Retracing an old journey in variegate porphyria

Variegate porphyria (VP), one of the three autosomal dominant acute porphyrias, is probably best known in the U.K. because of its now largely discredited association with the royal family. This inherited disorder is panethnic, and although rare with a prevalence of approximately 1 : 200000, most frequently presents to dermatologists because of skin fragility, blistering, milia and pigmentary changes in sun-exposed skin. Unlike porphyria cutanea tarda, the commonest of the bullous porphyrias, these cutaneous features are more typically seen in young female subjects, and porphyrin biochemistry is essential in making the correct diagnosis and offering appropriate counselling and family studies. While in the U.K. and elsewhere in Europe most families have a distinct mutation, which means mutation testing requires analysis of the entire protoporphyrinogen oxidase gene, in South Africa a true founder effect has resulted in a large population of VP patients with an identical mutation (R59W), which simplifies testing. The report of extended haplotype studies in South African and Dutch VP families in this issue builds on the work of Geoffrey Dean whose genealogical detective work in South Africa traced affected Afrikaner families back generation by generation. Driven as a medical practitioner by the observation of frequent anaesthetic deaths among particular Afrikaner families, he noted that a previously relatively benign condition of skin fragility had been transformed by modern pharmacology, particularly the use of barbiturates, into a potentially lethal condition. This remains true today, and is the main reason why tracing and identifying affected relatives is so important in managing families with this condition in the U.K. and elsewhere. Aided by a highly ordered social etiquette in naming offspring, meticulous record keeping by the Dutch Reformed Church and prior published studies of established Cape families, he was able to trace the condition back to a single immigrant couple – Gerrit Jansz from Deventer, one of the original free burghers of the Cape, and Ariaantje Jacobs, an orphan from Rotterdam, who married in 1688 within weeks of her arrival. The work described in this journal uses haplotype analysis to formally link VP families from South Africa and the Netherlands, specifically the part of the Netherlands from which Gerrit Jansz is purported to have emigrated, and to support Dean’s hypothesis that the mutation existed in the Netherlands before the Dutch colonization of the Cape. What is needed now is another piece of genealogical detective work among the Dutch archives, firstly to exclude back migration from South Africa as the explanation for the common haplotype, as would be the case in the U.K. where increasing numbers of R59W-positive VP patients are being diagnosed, and secondly, to complete the last piece in the jigsaw puzzle and identify whether Gerrit or Ariaantje was the VP founder. Unfortunately, the Rotterdam archives were destroyed during the second world war, so researching the affected Dutch families reported in this study to see if they can be linked to Gerrit Jansz, as Dean would have done, is likely to be most productive in concluding this fascinating story.