Summary of the Dutch S3-guidelines on the treatment of psoriasis 2011. Dutch Society of Dermatology and Venereology.

This document provides a summary of the Dutch S3-guidelines on the treatment of psoriasis. These guidelines were finalized in December 2011 and contain unique chapters on the treatment of psoriasis of the face and flexures, childhood psoriasis as well as the patient's perspective on treatment. They also cover the topical treatment of psoriasis, photo(chemo)therapy, conventional systemic therapy and biological therapy.

[Genetic hair diseases. An update]. / Genetisch bedingte Haarerkrankungen. Ein Update.

Patients suffering from hair loss or undesirable excessive hair growth are a challenge for dermatologists because the pathogenesis of most hair diseases is not well understood and therapeutic options are limited. This particularly holds true for genetic hair disorders, in which all current treatment attempts are unsuccessful. Furthermore, these diseases also pose a diagnostic challenge due to a broad range of clinical and genetic heterogeneity. However, the enormous progress in molecular biology over the past 20 years, in particular the availability of different new techniques such as whole exome and genome sequencing, has enabled us to elucidate the genetic basis of most monogenic hair disorders, given the availability of suitable index patients and families as well as adequate technical equipment and sufficient financial resources. In this review we provide an update on clinical and genetic aspects of selected monogenic and polygenic hair diseases manifesting with hypertrichosis and hypotrichosis.

Extended haplotype studies in South African and Dutch variegate porphyria families carrying the recurrent p.R59W mutation confirm a common ancestry.

BACKGROUND: Variegate porphyria (VP) is due to a partial deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in the haem biosynthetic pathway. Clinically, VP is characterized by photosensitivity and acute neurovisceral attacks that can manifest separately or together in affected individuals. The disease is inherited in an autosomal dominant fashion with incomplete penetrance and PPOX gene mutations associated with VP are usually unique to patients and their families. In South Africa, however, VP is highly prevalent as the result of a founder mutation, designated p.R59W. Previous genealogical and haplotype studies showed a link between South African and Dutch carriers of p.R59W and it was suggested that this mutation was introduced to South Africa by Dutch settlers at the end of the 17th century. OBJECTIVES: To perform extended haplotype analysis in six South African and Dutch VP families with the p.R59W mutation. METHODS: Haplotyping of 13 microsatellite markers flanking the PPOX gene on chromosome 1q22-23 and five informative single nucleotide polymorphisms within and around the gene. RESULTS: A core haplotype cosegregated in all families studied. CONCLUSIONS: Our data deliver further confirmation that the South African and Dutch VP families carrying mutation p.R59W shared a common ancestor.

[Hereditary metabolic diseases with cutaneous manifestations : An update]. / Hereditäre Stoffwechselerkrankungen mit kutaner Manifestation : Ein Update.

Hereditary metabolic diseases are very diverse with variable pathogenetic mechanisms and clinical findings. They can manifest in different organs and, in this respect, dermatologists may play a crucial role in making the right diagnosis if they know to interpret the signs on the skin correctly. Although these are usually rare diseases, the elucidation of the underlying genetic defects has delivered an invaluable contribution to the better pathogenetic understanding of several common diseases over the last years. This is mainly attributable to the fact that the proteins encoded by these genes are often key players within important metabolic signaling pathways of the human organism. We report on new developments in the field of selected porphyria types, hereditary angioedema, pseudoxanthoma elasticum, and hereditary cutaneous leiomyomatosis, all of which constitute a challenge for both dermatologists and other specialists.

The porphyrias: clinic, diagnostics, novel investigative tools and evolving molecular therapeutic strategies.

The porphyrias are clinically and genetically heterogeneous metabolic disorders resulting from a predominantly hereditary dysfunction of specific enzymes involved in heme biosynthesis. Today, the clinical, biochemical, and genetic characteristics of this fascinating group of diseases are well established. Recently, different in vitro and animal models have facilitated the investigation of etiopathologic mechanisms in the different types of porphyria and the development of causal treatment strategies such as pathway interference, enzyme replacement, and gene therapy. The continuous progress in basic science has made an invaluable contribution to the rapid translation of discoveries made in the laboratory into new diagnostics and therapeutics in the near future.

Identification and characterization of HMBS gene mutations in Spanish patients with acute intermittent porphyria.

Acute intermittent porphyria (AIP), the most common acute hepatic porphyria, is an autosomal dominant disorder with low penetrance that results from a partial deficiency of hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway. The disease is clinically characterized by acute neurovisceral attacks that are precipitated by several factors including certain drugs, steroid hormones, alcohol and fasting. Early diagnosis and counselling are essential to prevent attacks, being mutation analysis the most reliable method to identify asymptomatic carriers in AIP families. In this study we have investigated the molecular defect in 15 unrelated Spanish AIP patients. Mutation analysis of the HMBS gene revealed a total of fourteen mutations including six novel ones, two of them were on the same allele in one patient. The novel mutations were three missense (R26L, R173G and D178H), two frameshift (c.749_765dup and c.874insC) and one intronic deletion (IVS12+3_+11delAGGGCCTGT). RT-PCR and sequencing demonstrated that the intronic mutation caused abnormal splicing and exon 12 skipping. Prokaryotic expression of the novel missense mutations showed that only D178H had significant residual activity. These findings will facilitate the accurate identification of presymptomatic AIP carriers in these families and they further emphasize the molecular heterogeneity of AIP in Spain.

Identification of a recurrent mutation in the protoporphyrinogen oxidase gene in Swiss patients with variegate porphyria: clinical and genetic implications.

Variegate porphyria (VP), one of the acute hepatic porphyrias, results from an autosomal dominantly inherited deficiency of protoporphyrinogen oxidase (PPOX), the seventh enzyme in heme biosynthesis. Affected individuals can develop both cutaneous symptoms and potentially life-threatening neurovisceral attacks. Thirty unrelated VP index patients and families are currently known in the Swiss Porphyrin Reference Laboratory in Zürich. In 16 of a total of 24 genetically tested families, we detected a recurrent mutation in the PPOX gene, designated 1082-1083insC, reflecting a prevalence of 67%. Haplotype analysis revealed that 1082-1083insC arose on a common genetic background and, thus, represents a novel founder mutation in the Swiss population. Knowledge on the carrier status within a family does not only allow for adequate genetic counseling but also for prevention of the potentially life-threatening acute porphyric attacks. Hence, future molecular screening in Swiss VP patients might be facilitated by first seeking for mutation 1082-1083insC.

Nodular vasculitis in systemic lupus erythematosus.

A 42-year-old man presented with fever, photosensitivity, headaches, myalgia, hyperhidrosis, muscle weakness, alopecia, nasal crustae, weight loss, painful nails, arthritis, oral ulcers, erythema, discoid cutaneous lesions, and painful subcutaneous nodes. We made a diagnosis of systemic lupus erythematosus (SLE), type II cryoglobulinemia, and nodular vasculitis. In the skin, different types of vasculitis may be observed. Typically, histology shows leukocytoclastic vasculitis of superficial vessels both in SLE and mixed cryoglobulinemia, which clinically results in palpable purpura. In our patient, however, histopathological examination of the subcutaneous nodes not only revealed leukocytoclastic vasculitis of the superficial vasculature but also showed even more extensive involvement of dermal and subdermal small and medium sized vessels, giving rise to a nodular vasculitis.

Molecular heterogeneity of familial porphyria cutanea tarda in Spain: characterization of 10 novel mutations in the UROD gene.

BACKGROUND: Porphyria cutanea tarda (PCT) results from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. In the majority of patients, the disease is sporadic (S-PCT or type I) and the enzyme deficiency is limited to the liver. Familial PCT (F-PCT or type II) is observed in 20-30% of patients in whom mutations on one allele of the UROD gene reduce UROD activity by approximately 50% in all tissues. Another variant of PCT (type III) is characterized by family history of the disease although it is biochemically indistinguishable from S-PCT. OBJECTIVES: To investigate the molecular basis of PCT in Spain and to compare enzymatic and molecular analysis for the identification of patients with F-PCT. METHODS: Erythrocyte UROD activity measurement and mutation analysis of the UROD gene were carried out in a cohort of 61 unrelated Spanish patients with PCT and 50 control individuals. Furthermore, each novel missense mutation identified was characterized by prokaryotic expression studies. RESULTS: Of these 61 patients, 40 (66%) were classified as having S-PCT, 16 (26%) as having F-PCT and five (8%) as having type III PCT. Discordant results between enzymatic and molecular analysis were observed in two patients with F-PCT. In total, 14 distinct mutations were found, including 10 novel mutations: five missense, one nonsense, three deletions and an insertion. Prokaryotic expression of the novel missense mutations demonstrated that each results in decreased enzyme activity or stability. CONCLUSIONS: These results confirm the high degree of molecular heterogeneity of F-PCT in Spain and emphasize the usefulness of molecular genetic analysis to distinguish between F-PCT and S-PCT.

[From gene to disease; cutaneous leiomyomatosis]. / Van gen naar ziekte; leiomyomatosis cutis.

Multiple cutaneous and uterine leiomyomatosis (MCUL; OMIM 150800) is an autosomal dominantly inherited disease characterized by leiomyomas of the skin and uterine leiomyomas. MCUL can be associated with various types of renal cancer. This syndrome is known as hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839). Both disorders result from heterozygous germline mutations in the fumarate hydratase (FH) gene.

Mutations in the gene encoding the Wnt-signaling component R-spondin 4 (RSPO4) cause autosomal recessive anonychia.

Anonychia is an autosomal recessive disorder characterized by the congenital absence of finger- and toenails. In a large German nonconsanguineous family with four affected and five unaffected siblings with isolated total congenital anonychia, we performed genomewide mapping and showed linkage to 20p13. Analysis of the RSPO4 gene within this interval revealed a frameshift and a nonconservative missense mutation in exon 2 affecting the highly conserved first furin-like cysteine-rich domain. Both mutations were not present among controls and were shown to segregate with the disease phenotype. RSPO4 is a member of the recently described R-spondin family of secreted proteins that play a major role in activating the Wnt/ beta -catenin signaling pathway. Wnt signaling is evolutionarily conserved and plays a pivotal role in embryonic development, growth regulation of multiple tissues, and cancer development. Our findings add to the increasing body of evidence indicating that mesenchymal-epithelial interactions are crucial in nail development and put anonychia on the growing list of congenital malformation syndromes caused by Wnt-signaling-pathway defects. To the best of our knowledge, this is the first gene known to be responsible for an isolated, nonsyndromic nail disorder.

[Hereditary photodermatoses]. / Hereditäre Photodermatosen.

Hereditary photodermatoses are characterized by an increased photosensitivity caused by an inherited single gene defect. With few exceptions, they manifest in early childhood, reveal heterogeneous clinical symptoms, and are difficult to treat. Although these diseases are rare, it is very important to make an accurate diagnosis on the basis of clinical symptoms, specific diagnostic tests, and direct DNA analysis. We review the spectrum of inherited photodermatoses, including porphyria cutanea tarda, erythropoietic protoporphyria, actinic prurigo, Kindler syndrome, and disorders associated with a defect in DNA repair, including xeroderma pigmentosum, trichothiodystrophy, Cockayne syndrome, and Bloom syndrome. Early diagnosis may prevent complications associated with prolonged unprotected exposure to sunlight and makes it possible to offer genetic counseling and, when indicated, prenatal diagnosis to families at risk for these rare heritable disorders.

[Laboratory tests and therapeutic strategies for the porphyrias]. / Labordiagnostik und Therapie der Porphyrien.

The porphyrias are a heterogeneous group of predominantly hereditary metabolic diseases resulting from a dysfunction of heme biosynthesis. Most of the porphyrias can manifest with a broad range of cutaneous symptoms on the sun-exposed areas of the body, whereas other variants reveal life-threatening acute neurological attacks. Further, mixed types of porphyrias exist. Besides the skin, other organs can be affected, such as the liver and the central nervous system. Therefore, interdisciplinary supervision of these patients is mandatory. In this review we will first present the clinical picture and diagnosis of the porphyrias, including the specific biochemical laboratory tests and a diagnostic algorithm. Thereafter, the current therapeutic concepts will be briefly addressed. Finally, we introduce the European Porphyria Initiative (EPI), an association of various European porphyria centers that is aiming at gathering the broad experience of internationally renowned porphyria experts for the development of European consensus guidelines for diagnosis and treatment of these metabolic disorders.

The porphyrias: clinical presentation, diagnosis and treatment.

The porphyrias comprise a clinically and genetically heterogeneous group of diseases mostly arising from a genetically determined dysfunction of specific enzymes along the pathway of heme biosynthesis. Based on the occurrence or absence of cutaneous symptoms and life-threatening acute neurological attacks, the different types of porphyrias can either be classified into cutaneous and non-cutaneous forms or acute and non-acute forms. Establishing an accurate diagnosis might be difficult for two reasons: i) the porphyrias can manifest with a broad but unspecific spectrum of clinical symptoms mimicking several other disorders, and ii) biochemical examination of urine, feces, and blood can reveal overlapping findings. Fortunately, however, the advances in the fields of molecular genetics during recent years have provided us with the possibility of overcoming these diagnostic pitfalls. Therefore, in controversial cases the correct diagnosis can finally be made using molecular biological techniques. Due to the various facets of the porphyrias, diagnosis and treatment should always imply a close interdisciplinary collaboration to counsel and help patients and their families most efficiently.

A Chilean boy with severe photosensitivity and finger shortening: the first case of homozygous variegate porphyria in South America.

A 7-year-old Chilean boy presented with severe photosensitivity, blistering, erosions and scarring on sun-exposed areas of the body since the age of 6 months. Additionally, he showed a short stature and shortening of the fingers. Laboratory examination revealed greatly elevated protoporphyrin levels in the blood. Such biochemical findings can be observed in homozygous variants of usually autosomal dominantly inherited acute porphyrias such as variegate porphyria (VP) and hereditary coproporphyria, which usually do not become manifest before the second or third decade of life in heterozygotes. Using polymerase chain reaction-based techniques we identified a missense mutation in exon 7 on the paternal allele and a frameshift mutation in exon 13 on the maternal allele of the protoporphyrinogen oxidase gene that harbours the mutations underlying VP. This is the first homozygous case of VP in South America. As VP represents the most frequent type of acute porphyria not only in Chile but also in South Africa, more such cases could be expected in the future, particularly because a founder mutation for this disease has already been described in the Chilean and South African population.