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Richard J H Smith - One of the best experts on this subject based on the ideXlab platform.
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Pendred syndrome, DFNB4, and PDS/SLC26A4 identification of eight novel mutations and possible genotype-phenotype correlations.
Human Mutation, 2020Co-Authors: Colleen A. Campbell, Robert A. Cucci, Sai Prasad, Glenn E. Green, J. Bradley Edeal, Chad E. Galer, Lawrence P. Karniski, Val C. Sheffield, Richard J H SmithAbstract:Mutations in PDS (SLC26A4) cause both Pendred syndrome and DFNB4, two autosomal recessive disorders that share hearing loss as a common feature. The hearing loss is associated with temporal bone abnormalities, ranging from isolated enlargement of the vestibular aqueduct (dilated vestibular aqueduct, DVA) to Mondini dysplasia, a complex malformation in which the normal cochlear spiral of 2½ turns is replaced by a hypoplastic coil of 1½ turns. In Pendred syndrome, thyromegaly also develops, although affected persons usually remain euthyroid. We identified PDS mutations in the proband of 14 of 47 simplex families (30%) and nine of 11 multiplex families (82%) (P=0.0023). In all cases, mutations segregated with the disease state in multiplex families. Included in the 15 different PDS allele variants we found were eight novel mutations. The two most common mutations, T416P and IVS8+1G>A, were present in 22% and 30% of families, respectively. The finding of PDS mutations in five of six multiplex families with DVA (83%) and four of five multiplex families with Mondini dysplasia (80%) implies that mutations in this gene are the major genetic cause of these temporal anomalies. Comparative analysis of phenotypic and genotypic data supports the hypothesis that the type of temporal bone anomaly may depend on the specific PDS allele variant present. Hum Mutat 17:403–411, 2001. © 2001 Wiley-Liss, Inc.
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Genotype–phenotype correlations for SLC26A4-related deafness
Human Genetics, 2007Co-Authors: Hela Azaiez, Sai Prasad, Tao Yang, Jessica L. Sorensen, Carla J. Nishimura, William J. Kimberling, Richard J H SmithAbstract:Pendred syndrome (PS) and non-syndromic enlarged vestibular aqueduct (EVA) are two recessive disorders characterized by the association of sensorineural hearing loss (SNHL) with inner ear malformations that range from isolated EVA to Mondini dysplasia, a complex malformation that includes a cochlear dysplasia and EVA. Mutations in the SLC26A4 gene, coding for the protein pendrin, have been implicated in the pathophysiology of both disorders. In order to determine whether SLC26A4 genotypes can be correlated to the complexity and severity of the phenotypes, we ascertained 1,506 deaf patients. Inner ear abnormalities were present in 474 patients (32%). Mutation screening of SLC26A4 detected two mutations in 16% of patients, one mutation in 19% of patients and zero mutation in 65% of patients. When the distribution of SLC26A4 genotypes was compared across phenotypes, a statistically significant difference was found between PS patients and non-syndromic EVA–Mondini patients ( P = 0.005), as well as between EVA patients and Mondini patients ( P = 0.0003). There was a correlation between phenotypic complexity of inner ear malformations and genetic heterogeneity—PS patients have the most severe phenotype and the most homogeneous etiology while EVA patients have the least severe phenotype and the most heterogeneous etiology. For all patients, variability in the degree of hearing loss is seen across genotypes implicating other genetic and/or environmental factors in the pathogenesis of the PS–Mondini–EVA disease spectrum.
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split hand split foot malformation associated with sensorineural deafness inner and middle ear malformation hypodontia congenital vertical talus and deletion of eight microsatellite markers in 7q21 1 q21 3
Journal of Medical Genetics, 2001Co-Authors: E Haberlandt, Judith Loffler, Almut Hirststadlmann, Bernd Stockl, Werner Judmaier, H Fischer, Peter Heinzerian, Thomas Muller, Gerd Utermann, Richard J H SmithAbstract:Editor—The split hand/split foot malformation (SHFM, MIM 183600) is a central reduction defect of the hands and feet and occurs both as an isolated malformation and as part of several syndromes including the EEC syndrome (MIM 129900). We report on a 2 year old boy with SHFM associated with features of ectodermal hypoplasia, a submucous cleft palate, congenital vertical talus, malformations of the middle ear, profound sensorineural hearing loss resulting from Mondini dysplasia, and a de novo deletion of the paternal chromosome 7q21.1-q21.3. This patient with syndromic SHFM represents a case of atypical EEC syndrome, but also displays abnormalities previously not associated with SHFM or EEC syndrome. The classical features of the autosomal dominant inherited EEC syndrome are ectrodactyly, ectodermal dysplasia, and clefting of the lip/palate. In most patients, there are additional anomalies typically affecting the urogenital and lacrimal systems.1 2 Some patients also have dysmorphic facies, a tendency to infectious disease, endocrine disorders, and mental retardation. This phenotypic variability has become increasingly apparent over the last 15 years3 4 and numerous related and overlapping syndromes have been delineated by many investigators.5 In an attempt to clarify classification, major and minor criteria for the diagnosis of EEC syndrome have been elaborated.3 4 Dominant inheritance of EEC has been documented in several large multigenerational families.6 At least 15 patients have been reported to have cytogenetic abnormalities of chromosome 7q21.2-7q22.1, including nine patients with interstitial deletions.7-9 In addition, mutations in the gene encoding the transactivation factor p63 on chromosome 3q27 have been identified in familial and sporadic cases of EEC syndrome.10 A third locus was mapped to chromosome 19q,11 further delineating the genetic heterogeneity of this syndrome. The reason for the phenotypic heterogeneity in EEC syndrome patients with 7q abnormalities is unclear …
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Mondini dysplasia is not associated with meningitis and cerebrospinal fluid fistula reply
Archives of Otolaryngology-head & Neck Surgery, 1991Co-Authors: Richard J H Smith, Laurie A Ohlms, Bobby R Alford, Morven S EdwardsAbstract:The points raised by Drs Phelps and Lloyd, acknowledged experts in temporal bone radiology, are appreciated. We would agree that distinguishing among the various types of morphogenetic deformities that can affect the inner ear is of the utmost importance. The problem becomes one of semantics. The traditional schemata used to classify congenital anomalies of the inner ear are based on only a few case reports; Michel 1 reported a case in 1863; Mondini 2 reported an example of an inner ear anomaly in 1791; Schiebe 3,4 reported two cases in 1892 and 1895; and Alexander 5 described a type of malformation in 1927. Some of the limitations of this classification scheme have been explored in an excellent article by Jackler et al. 6 Concentrating on the vast spectrum of morphogenetic defects, these investigators used polytomography and thinslice, high-resolution computed tomography to study development of the bony labyrinth. A more representative classification scheme for morphogenetic deformities
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recurrent meningitis and Mondini dysplasia
Archives of Otolaryngology-head & Neck Surgery, 1990Co-Authors: Laurie A Ohlms, Morven S Edwards, Edward O Mason, Makoto Igarashi, Bobby R Alford, Richard J H SmithAbstract:• Three infants with cerebrospinal fluid otorrhea and recurrent meningitis due to Mondini dysplasia have been treated at Baylor College of Medicine, Houston, Tex; 39 other patients with this association have been described. This review highlights the characteristics and embryologic basis of the malformation. The clinical evaluation of an infant with recurrent meningitis is outlined, and the importance of brain-stem response audiometry and thincut computed tomography of the temporal bones is discussed. Surgical management depends on the functional status of the dysplastic ear; usually, a stapedectomy is performed and the vestibule is obliterated. Although the surgical failure rate is 30% after one procedure, early identification of the dysplasia and prompt surgical management diminish morbidity and mortality and permit early habilitation of the child with congenital hearing impairment. (Arch Otolaryngol Head Neck Surg. 1990;116:608-612)
Peter Wieacker - One of the best experts on this subject based on the ideXlab platform.
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Refinement of the deletion in 7q21.3 associated with split hand/foot malformation type 1 and Mondini dysplasia.
Journal of Medical Genetics, 2004Co-Authors: Ilse Wieland, Petra Muschke, Sibylle Jakubiczka, Marianne Volleth, B Freigang, Peter WieackerAbstract:Split hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22.1 The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation.2,3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases.4,5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617).5,6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9–17 cM of the paternal chromosome 7q21.1–q21.3.7 So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.8,9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3.9 This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distal-less homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who …
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refinement of the deletion in 7q21 3 associated with split hand foot malformation type 1 and Mondini dysplasia
Journal of Medical Genetics, 2004Co-Authors: Ilse Wieland, Petra Muschke, Sibylle Jakubiczka, Marianne Volleth, B Freigang, Peter WieackerAbstract:Split hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22.1 The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation.2,3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases.4,5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617).5,6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9–17 cM of the paternal chromosome 7q21.1–q21.3.7 So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.8,9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3.9 This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distal-less homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who …
Ilse Wieland - One of the best experts on this subject based on the ideXlab platform.
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Refinement of the deletion in 7q21.3 associated with split hand/foot malformation type 1 and Mondini dysplasia.
Journal of Medical Genetics, 2004Co-Authors: Ilse Wieland, Petra Muschke, Sibylle Jakubiczka, Marianne Volleth, B Freigang, Peter WieackerAbstract:Split hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22.1 The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation.2,3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases.4,5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617).5,6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9–17 cM of the paternal chromosome 7q21.1–q21.3.7 So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.8,9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3.9 This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distal-less homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who …
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refinement of the deletion in 7q21 3 associated with split hand foot malformation type 1 and Mondini dysplasia
Journal of Medical Genetics, 2004Co-Authors: Ilse Wieland, Petra Muschke, Sibylle Jakubiczka, Marianne Volleth, B Freigang, Peter WieackerAbstract:Split hand/foot malformation type I (SHFM1, OMIM *183600) is an autosomal dominant developmental disorder of limb formation that results in the absence of the central digital rays, deep median clefts, and syndactyly of the remaining digits. Patients with SHFM1 harbour deletions, translocations, and inversions in chromosomal region 7q21–q22.1 The deletions at 7q21–q22 encompass different genomic regions and probably result in a contiguous gene syndrome that includes growth impairment, microcephaly, craniofacial manifestations, hernias, hearing loss, and mental retardation.2,3 Cases with translocations do not show this broad pattern of abnormalities but are associated with hearing loss in most cases.4,5 Split hand/foot malformation type I is the only form of split hand/foot malformation associated with sensorineural hearing loss, and it has been designated SHFM1D (OMIM *605617).5,6 Recently, SHFM1D was shown to result from Mondini dysplasia in a boy with a de novo deletion of about 8.9–17 cM of the paternal chromosome 7q21.1–q21.3.7 So far, microdeletions at 7q21.3 have been described in only two cases: one in a boy with split hand/foot malformation plus mild mental retardation, growth retardation of post-natal onset, and hypotonia and another in a patient with ectrodactyly, ectodermal dysplasia, and cleft lip/palate (EEC) syndrome.8,9 Mapping of the deletion and translocation breakpoints in several patients showed a critical interval of about 1 Mb for the SHFM1 locus at 7q21.3.9 This interval included a 500 kb region that spanned five of seven known translocation breakpoints. In this region, the candidate genes DLX5 and DLX6 (human homologues of the Drosophila distal-less homeobox gene family) and DSS1 (deleted in the split hand/split foot SHFM1 region) were identified. No mutations were detected in patients with sporadic split hand/foot malformation with translocations or two families with split hand/foot malformation, sensorineural deafness, and normal chromosomes who …
Peijer Chen - One of the best experts on this subject based on the ideXlab platform.
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Prevalent SLC26A4 Mutations in Patients with Enlarged Vestibular Aqueduct and/or Mondini dysplasia: A Unique Spectrum of Mutations in Taiwan, Including a Frequent Founder Mutation†
Laryngoscope, 2005Co-Authors: Chenchi Wu, Peijer ChenAbstract:Objectives/Hypothesis: The purpose of the study is to elucidate the mutation spectrum of SLC26A4 among patients with enlarged vestibular aqueduct and/or Mondini dysplasia in Taiwan and to explore the origin of the most common mutation, IVS7-2A>G. The correlation between the genotypes and the phenotypes is also investigated, with special emphasis placed on comparison between the genotypes and hearing levels. Study Design: A 3-year prospective clinical genetic study at a tertiary care university hospital. Method: Mutations on SLC26A4 were screened in 38 families that fulfilled the criteria of enrollment, and single nucleotide polymorphisms (SNPs) in the vicinity of IVS7-2A>G were typed. The presence of goiter, radiologic findings, and audiologic results of the probands were then compared according to the genotypes. Results: A total of eight mutations were detected in 33 families, and IVS7-2A>G accounted for 84% (48157) of the mutated alleles. SNP analysis confirmed the founder effect of IVS7-2A>G. Meanwhile, no obvious correlation was observed between SLC26A4 genotypes and phenotypes. Conclusion: The present study disclosed the unique SLC26A4 mutation spectrum in Taiwan, confirmed that IVS7-2A>G arose from a common ancestor, and demonstrated the lack of correlation between genotypes and phenotypes. High prevalence of certain SLC26A4 mutations in East Asians, as revealed here and previously, might largely facilitate mutation screening and genetic counseling in these areas.
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prevalent slc26a4 mutations in patients with enlarged vestibular aqueduct and or Mondini dysplasia a unique spectrum of mutations in taiwan including a frequent founder mutation
Laryngoscope, 2005Co-Authors: Chenchi Wu, Peijer ChenAbstract:Objectives/Hypothesis: The purpose of the study is to elucidate the mutation spectrum of SLC26A4 among patients with enlarged vestibular aqueduct and/or Mondini dysplasia in Taiwan and to explore the origin of the most common mutation, IVS7-2A>G. The correlation between the genotypes and the phenotypes is also investigated, with special emphasis placed on comparison between the genotypes and hearing levels. Study Design: A 3-year prospective clinical genetic study at a tertiary care university hospital. Method: Mutations on SLC26A4 were screened in 38 families that fulfilled the criteria of enrollment, and single nucleotide polymorphisms (SNPs) in the vicinity of IVS7-2A>G were typed. The presence of goiter, radiologic findings, and audiologic results of the probands were then compared according to the genotypes. Results: A total of eight mutations were detected in 33 families, and IVS7-2A>G accounted for 84% (48157) of the mutated alleles. SNP analysis confirmed the founder effect of IVS7-2A>G. Meanwhile, no obvious correlation was observed between SLC26A4 genotypes and phenotypes. Conclusion: The present study disclosed the unique SLC26A4 mutation spectrum in Taiwan, confirmed that IVS7-2A>G arose from a common ancestor, and demonstrated the lack of correlation between genotypes and phenotypes. High prevalence of certain SLC26A4 mutations in East Asians, as revealed here and previously, might largely facilitate mutation screening and genetic counseling in these areas.
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common clinical features of children with enlarged vestibular aqueduct and Mondini dysplasia
Laryngoscope, 2005Co-Authors: Chenchi Wu, Yuhshyang Chen, Peijer ChenAbstract:Objectives/Hypothesis: The purpose of the study was to investigate the etiological factors and the audiological data of different types of inner ear malformations, which the authors thought might be helpful in elucidating the inter-relation among malformations and shedding light on pathogenesis. Study Design: Retrospective study from 1998 to 2002 at a tertiary care university hospital. Methods: One hundred sixty consecutive children with a total of 302 affected ears undergoing high-resolution computed tomography of the temporal bone for sensorineural hearing loss were enrolled. The image results were correlated with causes and origins, hearing loss patterns, hearing levels, and audiogram configurations. Results: Inner ear malformation was present in 114 (38%) ears. The most common malformations were enlarged vestibular aqueduct, incomplete partition of cochlea (Mondini dysplasia), large vestibule, and semicircular canal dysplasia, presenting either as isolated finding or in combination. Eighty-four (74%) ears had abnormalities confined to these four malformations; only 30 (26%) ears showed other malformations. Patients with complex of enlarged vestibular aqueduct, Mondini dysplasia, large vestibule, and semicircular canal dysplasia (EMVS complex) demonstrated a significantly higher incidence of fluctuating hearing loss (93%) and a better hearing level compared with those with other malformations. Homogeneity in audiological features among these four malformations was also disclosed. Conclusion: The authors identified a distinct clinical entity, the EMVS complex, which is characterized by fluctuating hearing loss and a better hearing level. The authors proposed that malformations belonging to this complex result from a common pathogenetic mechanism.
Maria Bitner-glindzicz - One of the best experts on this subject based on the ideXlab platform.
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Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts
BMC Medical Genetics, 2013Co-Authors: Priya Landa, Ann-marie Differ, Kaukab Rajput, Lucy Jenkins, Maria Bitner-glindziczAbstract:Background Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormonogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4. Two genes, KCNJ10, encoding an inwardly rectifying potassium channel and FOXI1, a transcriptional factor gene, are thought to play a role in the disease phenotypes.
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Lack of significant association between mutations of KCNJ10 or FOXI1 and SLC26A4 mutations in pendred syndrome/enlarged vestibular aqueducts
BMC Medical Genetics, 2013Co-Authors: Priya Landa, Ann-marie Differ, Kaukab Rajput, Lucy Jenkins, Maria Bitner-glindziczAbstract:Background Pendred syndrome is a common autosomal recessive disorder causing deafness. Features include sensorineural hearing impairment, goitre, enlarged vestibular aqueducts (EVA) and occasionally Mondini dysplasia. Hearing impairment and EVA may occur in the absence of goitre or thyroid dyshormonogensis in a condition known as non-syndromic EVA. A significant number of patients with Pendred syndrome and non-syndromic EVA show only one mutation in SLC26A4 . Two genes, KCNJ10 , encoding an inwardly rectifying potassium channel and FOXI1 , a transcriptional factor gene, are thought to play a role in the disease phenotypes. Methods Using Polymerase Chain Reaction and Sanger sequencing, sixty-eight patients with monoallelic mutations of SLC26A4 were tested for mutations in KCNJ10 and FOXI1 . Results Two variants were observed in the KCNJ10 gene, p.Arg271Cys in three patients and p.Arg18Gln in one patient; only one variant, p.Arg123Trp was observed in the FOXI1 gene in a single patient. Both p.Arg271Cys and p.Arg18Gln are likely to be polymorphisms as judged by their frequency in the general population. Conclusion Therefore we found no evidence for a significant association between mutations of KCNJ10 and FOXI1 with SLC26A4 . It was also observed that the variant, p.Arg271Cys in KCNJ10 , previously thought to have a protective effect against seizure susceptibility, was found in a patient with Pendred syndrome with co-existing epilepsy.