Cutaneous Porphyria Research Articles

Porphyria cutanea tarda in Scotland: underlying associations and treatment approaches.

Despite its rarity, porphyria cutanea tarda (PCT) is globally recognized as the most common form of cutaneous porphyria. This study aims to review the underlying associations and treatment of PCT in Scotland. We retrospectively reviewed data on 27 patients diagnosed with PCT between 1987 and 2022 at the Scottish Cutaneous Porphyria Service. Males slightly predominated (66.7%). The mean ± standard deviation (SD) age at diagnosis was 55.6 ± 12.5 years. Common associated factors were heavy alcohol intake (88.5%), genetic hemochromatosis (72%), smoking (45.5%), and hepatitis C virus infection (16%). Most had multiple associated factors (70.4%). Patients with genetic hemochromatosis with the C282Y genotype exhibited higher median transferrin saturation (69.5 vs. 35, P = 0.004) and ferritin levels (observed in males only) (1175 vs. 339; P = 0.014) than those with the H636D genotype. Most (52%) received combination therapy of venesection and antimalarials, followed by venesection monotherapy (32%) and antimalarial monotherapy (16%). Overall, 95.2% achieved biochemical improvement. Median time to improvement was 7, 5, and 9 months with venesection, antimalarial, and combined treatments, respectively (P = 0.173). Biochemical remission was achieved in 50% of patients. Remission occurred in 2/4 of patients with antimalarial monotherapy (median time 19 months) and 9/13 patients with combined treatment (median time 26 months). Biochemical relapse was found in three patients, all of whom received combination therapy. Excess alcohol intake and genetic hemochromatosis were the most common underlying associations with PCT in our Scottish cohort. Treatment for PCT should be individualized, and long-term follow-up is needed to monitor for disease relapse.

Liver transplantation and primary liver cancer in porphyria.

The porphyrias are a heterogeneous group of metabolic disorders that result from defects in heme synthesis. The metabolic defects are present in all cells, but symptoms are mainly cutaneous or related to neuropathy. The porphyrias are highly relevant to hepatologists since patients can present with symptoms and complications that require liver transplantation (LT), and some porphyrias are associated with a high risk for primary liver cancer (PLC). Among the cutaneous porphyrias, erythropoietic protoporphyria (EPP) can lead to cholestatic liver failure where LT cures the liver disease but not the porphyria. In acute porphyria (AP), neurotoxic porphyrin precursors are produced in the liver and LT is a curative treatment option in patients with recurrent severe neuropathic attacks. Patients with AP, mainly acute intermittent porphyria, have a significantly increased risk for PLC that warrants surveillance and adequate follow-up of high-risk groups. LT is well established in both EPP with liver failure and AP with recurrent attacks, but most transplant centres have little porphyria experience and cooperation between transplant hepatologists, and porphyria experts is important in the often-difficult decisions on timing and management of comorbid conditions.

SAT292 Adrenal Insufficiency Associated With Biallelic Mutations In Porphyria Genes

Abstract Disclosure: C. Smith: None. A. Jackson: None. A. Al-Salihi: None. A. Janecke: None. E. Steichen: None. D. Darby: None. L. Griffin: None. S. Banka: None. S. Elsayed: None. L. Chan: None. L. Metherell: None. Adrenal insufficiency (AI) is life-threatening and can present alone or in combination with other co-morbidities. Here we describe families with a novel association of AI with porphyria caused by biallelic mutations in protoporphyrinogen oxidase (PPOX) or coproporphyrinogen oxidase (CPOX). The porphyrias are a group of disorders caused by defects in one of eight enzymes within the haem biosynthetic pathway, divided into acute porphyrias, resulting in mainly neurovisceral symptoms, or cutaneous porphyrias, mainly affecting the skin. Acute porphyria attacks can be life-threatening, resulting in permanent disability or death. Variegate porphyria and hereditary coproporphyria are associated with autosomal dominant mutations in PPOX and CPOX respectively, with biallelic inheritance rarely reported and knockout mice that are embryonic lethal.We performed whole exome sequencing (WES), array Comparative Genomic Hybridization (aCGH) and whole genome sequencing (WGS) in 3 families with AI and variegate or hereditary porphyria. In kindred 1, with 4 affected individuals, WES revealed a homozygous mutation, p.Glu339Lys, in PPOX. aCGH and WGS revealed no Copy Number Variants (CNVs) and no other variants, in genes causing AI, common to all affected individuals. In families 2 and 3, homozygous mutations in CPOX p.(Pro367Ala) in one patient and p.(Ser28Ter) in two siblings were identified by WGS and WES respectively, with a clinical picture of AI and hereditary coproporphyria. Unlike other acute porphyria kindreds, the heterozygous parents were asymptomatic, manifesting neither porphyria nor AI, suggesting that the level of enzyme function is key for both phenotypes.Reduced PPOX/CPOX activity could cause AI through either; (i) a dearth of haem for steroidogenic CYP450 enzyme action, (ii) toxicity of intermediate porphyrins or (iii) increased oxidative stress. To investigate the mechanism, we first created H295R, human adrenocortical cells, with differing degrees of PPOX-knockdown (KD) by shRNA. Proliferation, measured by MTT assay or GFP accumulation, was lower in PPOX-KD cells at 72 hours and mitochondrial respiration was diminished, possibly due to toxicity of porphyrin precursors. CYP11A1 expression was unaltered whereas STAR and CYP17A1 were significantly lower in PPOX-KD cells. GSH/GSSG ratio, a marker of oxidative stress, was lower in KD cells suggesting increased ROS in these cells. Finally, and definitively, knockdown of at least 60% PPOX protein in H295R cells reduced cortisol output by 2.2-fold (p<0.01) at baseline and 1.9-fold (p<0.0001) in forskolin stimulated cells. Similar CPOX studies are underway.These studies show that cortisol is reduced in individuals with biallelic PPOX/CPOX mutations and, in conjunction with previous cases of AI in association with other genes in the pathway, suggests adrenal function should be monitored in individuals with porphyria. Presentation: Saturday, June 17, 2023

Porphyria: A metabolic disorder

Porphyrias are heterogenous group of metabolic disorders arising from defects in the heme biosynthetic pathway, each being characterized by a specific partial enzyme deficiency. Also, a flawed gene that control the action of enzyme in the heme synthesis creates a lack of heme and build up of porphyrin. Porphyria can be triggered by environmental factors such as; infections, cigarette smoking, antibiotics, etc. Porphyria can be classified into acute porphyria that causes neurological symptoms, and cutaneous porphyria that cause photosensitivity, affecting the skin. In cutaneous porphyria, the two distinct pattern of skin disease seen are the immediate photosensitivity and vesiculo-erosive skin disease. Symptoms include; abdominal pain, muscle weakness, hallucination, pain in the back or chest, burning pain on the skin, red or brown urine. Long term complication include paralysis, skin scarring, permanent hair loss, gall stones, breathing difficulties, dehydration. It can be diagnosed using blood, urine and stool samples, urine estimation of porphobilinogen is also done. Treatment of porphyria include; administration of heme arginate, regular blood removal, low doses of antimalarial drug, narrow band UVB therapy, avoidance of triggers. It can be prevented by avoiding factors that precipitate it such as; stress, fasting, infection, alcohol.

CD08 Double bubble trouble

Abstract A 29-year-old woman of Lithuanian heritage was referred to dermatology with a 3-year history of recurrent blistering to the hands and, occasionally, feet. The patient’s own photographs revealed small, tense blisters on the sides of her fingers and one on the foot. In the general dermatology clinic, she was noted to have acrylic nails, which she had been applying at home with her own gel nail kit for over 5 years. In recent years, the patient had noticed that use of the acrylic nail kit exacerbated her blistering. There was no prior history of skin disease or atopy. She was otherwise well, with no known allergies. She worked in the food-packing industry where she wore nonlatex gloves. In light of her frequent, prolonged use of acrylic nails and exacerbation of blistering on use of the home kit, she was suspected to have allergic contact dermatitis (ACD) to acrylates and was referred to the patch test clinic. Patch testing was performed to the British standard, facial, rubber and acrylate series. She had positive reactions to five different acrylates, confirming a clinical diagnosis of ACD relevant to her use of acrylic nails and gel polish. However, she was noted to have several unusual features. Clinically, she had small round scars on the dorsum of both hands. On questioning, she described scars occurring after each blister. Blisters occurred all year round but were significantly more frequent in the summer months. Exposure of her gel nails to ultraviolet (UV) light was felt to trigger the blistering. This prompted additional tests to investigate possible photosensitivity. Both urine and plasma porphyrin levels were significantly elevated, confirming cutaneous porphyria. This is an unusual case of a dual pathology causing blistering of the hands: ACD to acrylates and cutaneous porphyria. In most circumstances, it is ACD that is the overlooked diagnosis, but here, an important general medical diagnosis may have been missed. It is important to remember that blistering caused by gel nail kits may be multifactorial, with acrylates causing ACD and UV light possibly triggering cutaneous porphyria.

PD01 First UK report of pregnancy and childbirth in X-linked erythropoietic protoporphyria

Abstract X-linked erythropoietic protoporphyria (XLEPP), an exceptionally rare form of cutaneous porphyria, is characterized by significant acute painful photosensitivity and a risk of both reduced bone mineral density and protoporphyric hepatopathy that may progress to liver failure. Diagnosis requires demonstration of significantly elevated red cell total porphyrins consisting of both zinc and free protoporphyrin analysed on venous whole blood. As the condition is X-linked, any offspring of an affected woman has a 50% chance of inheriting the disease-causing ALAS2 gain-of-function mutation. There are no reported cases of pregnancy in XLEPP in the literature, and no published experience of managing newborn infants that may have inherited XLEPP who develop neonatal jaundice, which requires treatment with phototherapy. Here we describe the clinical course of a 29-year-old woman with XLEPP (part of a four-generation XLEPP family) and idiopathic thrombocytopenia during pregnancy—the first documented case in the UK, to our knowledge. A multiprofessional team considered the potential risks posed by XLEPP and idiopathic thrombocytopenia for the pregnancy, birth and newborn. Haematological and biochemical indices were monitored throughout the pregnancy. The mother experienced increased photosensitivity and worsening idiopathic thrombocytopenia during the pregnancy, the majority of which occurred over summer. Idiopathic thrombocytopenia did not respond to treatment with steroids and immunoglobulin, necessitating a general anaesthetic for the planned caesarean section. A male infant was born in good condition at term. Maternal blood loss was only just above average. The baby remained well in the immediate postnatal period. Although the baby did not require treatment for jaundice, management planned in advance included minimizing factors predisposing to jaundice, including optimal timing of cord clamping and early feed support, the urgent analysis of cord blood erythrocyte porphyrins within 24 h, using a light-emitting diode phototherapy device with narrow spectrum emission between 450 and 470 nm and minimal emission at 400 nm, monitoring the baby closely for signs of distress and skin changes, and considering adjustment of the phototherapy thresholds or using alternative treatments should jaundice occur. Cord blood erythrocyte total porphyrin results suggested the baby had inherited XLEPP and would be photosensitive. This was later confirmed by mutation analysis.

Systematic review of the prevalence and incidence of the photodermatoses with meta-analysis of the prevalence of polymorphic light eruption.

Information about the prevalence of photodermatoses is lacking, despite their substantial impact on life quality. Our objective was to systematically review the literature to establish what is known regarding prevalence and incidence of photodermatoses. We searched Medline, CINAHL and Embase from inception to 2021 to identify original population-based studies in English literature reporting the prevalence and/or incidence of photodermatoses. Information was extracted according to geographical location and risk of bias was assessed using a 10-point risk of bias tool for prevalence studies. Primary outcome was the population prevalence of photodermatoses. Prevalence data for polymorphic light eruption (PLE) were used to calculate the global pooled prevalence of PLE. Twenty-six studies were included; 15 reported prevalence of photodermatoses based on samples of the general population and 11 on prevalence and/or incidence from national and international registry data. The general population studies involved PLE (nine studies), unspecified photosensitivity (2), actinic prurigo (2), juvenile spring eruption (1), chronic actinic dermatitis (1) and variegate porphyria (1), while registry studies reported on cutaneous porphyrias and genophotodermatoses (nine and two studies, respectively). Worldwide the prevalence of PLE between countries ranged from 0.65% (China) to 21.4% (Ireland). The pooled estimated prevalence of PLE was 10% (95% CI 6%-15%) among the general population (n= 19,287), and PLE prevalence increased with distance from the equator (r= 0.78, p< 0.001). While several photodermatoses are rare, photosensitivity can be prevalent at wide-ranging world locations, including Egypt where photosensitivity was found in 4% of children and 10% of adults. This study showed that PLE is highly prevalent in many populations and that its prevalence shows a highly significant correlation with increasing northerly or southerly latitude. Available population-based studies for photodermatoses suggest they can be prevalent at a range of world locations; more attention is required to this area.

REFERRAL FOR SUN ALLERGY – A CASE OF ERYTHROPOIETIC PROTOPORPHYRIA

<h3>Introduction</h3> Erythropoietic protoporphyria (EPP) is an inherited cutaneous porphyria characterized by painful, non-blistering photosensitivity usually noted in early childhood and occurring acutely after sunlight exposure. Cutaneous lesions develop within minutes of sun exposure with diffuse edema of the skin in sun-exposed areas, resembling angioedema. EPP is now recognized as the most common porphyria in children and the third most common in adults. In the review of over 100 cases in the United States, the average delay diagnosis of EPP was 13 years. <h3>Case Description</h3> A 29-year-old female with a PMH of polyglandular autoimmune disease presented to the Allergy clinic as a referral for "Sun Allergy". The patient reported a near lifelong history of a photosensitive rash. The rash typically begins 10-20 minutes after sun exposure, sparing covered areas. The rash is described as burning/stinging in nature, a 10/10 on the pain scale. She additionally reported intermittent, small bullae in affected areas. She denied pruritus and urticaria. Patient denied recent NSAID and antibiotic use. She denied the use of topicals, including sunscreen. Patient has one full sibling with a similar clinical course. Patient denied history of substance use disorder. Porphyria became the leading differential diagnosis. Serum porphyrins with reflex porphyrins were obtained and indicated elevated total serum porphyrins with notable reflex indicating elevated protoporphyrins. The patient was diagnosed with Erythropoietic Porphyria and referred to Dermatology for further management. <h3>Discussion</h3> This case highlights the importance of including porphyrias in the differential diagnosis of photosensitive rashes, which may be referred to Allergy and Immunology clinics for evaluation.

Development and validation of diagnostic algorithms for the laboratory diagnosis of porphyrias.

Porphyrias are rare metabolic disorders of the haem synthesis. They can present with acute neurovisceral attacks, cutaneous symptoms, or a combination of both. As they present with a wide variety of clinical symptoms, diagnosis is often delayed and correct interpretation of porphyria-related tests remains a challenge for many physicians. We developed and validated two algorithms for the laboratory diagnosis of porphyrias based on presenting symptoms. Based on a literature search and clinical/laboratory expertise, we developed algorithms for acute and cutaneous porphyrias. We validated these algorithms using all porphyria related laboratory test requests between January 1st 2000 and September 30th 2020 in UZ Leuven. In addition, we also evaluated our algorithm using samples from the European porphyria network (EPNET) external quality assessment scheme (2010-2021). Sensitivity of the algorithm for acute porphyria was 100.0% [74.9%-100.0%] (13 acute intermittent porphyria (AIP) and 1 variegate porphyria [VP]) with a specificity of 98.5% [91.0%-100.0%] (65 patients). Sensitivity of the algorithm for cutaneous porphyria was 100% [95.1%-100.0%] (7 VP, 59 porphyria cutanea tarda (PCT), 23 erythropoietic protoporphyria (EPP), 2 X-linked erythropoietic protoporphyria [XLEPP]) with a specificity of 93.9% [82.9%-98.5%]. There were no diagnostic samples of other types of porphyria. The algorithms correctly identified 18 of the 19 EPNET porphyria cases. One of the two hereditary coproporphyria cases was missed. The algorithms for acute and cutaneous porphyria showed high sensitivity and specificity and can be used to aid the clinician in correctly interpreting the laboratory findings of porphyria-related tests.

Extrahepatic manifestations of chronic viral hepatitis C

Chronic viral diseases of the liver are frequently characterized by clinical signs of intrahepatic complications. Infection caused by the hepatitis C virus should be considered as a systemic disorder associated with the frequent development of various extrahepatic complications, such as cryoglobulinemia, glomerulopathy, lymphoproliferative diseases, seronegative arthritis, type 2 diabetes mellitus, lichen planus, and late cutaneous porphyria. Often, extrahepatic complications become the main features of the clinical disease picture, forcing patients to seek medical help from various specialists and delaying diagnosis. In some cases, the treatment of extrahepatic manifestations becomes an independent, complex task, surpassing the actual treatment of chronic hepatitis C. The relationship between hepatic and extrahepatic complications of viral hepatitis C is not linear; rather, extrahepatic manifestations often outstrip the development of liver damage. The effects of hepatitis C virus on the organs and systems of the body are caused by the direct action of the virus, pathogenetically induced by the development of steatosis/steatohepatitis, and by the disruption of system regulation of hepatokines and cytokines. Treatment of chronic hepatitis C virus infection should be comprehensive and should include antiviral therapy, treatment of metabolic-associated fatty liver disease and treatment of hepatic-related disorders. Antiviral therapy with preparations of direct antiviral action allows the prevention of not only liver complications but also of many extrahepatic complications of hepatitis C virus. Comorbid states significantly increase the natural progression of chronic hepatitis C infection and vice versa: the hepatitis C virus increases the clinical manifestations of co-pathology. In the age of direct antiviral drugs, it is possible to eliminate the hepatitis C virus, but in some cases, elimination alone does not arrest the progression of liver disease.

Endoscopic thyroidectomy to minimize light exposure of an erythropoietic protoporphyria patient: A case report

Introduction and importanceErythropoietic protoporphyria is a rare form of cutaneous porphyria that presents with photosensitivity. During surgery, light shielding is required to prevent acute attacks due to photosensitivity. In this study, we report a case of successful endoscopic thyroidectomy using video-assisted neck surgery (VANS) method for a thyroid tumor in a patient with erythropoietic protoporphyria.Case presentationA 32-year-old woman with a history of erythropoietic protoporphyria and an enlarged left thyroid gland was referred to our hospital. The referring physician had noted a left lobe tumor of the thyroid gland with a maximum diameter of 5 cm. Computed tomography and ultrasonography showed the tumor shape as smooth and well-defined. A lobectomy of the thyroid gland was performed using the VANS method through a 3-cm incision on the skin. Surgical light was not used and exposure to ambient light was minimized by covering the patient's neck with a drape. No acute attack of porphyria or photosensitivity was observed during the surgery or the follow-up. Postoperative complications such as asphyxia, blood loss, or nerve palsy were absent. The patient was discharged 5 days after the surgery.Clinical discussionWhile the VANS method is known to have mainly cosmetic advantages, this case demonstrates that it is also a method that can minimize the exposure of the patient's skin to light with using an additional drape.ConclusionThe VANS method should be considered as an option for thyroidectomy in patients with protoporphyria because it can reduce the exposure to light during surgery.

Porphyrias in the Age of Targeted Therapies.

The porphyrias are a group of eight rare genetic disorders, each caused by the deficiency of one of the enzymes in the heme biosynthetic pathway, resulting in the excess accumulation of heme precursors and porphyrins. Depending on the tissue site as well as the chemical characteristics of the accumulating substances, the clinical features of different porphyrias vary substantially. Heme precursors are neurotoxic, and their accumulation results in acute hepatic porphyria, while porphyrins are photoactive, and excess amounts cause cutaneous porphyrias, which present with photosensitivity. These disorders are clinically heterogeneous but can result in severe clinical manifestations, long-term complications and a significantly diminished quality of life. Medical management consists mostly of the avoidance of triggering factors and symptomatic treatment. With an improved understanding of the underlying pathophysiology and disease mechanisms, new treatment approaches have become available, which address the underlying defects at a molecular or cellular level, and promise significant improvement, symptom prevention and more effective treatment of acute and chronic disease manifestations.

“They Won’t Let Me Return to Work.” A Carpenter Diagnosed with Porphyria Cutanea Tarda

Porphyria cutanea tarda (PCT) is characterized by a skin blistering eruption that develops in sun exposed areas of the skin. It is the most common cutaneous porphyria world-wide, and classically associated with hepatic injury but also estrogen use, cigarette smoking, and HIV. In any case of photodistributed persistent blistering skin condition, PCT must be high on the differential. This case of a carpenter diagnosed with PCT not only illustrates a classic case but also the opportunity to achieve significant response to therapy in a motivated patient particularly with improved access to direct-acting antivirals (DAA) for hepatitis C treatment.

Clinical features of genetic cutaneous porphyrias in Israel: A nationwide survey.

There are three major types of genetic cutaneous porphyrias (GCP): erythropoietic protoporphyria (EPP), variegate porphyria (VP), and hereditary coproporphyria (HCP). Scarce data are available regarding their impact on patients' quality of life in the Mediterranean region. To describe the cutaneous features of GCP in Israel. An established nationwide cohort of patients with GCP diagnosed during 1988-2019 was surveyed by telephone for cutaneous features of GCP. Impact on quality of life was assessed using the Dermatology Life Quality Index. Of the 95 patients with GCP, 71 (75%) completed the survey (21 HCP; 40 VP; 10 EPP). All EPP patients reported cutaneous symptoms compared with 58% of VP and 5% of HCP (P<.001). Mean age at symptom onset was 7±6years in EPP and 25±15years in VP (P<.001). Photosensitivity was the most common symptom in EPP (90%). In VP photosensitivity (52%), blistering (52%) and scarring (74%) were all common symptoms. In both VP and EPP, the dorsal hands/forearms were the most affected regions (≥96%), and in≥78%, symptoms occurred on an almost daily basis. All EPP patients changed their lifestyle due to cutaneous symptoms vs 57% in VP. Major effect on quality of life was observed among EPP patients compared with a moderate effect in VP. No treatment was effective in EPP, while phototherapy and moisturizers were effective in 5 of 7 (71%) VP patients. This study sheds light on the cutaneous features of the GCP, which have a substantial effect on patients' quality of life.

Photoprotection against visible light: Implications for clinical practice.

We read with interest the case report of a patient with solar urticaria exacerbated by visible light (VL) published by Wright and colleagues.1 Dermatologists often highlight the importance of the use of sunblock with sun protection factor against ultraviolet A and B rays, yet many sunblocks fail to protect against VL. There is enough evidence at present to highlight the harmful effects of VL and its implication upon several photodermatoses including chronic actinic dermatitis, cutaneous porphyrias and solar urticaria, in addition to hyperpigmentary disorders.2.

Neuropsychiatric Manifestations of Acute Intermittent Porphyria – A Diagnostic Dilemma

Porphyrias are a group of inherited or acquired disorders of certain enzymes in the heme bio-synthetic pathway (also called porphyrin pathway). They are broadly classified as acute (hepatic) porphyrias and cutaneous (erythropoietic) porphyrias, based on the site of the overproduction and accumulation of the porphyrins or their chemical precursors. They manifest with either neuropsychiatric complications or skin problems or occasionally both. A clinically induced and histologically identical condition is called pseudo porphyria which is characterized by normal serum and urine porphyrin levels.

Variegate Porphyria Triggered by Acute Hepatitis A Infection.

BackgroundVariegate porphyria (VP) is a rare disorder of haem biosynthesis. We report a novel association with hepatitis A infection.Patient and methodsA 31-year-old man was diagnosed with acute hepatitis A infection. During recovery, he presented with abdominal pain and a photoaggravated blistering skin eruption.ResultsUrine porphyrin precursors were markedly raised with high coproporphyrin III isomer levels. Faecal protoporphyrin levels were markedly increased and a maximum plasma fluorescence emission at 629 nm was noted.DiscussionAcute hepatitis A infection, and the associated metabolic stress exerted on the haem biosynthetic pathway, induced overt presentation of latent VP.LEARNING POINTSThere should be a high index of suspicion for an acute cutaneous porphyria when a photosensitive rash is accompanied by neurovisceral symptoms.Latent porphyria may be overtly manifested after appropriate triggers which stress the metabolic haem biosynthetic pathway. One such trigger demonstrated by this case presentation is acute hepatitis A infection.The diagnostic approach to the investigation of a suspected acute cutaneous porphyria is initially with light-protected samples for urinary porphyrin precursors and plasma for fluorescence scanning. These should be sampled ideally during symptomatic periods. Further specialist analysis with fractionation of urinary and faecal porphyrins is necessary to distinguish between the two different acute cutaneous porphyrias.

Epidemiology of cutaneous porphyria in Israel: a nationwide cohort study.

From a dermatologist's perspective, there are four major types of cutaneous porphyrias (CPs): porphyria cutanea tarda (PCT), erythropoietic protoporphyria (EPP), variegate porphyria (VP) and hereditary coproporphyria (HCP). Scarce data are available regarding the epidemiology of CPs. To describe the epidemiology of CPs in Israel, including distribution, incidence and prevalence rates of major types. This retrospective study includes all patients who were diagnosed with CPs between the years 1988-2018. It is based on data from Israel's National Service for the Biochemical Diagnoses of Porphyrias, and Israeli patients' nationwide electronic medical charts. Incidence and prevalence rates were calculated. Of 173 patients with CPs diagnosed during a 30-year period, 65 (38%) had VP, 62 (36%) had PCT, 31 (18%) had HCP and 15 (9%) had EPP; with incidence rates of 0.29, 0.30, 0.17, 0.07, and prevalence rates of 6.3, 4.8, 2.9, 1.6, respectively, per million population. Characteristics of patients with PCT differed from those with other CPs with regard to lack of family history, older mean age at diagnosis [51 vs. 36 (VP), 35 (HCP) and 25 (EPP) years] and male predominance (81% vs. similar distribution). All patients with PCT were diagnosed at adulthood, while 20%, 19% and 15% of patients with VP, HCP and EPP, respectively, were diagnosed during childhood or adolescence. Variegate porphyria and PCT were found to be the most prevalent in Israel; however, CPs might be underdiagnosed, thus dermatologists' awareness of these rare disorders is highly important.

Porphyries cutanées

The porphyrias are a group of metabolic disorders resulting from an innate abnormality in haem biosynthesis, and the clinical settings of which vary according to the genetic enzyme abnormality in question. These are genetic disorders with autosomal dominant or recessive inheritance of varying penetrance, and whose clinical expression differs according to the preferential location of haem precursors. Different classifications have been proposed according to genetic inheritance, the enzyme anomaly at issue, and clinical expression. The clinical classification distinguishes between acute porphyria (acute intermittent porphyria, porphyria variegata, hereditary coproporphyria), bullous cutaneous porphyrias (porphyria cutanea tarda, porphyria variegata and hereditary coproporphyria), painful photosensitive acute cutaneous porphyrias (erythropoietic protoporphyria and X-linked dominant protoporphyria), and rare recessive porphyrias (congenital erythropoietic porphyria, Doss porphyria, hepatoerythropoietic porphyria and harderoporphyria). Treatment depends on the clinical expression of the disorder.

Porphyria cutanea tarda and hepatoerythropoietic porphyria: Identification of 19 novel uroporphyrinogen III decarboxylase mutations

Porphyria Cutanea Tarda (PCT) is a cutaneous porphyria that results from the hepatic inhibition of the heme biosynthetic enzyme uroporphyrinogen decarboxylase (UROD), and can occur either in the absence or presence of an inherited heterozygous UROD mutation (PCT subtypes 1 and 2, respectively). A heterozygous UROD mutation causes half-normal levels of UROD activity systemically, which is a susceptibility factor but is not sufficient alone to cause type 2 PCT. In both Types 1 and 2 PCT, the cutaneous manifestations are precipitated by additional factors that lead to generation of an inhibitor that more profoundly reduces hepatic UROD activity. PCT is an iron-related disorder, and many of its known susceptibility factors, which include infections (e.g. hepatitis C virus, HIV), high alcohol consumption, smoking, estrogens, and genetic traits (e.g. hemochromatosis mutations) can increase hepatic iron accumulation. Hepatoerythropoietic Porphyria (HEP) is a rare autosomal recessive disease that results from homozygosity or compound heterozygosity for UROD mutations and often causes infantile or childhood onset of both erythropoietic and cutaneous manifestations.During the 11-year period from 01/01/2007 through 12/31/2017, the Mount Sinai Porphyrias Diagnostic Laboratory provided molecular diagnostic testing for 387 unrelated patients with PCT and four unrelated patients with HEP. Of the 387 unrelated individuals tested for Type 2 PCT, 79 (20%) were heterozygous for UROD mutations. Among 26 family members of mutation-positive PCT patients, eight (31%) had the respective family mutation. Additionally, of the four unrelated HEP patients referred for UROD mutation analyses, all had homozygosity or compound heterozygosity for UROD mutations, and all eight asymptomatic family members were heterozygotes for UROD mutations. Of the UROD mutations identified, 19 were novel, including nine missense, two nonsense, one consensus splice-site, and seven insertions and deletions. These results expand the molecular heterogeneity of PCT and HEP by adding a total of 19 novel UROD mutations. Moreover, the results document the usefulness of molecular testing to confirm a genetic susceptibility trait in Type 2 PCT, confirm a diagnosis in HEP, and identify heterozygous family members.