Pendred syndrome (PDS) is an autosomal recessive disorder characterized by prelingual, bilateral sensorineural hearing loss. It is also associated with the development of euthyroid or hypothyroid goiter in late childhood or early adulthood, with a high variability of both symptoms even within the same family. In addition, malformations of the inner ear may occur. Between 80 and 100% of patients have a dilated aquaeductus vestibuli, while approximately 20% exhibit Mondini malformation of the cochlea. Due to the hearing impairment, which is usually present from birth, patients often have a delay or complete absence of language acquisition. The biochemical cause for the development of goiter is a defect in the conversion of iodide into an organic bond within the thyroid gland, which leads to a disturbance in the synthesis of thyroid hormone (T4). As a result, patients often show decreased levels of free T4 in their blood.
Pathogenic variants in the SLC26A4 gene, which codes for the protein pendrin, are causative for Pendred syndrome and simultaneously for autosomal recessive sensorineural nonsyndromic hearing loss DFNB4. Clinical differentiation is almost impossible, especially in early childhood. Pendrin is an anion exchanger expressed predominantly in the epithelial cells of the inner ear, thyroid, and kidney and transports Cl-, I-, HCO3-, among others, across the cell membrane.
Besides the SLC26A4 gene, pathogenic variants in the FOXI1 and KCNJ10 genes can also cause aquaeductus vestibuli syndrome, through a process known as digenic inheritance. The aquaeductus vestibuli is a bony canal that surrounds the endolymphatic duct between the vestibule and the surface of the petrous pyramid. It merges into the saccus endolymphaticus. The dilated aquaeductus vestibuli is the most common malformation of the inner ear that can be diagnosed by CT or MRI. It is morphologically a dilatation of the ductus and saccus endolymphaticus. An expansion of more than 1.5 mm to 2 mm is considered pathological. Typical of this clinical picture is sensorineural hearing loss, which worsens episodically, often after minor trauma. Increased intracranial pressure, which is transmitted to the endolymphatic space, is thought to be the cause.
The prevalence of Pendred syndrome is unknown. However, it is estimated to account for 7.5% of all cases of congenital hearing loss. Thus, if these estimates are accurate, the prevalence of Pendred syndrome would be relatively high. According to recent studies, pathogenic variants in the SLC26A4 gene account for approximately 1-12% of all cases of sensorineural hearing loss in children. This would position it as the second most common cause of this disorder, following pathogenic alterations in the DFNB1 locus (as seen in the autosomal recessive, non-syndromic hearing loss associated with mutations in the GJB2 and GJB6 genes).
References
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