Genetic Causes of Goiter and Deafness: Pendred Syndrome in a Girl and Cooccurrence of Pendred Syndrome and Resistance to Thyroid Hormone in Her Sister

Abstract

Goiter and deafness can be associated in some genetic syndromes, e.g. Pendred syndrome (PS) and resistance to thyroid hormone (RTH). PS is an autosomal recessive disorder characterized by goiter and sensorineural hearing impairment with an enlarged vestibular aqueduct bilaterally. RTH is an autosomal dominant condition of reduced tissue sensitivity to thyroid hormone in which goiter is very frequent and hearing loss occurs in about 20% of patients. OBJECTIVE, PATIENTS, AND DESIGN: The objective of this study was to identify the cause of goiter and deafness in two sisters born to healthy unrelated parents. We present their history, clinical presentation, and follow-up and report the results of molecular genetic investigations. The elder sister had an elevated TSH level at newborn screening followed by subclinical hypothyroidism, childhood-onset goiter, and bilateral progressive sensorineural hearing impairment with enlarged vestibular aqueducts, consistent with a diagnosis of PS. Her younger sister had congenital goiter, elevated free T3 and free T4 concentrations with unsuppressed TSH, sinus tachycardia, and bilateral progressive sensorineural hearing impairment with enlarged vestibular aqueducts. This clinical presentation was consistent with a diagnosis of RTH, in which, however, inner ear malformations are uncommon. Interestingly, molecular genetic testing showed that, whereas the elder sister is affected by PS, the younger sister has both PS (due to compound heterozygous SLC26A4 mutations) and RTH (due to a novel de novo heterozygous THRB mutation). This is the first report of the cooccurrence, in the same individual, of PS and RTH, two genetic syndromes both associated with goiter and hearing impairment.