Diagnostic Criteria And Differential Diagnosis

The complex, progressive, and variable nature of the WS clinical phenotype makes the clinical diagnosis of WS challenging. This is especially true in young adults, where there are often few convincing signs or changes and where there may be no family history of WS to raise clinical suspicion. There are no universally accepted criteria for the diagnosis of WS. However, a useful set of diagnostic criteria and a scoring system have been developed by investigators at the International Registry for Werner Syndrome (Table 80.1, bottom panel; see also Recommended Resources). These criteria, together with molecular approaches to identify common WRN mutations or the loss of WRN protein expression (see later), can be used in most instances to confirm or exclude a diagnosis of WS in suspected affected individuals. The ability to couple clinical and molecular diagnostic approaches, as noted later, now allows the unambiguous identification of affected or at-risk homozygous mutant individuals, and of heterozygous carriers in families regardless of age or clinical findings.

The availability of a consistent set of clinical diagnostic criteria and of molecular diagnostic criteria for WS have provided sharper definition of WS as a disease entity, and provide a way to distinguish WS from other human diseases and syndromes that may mimic WS. Two groups of patients who may be confused with, or not easily distinguished from, typical or classic WS include patients who fulfill the clinical diagnostic criteria for WS as outlined in Table 80.1, though lack mutations in the WRN

gene; and patients who resemble WS patients though fail to fulfill the diagnostic criteria outlined in Table 80.1. This second group is often ascertained as potential variant or atypical WS. Both of these groups of patients are rare, and from the experience of the International Registry of Werner Syndrome together represent no more than a small fraction of suspected WS patients.

Despite their rarity, these WS look-alikes are of considerable clinical and biological interest as they are likely to be highly enriched for rare mutations in proteins that act with—or act on—WRN to modify or target its function in vivo. There are strong theoretical grounds for proposing the existence of these individuals, in light of the growing number of proteins that may act with WRN (see later). There are experimental hints, for example, of at least one additional complementation group for WS in addition to the group represented by inactivating mutations in the WRN gene (Prince et al., 1999). These WS phenocopies or partial phenocopies represent an important area for additional clinical and molecular diagnostic work.

A portion of the second group of patients just mentioned, with what has been termed atypical Werner syndrome, share some clinical features of WS (see Table 80.1), though lack mutations in the WRN gene. A small number of these patients were recently found to carry germline mutations that alter splicing of the LMNA or lamin A/C gene (Chen et al., 2003). A subset of different LMNA mutations that alter the splicing of LMNA mRNA have been found in patients with Hutchinson-Gilford progeria (HGPS), a rare, heritable, severe, and rapidly progressive disease that is often referred to simply as progeria or childhood progeria. Of note, other mutations that alter splicing or the properties of LMNA or lamin A/C have been associated with at least eight other clinically distinguishable diseases that have been collectively termed the laminopathies. This fascinating group of diseases affect predominantly nerve, muscle, connective tissue, or adipocytes (Broers et al., 2005). HGPS and WS show little clinical overlap, and are unlikely to share any deep mechanistic similarities. Thus the existence of atypical WS as a distinct clinical entity has been controversial. It would appear to make the best sense at present to consider atypical WS patients with LMNA mutations that affect RNA splicing as having an atypical form of HGPS, rather than a variant form of WS (Hegele, 2003).

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