Pendred Syndrome

Pendred syndrome is an autosomal recessive disorder caused by biallelic variants in SLC26A4, giving sensorineural hearing loss, an enlarged vestibular aqueduct or cochlear malformation, and goitre from a partial defect in iodide organification.

It accounts for an estimated 5% of congenital hearing loss. The deafness is present at birth or early childhood and may progress. Goitre appears in late childhood or adulthood.

Thyroid function is usually normal, and subclinical or mild hypothyroidism can develop, especially with low iodine intake.

Pathophysiology.

SLC26A4 encodes pendrin, an anion exchanger in the inner ear and in the apical membrane of thyroid follicular cells, where it moves iodide into the colloid. Loss of function impairs iodide organification, and in the ear it disturbs endolymph composition and development.

• Sensorineural hearing loss (often severe, may fluctuate and decline after minor head injury), sometimes vestibular symptoms.
• Goitre, usually diffuse then nodular, from late childhood or adulthood.
• Mild hypothyroidism in a minority.

• Audiometry, newborn hearing screen and temporal bone MRI or CT: enlarged vestibular aqueduct, with incomplete partition of the cochlea.
• Thyroid stimulating hormone with free thyroxine, thyroid ultrasound, and thyroglobulin. Thyroid peroxidase antibodies are negative.
• SLC26A4 sequencing confirms two pathogenic variants. Add FOXI1 and KCNJ10 if only one is found.
• Perchlorate discharge test (more than 10% release of radioiodine after potassium perchlorate) is rarely used now.
• ECG if there is profound deafness, to exclude long QT syndrome.

Differential diagnosis.

• Non-syndromic enlarged vestibular aqueduct (DFNB4).
• Branchio-oto-renal syndrome, Usher syndrome and Jervell and Lange-Nielsen syndrome (long QT).
• Congenital hypothyroidism from dyshormonogenesis and iodine deficiency goitre.
• Hashimoto thyroiditis.

• Hearing: hearing aids, early cochlear implantation if aids are not enough, and speech and language support. Avoid contact sports and head trauma.
• Levothyroxine for hypothyroidism at about 1.6 micrograms/kg daily (dose by age in children). Treatment for goitre suppression is not routine.
• Surgery for compressive goitre or suspicious nodules. Thyroid cancer risk is not clearly raised.
• Ensure adequate iodine intake.

Special groups. Genetic counselling (25% recurrence risk in siblings) and testing of siblings. Pregnancy: check thyroid stimulating hormone each trimester and ensure adequate iodine intake.

Monitoring. Thyroid function and goitre yearly, and audiology at intervals set by age.

Referral and escalation. Audiology and otolaryngology for all patients, with endocrinology and clinical genetics.