Waardenburg Syndrome, Type 3

A number sign (#) is used with this entry because Waardenburg syndrome type 3 (WS3) is caused by heterozygous or homozygous mutation in the PAX3 gene (606597) on chromosome 2q36.

Waardenburg syndrome type 1 (WS1; 193500) is also caused by heterozygous mutation in the PAX3 gene.

Description

Waardenburg syndrome type 3 is an auditory-pigmentary syndrome characterized by pigmentary abnormalities of the hair, skin, and eyes; congenital sensorineural hearing loss; presence of 'dystopia canthorum,' the lateral displacement of the ocular inner canthi; and upper limb abnormalities (reviews by Read and Newton, 1997 and Pingault et al., 2010). WS type 3 is also referred to as 'Klein-Waardenburg syndrome' (Gorlin et al., 1976).

Clinical Variability of Waardenburg Syndrome Types 1-4

Waardenburg syndrome has been classified into 4 main phenotypes. Type I Waardenburg syndrome (WS1; 193500) is characterized by pigmentary abnormalities of the hair, including a white forelock and premature graying; pigmentary changes of the iris, such as heterochromia iridis and brilliant blue eyes; congenital sensorineural hearing loss; and 'dystopia canthorum.' WS type II (WS2) is distinguished from type I by the absence of dystopia canthorum. WS type III has dystopia canthorum and is distinguished by the presence of upper limb abnormalities. WS type IV (WS4; 277580), also known as Waardenburg-Shah syndrome, has the additional feature of Hirschsprung disease (reviews by Read and Newton, 1997 and Pingault et al., 2010).

Clinical Features

Klein (1950) first reported the association of limb anomalies with what has come to be recognized as the hallmarks of Waardenburg syndrome type 1, including pigmentary defects and sensorineural hearing loss. Single cases were reported by Wilbrandt and Ammann (1964) and and Mossallam et al. (1974).

Klein (1981) visited the patient of Marx and Bertrand (1968) and found that he had an 11-year-old son with classic facial changes of Waardenburg syndrome and winged scapulae, but no gross or radiographic changes in the arms.

Goodman et al. (1982) documented the combination of upper limb abnormalities and the facial and ocular abnormalities of the Waardenburg syndrome in a Yemenite Jewish brother and sister, and reviewed this association in 4 patients reported earlier. The bilateral upper limb anomalies included hypoplasia of the musculoskeletal system, flexion contractures, fusion of the carpal bones, and syndactyly. The brother, at age 23 years, had a head circumference of only 55 cm (height 161 cm), but presumably normal intelligence. The sister, at age 25 years, had marked microcephaly (head circumference 47 cm), severe mental retardation, and spastic paraplegia. Parental consanguinity was denied. Sheffer and Zlotogora (1992) provided follow-up of the family reported by Goodman et al. (1982). Sheffer and Zlotogora (1992) described a brother and sister with dystopia canthorum, blepharophimosis, and bilateral flexion contractures of the fingers. The father of these sibs and his sister, who had previously been reported by Goodman et al. (1982), showed the same features. The flexion contractures in both the proposita and her father were pictured by Sheffer and Zlotogora (1992).

In their Figure 2, Tassabehji et al. (1995) pictured the hands of a man noted to have flexion contractures of the fingers characteristic of WS3. A nonsense mutation with predicted truncation of the PAX3 gene product was found: deletion of a cytosine at nucleotide 916 in exon 6 in the homeodomain. The daughter, who was also pictured, and the mother of the proband were said to have WS1.

From a systematic literature search, Song et al. (2016) determined that the prevalence of hearing loss in patients with Waardenburg syndrome differed according to the genotype: the prevalence in those with WS3 due to PAX3 mutations was 57.1%.

Clinical Variability

Goodman et al. (1980) reported the cases of 2 Ashkenazi Jewish brothers with a 'new' syndrome of white forelock (poliosis), distinctive facial features and congenital malformations of the ocular, cardiopulmonary and skeletal systems. Ocular hypertelorism, atrial septal defect, prominent thoracic and abdominal veins, hypoplastic or absent terminal phalanges of toes, and segmental bronchomalacia with atelectasis were features.

Inheritance

Goodman et al. (1982) favored autosomal dominant inheritance. Follow-up of this family by Sheffer and Zlotogora (1992) appeared to confirm autosomal dominant inheritance.

Molecular Genetics

Milunsky et al. (1992) and Hoth et al. (1993) identified a heterozygous mutation in the PAX3 gene (N47H; 606597.0011) in a Yemenite/Russian Jewish family with the Klein-Waardenburg syndrome (Goodman et al., 1982 and Sheffer and Zlotogora, 1992). The father, his 2 children, and his sister had signs of the disorder, but neither of the father's parents were affected.

Tekin et al. (2001) described a mother and son with typical clinical findings of WS type 3 segregating with a heterozygous 13-bp deletion in the paired domain in exon 3 of the PAX3 gene (606597.0012).

Zlotogora et al. (1995) presented evidence that homozygosity for a PAX3 mutation can cause WS type 3 (see GENOTYPE/PHENOTYPE CORRELATIONS).

Genotype/Phenotype Correlations

Zlotogora et al. (1995) presented evidence that homozygosity for a PAX3 mutation can cause WS type 3. In a large kindred, including many individuals affected with WS type 1, a child was born affected with a very severe form of WS type 3. The child presented with dystopia canthorum, partial albinism, and very severe upper-limb defects. His parents were first cousins and both were affected with a mild form of WS1. Molecular analysis identified a heterozygous mutation in the PAX3 gene (S84F; 606497.0009). Individuals with WS type 1 were heterozygous for the mutation and the child with WS type 3 was homozygous. The observation that the PAX3 homozygote survived at least into early infancy and did not suffer from a neural tube defect was unexpected, since, in all the Pax3 mutations known in the mice, homozygosity leads to severe neural tube defects and intrauterine or neonatal death. Ayme and Philip (1995) likewise described possible homozygosity for a PAX3 mutation in a fetus with exencephaly and severe contractures and webbing of the limbs.

Wollnik et al. (2003) reported a family in which both parents were heterozygous for a Y90H mutation in PAX3 (606597.0013) and had Waardenburg syndrome type 1; the offspring was homozygous for the mutation and had Waardenburg syndrome type 3.

Cytogenetics

In a patient with Waardenburg syndrome type 3 with characteristic features of severe neurosensory deafness, diagnostic dysmorphic facial features, hypopigmentation, and severe axial and limb skeletal anomalies, Pasteris et al. (1992) identified a de novo deletion of 2q35-q36. Chromosome 2 homologs could not be distinguished by bivariant fluorescent-activated chromosome sorting, suggesting that the deletion was less than 5% of the chromosome length, i.e., less than 12.5 megabases. Densitometric hybridization analyses showed that the patient was hemizygous for loci HuP2 (PAX3) and COL4A3 (120070) and that flanking loci INHA (147380) and ALPI (171740) were present in 2 copies. Analyses of somatic cell hybrids selectively retaining the chromosome 2 showed that the deletion was paternal in origin. Physical mapping confirmed the deletion of 2q35-q36 and showed that COL4A3 is telomeric to PAX3. From these studies, Pasteris et al. (1992) concluded that Waardenburg syndrome type 3 is a contiguous gene syndrome. By molecular analysis of a chromosome 2 deletion mapping panel, Pasteris et al. (1993) determined that the order of loci on 2q is as follows: cen--(INHA, DES)--PAX3--COL4A3--(ALPI, CHRND)--tel. They also studied a patient with cleft palate and lip pits who lacked diagnostic WS features and found that the del(2)(q33q35) deletion involved the PAX3 locus. The finding suggested that not all PAX3 mutations are associated with a WS phenotype and that additional loci in the region may modify or regulate the PAX3 locus and/or the development of the WS phenotype.

Animal Model

Homozygosity in the 'splotch' mouse, a mouse model for Waardenburg syndrome due to a PAX3 deletion, leads to neural tube defect in addition to severe limb defects Epstein et al. (1991).