Waardenburg Syndrome Research Articles

First report of Klein-Waardenburg Syndrome in Iran and a novel pathogenic splice site variant in PAX3 gene

ObjectivesWaardenburg Syndrome (WS) as a congenital auditory-pigmentary syndrome is a clinically and genetically heterogeneous disorder. Based upon clinical manifestations, it can be classified into four types. Loss of function mutations in PAX3 gene cause WS1 and WS3 (Klein-Waardenburg syndrome). While WS2 and WS4 have locus heterogeneity with multiple causative genes. Here we report a novel splice site variant in a pedigree with multiple affected members. Based on diagnostic criteria, three of them are associated with WS3. The remained patients classified as type 1. MethodsPCR amplification and Sanger sequencing were performed for all exons and all exon-intron boundaries of PAX3 (NM_181,459) gene of the proband. Then available symptomatic and asymptomatic members were screened for the detected variant. Interpretation and classification of the variant were done based on the current guidelines. ResultsWe identified a novel heterozygous splice site variant (c.586+2T > C) in donor site of intron 4 of PAX3 gene in our proband. Moreover, this variant was co-segregated with the disease in other available five affected members. Also, the detected variant was not detected in any of the investigated asymptomatic members. This variant was classified as a pathogenic variant. ConclusionsThis study shows significant intra-familial clinical heterogeneity and absence of phenotype-genotype correlation in a pedigree with Waardenburg Syndrome. However, severity of phenotypes and additional symptoms in the patients can be related to alternative splicing and different levels of PAX3 gene expression. Detailed evaluation of more cases can shed light on this and case-reports are valuable traffic sign in the road. This article is the first report of Waardenburg syndrome type 3 in Iran.

COMMAD: a novel syndrome caused by biallelic mutation of the MITF gene

Waardenburg syndrome, type2a (WS2a), is caused by mutations in the basic helix-loop-helix zipper gene, MITF, and often includes prominent ophthalmic features. Biallelic mutations in MITF have recently been found to cause COMMAD (coloboma, osteopetrosis, macrocephaly, microphthalmia, albinism and deafness) syndrome.

A rare case of seven siblings with Waardenburg syndrome: a case report

BackgroundWaardenburg syndrome is a group of rare genetic conditions. It is determined by the absence of melanocytes from the eyes, hair, and skin. There are four types of Waardenburg syndrome with specific criteria to diagnosis the different types. The main clinical manifestations are facial abnormalities, pigmentary defects, and hearing loss with no specific predilection with regard to sex or race.Case presentationAn Arabic Syrian family, consisting of 14 siblings from third-degree relative parents with a low income, living in the Syrian countryside, presented to our institute with their 8-year-old son who had congenital hearing loss that had led to his inability to speak.He has six siblings who had congenital sensory hearing loss proven by auditory brainstem response tests at an early age. An otoacoustic emissions test and a pure-tone audiogram were performed for our patient and showed sensory hearing loss.An interesting feature in the last seven siblings was that some of them have heterochromia iris, and the others have segmental heterochromia in their iris.An ophthalmology consultation was performed to detect any other features or disorders. A dermatology consultation, laboratory tests, and chest X-ray were also performed for all the siblings and revealed no abnormalities. There was no history for musculoskeletal system or intestinal disorders. Based on the Waardenburg criteria, our patient and his six siblings all have Waarenburg syndrome.ConclusionsAlthough the inheritance of Waardenburg syndrome is autosomal dominant, de novo cases of this rare syndrome are mentioned in the medical literature. We report a unique case of seven siblings with Waardenburg syndrome. This case report shows the crucial role of consanguineous parents on this syndrome, and indicates that the number of children with this rare syndrome is increasing.

Role of Targeted Next Generation Sequencing in the Etiological Work-Up of Congenitally Deaf Children.

The purpose of this study is to report the results of a comprehensive etiological work-up for congenitally deaf children including targeted next generation sequencing. Retrospective case review. Tertiary referral center. Fifty children with congenital, bilateral profound hearing loss (HL) (>90 dBnHL). Etiological work-up included testing for pathogenic variants in GJB2, a phenotype driven genetic analysis, screening for congenital infections and imaging. When no etiology could be found, comprehensive genetic testing was performed using a HL gene panel including 45 syndromic and 96 non-syndromic HL genes. Eleven patients carried bi-allelic pathogenic variants in GJB2. Phenotype driven genetic analysis identified two homozygous KCNQ1 patients (Jervell and Lange Nielsen syndrome) and one heterozygous CHD7 patient (CHARGE syndrome). One patient was diagnosed with achondroplasia and one had a clinical diagnosis of Waardenburg syndrome. A deafness gene panel evaluated 16 patients. In 12 out of 16, we identified a pathogenic (n = 12) or likely pathogenic (n = 2) variant and one variant of unknown significance (VUS). A definite diagnosis of non-syndromic or syndromic HL was made in 18 and seven patients, respectively. Non-genetic causes were congenital cytomegalovirus infection (n = 11), anatomic abnormalities (n = 2), neurological/metabolic/polymalformative conditions (n = 3), meningitis (n = 1), and auditory neuropathy (n = 1). A definite genetic cause was found in 25 (50%) of congenital, bilaterally deaf children. Our data show that implementation of a gene panel improves the diagnostic yield for etiological work-up of congenital profound HL to 86%. Identification of the etiology of congenital HL may contribute to predicting outcomes of cochlear implantation.

Uveopapillitis due to Behcet’s disease in a patient with Waardenburg syndrome

Waardenburg syndrome is a rare congenital plurimalformatif syndrome combining mainly ocular, auditory, and dermatological lesions. This syndrome is due to developmental abnormalities of melanocytes during embryogenesis. Behcet's disease is a systemic vasculitis of arterial or venous vessels of different sizes. The association with Waardenburg syndrome appears to be incidental. We report a case of a unilateral uveopapillitis related to Behcet's disease in a patient with Waardenburg syndrome type II. The association between Behcet's disease and Waardenburg syndrome has never been described in the literature, which may lead this case report to be a front-runner in the description of a new Waardenburg syndrome type.

WAARDENBURG SYNDROME: ABOUT 7 CASES.

WAARDENBURG SYNDROME: ABOUT 7 CASES.

Waardenburg syndrome with isolated deficiency of myenteric ganglion cells at the sigmoid colon and rectum.

Waardenburg syndrome (WS) has the characteristic clinical features caused by the embryologic abnormality of neural crest cells. WS patients sometimes suffer from functional intestinal obstruction. When it is Hirschsprung disease (HD), the WS is diagnosed as type 4 WS. We report a case of WS which did not have myenteric ganglion cells in the sigmoid colon and rectum. Whether to diagnosis this case as type 1 or 4 WS is controversial. Moreover, this is the third report which has peristalsis failure caused by abnormal myenteric plexus. In all three cases, the eosinophils had aggregated in the myenteric layer of the transition zone. During embryonic life, enteric ganglion cells migrate to the myenteric layer from the proximal to the distal side sequentially and, subsequently, to the submucosal layer through the circular muscle. Therefore, we hypothesize that myenteric ganglion cells that had already migrated were eliminated by an eosinophil-mediated mechanism in these three cases. We believe this report may be helpful to elucidate the pathogenesis of some types of HD.

A case report of reversible generalized seizures in a patient with Waardenburg syndrome associated with a novel nonsense mutation in the penultimate exon of SOX10

BackgroundWaardenburg syndrome type 1 (WS1) can be distinguished from Waardenburg syndrome type 2 (WS2) by the presence of dystopia canthorum. About 96% of WS1 are due to PAX3 mutations, and SOX10 mutations have been reported in 15% of WS2.Case presentationThis report describes a patient with WS1 who harbored a novel SOX10 nonsense mutation (c.652G > T, p.G218*) in exon 3 which is the penultimate exon. The patient had mild prodromal neurological symptoms that were followed by severe attacks of generalized seizures associated with delayed myelination of the brain. The immature myelination recovered later and the neurological symptoms could be improved. This is the first truncating mutation in exon 3 of SOX10 that is associated with neurological symptoms in Waardenburg syndrome. Previous studies reported that the neurological symptoms that associate with WS are congenital and irreversible. These findings suggest that the reversible neurological phenotype may be associated with the nonsense mutation in exon 3 of SOX10.ConclusionsWhen patients of WS show mild prodromal neurological symptoms, the clinician should be aware of the possibility that severe attacks of generalized seizures may follow, which may be associated with the truncating mutation in exon 3 of SOX10.

Pulmonary sequestration in children. postnatal course, diagnosis and surgical treatment

The aim — to optimize the diagnostic and treatment of pulmonary sequestration in children on the basis of clinical and diagnostic data and treatment results study.Materials and methods. The study included 14 patients aged 8 days to 17 years, 3 of which were newborns, 4 — from 1 to 12 months, 3 — from 1 to 3 years, 2 — 7­8 years, and 2 — 15 — 17 years old. There were 8 (57.1 %) boys and 6 (42.9 %) girls. Postnatal diagnosis was based on contrast computed tomography or angiography. In all cases the surgical treatment was performed. In 5 cases, the diagnosis of pulmonary sequestration was established intraoperatively during the surgery for mediastinal tumor, congenital diaphragmatic hernia or polycystic lung.Results and discussion. Ten (71.4 %) patients had intralobar sequestration and another 4 (28.6 %), extralobar one (p = 0.099), left­side localization was in 9 (64.3 %) cases, right­side in 5 (35.7 %). Associated malformations were found in 7 (50.0 %) patients and included polycystic lung (n = 3), lung hypoplasia (n = 2), diaphragmatic hernia (n = 2), pericardial defect (n = 1), thoracic dystopia of kidney (n = 1), Waardenburg syndrome (n = 1). Twelve (85.7 %) patients had a symptomatic disease presented with respiratory or hemodynamic disorders, signs of inflammation and hemophtysis. Lobectomy (n = 4), segmental lung resection (n = 4) or division of aberrant vessels (n = 2) were used in cases of intralobar disease depending on the extent of lesion while sequesterectomy (n = 4) was performed in extralobar sequestration. Simultaneous diaphragmoplasty, including that with use of bounded autopericardial flap (n = 1) was performed in 2 cases of associated diaphragmatic hernia. There were no postoperative complications and mortality. Late follow­up examination within the period from 4 to 22 years after the operation showed positive results in all 100 % of cases.Conclusions. Pulmonary sequestration, since the diagnosis is established, is subject to compulsory surgical correction, the effectiveness of which reaches 100 %. Correction of intralobar sequestration consists of lobectomy or segmental resection of the lungs, in the case of extralobar disease sequesterectomy is indicated. Associated congenital diaphragmatic hernia can be effectively corrected by diaphragmoplasty, including that with use of autopericardium.

WAARDENBURG SYNDROME: ABOUT 7 CASES.

WAARDENBURG SYNDROME: ABOUT 7 CASES.

A patient with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and severe hypoganglionosis associated with a novel SOX10 mutation.

In this report, we present the case of a female infant with peripheral demyelinating neuropathy, central dysmyelinating leukodystrophy, Waardenburg syndrome, and Hirschsprung disease (PCWH) associated with a novel frameshift mutation (c.842dupT) in exon 5, the last exon of SOX10. She had severe hypoganglionosis in the small intestine and entire colon, and suffered from frequent enterocolitis. The persistence of ganglion cells made both the diagnosis and treatment difficult in the neonatal period. She also showed hypopigmentation of the irises, hair and skin, bilateral sensorineural deafness with hypoplastic inner year, severe demyelinating neuropathy with hypotonia, and diffuse brain hypomyelination. The p.Ser282GlnfsTer12 mutation presumably escapes from nonsense-mediated decay and may generate a dominant-negative effect. We suggest that hypoganglionosis can be a variant intestinal manifestation associated with PCWH and that hypoganglionosis and aganglionosis may share the same pathoetiological mechanism mediated by SOX10 mutations.

Wnt signaling pathway involvement in genotypic and phenotypic variations in Waardenburg syndrome type 2 with MITF mutations

Mutation in the gene encoding microphthalmia-associated transcription factor (MITF) lead to Waardenburg syndrome 2 (WS2), an autosomal dominantly inherited syndrome with auditory-pigmentary abnormalities, which is clinically and genetically heterogeneous. Haploinsufficiency may be the underlying mechanism for WS2. However, the mechanisms explaining the genotypic and phenotypic variations in WS2 caused by MITF mutations are unclear. A previous study revealed that MITF interacts with LEF-1, an important factor in the Wnt signaling pathway, to regulate its own transcription through LEF-1-binding sites on the MITF promoter. In this study, four different WS2-associated MITF mutations (p.R217I, p.R217G, p.R255X, p.R217del) that are associated with highly variable clinical features were chosen. According to the results, LEF-1 can activate the expression of MITF on its own, but MITF proteins inhibited the activation. This inhibition weakens when the dosage of MITF is reduced. Except for p.R217I, p.R255X, p.R217G, and p.R217del lose the ability to activate TYR completely and do not inhibit the LEF-1-mediated activation of the MITF-M promoter, and the haploinsufficiency created by mutant MITF can be overcome; correspondingly, the mutants’ associated phenotypes are less severe than that of p.R217I. The dominant negative of p.R217del made it have a second-most severe phenotype. This study’s data imply that MITF has a negative feedback loop of regulation to stabilize MITF gene dosage that involves the Wnt signaling pathway and that the interaction of MITF mutants with this pathway drives the genotypic and phenotypic differences observed in Waardenburg syndrome type 2 associated with MITF mutations.

Waardenburg syndrome: Novel mutations in a large Brazilian sample

This paper deals with the molecular investigation of Waardenburg syndrome (WS) in a sample of 49 clinically diagnosed probands (most from southeastern Brazil), 24 of them having the type 1 (WS1) variant (10 familial and 14 isolated cases) and 25 being affected by the type 2 (WS2) variant (five familial and 20 isolated cases). Sequential Sanger sequencing of all coding exons of PAX3, MITF, EDN3, EDNRB, SOX10 and SNAI2 genes, followed by CNV detection by MLPA of PAX3, MITF and SOX10 genes in selected cases revealed many novel pathogenic variants. Molecular screening, performed in all patients, revealed 19 causative variants (19/49 = 38.8%), six of them being large whole-exon deletions detected by MLPA, seven (four missense and three nonsense substitutions) resulting from single nucleotide substitutions (SNV), and six representing small indels. A pair of dizygotic affected female twins presented the c.430delC variant in SOX10, but the mutation, imputed to gonadal mosaicism, was not found in their unaffected parents. At least 10 novel causative mutations, described in this paper, were found in this Brazilian sample. Copy-number-variation detected by MLPA identified the causative mutation in 12.2% of our cases, corresponding to 31.6% of all causative mutations. In the majority of cases, the deletions were sporadic, since they were not present in the parents of isolated cases. Our results, as a whole, reinforce the fact that the screening of copy-number-variants by MLPA is a powerful tool to identify the molecular cause in WS patients.

ASSOCIATION OF HIRSCHSPRUNG DISEASE WITH WAARDENBURG SYNDROME AND ROLE OF GENE STUDIES: A REVIEW OF 2 CASES

Background: Waardenburg-Shah syndrome type 4 is an association of Waardenburg syndrome with Hirsch sprung disease. Three disease-causing genes have been identified so far: Endothelin receptor type B encoding the endothelia-B receptor, EDN3 encoding an endothelia receptor ligand and Sry-like HMG bOX10 (SOX10) encoding the SOX10 transcription factor. Case Report: This is a review of 2 cases with variable onset of presentation and extent of aganglionic segment. Intervention/Outcome: In case 1, primary pull-through, as definitive surgical correction was done as a single procedure, whereas in case 2, required ileostomy with a plan of definitive surgery later on. Message: Mutation studies are helpful in characterization of the syndrome and counseling to the family. Furthermore, prognosis depends on the length of the ganglionic segment.

Analysis of the human SOX10 mutation Q377X in mice and its implications for genotype-phenotype correlation in SOX10-related human disease.

Human SOX10 mutations lead to various diseases including Waardenburg syndrome, Hirschsprung disease, peripheral demyelinating neuropathy, central leukodystrophy, Kallmann syndrome and various combinations thereof. It has been postulated that PCWH as a combination of Waardenburg and Hirschsprung disease, peripheral neuropathy and central leukodystrophy is caused by heterozygous SOX10 mutations that result in the presence of a dominantly acting mutant SOX10 protein in the patient. One such protein with postulated dominant action is SOX10 Q377X. In this study, we generated a mouse model, in which the corresponding mutation was introduced into the Sox10 locus in such a way that Sox10 Q377X is constitutively expressed. Heterozygous mice carrying this mutation exhibited pigmentation and enteric nervous system defects similar to mice in which one Sox10 allele was deleted. However, despite presence of the mutant protein in Schwann cells and oligodendrocytes throughout development and in the adult, we found no phenotypic evidence for neurological defects in peripheral or central nervous systems. In the nervous system, the mutant Sox10 protein did not act in a dominant fashion but rather behaved like a hypomorph with very limited residual function. Our results question a strict genotype-phenotype correlation for SOX10 mutations and argue for the influence of additional factors including genetic background.

Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics.

Congenital hearing loss is one of the most common birth defects worldwide, with around 1 in 500 people experiencing some form of severe hearing loss. While over 400 different syndromes involving hearing loss have been described, it is important to be familiar with a wide range of syndromes involving hearing loss so an early diagnosis can be made and early intervention can be pursued to maximize functional hearing and speech-language development in the setting of verbal communication. This review aims to describe the presentation and genetics for some of the most frequently occurring syndromes involving hearing loss, including neurofibromatosis type 2, branchio-oto-renal syndrome, Treacher Collins syndrome, Stickler syndrome, Waardenburg syndrome, Pendred syndrome, Jervell and Lange-Nielsen syndrome, Usher syndromes, Refsum disease, Alport syndrome, MELAS, and MERRF.

A Comprehensive Genetic and Clinical Evaluation of Waardenburg Syndrome Type II in a Set of Iranian Patients.

Waardenburg syndrome (WS) is a neurocristopathy with an autosomal dominant mode of inheritance, and considerable clinical and genetic heterogeneity. WS type II is the most common type of WS in many populations presenting with sensorineural hearing impairment, heterochromia iridis, hypoplastic blue eye, and pigmentary abnormalities of the hair and skin. To date, mutations of MITF, SOX10, and SNAI2 have been implicated in the pathogenesis of WS2. Although different pathogenic mutations have been reported in many ethnic groups, the data on Iranian WS2 patients is insufficient. 31 WS2 patients, including 22 men and 9 women from 14 families were included. Waardenburg consortium guidelines were employed for WS2 diagnosis. WS2 patients underwent screening for MITF, SOX10, and SNAI2 mutations using direct sequencing and MLPA analysis. Clinical evaluation revealed prominent phenotypic variability in Iranian WS2 patients. Sensorineural hearing impairment and heterochromia iridis were the most common features (67% and 45%, respectively), whereas anosmia was the least frequent phenotype. Molecular analysis revealed a de novo heterozygous c.640C>T (p.R214X) in MITF and a de novo heterozygous SOX10 gross deletion in the study population. Our data help illuminate the phenotypic and genotypic spectrum of WS2 in an Iranian series of patients, and could have implications for the genetic counseling of WS in Iran.

A recalcitrant case of Jacquet erosive diaper dermatitis after surgery for Hirschsprung disease in a boy with Waardenburg-Shah syndrome

We herein present a 4 year-old boy with Waardenburg-Shah syndrome who developed Jacquet erosive diaper dermatitis following a total colectomy and ileoanal anastomosis procedure for Hirschsprung disease. The diagnosis was made according to history and typical clinical findings. Complete resolution of the recalcitrant lesions after an ileostomy procedure supported the diagnosis. This case highlights the importance of being familiar with the predisposing factors and clinical presentation of this rare and severe form of chronic irritant dermatitis, since it may easily be misdiagnosed as other diseases in children and may lead to unnecessary diagnostic procedures, treatments, and anxiety due to suspicion of child abuse.

Wardenburg syndrome type 2 in a woman with no genomic mutation commonly associated with the syndrome

Waardenburg Syndrome (WS) is a condition characterized by pigmentary changes of the hair or skin, hearing loss, heterochromia iridis, and dystopia canthorum. There are four main types of WS, which can be commonly caused by mutations in the PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 genes. Herein, we present a patient with Waardenburg Syndrome type 2 with no findings of mutations in the commonly associated genes.

An unusual case of Waardenburg syndrome in a female child

Ocular albinism is characterized by congenital nystagmus, reduced visual acuity, hypopigmentation of the iris pigment epithelium and the ocular fundus and foveal hypoplasia. We report a case with clinical manifestations consistent with the phenotypes of WS1. The differentiating feature from uniocular albinism is the presence of dystopia canthorum.