Waardenburg syndrome is a group of genetic conditions that can cause hearing loss and pigmentation deficiency of the hair, skin, and eyes. Klein-Waardenburg syndrome (Waardenburg syndrome type 3) represents a distinct presentation of Waardenburg syndrome type 1 and includes musculoskeletal abnormalities in addition to dystopia canthorum hearing loss and pigmentary changes. Heterozygous or homozygous variants in the PAX3 gene cause Klein-Waardenburg syndrome. Here we report on a new severely affected child, with a homozygous PAX3 variant (c.251C>T; p.Ser84Phe), review the features of the syndrome, and propose a new classification. The designation of Waardenburg syndrome should be given only to patients with monoallelic pathogenic variants in PAX3 whether or not musculoskeletal abnormalities are present. Patients with biallelic PAX3 variants should be outlined as a distinct group and designated Klein syndrome.

Waardenburg syndrome subtypes 1 and 3 are caused by pathogenic variants in PAX3. We investigated 12 individuals from four unrelated families clinically diagnosed with Waardenburg syndrome type 1/3. Novel pathogenic variants identified in PAX3 included single nucleotide variants (c.166C>T, c.829C>T), a 2-base pair deletion (c.366_367delAA) and a multi-exonic deletion. Two novel variants, c.166C>T and c.829C>T and a previously reported variant, c.256A>T in PAX3 were evaluated for their nuclear localization and ability to activate MITF promoter. The coexistence of two subtypes of Waardenburg syndrome with pathogenic variants in PAX3 and EDNRB was seen in one of the affected individuals. Multiple genetic diagnoses of Waardenburg syndrome type 3 and autosomal recessive deafness 1A was identified in an individual. We also review the phenotypic and genomic spectrum of individuals with PAX3-related Waardenburg syndrome reported in the literature.

Waardenburg 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. PCR 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. We 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. This 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.

Waardenburg syndrome is a known autosomal dominant cause of congenital hearing loss. It is characterized by a distinctive phenotypic appearance and often involves sensorineural hearing loss. Temporal bone abnormalities and inner ear dysmorphisms have been described in association with the disease. However, middle ear abnormalities as causes of conductive hearing loss are not typically seen in Waardenburg syndrome. We discuss a case of an 8-year-old female who meets diagnostic criteria for Waardenburg syndrome type 3 and who presented with a bilateral conductive hearing loss associated with congenital stapes fixation. We discuss management strategy in this previously unreported phenotype.