Watson Syndrome

A number sign (#) is used with this entry because of evidence that Watson syndrome (WTSN) is caused by heterozygous mutation in the NF1 gene (613113) on chromosome 17q11.

Description

Watson syndrome is an autosomal dominant disorder characterized by pulmonic stenosis, cafe-au-lait spots, decreased intellectual ability (Watson, 1967), and short stature (Partington et al., 1985). Most affected individuals have relative macrocephaly and Lisch nodules and about one-third of those affected have neurofibroma (Allanson et al., 1991).

Clinical Features

Watson (1967) described 15 persons from 2 generations of each of 3 families with pulmonic stenosis (8/15), cafe-au-lait spots (15/15) and low normal or dull intelligence (12/15). There were 8 males and 7 females; male-to-male transmission was noted. There were no signs of neurofibromata.

Partington et al. (1985) described a father (aged 57 years), his daughter (aged 20) and his son (aged 18), all with pulmonary stenosis, cafe-au-lait spots, and dull intelligence. The daughter also had soft tissue limitation of movement of the knees and ankles and the father had ectasia of the coronary arteries. None had neurofibromas, Lisch nodules, lentigines, or deafness. Partington et al. (1985) contended that the Watson syndrome is distinct from both neurofibromatosis I (NF1; 162200) and the LEOPARD syndrome (151100). Although it was not obvious from the original description, short stature is a universal feature of the Watson syndrome.

Allanson et al. (1989) reviewed the 2 largest reported families including members of the extended family who had not previously been examined. They expanded the clinical phenotype to include relative macrocephaly and Lisch nodules in most affected individuals and neurofibromata in at least 4 family members. Allanson et al. (1991) extended their review to an additional family. Neurofibromas were found in about one-third of affected persons.

Mapping

Because of clinical similarities between Watson syndrome and neurofibromatosis, Allanson et al. (1991) performed linkage studies in families with Watson syndrome, using probes known to flank the NF1 gene on chromosome 17. Tight linkage with Watson syndrome was found (maximum lod = 3.29 at theta = 0.0).

Upadhyaya et al. (1989, 1990) performed a linkage study of a 3-generation family with Watson syndrome. Close linkage with DNA marker D17S33 was found; maximum lod = 3.28 at theta = 0.00. This marker is also the closest marker to NF1. Thus, Watson syndrome and NF1 may be allelic, or it is possible that pulmonic stenosis is the result of a change in an adjacent gene.

Using probes flanking the NF1 gene on chromosome 17, Allanson et al. (1991) found tightest linkage with probe HHH202; maximum lod score = 3.59 at theta = 0.0. They interpreted this to indicate that either the Watson syndrome and NF1 are allelic or that there is a group of contiguous genes responsible for the several features of the Watson syndrome.

Relevant to the question of whether the Watson syndrome is a contiguous gene syndrome resulting from deletion of both the NF1 gene and a gene for Noonan syndrome, Sharland et al. (1992), in a linkage study in 11 families with Noonan syndrome in 2 or 3 generations, excluded the proximal region of 17q as the location of the gene.

Molecular Genetics

Supporting the conclusion that Watson syndrome is allelic to NF1 is the finding by Upadhyaya et al. (1992) of an 80-kb deletion in the NF1 gene (613113.0011) in a patient with Watson syndrome. Similarly, Tassabehji et al. (1993) demonstrated an almost perfect in-frame tandem duplication of 42 bases in exon 28 of the NF1 gene in 3 members of a family with Watson syndrome (613113.0010).