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Summary

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X-linked dominant protoporphyria (XLDPP) was first reported in the genetics literature in 2008. It has a phenotype very similar to erythropoietic protoporphyria (EPP), but is distinguished from EPP by higher concentrations of erythrocyte protoporphyrin (of which a high proportion is zinc-chelated), its apparently higher incidence of liver disease, and an X-linked dominant pattern of inheritance. Dermatologists should understand how XLDPP differs from EPP, in order to advise newly diagnosed patients correctly about the genetic implications and the long-term management strategy. We present a case series of XLDPP to introduce this condition to the dermatology literature.

X-linked dominant protoporphyria (XLDPP) was first reported in the genetics literature in 2008.[1] It has a clinical phenotype that is indistinguishable from erythropoietic protoporphyria (EPP).[2] The diagnosis of XLDPP is suggested by generally higher concentrations of erythrocyte protoporphyrin, of which a high proportion is zinc-bound. The first publication on XLDPP reported a higher incidence of liver disease compared with EPP.[1] We present a case series of XLDPP to introduce this condition to the dermatology literature.

Report

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An 18-year-old woman presented to our dermatology clinic in 2011, with a history of lifelong photosensitivity. Her skin became intensely painful with a ‘burning’ sensation after minimal sun exposure, in the absence of any specific rash. Her symptoms were worst between March and September, with only a partial response to sunscreen and no protection from window glass. She was otherwise well, and was taking no photosensitizing medication.

On further questioning, the patient's mother (who had accompanied her to the consultation) reported identical symptoms, and explained that her own father and (deceased) grandmother had also been affected; a pattern of inheritance spanning four generations, suggesting a dominantly inherited disease (Fig. 1).

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Figure 1. Family pedigree. Filled shapes represent symptomatic individuals, and the index patient is indicated with an error.

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On physical examination, the patient was found to have normal, untanned skin, consistent with lifelong photo-avoidance (Fig. 2), which may have accounted for her delayed presentation. A provisional diagnosis of EPP was made on the basis of the characteristic symptoms, despite the pattern of inheritance through several generations.

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Figure 2. The index patient had normal but unpigmented skin.

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Samples of urine, faeces and blood from the index patient, her mother and her grandfather were sent for porphyrin analysis. The index patient's erythrocyte protoporphyrin concentration was high at 60.6 μmol/L (reference range 0.4–1.7 μmol/L), and it was also increased in the mother and grandfather. All three had a high proportion of zinc chelated to free protoporphyrin, suggestive of XLDPP in each case.

Sequencing of exon 11 of the gene encoding for 5-aminolaevulinic acid synthase 2 (ALAS2) on the X chromosome confirmed the diagnosis, as all three individuals carried an ALAS2 allele with one of the deletions (c.1706–1709 delAGTG, p.E569GfsX24) previously reported by Whatley et al. in 2008.[1] This mutation results in a frameshift affecting the 19–20 C-terminal residues of the ALAS enzyme, which significantly increases its activity.

All three individuals were prescribed reflectant sunscreen (Dundee Reflectant Sunscreen; Tayside Pharmaceuticals Ltd, Dundee, UK) for protection against visible light. The index patient was also referred for treatment with narrowband ultraviolet B (NB-UVB) 3 times/week for 4 weeks and then weekly for a further 12 weeks throughout the summer months, with the aim of improving her tolerance to sun exposure, although with little benefit. She was also referred to a hepatologist for liver monitoring.

XLDPP remains a very rare condition, with < 50 cases reported worldwide. Initial publications indicated a higher incidence of protoporphyrin-induced liver disease, but this has yet to be confirmed; however, it is not unreasonable to assume that the significantly higher levels of protoporphyrin IX that characterize XLDPP would lead to a significant increase in risk of liver disease. This raises the need for carefully designed research to quantify this risk and evaluate therapeutic interventions.

XLDPP is distinguished from EPP by higher concentrations of erythrocyte protoporphyrin (of which a high proportion is zinc-bound). In families with a positive history, individuals affected with XLDPP may be of either sex. Furthermore, the absence of father-to-son inheritance supports the diagnosis of XLDPP.

Treatment of the painful photosensitivity, mediated by the excess of protoporphyrin IX, is difficult. β-carotene was found to be no more effective than placebo in a randomized controlled trial (RCT),[3] and in practice, few patients with EPP find the treatment worthwhile.[4] NB-UVB has yet to be assessed formally in the treatment of EPP (or XLDPP), although anecdotal evidence suggests that it may be of benefit.[5, 6] Recent reports showing efficacy of subcutaneous, slow-release implants of a synthetic derivative of α-melanocyte-stimulating hormone show promise,[7] but this treatment remains unlicensed and unavailable for most patients. A recent report of oral zinc in the treatment of EPP is of interest,[8] but formal evaluation of this novel therapy in an RCT has yet to occur. Meanwhile, this treatment is cheap and freely available.

It is important for dermatologists to recognize and distinguish XLDPP from EPP, as the protoporphyrin levels are much lower than in EPP, which probably leads to more intense and severe photosensitivity, and to an increased risk of liver disease in the latter. Additionally, the genetic counselling required for XLDPP is different from EPP, a condition with which more than one sibling may be affected, but for which subsequent disease expression in further generations is unlikely (and easily predicted in affected individuals by testing their partner for the low-expression allele). By contrast, genetic counselling for XLDPP requires care and sensitivity, as the prognosis for the condition has yet to be clearly defined, and the chance of transmission to subsequent generations is much higher than for EPP.

Learning points
  •  XLDPP is a recently discovered porphyria.
  •  Clinical reports of XLDPP have to date been absent from the peer-reviewed dermatology literature.
  •  XLDPP presents with an identical clinical phenotype to EPP.
  •  In some patients, the diagnosis may be suggested by a family history with a dominant pattern and an absence of father-to-son transmission.
  •  XLDPP is caused by a gain-of-function mutation in the ALAS2 gene.
  •  XLDPP is distinguished from EPP by higher concentrations of erythrocyte protoporphyrin (of which a high proportion is zinc-bound).
  •  Treatment of XLDPP is along the same lines as EPP because of their biochemical and phenotypic similarities.

References

  1. Top of page
  2. Summary
  3. Report
  4. References