Pendred Syndrome Research Articles

Maternal UPD of chromosome 7 in a patient with Silver‐Russell syndrome and Pendred syndrome

BackgroundSilver‐Russell syndrome (SRS) is a heterogeneous imprinting disorder featuring severe intrauterine and postnatal growth retardation and dysmorphic features. Pendred syndrome (PDS) is an autosomal recessive disorder caused by mutations in the SLC26A4 gene characterized by sensorineural hearing loss.MethodsKaryotyping analysis was performed to investigate any chromosomal abnormalities. Whole‐genome copy number variation and loss of heterozygosity were analyzed using an Affymetrix CytoScan 750 K Microarray. Variant screening was performed by targeted next‐generation sequencing on all known deafness‐causing genes.ResultsThe proband was a patient with SRS caused by maternal uniparental disomy 7. The PDS of the proband was caused by homozygous variant c.919‐2A > G of SLC26A4; both mutated alleles were inherited from his mother.ConclusionThis is the first report of uniparental disomy 7 leading to SRS and Pendred syndrome. Patients with intrauterine growth retardation or those born small for gestational age and exhibiting postnatal growth failure should undergo molecular testing to reach a clinical diagnosis.

Genotype-Phenotype Correlation for Predicting Cochlear Implant Outcome: Current Challenges and Opportunities.

The use and utility of cochlear implantation has rapidly increased in recent years as technological advances in the field have expanded both the efficacy and eligible patient population for implantation. This review aims to serve as a general overview of the most common hearing disorders that have favorable auditory outcomes with cochlear implants (CI). Hearing loss in children caused by congenital cytomegalovirus infection, syndromic conditions including Pendred Syndrome, and non-syndromic genetic conditions such as hearing impairment associated with GJB2 mutations have shown to be successfully managed by CI. Furthermore, cochlear implantation provides the auditory rehabilitation for the most common etiology of hearing loss in adults and age-related hearing loss (ARHL) or presbycusis. However, in some cases, cochlear implantation have been associated with some challenges. Regarding implantation in children, studies have shown that sometimes parents seem to have unrealistic expectations regarding the ability of CI to provide auditory rehabilitation and speech improvement. Given the evidence revealing the beneficial effects of early intervention via CI in individuals with hearing disorders especially hearing loss due to genetic etiology, early auditory and genetic screening efforts may yield better clinical outcomes. There is a need to better understand genotype-phenotype correlations and CI outcome, so that effective genetic counseling and successful treatment strategies can be developed at the appropriate time for hearing impaired individuals.

The hypokalemia mystery: distinguishing Gitelman and Bartter syndromes from 'pseudo-Bartter syndrome'.

The Gitelman and Bartter syndromes (GS and BS, respectively) are characterized by the constellation of hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemic hyperaldosteronism, low to normal blood pressure and juxtaglomerular apparatus hypertrophy. These are due to pathogenic variants in the genes that encode the thiazide-sensitive sodium–chloride cotransporter NCC (SLC12A3) in the distal convoluted tubule or transporters involved in sodium chloride reabsorption in the loop of Henle. ‘Pseudo-Bartter syndrome’ (PBS) is caused by extrarenal or acquired renal salt losses and shares the same plasma electrolyte profile and acid–base disturbances, making the distinction from the genetic forms very challenging. PBS has various etiologies, including diuretic and laxative abuse, self-induced vomiting and the side effects of some antimicrobials. Additionally, congenital chloride diarrhea, cystic fibrosis, Pendred syndrome and chloride-deficient diet can manifest as PBS. In this review we focus on factitious PBS secondary to diuretic abuse, laxative abuse or self-induced vomiting, whereby we point out some clinical and laboratory clues to help clinicians make the correct diagnosis.

The Case | Hypokalemia and severe renal loss of sodium

A 32-year-old woman was referred to our nephrology department because of chronic hypokalemia with blood K+ concentration ∼2.1 mM. She had a history of Pendred syndrome (MIM #274600) diagnosed at adolescence because of deafness and compressive goiter requiring thyroidectomy. No history of diarrhea, vomiting, or diuretic or laxative abuse was found. The patient had consanguineous parents; she had 4 healthy living sisters and 1 brother who died at birth. Her blood pressure was in the lower normal range (93/64 mm Hg) with frequent tachycardia, and she exhibited craving for salt.

Enlarged vestibular aqueduct syndrome-dehiscence syndromes-honeycomb mastoid : Pathophysiology and evidence for clinical differentiation

Differential diagnosis of dizziness with hearing loss requires standardized procedures for detection and classification of rare congenital and acquired malformations of the petrous part of the temporal bone. The aim of this study was to present the physiology and pathophysiology of endolymphatic and perilymphatic pressure regulation, diagnostic guidelines, and aspects of prognosis and treatment. Relevant publications and guidelines were evaluated and own cases are reported. Enlarged vestibular aqueduct (EVA) is the most frequently observed malformation of the inner ear, which leads to increased internal hydrostatic pressure and cochleovestibular dysfunction. Non-syndromic and syndromic forms, e.g., Pendred syndrome, are known. Other pressure-relevant malformations are semicircular canal dehiscence syndrome (SCDS) and enlargement of the cochlear aqueduct. There are currently no treatment options for EVAS and enlarged cochlear aqueduct. Pendred syndrome generally requires treatment with cochlea implants (CI) in early childhood. Dizziness and autophony in patients with SCDS syndrome can be effectively treated by semicircular canal occlusion and coverage. Complaints in non-syndromic EVA and SCD syndrome are mainly caused by exposure of the inner ear to provoked and spontaneous pressure increases. Deafness and vestibular dysfunction in syndromic EVA (i.e.,Pendred syndrome, branchiootorenal syndrome) are caused by malformation of the cochlea, genetic maldevelopment of the hair cells, and pressure effects.

Congenital chloride diarrhea and Pendred syndrome: case report of siblings with two rare recessive disorders of SLC26 family genes

BackgroundCongenital chloride diarrhea (CLD; OMIM 214700) is a rare autosomal recessive disorder caused by pathogenic variations in the solute carrier family 26 member A3 (SLC26A3) gene. Without salt substitution, this chronic diarrheal disorder causes severe dehydration and electrolyte disturbances. Homozygous variants in the nearby gene SLC26A4 disrupt anion exchange in the inner ear and the thyroid, causing Pendred syndrome (PDS; OMIM 274600), which is the most frequent form of syndromic deafness.Case presentationWe report an unusual co-occurrence of two rare homozygous mutations in both the SLC26A3 and SLC26A4 genes, causing a rare combination of both CLD and PDS in two siblings. Although the clinical pictures were typical, the combined loss of these anion transporters might modulate the risk of renal injury associated with CLD.ConclusionsFamilial presentation of two rare autosomal recessive disorders with loss of function of different SLC26 anion transporters is described. Independent homozygous variants in the SLC26A3 and SLC26A4 genes cause CLD and PDS in siblings, shedding light on co-occurrence of rare recessive traits in the progeny of consanguineous couples.

Digenic inheritance of mutations in EPHA2 and SLC26A4 in Pendred syndrome

Enlarged vestibular aqueduct (EVA) is one of the most commonly identified inner ear malformations in hearing loss patients including Pendred syndrome. While biallelic mutations of the SLC26A4 gene, encoding pendrin, causes non-syndromic hearing loss with EVA or Pendred syndrome, a considerable number of patients appear to carry mono-allelic mutation. This suggests faulty pendrin regulatory machinery results in hearing loss. Here we identify EPHA2 as another causative gene of Pendred syndrome with SLC26A4. EphA2 forms a protein complex with pendrin controlling pendrin localization, which is disrupted in some pathogenic forms of pendrin. Moreover, point mutations leading to amino acid substitution in the EPHA2 gene are identified from patients bearing mono-allelic mutation of SLC26A4. Ephrin-B2 binds to EphA2 triggering internalization with pendrin inducing EphA2 autophosphorylation weakly. The identified EphA2 mutants attenuate ephrin-B2- but not ephrin-A1-induced EphA2 internalization with pendrin. Our results uncover an unexpected role of the Eph/ephrin system in epithelial function.

Computational analysis of functional single nucleotide polymorphisms associated with SLC26A4 gene.

Single Nucleotide Polymorphisms (SNPs) are the most common candidate mutations in human beings that play a vital role in the genetic basis of certain diseases. Previous studies revealed that Solute Carrier Family 26 Member 4 (SLC26A4) being an essential gene of the multi-faceted transporter family SLC26 facilitates reflexive movement of Iodide into follicular lumen through apical membrane of thyrocyte. SLC26A4 gene encodes Pendred protein, a membrane glycoprotein, highly hydrophobic in nature, present at the apical membrane of thyrocyte functioning as transporter of iodide for thyroid cells. A minor genetic variation in SLC26A4 can cause Pendred syndrome, a syndrome associated with thyroid glands and deafness. In this study, we performed in-silico analysis of 674 missense SNPs of SLC26A4 using different computational platforms. The bunch of tools including SNPNEXUS, SNAP-2, PhD-SNP, SNPs&GO, I-Mutant, ConSurf, and ModPred were used to predict 23 highly confident damaging and disease causing nsSNPs (G209V, G197R, L458P, S427P, Q101P, W472R, N392Y, V359E, R409C, Q235R, R409P, G139V, G497S, H723R, D87G, Y127H, F667C, G334A, G95R, S427C, R291W, Q383H and E384G) that could potentially alter the SLC26A4 gene. Moreover, protein structure prediction, protein-ligand docking and Molecular Dynamics simulation were performed to confirm the impact of two evident alterations (Y127H and G334A) on the protein structure and function.

Hypokalemia and metabolic alkalosis in an Egyptian boy with Pendred syndrome

Pendred syndrome (PDS) is manifested by congenital sensorineural deafness in association with goiter due to defective organic binding of iodine in the thyroid gland. Herein, we report on an unusual case of a 14-year-old Egyptian boy with PDS presenting with hypokalemia and metabolic alkalosis.

Pendred syndrome with hyperthyroidism.

Objectives: Pendred syndrome is an autosomal recessive disorder characterized by the combination of sensorineural deafness and goiter and is caused by biallelic mutations in the SLC26A4/PDS gene. Thyroid function is generally reported as euthyroid or hypothyroid in this condition. We present a case of Pendred syndrome with hyperthyroidism.Patient: An 83-year-old woman with congenital deaf–mutism presented with complaints of nausea. She developed a large goiter and had hearing impairment. Her hearing level was 105 dB in both ears. She presented with hyperthyroidism and was treated with thiamazole.Results: She had a homozygous mutation in c.1579A>C:p.T527P of the SLC26A4 gene, confirming a diagnosis of Pendred syndrome.Conclusion: Pendred syndrome may develop into hyperthyroidism if the size of the goiter increases. Moreover, a homozygous mutation in c.1579A>C:p.T527P of the SLC26A4 gene, which was previously reported to be associated with nonsyndromic hearing loss with enlarged vestibular aqueduct, may also cause Pendred syndrome.

Goiter and Sensorineural Hearing Loss: Pendred Syndrome Should Be Suspected: A Case Report

BACKGROUND: Pendred syndrome (PS) is an autosomal recessive disorder, caused by biallelic mutations in the SLC26A4 gene which codes for the pendrin protein. It is characterized by sensorineural hearing loss associated with dyshormonogenic goiter. Which is a common cause of congenital deafness. CASE PRESENTATION: Hereby we describe a case of a 21- year-old women who presented to the ORL department with an anterior cervical mass that gradually increased in volume over 3 years associated with severe hearing loss since birth for which the patient was provided with hearing aids. Pendred syndrome is suspected because of the present of goiter and congenital hearing loss. CONCLUSIONS: Clinical presentation is very variable. However, the association of goiter and progressive deafness suggests the diagnosis of Pendred syndrome.

Analysis of thyroid hormone levels in patients with hearing disorders in the Republic of Buryatia: search for Pendred syndrome phenotypes

Analysis of thyroid hormone levels in patients with hearing disorders in the Republic of Buryatia: search for Pendred syndrome phenotypes

Viewing Cortical Collecting Duct Function Through Phenotype-guided Single-Tubule Proteomics.

The revolution of the omics technologies has enabled profiling of the molecules of any sample. However, the heterogeneity of the kidney with highly specialized nephron segments like the cortical collecting duct (CCD) poses a challenge regarding integration of omics data and functional analysis. We examined function and proteome from the same single CCDs of C57Bl6 mice by investigating them in a double-barreled perfusion system before targeted mass spectrometry. Transepithelial voltage (Vte), transepithelial resistance, as well as amiloride-sensitive voltage (ΔVteamil) were recorded. CCDs were of 400–600 µm of length, showed lumen negative Vte between −8.5 and −32.5 mV and an equivalent short circuit current I’sc between 54 and 192 µA/cm2. On a single-tubule proteome level, intercalated cell (IC) markers strongly correlated with other intercalated cell markers and negatively with principal cell markers. Integration of proteome data with phenotype data revealed that tubular length correlated with actin and Na+-K+-ATPase expression. ΔVte(amil) reflected the expression level of the β-subunit of the epithelial sodium channel. Intriguingly, ΔVte(amil) correlated inversely with the water channel AQP2 and the negative regulator protein NEDD4L (NEDD4-2). In pendrin knockout (KO) mice, the CCD proteome was accompanied by strong downregulation of other IC markers like CLCNKB, BSND (Barttin), and VAA (vH+-ATPase), a configuration that may contribute to the salt-losing phenotype of Pendred syndrome. Proteins normally coexpressed with pendrin were decreased in pendrin KO CCDs. In conclusion, we show that functional proteomics on a single nephron segment scale allows function–proteome correlations, and may potentially help predicting function from omics data.

Receptive language acquisition in a pediatric population with Pendred syndrome and non-syndromic enlarged vestibular aqueduct

Background: Children with Pendred syndrome (PS) and non-syndromic enlarged vestibular aqueduct (NSEVA) represent a group of pre-lingual hearing-impaired individuals with rehabilitation challenges.Objective: To evaluate receptive language capabilities in a pediatric cohort with PS and NSEVA.Materials and methods: Twenty-four (24) children diagnosed with either PS or NSEVA, were examined using the Peabody Picture Vocabulary Test (PPVT) and compared to a cohort of 55 Danish children with normal hearing, as well as to a mixed group of 29 children with hearing impairment of congenital and hereditary non-syndromal type. In addition, test results were compared to normative data (PPVT-4 US standard scores).Results: PS/NSEVA children’s PPVT-4 test scores fall within the normative data for the PPVT-4 (US) but proved to be significantly lower statistically, when compared to Danish children with normal hearing (p<.0001) or to children with mixed non-syndromic hereditary hearing impairment (p=.006). Implantation age was significantly later for the PS/NSEVA group (median = 43 months), compared to the mixed non-syndromic hereditary congenial hearing impairment group (median = 11 months).Conclusions and significance: Children with PS/NSEVA perform below age equivalent for receptive vocabulary outcome when compared to both children with normal hearing, and children with non-syndromic mixed hereditary congenital hearing impairment who receive cochlear implants earlier.

Comprehensive analysis of syndromic hearing loss patients in Japan

More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.

Generation of a human iPS cell line (CGMH.SLC26A4919-2) from a Pendred syndrome patient carrying SLC26A4 c.919-2A>G splice-site mutation.

SLC26A4 is the second most frequent gene implicated in congenital hearing loss after GJB2 mutations. Here, we report the generation of induced pluripotent stem cells (iPSCs), from a patient who was carrying a homozygous c.919-2A>G variant in the SLC26A4 gene. This is the most common variant of SLC26A4 gene in the Chinese population and the second most prevalent one in other Asian countries. The established patient-derived iPSC displayed all the features of pluripotent stem cell markers and had the ability to differentiate into all of the three germ layers and possessed a normal karyotype.

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Novel pendrin inhibitor attenuates airway hyperresponsiveness and mucin expression in experimental murine asthma

Congenital goitrous hypothyroidism is caused by dysfunction of the iodide transporter SLC26A7

Iodide transport and storage in the thyroid follicles is crucial for thyroid hormone synthesis. Pendrin, the iodide exporter that transports iodide to thyroid follicles, is responsible for Pendred syndrome, a disorder characterized by congenital hypothyroidism and hearing loss. However, thyroid hormone levels are basically normal in patients with Pendred syndrome, indicating the presence of another unknown iodide transporter. Here, we show that SLC26A7 is a novel iodide transporter in the thyroid. We observe that SLC26A7 is specifically expressed in normal thyroid tissues and demonstrate its function in iodide transport. Using whole-exome sequencing, we also find a homozygous nonsense mutation in SLC26A7 (c.1498 C > T; p.Gln500Ter) in two siblings with congenital goitrous hypothyroidism. The mutated SLC26A7 protein shows an abnormal cytoplasmic localisation and lacks the iodide transport function. These results reveal that SLC26A7 functions as a novel iodide transporter in the thyroid and its dysfunction affects thyroid hormonogenesis in humans and causes congenital goitrous hypothyroidism.

SLC26A4-linked CEVA haplotype correlates with phenotype in patients with enlargement of the vestibular aqueduct

BackgroundRecessive mutations of coding regions and splice sites of the SLC26A4 gene cause hearing loss with enlargement of the vestibular aqueduct (EVA). Some patients also have a thyroid iodination defect that can lead to multinodular goiter as part of Pendred syndrome. A haplotype of variants upstream of SLC26A4, called CEVA, acts as a pathogenic recessive allele in trans to mutations affecting the coding regions or splice sites of SLC26A4. Our first hypothesis is that CEVA, acting as a pathogenic recessive allele, is correlated with a less severe phenotype than mutations affecting the coding regions and splice sites of SLC26A4. Our second hypothesis is that CEVA acts as a modifier of the phenotype in patients with EVA caused by mutations affecting the coding regions or splice sites of both alleles of SLC26A4 or EVA caused by other factors.MethodsThis was a prospective cohort study of 114 individuals and 202 ears with EVA. To test our first hypothesis, we compared the thyroid and auditory phenotypes of subjects with mutations affecting coding regions of both alleles of SLC26A4 with those of subjects carrying CEVA in trans to mutations affecting the coding regions. To test our second hypothesis, we compared the phenotypes associated with the presence versus absence of CEVA among subjects with no coding region mutations, as well as among subjects with mutations affecting coding regions of both alleles.ResultsSubjects carrying CEVA in trans to a mutation of SLC26A4 have a normal thyroid phenotype and less severe hearing loss in comparison to individuals with mutations affecting coding regions of both alleles of SLC26A4. In subjects with no mutant alleles of SLC26A4, hearing loss was more severe in subjects who carry the CEVA haplotype in comparison to non-carriers. There was no correlation of CEVA with the phenotype of subjects with mutations affecting coding regions of both alleles.ConclusionsCEVA, acting as a likely pathogenic recessive allele, is associated with a less severe phenotype than alleles with a mutation affecting the coding regions or splice sites of SLC26A4. CEVA may act as a genetic modifier in patients with EVA caused by other factors.

A pathogenic variant in SLC26A4 is associated with Pendred syndrome in a consanguineous Iranian family

Objective: Hearing loss (HL) is a common sensory deficit with high phenotypic and genotypic heterogeneity. A large Iranian family with HL was genetically assessed in this study.Design: A proband from a consanguineous multiplex HL family from Iran was examined via Targeted Next-Generation Sequencing (TNGS). Sanger sequencing allowed the segregation analysis of the variant of interest and the investigation of its presence in a cohort of 50 ethnicity-matched healthy control individuals. The gene was previously associated with HL. Therefore, to determine whether the variant was specifically associated with Pendred Syndrome (PDS) or DFNB4, biochemical analyses, PTA, thyroid scans by Tc99m, perchlorate discharge test and high-resolution CT scan of the temporal bone were carried out on the affected family members.Study sample: Ten members of a large multiplex Iranian family with HL were recruited in this study. In addition, 50 unrelated healthy controls of the same ethnic group were randomly selected to genotype the variant.Results: A homozygous missense variant (NM_000441.1: c.1211C > T/p.Thr404Ile) in exon 10 was found segregating in the family. Based on the ACMG’s guidelines, the variant was classified as pathogenic.Conclusion: This study expands the spectrum of SLC26A4 pathogenic variants in hearing loss.