Perspectives on the revised Ghent criteria for the diagnosis of Marfan syndrome

Abstract

Three international nosologies have been proposed for the diagnosis of Marfan syndrome (MFS): the Berlin nosology in 1988; the Ghent nosology in 1996 (Ghent-1); and the revised Ghent nosology in 2010 (Ghent-2). We reviewed the literature and discussed the challenges and concepts of diagnosing MFS in adults. Ghent-1 proposed more stringent clinical criteria, which led to the confirmation of MFS in only 32%-53% of patients formerly diagnosed with MFS according to the Berlin nosology. Conversely, both the Ghent-1 and Ghent-2 nosologies diagnosed MFS, and both yielded similar frequencies of MFS in persons with a causative FBN1 mutation (90% for Ghent-1 versus 92% for Ghent-2) and in persons not having a causative FBN1 mutation (15% versus 13%). Quality criteria for diagnostic methods include objectivity, reliability, and validity. However, the nosology-based diagnosis of MFS lacks a diagnostic reference standard and, hence, quality criteria such as sensitivity, specificity, or accuracy cannot be assessed. Medical utility of diagnosis implies congruency with the historical criteria of MFS, as well as with information about the etiology, pathogenesis, diagnostic triggers, prognostic triggers, and potential complications of MFS. In addition, social and psychological utilities of diagnostic criteria include acceptance by patients, patient organizations, clinicians and scientists, practicability, costs, and the reduction of anxiety. Since the utility of a diagnosis or exclusion of MFS is context-dependent, prioritization of utilities is a strategic decision in the process of nosology development. Screening tests for MFS should be used to identify persons with MFS. To confirm the diagnosis of MFS, Ghent-1 and Ghent-2 perform similarly, but Ghent-2 is easier to use. To maximize the utility of the diagnostic criteria of MFS, a fair and transparent process of nosology development is essential.

Keywords: FBN1; Ghent nosology; Marfan syndrome; aorta; diagnosis; mutation.

Figure 1

Dilemma, quality and utility of diagnosis of Marfan syndrome. Notes: (A) The rarity of MFS poses a dilemma, where an unknown fraction of persons with MFS may not be suspected of having MFS, or he or she may only be identified by major complications or at necropsy. (B) Criteria to estimate the quality of diagnostic criteria, such as the Ghent nosologies, comprise objectivity, reliability, and validity, where objectivity is a prerequisite for reliability, and reliability a prerequisite for validity. When a diagnosis is reliable, then all three qualities should converge. (C) The utility of diagnostic criteria includes medical, social, and psychological dimensions, which depend on context and may diverge. To maximize the overlap of all three dimensions, negotiation, compromise, and consensus are useful for developing diagnostic criteria. Abbreviation: MFS, Marfan syndrome.

Figure 2

“Seven-signs” of Marfan syndrome may be used for targeted screening of Marfan syndrome in adults of the general population. Notes: The screening tool assigns four score points to ectopia lentis, two points to a family history of Marfan syndrome, and one point to previous thoracic aortic surgery, to pectus excavatum, to a wrist and thumb sign, to previous pneumothorax, and to skin striae. According to the total score, the pretest probability of Marfan syndrome may be assessed as low (≤1 point), moderate (>1–3.5 points), or high (>3.5 points).