Validation of a novel patient reported tool to assess the impact of treatment in erythropoietic protoporphyria: the EPP-QoL.

BACKGROUND: A novel treatment has been developed for erythropoietic protoporphyria (EPP) (a rare condition that leaves patients highly sensitive to light). To fully understand the burden of EPP and the benefit of treatment, a novel patient reported outcome (PRO) measure was developed called the EPP-QoL. This report describes work to support the validation of this measure. METHODS: Secondary analysis of trial data was undertaken. These analyses explored the underlying factor structure of the measure. This supported the deletion of some items. Further work then explored the reliability of these factors, their construct validity and estimates of meaningful change. RESULTS: The factor analyses indicated that the items could be summarised in terms of two factors. One of these was labelled EPP Symptoms and the other EPP Wellbeing, based on the items included in the domain. EPP Symptoms had evidence to support its reliability and validity. EPP Wellbeing had poor psychometric properties. CONCLUSIONS: Based on the analysis it was recommended to drop the EPP Wellbeing domain (and associated items). EPP Symptoms, despite limitations in the development of items, showed evidence of validity. This work is consistent with the recommendations of a task force that provided recommendations regarding the development, modification and use of PROs in rare diseases.

[Diagnosis of the porphyrias : From A (as in aminolevulinic acid) to Z (as in zinc protoporphyrin)]. / Diagnostik der Porphyrien : Von A (wie Aminolävulinsäure) bis Z (wie Zink-Protoporphyrin).

The porphyrias comprise a clinically, biochemically, and genetically heterogeneous group of predominantly hereditary metabolic disorders resulting from a dysfunction along the heme biosynthetic pathway. Whereas most variants can manifest with different cutaneous symptoms, some types only reveal life-threatening acute neurovisceral attacks. Therefore, interdisciplinary care of these patients is advisable. In this article, we provide an overview of characteristic clinical and laboratory findings in the various forms of porphyria and a diagnostic algorithm.

[Congenital erythropoietic porphyria : An update]. / Kongenitale erythropoetische Porphyrie : Ein Update.

BACKGROUND: Congenital erythropoetic porphria is a very rare type of autosomal recessive nonacute porphyria. Homozygous or compound heterozygous mutations in the uroporphyrinogen III consynthase gene cause a marked enzymatic deficiency of uroporphyrinogen III consynthase, the fourth enzyme along the heme biosynthetic pathway. CLINICAL PRESENTATION: Clinically, affected patients are characterized by a moderate to severe photosensitivity. Starting early in infancy, they develop blisters, erosions, and exulcerations in sun-exposed areas of the body, often resulting in scar formation and mutilation. Besides the cutaneous changes, hemolytic anemia, transfusion-dependent pancytopenia, hepatosplenomegaly and liver cirrhosis can occur. Due to increased susceptibility for infections and because of the hematological and hepatic complications, affected individuals have a decreased life expectancy, rarely exceeding 40 years of age. TREATMENT: Currently, no causal treatment is available for the disorder. Therefore, the most important therapeutic modality is strict avoidance of sunlight, preferably by inversion of the day-night rhythm, or at least consequent photoprotection with adequate clothing. In severe cases, bone marrow or stem cell transplantation should be considered.

[Erythropoietic protoporphyria : Clinical manifestations, diagnosis and new therapeutic possibilities]. / Erythropoetische Protoporphyrie : Klinik, Diagnostik und neue therapeutische Möglichkeiten.

BACKGROUND: Erythropoietic protoporphyria, the second most common type of the cutaneous porphyrias, is due to an enzymatic deficiency of ferrochelatase, the last enzyme in heme biosynthesis. The enzyme defect leads to an accumulation of protoporphyrin IX in erythrocytes and an elevated excretion of this metabolite in the feces. CLINICAL PRESENTATION: Usually, disease onset is in early infancy, characterized by increased photosensitivity. During or shortly after sunlight exposure, affected individuals suffer from burning, stinging, itching, and pain in sun-exposed skin areas. These symptoms lead to a considerably reduced quality of life and strict avoidance of sunlight exposure. Subacute symptoms include visible changes like edema and erythema. In the further course of the disease, chronic signs such as lichenification and scarring may occur. A severe complication of hepatic protoporphyrin IX accumulation is the development of a potentially life-threatening fulminant liver failure. Therefore, hepatic laboratory tests and ultrasound of the liver should be performed regularly. THERAPY: Traditionally, therapy merely consisted of consequent photoprotection and orally administered ß-carotene. A novel treatment option is afamelanotide (Scenesse®), a synthetic analogue of the naturally occurring α-melanocyte stimulating hormone. Afamelanotide, administered as a subcutaneous implant, induces eumelanin production, independent of preceding UV light exposure. This may enable patients with erythropoietic protoporphyria to stay in sunlight significantly longer than previously possible without complaints, thus, substantially improving quality of life.

Phototoxicity of narrowband ultraviolet (UV) B (311 nm) compared with broadband UVB in the photo hen's egg test.

BACKGROUND: Broadband ultraviolet B (BB-UVB) is a well-established treatment option in dermatology. However, during the last decade BB-UVB has increasingly been replaced by narrowband UVB 311 nm (NB-UVB), especially in the therapy of psoriasis, atopic eczema and vitiligo. Several studies have indicated a better therapeutic response for almost all indications compared with BB-UVB. OBJECTIVES: The aim of our study was to investigate the phototoxic effects of NB-UVB in comparison with BB-UVB in vivo. METHODS: Therefore, we employed the photo hen's egg test (PHET), an established phototoxic model, based on the yolk sac blood vessel system of incubated hen's eggs. NB-UVB and BB-UVB dosages increasing from 30 up to 1200 mJ cm(-2) were applied on 17 test groups (each n = 12 eggs) and two unirradiated test groups served as controls. Twenty-four hours after irradiation we observed the following test parameters: lethality, membrane discoloration and haemorrhages. RESULTS: Following our results, the lethal half dose (LD50) was 60 and 720 mJ cm(-2) for BB-UVB and NB-UVB, respectively. These LD50 dosages provoked severe membrane discoloration and haemorrhaging. Summarizing our results, the LD50 of NB-UVB was 12-fold higher than BB-UVB. CONCLUSIONS: Interestingly, these findings are in good accordance with the literature, where the minimal erythema dose (MED) of NB-UVB in human skin is up to 14 times higher than the MED of BB-UVB. These results show that the PHET is a valid test model to evaluate the phototoxic effects of various UVB wavelengths. Moreover, our results indicate that regarding the investigation of phototoxic effects the PHET might serve as a model representative for human skin, which might reduce the extent of photoprovocation in humans in the future.

[Porphyria cutanea tarda with sclerodermatous changes and hemochromatosis]. / Porphyria cutanea tarda mit sklerodermiformen Veränderungen und Hämochromatose.

A 55-year-old woman presented with blistering on the back of her hands and shiny, thickened skin in her décolletage. Laboratory examination revealed increased urinary total and high carboxylated porphyrins and homozygosity for mutation C282Y in the HFE gene. Histopathology showed thickened collagen fibers in the presternal region. Based on these findings we made the diagnosis of porphyria cutanea tarda with pseudoscleroderma and hemochromatosis. Pseudoscleroderma is a rare complication of PCT but can also constitute the first cutaneous symptom of the disease, leading the way to diagnosis. Usually, adequate treatment of PCT with normalization of porphyrin values also results in improvement of pseudoscleroderma.

[Phototoxic and photoallergic reactions]. / Phototoxische und photoallergische reaktionen.

Many artificial or naturally occurring substances are included under the term photosensitizer. After ultraviolet (UV) exposure such agents can lead to increased photosensitivity and subsequently to phototoxic or photoallergic reactions in the skin. From clinical observations and comprehensive studies typical reaction patterns can be deduced which can clarify the difference between phototoxic and photoallergic dermatitis.An illuminated epicutaneous test based on conventional epicutaneous tests, the photopatch test, was developed as a screening method for identification of photosensitizers. The diagnostic specificity and sensitivity of the test is comparable to conventional epicutaneous testing. If possible photosensitizers do not cause any relevant reactions with the photopatch test, other test procedures, such as the photoprick, photoscratch and illuminated intracutaneous tests are available. If the actual photosensitizer is not the test substance but a metabolite of the test substance, a systemic photoprovocation test can be indicated.

[Intracavernous injection: a treatment modality for erectile dysfunction]. / Schwellkörperinjektionstherapie bei erektiler Dysfunktion.

A 56-year-old man presented with a 12-year history of erectile dysfunction, which caused him extreme distress with episodes of depression. Attempts with sildenafil did not improve his erections. We tried intracavernous injection of alprostadil which enabled the patient to achieve a moderate erection. Thus, we instructed the patient for self-injection, which led to sufficient erections over the following months. We then restarted with tadalafil as a monotherapy which then was successful.

[Kallmann syndrome]. / Kallmann-Syndrom.

The Kallmann syndrome is a very rare congenital association of gonadotropin-releasing hormone deficiency and hyposmia or anosmia. Clinically it is characterized by low serum concentrations of testosterone and inadequate low levels of luteinizing hormone and follicle-stimulating hormone as well as incomplete sexual maturation, lack of secondary sexual features (facial and body hair growth, deepening of the voice), micropenis and sometimes even cryptorchidism. The reduced or absent sense of smell is typical for the Kallmann syndrome and distinguishes this syndrome from other causes of hypogonadotropic hypogonadism. Additional findings may include synkinesia, hearing loss, unilateral renal aplasia, brachy- or syndactyly, agenesis of corpus callosum, cleft palate and dental agenesis. A 19-year-old man presented to our male infertility clinic with delayed sexual maturation, eunuchoid habitus, micropenis, cryptorchidism, erectile dysfunction and absence of ejaculation, anemia and osteoporosis as well as low serum concentrations of luteinizing hormone, follicle-stimulating hormone and testosterone in combination with hyposmia.

[Scleredema diabeticorum: successful treatment with UVA-1 phototherapy]. / Scleroedema diabeticorum : Erfolgreiche Behandlung mit UV-A1-Phototherapie.

Scleredema adultorum is characterized by induration of the skin on the neck, shoulders and upper back caused by increased accumulation of collagen and aminoglycans in the dermis. The induration may progress and lead to pronounced restriction of mobility. Scleredema diabeticorum is one type of scleredema adultorum associated with diabetes mellitus. Multiple therapies have been tried, but most of them have not proven to be consistently effective. We report two cases of scleredema diabeticorum treated successfully with UVA-1- as well as physiotherapy and topical corticosteroids; this approach led to improvement in skin changes and mobility.

[Solarium-induced pseudoporphyria and variegate porphyria as rare differential diagnoses of porphyria cutanea tarda]. / Solariuminduzierte Pseudoporphyrie und Porphyria variegata als seltene Differenzialdiagnosen der Porphyria cutanea tarda.

Three patients presented with typical porphyria cutanea tarda-like vesicles, erosions and scars as well as increased fragility, primarily on the back of the hands. In two of the three, porphyrin workup was normal. Skin biopsy was compatible with porphyria cutanea tarda (PCT) or pseudoporphyria. The common aspect in the patients' history was the frequent use of solaria for many years, so that UV-induced pseudoporphyria was diagnosed. Treatment was strict abstention from UV radiation and regular dermatologic controls for signs of skin damage. Porphyrin analysis in the third patient showed normal excretion of total urine porphyrins and precursors; however, fecal porphyrins were elevated with dominating coproporphyrins in HPLC and the plasma fluorescence scan yielded a peak at 625 nm. Subsequent mutation analysis showed a mutation in the protoporphyrinogen oxidase gene, thereby confirming the diagnosis of variegate porphyria. Five months after the initial diagnosis the patient presented with the first acute attack. Further investigations revealed a metastasized carcinoma of the colon, which probably triggered the acute attack. Our cases show rare differential diagnoses in patients presenting with typical PCT-like skin lesions. The discrimination between porphyria cutanea tarda and its differential diagnoses is very important since it has an important impact not only on the treatment modality but also on the course and the prognosis of the disease.

Neurofibromatosis.

Neurofibromatosis (NF) is one of the most common genetic disorders. Inherited in an autosomal dominant fashion, this phacomatosis is classified into two genetically distinct subtypes characterized by multiple cutaneous lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1 (NF1), also referred to as Recklinghausen's disease, affects about 1 in 3500 individuals and presents with a variety of characteristic abnormalities of the skin and the peripheral nervous system. Neurofibromatosis type 2 (NF2), previously termed central neurofibromatosis, is much more rare occurring in less than 1 in 25 000 individuals. Often first clinical signs of NF2 become apparent in the late teens with a sudden loss of hearing due to the development of bi- or unilateral vestibular schwannomas. In addition NF2 patients may suffer from further nervous tissue tumors such as meningiomas or gliomas. This review summarizes the characteristic features of the two forms of NF and outlines commonalities and distinctions between NF1 and NF2.

[Considerable variation in the range of time for complications to appear after tattoos]. / Erhebliche zeitliche Variationsbreite von Komplikationen nach Tätowierungen.

Side effects after tattoos are being observed with greater frequency in dermatological practice. The complications that occur can be classified into systemic and local reactions. The time course of cutaneous side effects ranges from direct complications during or following tattooing to reactions that first appear several years thereafter. The majority of allergic complications can be explained by the delayed degradation of the color pigment used for the tattoo and then release of potent allergens sometimes not until years later.