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J Clin Pathol 65:200-205 doi:10.1136/jclinpath-2011-200276
  • Review

A review of the clinical presentation, natural history and inheritance of variegate porphyria: its implausibility as the source of the ‘Royal Malady’

Editor's Choice
  1. Peter N Meissner3,4
  1. 1Division of Medicine, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa
  2. 2Institute of Archaeology and Antiquity, University of Birmingham, UK
  3. 3Division of Medical Biochemistry, Department of Clinical Laboratory Sciences and Lennox Eales Porphyria Laboratories, Department of Medicine, University of Cape Town, Observatory, South Africa
  4. 4Institute for Infectious Disease and Molecular Medicine, University of Cape Town Medical School, Observatory, South Africa
  1. Correspondence to Peter N Meissner, Division of Medical Biochemistry, UCT Medical School, Observatory, 7925, South Africa; peter.meissner{at}uct.ac.za
  1. Contributors Richard J Hift: Contributed to the design and development of the review and arguments, including data assessment; wrote the second and subsequent drafts; contributed to the intellectual content; approved the final submitted manuscript. Timothy J Peters: Contributed to the design and development of the review; wrote an initial draft; assisted with writing and editing of all subsequent drafts; contributed to the intellectual content; approved the final submitted manuscript. Peter N Meissner: Responsible for the conception of the review; contributed to the data assessment and intellectual content; assisted with the writing and editing of all drafts; prepared and approved the final submission.

  • Accepted 18 September 2011
  • Published Online First 2 November 2011

Abstract

It has been suggested that King George III of Great Britain suffered from the haem biosynthetic disorder, variegate porphyria. This diagnosis is pervasive throughout the scientific and popular literature, and is often referred to as the ‘Royal Malady.’ The authors believe it inappropriate to view the case for porphyria purely in terms of symptoms, as has generally been the case in his presumptive acute porphyria diagnosis. Accordingly, this review provides a current description of the natural history and clinical presentation of the porphyrias, against which we measure the case for porphyria in George III and his relatives. The authors have critically assessed the prevalence of porphyria in a population, the expected patterns and frequency of inheritance, its penetrance and its expected natural history in affected individuals, and conclude that neither George nor his relatives had porphyria, based on four principal reasons. First, the rarity of the disease mandates a very low prior probability, and therefore implies a vanishingly low positive predictive value for any diagnostic indicator of low specificity, such as a historical reading of the symptoms. Second, penetrance of this autosomal dominant disorder is approximately 40%, and one may expect to have identified characteristic clinical features of porphyria in a large number of descendants without difficulty. Third, the symptoms of both George III and his relatives are highly atypical for porphyria and are more appropriately explained by other much commoner conditions. Finally, the natural history of the illnesses reported in this family is as atypical for variegate porphyria as are their symptoms.

Footnotes

  • Competing interests None.

  • Ethics approval Not required as the study does not involve research on human nor animal subjects

  • Provenance and peer review Not commissioned; externally peer reviewed.