Craniofacial-Deafness-Hand Syndrome

A number sign (#) is used with this entry because of evidence that craniofacial-deafness-hand syndrome (CDHS) is caused by heterozygous mutation in the PAX3 gene (606597) on chromosome 2q36.

Clinical Features

Sommer et al. (1983) reported a syndrome in mother and infant daughter with features of flat facial profile, hypertelorism, hypoplastic nose with slitlike nares, and a sensorineural hearing loss. Common radiologic findings included small maxilla, absent or small nasal bones, and ulnar deviation of the hands.

Sommer and Bartholomew (2003) provided a follow-up of the family reported by Sommer et al. (1983). A boy born 2 years after the birth of the index patient had precisely the same manifestations as his mother and sister. The mother and daughter were found to have congenital absence of nasolacrimal ducts. The sister and brother grew and developed normally, were very good students, and were active in sports. They were attending college and had goals to be a veterinary technician and a computer technologist, respectively.

Gad et al. (2008) described a 37-year-old woman, born to healthy nonconsanguineous parents, with some but not all of the characteristics of CDHS. She had bilateral sensorineural hearing loss, flat facial profile, ptosis, downslanting palpebral fissures, short broad nose, depressed nasal bridge, micrognathia, hypertelorism, telecanthus, high arched palate, limited movement of the wrist with ulnar deviation of the hands, mild flexion contractures of digits 2-5, and clinodactyly of the 5th digits. In addition, CT scan of the face showed underdevelopment of the sinuses ranging from mild to complete aplasia, which had not previously been described in patients with CDHS.

Molecular Genetics

Because dystopia canthorum, a midfacial alteration, is the most reliable indicator of a PAX3 mutation among Waardenburg syndrome type I families (193500), according to Farrer et al. (1994), and because during murine development the Pax3 gene was expressed in the nasal process (Goulding et al., 1991), Asher et al. (1996) explored the possibility that a mutant allele of PAX3 might be responsible for CDHS. In the mother and child reported by Sommer et al. (1983), Asher et al. (1996) found heterozygosity for a missense mutation (N47K; 606597.0010) in the paired domain of PAX3 by SSCP analysis followed by sequencing. A previously described missense mutation in the same codon (N47H; 606597.0011) was reported by Hoth et al. (1993) in association with Waardenburg syndrome type III (148820). A substitution of a basic amino acid for asparagine at residue 47, conserved in all known murine Pax and human PAX genes, appears to have a more drastic effect on the phenotype than missense, frameshift, and deletion mutations of PAX3 that cause Waardenburg syndrome type I. Among 24 unrelated individuals with WS1 mutations, no 2 had been found to have the same point mutation in the protein-coding region of PAX3, nor did they have a change in the same codon (Farrer et al., 1994). The finding in CDHS provided the first opportunity to compare molecular pathology and clinical heterogeneity between 2 different mutations in the same codon for PAX3.

In a patient with possible CDHS, Gad et al. (2008) performed sequencing of all 9 exons and 20 bp of the flanking introns of the PAX3 gene and did not identify any mutations. The presence of heterozygosity for a PAX3 polymorphism ruled out a full gene deletion, but a partial deletion remained a possible disease mechanism in this patient.