MED-NERD

Diagnosis of Pendred syndrome:

Molecular diagnosis (Genetic testing):
It is a confirmatory test. About 50% of Pendred syndrome patients have mutation in SLC26A4 gene. About 200 sequence variants where detected in SLC26A4 gene due to the diverse mutations. Detection of biallelic pathogenic variant in SLC26A4 gene or double heterozygous for one pathogenic variant in the same gene. Other genes like FOXII and KCNJI0 genes are mutated in less than 2% of Pendred syndrome patients.

Clinical diagnosis:
-Temporal bone abnormalities
-Sensorineural hearing loss (SNHL)
-Euthyroid goiter


Temporal bone abnormalities:
-A thin-cut Computerized Tomography (CT) scan >> to detect temporal bone abnormalities which include enlargement of the vestibular aqueducts and cochlear hypoplasia (cochlea with only 1.5 turns instead of the expected 2.75 turns). Coronal and axial sections of a high-resolution CT of temporal bone to detect and measure the enlargement of vestibular aqueduct. When the width of the middle portion of the descending limb of the vestibular aqueduct is over 1.5 mm, enlargement of vestibular aqueduct can be confirmed. The association of vestibular aqueduct enlargement with cochlear hypoplasia is known as Mondini malformation.


Thyroid enlargement:
The main thyroid abnormality in Pendred syndrome is euthyroid goiter. Assessment of the size of the gland, thyroid ultrasound (to detect the volume of thyroid enlargement, the size of the nodules and their structure) can be used in the evaluation of thyroid gland. Thyroid function tests are also performed. Autoimmune thyroiditis may be associated with Pendred syndrome.

Screening test for iodide organification disorders is known as Perchlorate test. This is done by administration of radioactive iodine and measurement of the intrathyroidal radioactive iodine content. Iodide organification disorders is detected when the results are less than 10%. Various factors may affect the test including the use of high-dose iodine intake therefore, a negative test does not exclude Pendred syndrome.


Sensorineural hearing loss (SNHL):
Usually, hearing loss in Pendred syndrome is progressive. A sudden hearing loss may occur after head injury with enlargement of the vestibular aqueduct. A positive Perchlorate discharge test and genetic testing can be used in the diagnosis.

Differential Diagnosis of Pendred syndrome:

A)Other causes of sensorineural hearing loss and thyroid disease:

-Nonsyndromic causes of congenital deafness due to trauma, exposure to autotoxic agents, or congenital infections such as Cytomegalovirus (CMV)
-Nonsyndromic enlarged vestibular aqueduct without  thyroid goiter. Differential diagnosis with nonsyndromic enlarged vestibular aqueduct (NSEVA) which is characterized by SNHL, temporal bone deformity in the form of enlargement of the vestibular aqueducts only (vestibular aqueduct exceeding 1.5 mm in width at its midpoint). About 50% of NSEVA cases have goiter.
-Congenital hypothyroidism associated with hearing disorder


B)Other causes of syndromic deafness:

-Alport syndrome >> hearing impairment, with renal and ocular involvement
-Waardenburg syndrome >> with pigmentation of hair and skin
-Perrault syndrome >> progressives sensorineural hearing loss with ovarian involvement in females
-Usher syndrome >> with retinitis pigmentosa
-Jervell and Lange-Nielsen >> with arrhythmia 
-Branchiootorenal (BOR) syndrome >> branchial cyst, hearing impairment, and renal involvement

Reference:

(1)Garabet Diramerian L, Ejaz S. Pendred Syndrome. 2022 Jun 27. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022 Jan–.
https://www.ncbi.nlm.nih.gov/books/NBK549839/
(2)Smith RJH, Iwasa Y, Schaefer AM. Pendred Syndrome / Nonsyndromic Enlarged Vestibular Aqueduct. 1998 Sep 28 [updated 2020 Jun 18]. In: Adam MP, Everman DB, Mirzaa GM, Pagon RA, Wallace SE, Bean LJH, Gripp KW, Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2023.
https://www.ncbi.nlm.nih.gov/books/NBK1467/
(3)Gettelfinger JD, Dahl JP. Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics. J Pediatr Genet. 2018 Mar;7(1):1-8.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809162/
(4)Biggs K, Lovett A, Metcalfe C, Muzaffar J, Monksfield P, Bance M. Outcomes of Cochlear Implantation in Patients with Pendred syndrome: A Systematic Review and Narrative Synthesis. J Int Adv Otol. 2020 Dec;16(3):432-442.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7901456/
(5)Pendred Syndrome,NIH national institute on deafness Nd other communication disorders
https://www.nidcd.nih.gov/health/pendred-syndrome