Pendred Syndrome: Symptoms, Types, Causes and Treatment

Pendred syndrome is a rare genetic disorder that affects hearing and thyroid function, often leading to progressive hearing loss and the development of a goiter. Understanding the complexities of this syndrome is crucial not only for affected individuals and their families but also for clinicians aiming to provide timely diagnosis and effective management. This article provides an in-depth look at the symptoms, types, underlying causes, and current treatment strategies for Pendred syndrome, synthesizing findings from recent scientific research.

Symptoms of Pendred Syndrome

Pendred syndrome manifests early in life, and its symptoms can vary widely between individuals—even among members of the same family. The hallmark features are progressive sensorineural hearing loss and thyroid abnormalities, but detailed clinical evaluation can reveal a broader spectrum of signs.

Symptom	Description	Onset/Age	Source(s)
Hearing Loss	Progressive, sensorineural, often congenital or early	Infancy/Childhood	1, 2, 3, 5, 6
Goiter	Enlargement of the thyroid gland (dyshormonogenetic)	Childhood to adolescence	2, 3, 4, 5, 6, 7
Cochlear Malformations	Hypoplasia (underdevelopment) of cochlea, Mondini malformation	Early childhood	1, 3, 6, 10
Enlarged Vestibular Aqueduct	Inner ear abnormality visible on imaging	Childhood	1, 3, 5, 6, 10
Thyroid Dysfunction	Hypothyroidism (variable), impaired iodide organification	Variable, sometimes absent	3, 4, 5, 6, 7
Others	Occasional balance issues, rare kidney symptoms	Variable	2, 13

Table 1: Key Symptoms

Progressive Hearing Loss

Sensorineural hearing loss is typically the earliest and most prominent symptom. It often presents congenitally or in early childhood and tends to worsen over time. The hearing loss can be profound, and in many cases, it is bilateral (affecting both ears). Imaging studies frequently reveal structural abnormalities such as a widened vestibular aqueduct and cochlear hypoplasia, further contributing to the degree of hearing impairment 1, 3, 6, 10.

Goiter and Thyroid Abnormalities

Goiter, or thyroid gland enlargement, is another classic feature of Pendred syndrome. The goiter usually develops during childhood or adolescence, though the onset can be variable. Thyroid function may range from normal (euthyroid) to mildly or overtly hypothyroid. Notably, the goiter results from a partial defect in iodide organification—the process by which iodine is incorporated into thyroid hormones 2, 3, 4, 5, 6, 7.

Cochlear and Inner Ear Malformations

Individuals with Pendred syndrome often have structural changes in the inner ear, most notably hypoplasia of the cochlea (sometimes referred to as Mondini malformation) and a widened vestibular aqueduct. These can be detected with advanced imaging techniques and may be associated with both hearing and balance difficulties 1, 3, 6, 10.

Additional Features

While less common, some individuals may experience balance problems due to inner ear malformations. Rarely, kidney involvement may occur, but most patients do not have significant renal symptoms under normal conditions 2, 13. Thyroid dysfunction is variable—some patients remain euthyroid despite the presence of goiter, while others may develop hypothyroidism 4, 6.

Types of Pendred Syndrome

Pendred syndrome is primarily defined as a single genetic disorder, but there is notable variability in how it presents. This phenotypic diversity, sometimes referred to as "types," is influenced by the specific genetic mutations and other modifying factors.

Type/Variant	Key Features	Distinction/Comments	Source(s)
Classic Pendred	Hearing loss, goiter, inner ear malformations	Typical triad, confirmed by genetics	2, 5, 6, 7, 9
Pseudo-Pendred	Similar symptoms but no SLC26A4/PDS mutation	Often autoimmune thyroid disease	5
DFNB4	Hearing loss and inner ear anomalies, no goiter	Allelic disorder, SLC26A4 mutations	10
Variable Expressivity	Intra-familial and inter-individual differences	Range from mild to severe symptoms	2, 6, 10, 12

Table 2: Types and Variants of Pendred Syndrome

Classic Pendred Syndrome

This is the most commonly recognized form, characterized by the triad of sensorineural hearing loss, thyroid goiter, and radiologically detectable inner ear malformations. Diagnosis is confirmed by identifying biallelic pathogenic mutations in the SLC26A4 (PDS) gene 2, 5, 6, 7, 9.

Pseudo-Pendred Syndrome

Pseudo-Pendred syndrome describes patients who exhibit similar clinical features (hearing loss, goiter) but do not have mutations in the SLC26A4 gene. These cases are often due to other causes, such as autoimmune thyroid disease combined with unrelated hearing loss 5.

DFNB4

DFNB4 is an autosomal recessive disorder caused by mutations in the same gene as Pendred syndrome (SLC26A4), but it differs in that affected individuals have hearing loss and inner ear anomalies without the development of goiter. This condition highlights the spectrum of disease associated with SLC26A4 mutations 10.

Variable Expressivity

There is significant variability in the presentation of Pendred syndrome, both within and between families. Symptoms can range from mild hearing loss and small goiters to profound deafness and large multinodular thyroids. This variability stems from allelic heterogeneity (different mutations in the same gene), modifier genes, and environmental factors such as iodine intake 2, 6, 10, 12.

Causes of Pendred Syndrome

Pendred syndrome is fundamentally a genetic disorder, but the underlying causes involve both genetic mutations and environmental influences.

Cause	Mechanism/Pathway	Comments	Source(s)
SLC26A4 Mutations	Biallelic, autosomal recessive inheritance	Encodes pendrin, anion transporter	2, 5, 6, 7, 8, 9, 10, 12
Pendrin Dysfunction	Impaired transport of chloride, iodide, bicarbonate	Affects thyroid, inner ear, kidney	2, 4, 5, 8, 13
Allelic Heterogeneity	Multiple distinct mutations in SLC26A4	Explains variable symptoms	6, 10, 12
Environmental Factors	Dietary iodine intake, stressors	Modifies thyroid function and symptom severity	4, 14, 15

Table 3: Causes and Mechanisms of Pendred Syndrome

Genetic Mutations in SLC26A4

Pendred syndrome is caused by mutations in the SLC26A4 gene (also known as PDS), which is inherited in an autosomal recessive pattern. The gene encodes the protein pendrin, a transmembrane anion exchanger 2, 5, 6, 7, 8, 9, 10, 12. Over 100 different disease-causing mutations have been identified, ranging from missense and nonsense mutations to frameshifts and splicing errors 6, 10, 12.

Pendrin Dysfunction

Pendrin functions as an anion transporter, moving chloride, iodide, and bicarbonate ions across cell membranes. It is expressed in the thyroid gland, inner ear, and kidney 2, 4, 5, 8, 13. In the thyroid, pendrin is vital for the proper organification of iodide, a step necessary for thyroid hormone synthesis. In the inner ear, it helps regulate the ionic composition of endolymph, essential for normal hearing and balance 2, 4, 8. Disrupted function leads to the characteristic symptoms of the syndrome.

Allelic Heterogeneity

The wide range of mutations in the SLC26A4 gene leads to significant clinical variability. Some mutations result in partial loss of function, while others abolish pendrin activity entirely. This allelic heterogeneity is a major reason for the variability in hearing loss severity, goiter development, and thyroid function among affected individuals 6, 10, 12.

Environmental and Modifier Factors

Environmental factors, particularly dietary iodine intake, can influence the severity of thyroid manifestations in Pendred syndrome 4. Additionally, new research suggests that cellular stress and other modifier genes may play a role in disease progression, especially regarding cochlear cell degeneration 14, 15.

Treatment of Pendred Syndrome

While there is currently no cure for Pendred syndrome, a combination of medical, surgical, and supportive therapies can significantly improve quality of life for affected individuals.

Treatment	Purpose/Target	Notes/Considerations	Source(s)
Hearing Aids & Cochlear Implants	Compensate for hearing loss	Selection depends on severity	1, 2, 3, 15
Speech Therapy	Facilitate language development	Early intervention critical	2, 15
Thyroid Hormone Replacement	Manage hypothyroidism	L-thyroxine common; requires monitoring	4, 6, 7, 17
Thyroidectomy	Remove multinodular or large goiters	Indicated if malignancy risk or compression	17
Genetic Counseling	Support for families	Informs about inheritance and recurrence risk	2, 6, 7
Experimental Therapies	Target underlying pathophysiology	Rapamycin, metformin, antisense oligonucleotides	14, 15, 16

Table 4: Overview of Treatment Strategies

Hearing Management

Most patients require intervention to address hearing loss. Options include:

• Hearing aids: Suitable for mild to moderate hearing loss; help amplify sound 1, 2, 3.
• Cochlear implants: Indicated for profound or progressive deafness; surgically implanted electronic devices can provide a sense of sound 15.
• Speech and language therapy: Early support is vital for children to achieve age-appropriate language and communication skills 2, 15.

Thyroid Management

Management of thyroid dysfunction and goiter involves:

• Thyroid hormone replacement: L-thyroxine is used to treat hypothyroidism and can sometimes slow goiter growth, though goiters may still enlarge over time 4, 6, 7, 17.
• Monitoring and imaging: Regular follow-up with ultrasound and thyroid function tests is recommended due to the risk of multinodular transformation and potential malignancy 17.
• Thyroidectomy: Surgical removal of the thyroid may be necessary if the gland becomes very large, compresses adjacent structures, or shows suspicious nodules 17.

Genetic Counseling

Given the autosomal recessive inheritance, genetic counseling is highly recommended for families. It provides information about carrier status, recurrence risk, and options for prenatal diagnosis 2, 6, 7.

Emerging and Experimental Therapies

Recent advances in research are opening promising avenues for disease-modifying treatments:

• Low-dose rapamycin and metformin: In cellular models, these drugs have reduced cochlear cell degeneration and may slow hearing loss progression 14, 15.
• Antisense oligonucleotide (ASO) therapy: Experimental ASOs can correct mis-splicing in certain SLC26A4 mutations, potentially restoring pendrin function 16.
• Gene therapy and iPSC models: Ongoing studies using patient-derived induced pluripotent stem cells (iPSCs) are helping to model disease and identify new treatments 14, 15.

Other Considerations

• Avoidance of head trauma: To reduce the risk of sudden hearing deterioration, children with Pendred syndrome should avoid activities that could result in head injury.
• Kidney monitoring: Although rare, some patients may be more sensitive to certain diuretics and may need careful electrolyte monitoring if treated 13.

Conclusion

Pendred syndrome is a complex, multisystem disorder with significant variability in its presentation and progression. Here’s a summary of the key points:

• Symptoms include progressive sensorineural hearing loss, thyroid goiter, and characteristic inner ear malformations.
• Types are primarily defined by clinical variability and genetic findings, with classic Pendred syndrome, pseudo-Pendred syndrome, and DFNB4 forming the main spectrum.
• Causes center on mutations in the SLC26A4 gene, leading to dysfunctional pendrin and impaired anion transport, with symptom severity modified by genetic and environmental factors.
• Treatment is multidisciplinary, involving hearing support, thyroid management, genetic counseling, and emerging therapies aimed at modifying disease progression.

Ongoing research continues to improve our understanding of Pendred syndrome, paving the way for more targeted and effective treatments that can greatly enhance the lives of those affected by this rare disorder.