatment and management strategies for Pendred syndrome focus on addressing hearing impairment and thyroid dysfunction, as well as monitoring for potential complications. According to GeneReviews, the following approaches are recommended:

• Hearing management: Evaluate the degree of hearing impairment and initiate appropriate treatment, including the use of hearing aids and cochlear implants.[13][20]
• Thyroid function management: Perform thyroid function tests every 2 to 3 years to detect and manage hypothyroidism.[13]
• Goiter management: In consultation with an endocrinologist, address goiter and any abnormal thyroid function with medical or surgical treatment.[13]  
• Thyroid ultrasound: Conduct baseline and periodic thyroid ultrasound examinations to monitor gland size and detect volumetric changes.
• Genetic testing: Provide genetic counseling for affected families, offer genetic testing to at-risk family members, and discuss reproductive options and outcomes for offspring.[13]
• Activity modification: Advise patients to avoid activities that may cause sudden increases in intracranial pressure, such as weightlifting or participating in contact sports, as these can exacerbate hearing loss.[13]  

Emerging therapies, such as the novel small molecule PC2-1, have demonstrated efficacy in preclinical studies for restoring function to mutated pendrin, potentially offering treatment options for conditions associated with pendrin dysfunction.[13][21]

Differential Diagnosis

The differential diagnosis for Pendred syndrome, considering its clinical presentation of hearing impairment, thyroid dysfunction, and inner ear malformations, includes several conditions. A thorough differential diagnosis is essential to distinguish Pendred syndrome from other syndromic and nonsyndromic causes of hearing loss, as well as endocrine and developmental disorders that may present with similar findings. Accurate diagnosis requires clinical evaluation, audiologic testing, imaging studies, and molecular genetic analysis.

The differential diagnosis includes other causes of sensorineural hearing loss and thyroid disease.

• Nonsyndromic causes:
  • Congenital deafness (eg, cytomegalovirus)
  • Exposure to autotoxic agents
  • Trauma
  • Nonsyndromic enlarged vestibular aqueduct without associated thyroid goiter [13]
  • Congenital hypothyroidism with coexisting hearing impairment [13]

• Syndromic causes:
  • Branchiootorenal syndrome: Characterized by branchial cysts, hearing impairment, and renal anomalies [22]
  • Waardenburg syndrome: Associated with pigmentary abnormalities of the hair, eyes, and skin [7][19]
  • Usher syndrome: Involves sensorineural hearing loss and progressive vision loss due to retinitis pigmentosa [19]
  • Alport syndrome: Presents with hearing impairment, renal disease, and ocular involvement [7]
  • Jervell and Lange-Nielsen syndrome: Associated with profound congenital hearing loss and cardiac arrhythmias (prolonged QT interval)[7][19]
  • Perrault syndrome: Characterized by progressive sensorineural hearing loss and ovarian dysfunction in females [7][19]

Prognosis

The prognosis for Pendred syndrome depends on the severity of hearing loss, thyroid involvement, and the presence of inner ear structural abnormalities. Most individuals affected by the condition experience significant sensorineural hearing loss that is either present at birth or develops in early childhood. This type of hearing loss tends to worsen over time and may fluctuate, but early use of hearing aids or cochlear implants can significantly improve communication and quality of life.

Thyroid function in Pendred syndrome can vary widely. While goiter is a common feature, many patients maintain normal thyroid hormone levels, particularly in areas where iodine intake is sufficient.[1] In cases where hypothyroidism does develop, it is often mild and easily managed with hormone replacement therapy. Ongoing monitoring of thyroid function is important to ensure timely treatment if dysfunction arises.

Inner ear abnormalities, including enlarged vestibular aqueducts and Mondini malformation, are common in Pendred syndrome and play a significant role in the development of hearing and balance disturbances. While these structural anomalies are important diagnostic indicators, they are generally stable and do not progress over time. However, their presence can complicate surgical interventions, such as cochlear implantation, which may be technically challenging due to the altered anatomy of the cochlea associated with the syndrome.[23] With appropriate interventions, including early hearing support, regular thyroid assessments, and management of balance issues, individuals with Pendred syndrome can lead healthy, functional lives. Long-term follow-up is crucial for monitoring new developments and maintaining overall well-being.

Complications

Pendred syndrome can lead to a range of complications that reflect its impact on multiple organ systems. One of the most prominent features is sensorineural hearing loss, which is often severe or profound and can be present at birth or develop in early childhood. This type of hearing impairment tends to be progressive and may fluctuate, significantly affecting communication and overall quality of life.

Thyroid dysfunction is another common complication, most often presenting as a goiter that typically develops in late childhood or adolescence. Although many patients maintain normal thyroid function, some may develop hypothyroidism, which can range from mild and subclinical to more overt forms requiring thyroid hormone replacement. Ongoing monitoring is essential for early detection and management.

Structural abnormalities of the inner ear, including an enlarged vestibular aqueduct and Mondini malformation, are frequently observed and contribute to hearing deficits and balance disturbances. These inner ear malformations may impair the function of the vestibular system, leading to unsteadiness or frequent falls, particularly in children. Although rare, metabolic alkalosis has been reported in some individuals due to disrupted acid-base regulation associated with pendrin dysfunction in the kidneys. This condition can become serious, especially when triggered by external factors that increase the body’s alkali load.[10]

A rare case report has described the co-occurrence of Pendred syndrome with Hoffmann syndrome, suggesting a potential but uncommon association between the 2 conditions.[24] Hoffmann syndrome is a rare form of hypothyroid myopathy characterized by muscle stiffness, weakness, pseudohypertrophy (especially of the calves), and delayed deep tendon reflexes. This condition typically results from longstanding, untreated hypothyroidism. Beyond the physical manifestations, Pendred syndrome can have a considerable psychosocial impact. Hearing impairment, balance problems, and challenges in managing chronic health conditions may impact academic performance, social development, and long-term employment prospects.