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Pendred Syndrome-Full Text
Introduction:
Pendred syndrome or Goiter-deafness syndrome; autosomal recessive sensorineural hearing impairment and goiter; Deafness with goiter.
Pendred syndrome is an autosomal recessive disorder characterized by a combination of profound to severe sensorineural hearing loss, thyroid goiter with or without hypothyroidism (A partial defect in iodide organification). The syndrome is caused by mutation in the PDS/SLC26A4 gene (OMIM 605646) on chromosome 7 that results in defected pendrin protein which is an ion transporter and a multifunctional anion exchanger protein that is mainly expressed in the thyroid, kidney, and the inner ear. The gene is important to maintain the composition of endolymph and to keep the endocochlear potential through the chloride/bicarbonate exchanger. Hearing loss is often sudden and eventually may result in deafness. Hearing loss is usually bilateral but one ear may be affected more than the other.
Pendred syndrome was first described in 1896 by Dr. Vaughan Pendred in an article in “The Lancet” showing the association between deaf-mutism and thyroid goiter. In 1996, the genetic mutation in Pendred syndrome was localized to SLC26A4/PDS gene on chromosome 7q21–34. The main presenting symptom is deafness and is often prelingual. The syndrome may be associated with inner ear malformations (such as enlargement of the endolymphatic system) and Mondini malformation.
In Pendred syndrome, there is an enlargement of the endolymphatic system that can be seen on magnetic resonance imaging (MRI) or computed tomography (CT) as an enlarged vestibular aqueduct (EVA).
It may also be associated with incomplete partition type II (Mondini dysplasia) which is a deficient interscalar septum in the distal coils of the cochlea. About 86% of Pendred syndrome cases are associated with abnormalities such as EVA with or without enlarged endolymphatic sac (EES) and/or Mondini malformation.
The thyroid may be enlarged up to obstruction of the airway but may be normal in size. More than 15% of radioiodide (radioiodide then becomes organified into thyroglobulin for the synthesis of thyroid hormones) is accumulated in thyrocytes in Pendred syndrome indicating impaired iodide organification ( the normal value is less than 10% of radioiodide accumulated in thyrocytes). However, most Pendred syndrome patients have euthyroid state (normal thyroid hormone level) except if associated with dietary iodine deficiency.
In the United states, researchers found that about 50-60% of hearing loss is genetic, and about 40-50% is due yo environmental causes.
About 10% of hereditary hearing loss is caused by Pendred syndrome (Incidence of 7.5 to 10 in 100,000). It is the most common cause of syndromic hearing loss and congenital hearing loss.
Etiology:
Pendrin/SLC26A4 Protein is a multifunctional anion exchanger that has affinity to multiple anions such as chloride. A mutation in the Pendrin Gene (PDS/SLC26A4) on chromosome 7 that encodes Pendrin/SLC26A4 Protein leads to Pendred syndrome. It is expressed in different organs such as thyroid, inner ear, kidney, and bronchial epithelial cells. It is an autosomal recessive disorder (A child to be affected has to receive two mutated PDS genes from parents).
The parents are carriers of the mutated genes therefore they do not present with disorders or symptoms related to Pendred syndrome. Genetic testing may be useful in parents suspected to be carriers of the mutated genes and family history of early hearing loss or family history of hearing loss and goiter, is an indicator for possibility of Pendred syndrome. However, family history may be absent so genetic testing of blood sample can be done.
Epidemiology:
Pendred syndrome represents about 10% of the congenital deafness causes and is considered the most common syndrome of deafness. Its prevalence is estimated between 7.5 and 10 per 100,000 individuals. Inheritance risk from heterozygous parents is 25%.Pathophysiology:
-Thyroid gland >> Pendrin acts as Cl-/I- exchanger on the apical membrane of thyrocyte which is essential to induce efflux of cellular iodide into the follicular lumen. Therefore, defect in this gene leads to dysfunction and defected thyroid organification. However, most Pendred syndrome patients have euthyroid state so the growth and development of children is usually not affected. The risk of goiter is increased in Pendred syndrome. Goiter usually develops in adolescence or early adulthood. Goiter may cause difficulties in breathing and swallowing due to compression effect.
-Inner Ear >> Pendrin is important to achieve proper function of inner ear, resorption of endolymphatic fluid, and acid-base balance. It is expressed in the inner ear in the cochlea and vestibule. Vestibular system is necessary to maintain balance. Despite the vestibular weakness that may occur in Pendred syndrome, the brain can usually compensate the defect in vestibular system so most children and adults do not have balance problems in Pendred syndrome cases. Delayed walking may be observed in some Pendred syndrome infants.
-Kidney >> Pendrin has important role in bicarbonate secretion to the tubular lumen and chloride reabsorption, regulation of blood pressure, and fluid balance by acting as a chloride/anion exchanger. It is expressed in the cortical collecting ducts at or near the apical membrane of type B and non A non B intercalated cells. Therefore, metabolic alkalosis may occur due to defect in Pendrin protein.
-Bronchial Epithelium >> Pendin acts as a Chloride/bicarbonate exchanger and regulates the airway surface liquid thickness where it is expressed at the apical membrane of bronchial epithelial cells. Moreover, it has a role in the innate defense mechanism of mucosal surfaces by secreting the antioxidant 'SCN' to the lumen. Therefore, a defect in Pendrin protein affects the production of mucus and has a relation to asthma and Chronic Obstructive Pulmonary Diseas (COPD).
Clinical Presentation:
-Thyroid abnormalities: Most cases of Pendred syndrome with thyroid involvement present with euthyroid goiter. Defect in organification of iodide can lead to enlargement of thyroid gland and goiter formation, however multinodular goiter may present later in childhood or early in puberty and even in adulthood. Goiter may be found in about 75% of Pendred syndrome cases. Most cases of goiter with Pendred syndrome are congenital with 50% having normal thyroid function which is known as subclinical hypothyroidism. With adequate iodine intake, most Pendred syndrome patients have normal thyroid gland size.
-Hearing loss: Hearing loss in Pendred syndrome ranges between mild to severe forms. It is mainly severe to profound and congenital but can progress later in infancy with increased impairment and worsening. It is mainly bilateral but asymmetrical forms may be present. Hearing impairment may be precipitated by trauma such as barotraumas, head injury, and acoustic traumas. A delay in language development and absence of a reaction to sound are examples of early signs of hearing impairment.
-Vestibular impairment: Vestibular problems may be noticed while performing motor skills or actions that require balance or during progressive hearing loss period. Temporal bone deformities may be present in some cases such as bilateral enlarged vestibular aqueduct with or without cochlear hypoplasia.
-Renal impairment: Pendred syndrome may be associated with renal imapirment leading to severe metabolic alkalosis and fatal acid-base imbalance.
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:
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
Treatment of Pendred Syndrome:
The treatment of Pendred syndrome is non-specific and mainly symptomatic treatment based of the clinical presentation of patients.
Management of hearing impairment:
Hearing aids-Cochlear implants if needed.
Risks of Cochlear Implantation:
Risks of cochlear implants are not specific. The prognosis in general is good. Enlarged vestibular aqueduct (EVA) may be a risk for cerebrospinal fluid (CSF) leak.
Avoiding head injury through wearing head protection while doing activities such as skiing or bicycle riding. Avoiding barotrauma which is rapid extreme change in pressure for example hyperbaric oxygen treatment. These measures may reduce the progression of hearing loss.
Communication skills and training:
Cochlear implant does not completely restore healing so, children should learn skills such as sign language and should be trained to use hearing aids.
Management of thyroid disorder:
Medical or surgical treatment based on the thyroid function test and the thyroid gland size.
Genetic counseling:
For testing family members and expect the offspring outcome due to inheritance of the disease.
Therefore, the management of Pendred syndrome require cooperation between endocrinologists, genetic counselor, ENT specialists, speech-language pathologists, and surgeons.
Complications of Pendred syndrome:
-Hearing impairment which is progressive with inner ear malfotmations
-Fatal metabolic alkalosis due to renal impairment
-Rarely associated with Hoffmann syndrome
Prognosis of Pendred Syndrome:
Although cochlear implantation can provide optimal hearing rehabilitation, hearing impairment in Pendred syndrome is usually progressive and surgery may be difficult due to inner ear abnormalities and malformations. Pendred syndrome may also be associated with goiter or clinical hypothyroidism.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
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