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Journal der Deutschen Dermatologischen Gesellschaft : JDDG 20(10), 1387-1402 (2022). doi:10.1111/ddg.14830, Published by Wiley-Blackwell, Berlin

Pruritus ist ein fachübergreifendes Leitsymptom zahlreicher Erkrankungen und stellt eine interdisziplinäre diagnostische und therapeutische Herausforderung dar. Im Gegensatz zu akutem Pruritus ist chronischer Pruritus (CP) ein zumeist schwer behandelbares Symptom verschiedener Erkrankungen. Durch Kratzen und Ausbildung Kratz-assoziierter Hautveränderungen kann der ursprüngliche Hautstatus verändert werden. Bei Vorliegen eines Juck-Kratz-Zirkels können sich sogar sekundäre Krankheitsbilder wie die chronische Prurigo entwickeln. Chronischer Pruritus führt zu erheblichem subjektivem Leiden der Betroffenen, was sich in Einschränkungen der gesundheits-bezogenen Lebensqualität wie Schlafstörungen, Angst, Depressivität, Erleben von Stigmatisierung und/oder sozialem Rückzug bis hin zu klinisch relevanten psychischen Komorbiditäten führen kann. Die Versorgung der Patienten soll somit die (a) interdisziplinäre Diagnostik und Therapie der auslösenden Grunderkrankung, (b) Therapie der sekundären Folgesymptome des Pruritus (dermatologische Therapie, Schlafförderung, bei einer begleitenden oder zugrundeliegenden psychischen oder psychosomatischen Erkrankung eine entsprechende psychologisch-psychotherapeutische Behandlung) und (c) symptomatische antipruritische Therapie umfassen. Das Ziel dieser interdisziplinär erstellten Leitlinie ist es, das therapeutische Vorgehen, aber auch die interdisziplinäre Diagnostik bei CP zu definieren und zu standardisieren. Dies ist die Kurzversion der aktualisierten S2k-Leitlinie zu chronischem Pruritus. Die Langversion findet sich unter www.awmf.org.

Chronic nodular prurigo (CNPG) is a subtype of chronic prurigo, also called prurigo nodularis, and a chronic skin condition characterized by intensely pruritic nodular lesions. Although the exact cause of CNPG is unknown, it appears to result from a repetitive itch-scratch cycle induced by neuronal sensitization to chronic pruritus. CNPG is associated with an underlying dermatologic condition in about half of patients, and it can also be attributed to systemic, neurologic, psychogenic, or unknown causes. For most patients, multiple underlying causes are identified. Patients with CNPG often experience impaired quality of life, sleep disturbance, anxiety, and depression. To encourage consistent and accurate diagnosis and treatment of CNPG across regions, we are proposing a diagnostic and treatment algorithm that includes initial assessment of core symptoms, detailed dermatologic history and clinical examination, patient-reported outcomes, diagnostic workup, and recommended therapies. This information is supplemented with photographs to illustrate clinical appearance and disease severity. Because CNPG is often multifactorial and it can take months to years for lesions to heal, interdisciplinary cooperation and long-term management are important.

Neben dem Charcot-Fus wird auch von einer Charcot-Erkrankung oder Charcot-Arthropathie gesprochen. Basierend auf einer peripheren Neuropathie mit einhergehender gestorter Schmerzwahrnehmung, gestorter Vasomotorik mit vermehrter Vasodilatation und Fehlbelastungen resultiert eine aseptische Knochen- und Gelenkzerstorung des Fuses. Nicht selten spat diagnostiziert und damit primar auch falsch behandelt, entstehen oftmals schwerste Komplikationen. Ein 86-jahriger Patient wurde in reduziertem Allgemeinzustand notfallmasig mit der Diagnose eines Erysipels des rechten Fuses zugewiesen. Der Fus war glanzend odematos aufgequollen und wies eine Nekrose des Endgliedes des III. Digitus auf. Nach einer Laufstrecke von ca. 20 m bereitete ihm das Gehen Schmerzen. Neben dem Erysipel wurde bei bestatigter neuropathischer Arthropathie und radiologischen Kennzeichen fur einen Charcot-Fus als dritte Diagnose eine periphere arterielle Verschlusskrankheit (pAVK) gesichert. Trotz mehrfach umgestellter systemischer Antibiotikatherapie kam es zu einem progredienten Krankheitsverlauf mit steigenden Entzundungsparametern bei zunehmender Verschlechterung des Allgemeinzustandes. Trotz gefaschirurgischer und intensivmedizinischer Masnahmen kam es zu einer ausgepragten Befundverschlechterung und letztlich zum Tod des Patienten. Am vorliegenden Fall sollen die Kennzeichen und die jeweilige diagnostische Sicherung der 3 uberlappenden Diagnosen „Erysipel“, „Charcot-Fus“ und „pAVK“ erarbeitet werden.

Prurigo nodularis (PN) is a subtype of chronic prurigo presenting single to multiple symmetrically distributed, hyperkeratotic and intensively itching papules and nodules. PN evolves along with chronic pruritus in the context of diverse dermatological, systemic, neurological or psychiatric conditions. Permanent scratching is possibly a major trigger of PN, although its exact pathophysiology remains unclear. Current state-of-the-art therapy for PN consists of topical steroids, capsaicin, calcineurin inhibitors, ultraviolet (UV) therapy, systemic administration of gabapentinoids, μ-opioid receptor antagonists, antidepressants or immunosuppressants. Novel treatment concepts, such as inhibitors of neurokinin-1, opioid and interleukin-31 receptors, have been developed and are currently being clinically tested.

Associated with a host of different diseases, pruritus is a cardinal symptom that poses an interdisciplinary diagnostic and therapeutic challenge. Over time, that symptom may progress independently of the initial cause, thus losing its function as a warning sign and turning into a clinically relevant disease of its own. In Germany, approximately 13.5 % of the general population are affected by chronic pruritus, with an incidence of 7 %. All forms of chronic pruritus require targeted treatment consisting of (a) diagnosis and management of the underlying disease, (b) dermatological treatment of primary or secondary (for example, dry skin, scratch lesions) symptoms, (c) symptomatic antipruritic treatment, and (d) psychological/psychotherapeutic treatment in case of an underlying or associated psychological or psychosomatic condition. Medical care of patients with chronic pruritus should therefore include an interdisciplinary approach, in particular with respect to diagnosis and therapy of the underlying disease as well as in terms of the management of treatment and adverse events. The objective of the present interdisciplinary guidelines is to define and standardize diagnostic and therapeutic procedures in patients with chronic pruritus. This is a short version of the current S2 guidelines on chronic pruritus. The long version may be found at www.awmf.org.

Chronic prurigo (CPG) is a highly burdensome pruritic disease characterized by chronic itch, a prolonged scratching behavior and the development of localized or generalized hyperkeratotic pruriginous lesions. Neuronal sensitization and the development of an itch-scratch cycle contribute to the augmentation of pruritus and the chronicity of the disease. We provide here the first international guideline for a rational diagnostic and therapeutic approach for CPG. Recommendations are based on available evidence and expert opinion. The diagnosis of CPG is made clinically. A detailed medical history together with laboratory and radiological examinations are advised in order to determine the severity of CPG, identify the underlying origin of the itch and assist in the elaboration of a treatment plan. Therapeutically, it is advised to adopt a multimodal approach, including general strategies to control itch, treatment of the underlying pruritic conditions, and of the pruriginous lesions. Topical (corticosteroids, calcineurin inhibitors, capsaicin) and systemic antipruritic agents (eg, gabapentinoids, immunosuppressants, and opioid modulators) as well as physical treatment modalities (phototherapy, cryotherapy) should be employed in a step-wise approach. Psychosomatic or psychological interventions may be recommended in CPG patients with signs of psychiatric/psychological comorbidities. (Less)

Chronic pruritus is a highly prevalent, multifactorial symptom requiring extensive diagnostics, treatment and consideration of accompanying symptoms (reduced quality of life, sleep disorders, psychic factors). Patient care is thus complex and requires consideration of individual treatment goals. Patients indicate their wish for a symptom-free life an explanation of the causes and a trustful physician-patient relationship. The targeted use of questionnaires is thus advisable in order to structurally survey the history, pruritus intensity, quality of life and treatment progression. Nevertheless, there are many administrative and economical hurdles in the health care system to overcome in order to provide patients with chronic pruritus the best possible care, also per the recommended guidelines. The development of specialized centers and training courses for medical practitioners is thus urgently needed.

Pruritus is a frequent sensation in dermatoses, but its prevalence in patients in dermatological practices has not been fully studied. The aim of this cross-sectional study is to investigate its prevalence and characteristics in all patients attending a dermatology practice in Germany over a period of one week (n = 334; 52.7% female; median age 45.0 years). The point prevalence of pruritus in this study population was 36.2% (87.6% of whom had chronic pruritus). It inhibited the everyday life of 73.6% of all patients, with 77.7% reporting a frequently to permanently experienced moderate intensity. (5.2 ± 2.3 on the numerical rating scale). Of the patients, 52.1% had previously consulted their general practitioner, and 62% had visited the dermatologist due to pruritus. This study shows that pruritus is a highly prevalent, clinically and economically relevant symptom in dermatological practices. The majority of patients suffering from chronic pruritus are severely burdened and medically underserved. Dermatologists should be aware that pruritus also occurs frequently in patients who do not primarily present due to their symptoms.

Background The term prurigo has been used for many decades in dermatology without clear definition and currently used terminology of prurigo is inconsistent and confusing. Especially itch-related prurigo remains unexplored regarding the epidemiology, clinical profile, natural course, underlying causes, available treatments and economic burden, although burdensome and difficult to treat. Objective To address these issues, the multicenter European Prurigo Project (EPP) was designed to increase knowledge on chronic prurigo (CPG). In the first step, European experts of the EADV Task Force Pruritus (TFP) aimed to achieve a consensus on the definition, classification and terminology of CPG. Additionally, procedures of the cross-sectional EPP were discussed and agreed upon. Methods Discussions and surveys between members of the TFP served as basis for a consensus conference. Using the Delphi method, consensus was defined as an agreement ≥75% among the present members. Results Twenty-four members of the TFP participated in the consensus conference. Experts consented that CPG should be used as an umbrella term for the range of clinical manifestations (e.g. papular, nodular, plaque or umbilicated types). CPG is considered a distinct disease defined by the presence of chronic pruritus for ≥6 weeks, history and/or signs of repeated scratching and multiple localized/generalized pruriginous skin lesions (whitish or pink papules, nodules and/or plaques). CPG occurs due to a neuronal sensitization to itch and the development of an itch-scratch cycle. Conclusion This new definition and terminology of CPG should be implemented in dermatology in order to harmonize communication in the clinical routine, clinical trials and scientific literature. Acute/subacute forms of prurigo are separated entities, which need to be differentiated from CPG and will be discussed in a next step. In the near future the cross-sectional EPP will provide relevant clinical data on various aspects of CPG leading to new directions in the scientific investigation of CGP. This article is protected by copyright. All rights reserved.

Debates on actinic keratoses (AKs) are increasing. The notion that AKs are harmless precursor lesions is no longer accepted. AKs are now considered a smooth transition toward squamous cell carcinoma, a process that is confirmed by molecular and genomic analysis. Increasing age and life-spans, togeth

Der Begriff Prurigo wird in der Dermatologie bis heute fur primare Dermatosen und sekundare Reaktionsmuster verwendet. Eine eindeutige Definition und eine klinische Abgrenzung der verschiedenen Erkrankungen, die den Begriff Prurigo tragen, liegen nicht vor. Es besteht Unklarheit, fur welche Entitat der Begriff primar verwendet wurde und ob er immer im Zusammenhang mit Pruritus zu sehen ist. Der Begriff taucht schon in medizinischen Abhandlungen der sehr fruhen Geschichte auf. Bereits in den ersten Erwahnungen in der Dermatologie wird der Begriff Prurigo uneinheitlich genutzt und der Status als eigenstandiges Krankheitsbild wechselnd an- und aberkannt. Daruber hinaus wurde die Prurigo in viele verschiedene Formen eingeteilt, die sich in der Beschreibung zum Teil stark ahneln. Ein Ruckschluss auf die Klinik ist heute schwierig, wie die beiden haufig erwahnten Begrifflichkeiten Prurigo mitis und Prurigo formicans zeigen. Dagegen ist der Begriff Prurigo nodularis bis heute gebrauchlich. Der Beitrag zeichnet exemplarisch den Gebrauch des Begriffs Prurigo in den gangigen Lehrbuchern bis zur Definition der Prurigo nodularis nach.

In dermatologischen Kliniken und Praxen halt sich in der Regel eine Vielzahl von Menschen wie Patienten oder deren Begleitpersonen mit zahlreichen nichtdermatologischen Begleiterkrankungen auf, die zu medizinischen Notfallen fuhren konnen. Zusatzlich erfolgen auch in der Dermatologie diagnostische oder therapeutische Masnahmen, die lebensbedrohliche Komplikationen zur Folge haben konnen. Daher kann auch der klinisch tatige Dermatologe in der Klinik oder der Praxis jederzeit mit akuten allgemeinen Notfallen konfrontiert werden. Uberwiegend handelt es sich dabei um internistische Notfalle. Daher sind auch fur den Dermatologen notfallmedizinische Grundkenntnisse erforderlich, die im Rahmen des arztlichen Qualitatsmanagements regelmasig aufgefrischt werden sollten und es ermoglichen, lebensrettende Sofortmasnahmen bis zum Eintreffen des Notarztes zu ergreifen. Die allgemeinen Notfallmasnahmen werden hier aufgefuhrt, und das praktische Vorgehen bei unterschiedlichen Leitsymptomen wie Bewusstseins-, respiratorischen oder kardiozirkulatorischen Storungen wird dargestellt.

Summary Background The topical calcineurin inhibitors pimecrolimus and tacrolimus have been demonstrated to be an effective new anti-inflammatory therapy. The only clinically relevant side-effect reported is transient application site burning and stinging itch at the beginning of topical therapy. Objectives In order to understand the underlying mechanism of this effect, we examined whether or not the compounds are able to stimulate neuropeptide release in normal murine skin as well as in a mouse model of experimentally induced irritant contact dermatitis. Methods Balb/c mice were treated with 1% pimecrolimus cream or 0·1% tacrolimus ointment. Untreated and corresponding vehicle-treated mice served as controls. Skin specimens were investigated by light, immunofluorescence and electron microscopy as well as enzyme-linked immunosorbent assay and polymerase chain reaction. Results Topical application of pimecrolimus and tacrolimus was followed by an initial release of substance P and calcitonin gene-related peptide from primary afferent nerve fibres in murine skin during the early inflammatory response. The release of the neuropeptides and their binding to mast cells (MCs) led to MC degranulation. Mediators of MCs such as histamine and tryptase may induce pruritus and burning by binding to the corresponding receptors (histamine receptor 1, proteinase-activated receptor 2) on sensory nerve fibres, which explains the initial side-effects during therapy with calcineurin inhibitors. Conclusions It may be speculated that calcineurin inhibitors directly stimulate intracellular signalling pathways or bind to ion channels such as transient receptor potential vanilloid 1 or receptors involved in nociception.

Hintergrund und Fragestellung Neurotropes Wachstum von Plattenepithelkarzinomen des Kopf- und Halsbereiches ist selten und kann leicht verkannt werden. Diese Tumoren konnen unbehandelt entlang kutaner Nervenfasern in Hirnnerven vorwachsen und zu Schmerzen oder neurologischen Storungen fuhren. Neurotrope Plattenepithelkarzinome haben eine hohe Rezidiv- und/oder Metastasierungsrate und daher eine schlechte Prognose.

Patient care for those affected by chronic pruritus is remarkably complex due to its high prevalence and multifactorial nature. It requires a comprehensive assessment of the patient's medical history, extensive diagnostic procedures, and long treatment duration, including management of possible accompanying disorders such as sleep disturbances and mental distress. It is important to prioritize patient's needs when developing a therapeutic treatment plan. Standardized questionnaires and scales should be used to better analyze the patient history, quality of life, symptom intensity, and course of treatment. These can be distributed via digital platforms, allowing for more effective communication between the treating agents and gathering of large volumes of data in central databases. In today's health care system, it is essential for physicians with itch-related specializations and specialized itch centers to cooperate. It is thus crucial to focus efforts on the further development of specialized treatment centers and training courses for medical practitioners. There are, however, various regulatory and economic barriers to overcome in the modern health care system before patients with chronic pruritus can be offered the best possible care. Accordingly, health care authorities should be made aware of the difficulties associated with the management of chronic pruritus and of the high individual and societal burden it represents.

Moulagen wurden vom 17. Jahrhundert bis in die 50er-Jahre des 20. Jahrhunderts als Lehrmittel der Anatomie sowie verschiedener klinischer Facher, insbesondere der Dermatologie eingesetzt. Nachfolgend wurden sie von der Fotografie als Demonstrations- und Dokumentationsmittel abgelost. Viele europaische Sammlungen wurden daraufhin aufgelost oder vernichtet. Leider verlieren die Wachsmoulagen alterungsbedingt ihre ursprungliche Farbe. Dieses “Sterben der Moulagen”, wird nur bedingt aufzuhalten sein, da in Europa nur noch wenige Mouleure die Fahigkeit der Konservierung von Moulagen beherrschen. Umso mehr rucken die noch erhaltenen Modelle in ein medizinhistorisches Interesse, da sie die Entwicklung des Faches Dermatologie widerspiegeln. Die Munsteraner Hautklinik befindet sich im Besitz von 121 Moulagen, die Gegenstand dieses Artikels sein sollen.

Hintergrund und Fragestellung. Aufgrund der klinischen Ahnlichkeiten stellt die Onychomykose die wichtigste Differenzialdiagnose zu den psoriatischen Nagelveranderungen dar. Es soll die Haufigkeit der Pilzbesiedelung an den Nageln von Psoriatikern geklart werden. Patienten/Methodik. In einem Patientenkollektiv von 250 Personen mit und ohne psoriatischen Nagelveranderungen wurde die Haufigkeit der Pilzbesiedelung an den Nageln untersucht. Zum Vergleich der Ergebnisse diente eine Kontrollgruppe aus 102 hautgesunden Probanden. Ergebnisse. Es konnten keine wesentlichen Unterschiede der Infektionshaufigkeit mit Dermatophyten und Schimmelpilzen an den Nageln gesunder Probanden und von Psoriatikern festgestellt werden. Jedoch konnten Hefepilze statistisch deutlich vermehrt in psoriatisch veranderten Nageln nachgewiesen werden. Schlussfolgerungen. Bei den Nagelveranderungen von Psoriatikern handelt es sich uberwiegend um eine Nagelpsoriasis. Jedoch kommt es zu einer vermehrten sekundaren Besiedelung des psoriatisch veranderten Nagels mit Hefepilzen. Es bleibt zu klaren, warum es nicht zu einer haufigeren Dermatophytenbesiedelung psoriatischer Nagel kommt.

Induction of tolerance by subsequent UV exposures is the most effective therapy for solar urticaria; however, it is time-consuming and takes a long time until protection is achieved. Three patients with solar urticaria were exposed to multiple UVA irradiations at 1-hour intervals per day. With this rush hardening regimen, protection was achieved within 3 days.

The growing incident rates of skin cancer and their corresponding precursor lesions, e.g. actinic keratosis (AK), among Caucasians have become an important public health problem. A multicenter case-control study was conducted to identify the risk factors of AK of a prototypical Central European population. The study population comprised a total of 331 cases and 383 controls. Using multivariate analysis we identified ten independent variables predicting the AK risk. The five most crucial were age (OR 1.11; 95% CI 1.08-1,14), gender (OR 3.92; 95% CI 2.42-6.36), history of previous skin malignancies (OR 6.47; 95% CI 3.21-13.03), pale skin phototype (OR 2.5; 95% CI 1.53-4.06), and sun exposure for occupational reasons (OR 1.72; 95% CI 1.01-2.92). Additionally, sun exposure for recreational reasons, denial of the use of sunscreens, painful sunburn episodes before the age of 20, and a familial history of skin malignancies are also significant independent correlates of AK. Our epidemiological data suggest that constitutional susceptibility and sunlight exposure are equally involved in the onset of AK. Additional prophylactic and educational efforts should focus on increasing sun protection policies and educational programs especially aimed at outdoor workers, men, fair skinned individuals and patients with a history of previous skin malignancies. These measures should be able to reduce the excessive incidence rates of AK among Caucasians in Central Europe.

Summary Background: Adequate peripheral venous access is crucial for successful extracorporeal photopheresis (ECP). As this approach is not always feasible in older patients and patients with graft-versus-host disease, central venous catheters play an increasing role in providing long-term vascular access for ECP.However, not all catheters are able to deliver the minimum flow rate of 7 ml/min for ECP. Patients and Methods: Eight different permanent subcutaneous right atrial catheters were connected in vitro to the UVAR®-XTS™ photopheresis system and median flow rates were determined. In addition, in vivo flow rates of patients who received ECP, using either peripheral or central venous access, were determined. Results: Hemodialysis catheters with an internal diameter of 2.0 or 1.5 × 3.5 mm and a length up to 48 cm provided in vitro flow rates of 27–28 ml/min, almost identical to a peripheral access needle. Central venous catheters with a length of over 90 cm reached flow rates below 7 ml/min and are impractical for ECP. The analysis of 308 ECP collection cycles with peripheral vascular access revealed an average flow rate of 31.5 ± 6.4 ml/min. Only permanent subcutaneous right atrial catheters made for hemodialysis provided similar flow rates (Quinton PermCath Dual Lumen) (33.7 ± 4.7 ml/min, n = 198). Conclusions: Permanent subcutaneous hemodialysis catheters with a length of maximally 48 cm achieve optimal flow rates for ECP. They represent therefore the central venous access of choice in patients with inadequate peripheral vascular access.

Die Diagnosen der Munsteraner Moulagensammlung sind sehr heterogen und folgen keiner gangigen Systematik, was dem Charakter einer durch mehrere Personen zusammengetragenen Sammlung entspricht (⊡ Tab. 7.1). Diese Auswahl der Diagnosen veranschaulicht ferner die Zusammensetzung des Patientenguts der ersten Halfte des letzten Jahrhunderts. Geschlechtserkrankungen Die dargestellten Diagnosen umfassen in erster Linie Infektionskrankheiten (n = 78). Davon stellen 27 Moulagen (35 %) Geschlechtserkrankungen dar. Besonders um den 2. Weltkrieg bildeten die Geschlechtserkrankungen einen Hauptbestandteil des dermatologischen Krankengutes, welches in Munster sogar zu einer Erweiterung der dermatologischen Abteilung fuhrte. An erster Stelle ist hier die Syphilis zu nennen. In und nach dem 2. Weltkrieg kam es zu einem sprunghaften Anstieg dieser Erkrankung in ganz Europa. Somit ist sie nicht nur in der Munsteraner Sammlung uberwiegender Gegenstand vieler Moulagen. Auch in der Freiburger Klinik stellte der Mouleur Otto Vogelbacher zwischen 1906 und 1936 hauptsachlich Syphilis-Moulagen her, von denen viele nach Munster gelangt sind. Zum ersten Auftreten der Syphilis in Europa kam es 1493 in Barcelona. Diese breitete sich in der Folgezeit in ganz Spanien aus und wurde daher als die »spanische Krankheit« bezeichnet. In den folgenden Jahren fanden sich an Syphilis erkrankte Menschen auf dem gesamten europaischen Festland. 1495 wurden in Deutschland die ersten Falle der Erkrankung bekannt und 1497 erreichte sie die britischen Inseln. Die Syphilis wurde wahrscheinlich von Seeleuten und Soldaten, die aus Amerika zuruckkehrten, nach Europa und Asien eingeschleppt. 25 Munsteraner Moulagen zeigen vom Primaraffekt bis zur Sattelnase die verschie⊡ Tab. 7.1. Diagnosen und deren Anzahl der Munsteraner Moulagen

Hydroxyethyl starch (HES) is widely used as a plasma substitute. Serious side effects occur only rarely, whereas a high incidence of severe pruritus has been reported. Moreover, tissue storage of HES has been demonstrated in various organs. The aim of the current study has been to examine precisely the intracellular uptake and long-term storage of HES in the skin. Skin biopsies from 119 patients who received HES of various preparations and cumulative dosage were obtained 30 min to 130 months after infusion therapy. The samples were analysed by ultrastructural and immunoelectron microscopy with HES-specific monoclonal and polyclonal antibodies. A characteristic vacuolisation of perivascular histiocytes was a regular finding in all skin biopsies as early as 1 day after a single infusion of 30 g. Immunoreactivity for HES was demonstrable within the vacuoles. Generally, the size and number of vacuoles in the histiocytes increased concomitantly with the cumulative dosage. Following administration of higher HES dosages, vacuoles were demonstrable in endothelial cells of blood and lymphatic vessels, basal keratinocytes, epithelia of sweat glands and in small peripheral nerves, the last mentioned being associated with pruritus. A subsequent reduction of the vacuoles in size and number could be demonstrated within 52 months. In nerves, HES deposits persisted no longer than 17 months paralleling the cessation of pruritus. Biopsies taken after 94 months exhibited no HES deposits in the skin. The condensation and final dissolution of the vacuoles may either indicate the release and subsequent redistribution of HES into the circulation or lysosomal degradation.

Netherton syndrome (NTS) is an autosomal recessive congenital ichthyosis featuring chronic inflammation of the skin, hair anomalies, epidermal hyperplasia with an impaired epidermal barrier function, failure to thrive and atopic manifestations. The disease is caused by mutations in the SPINK5 gene encoding the serine proteinase inhibitor lympho-epithelial Kazal-type inhibitor (LEKTI). Sequence analyses of SPINK5 in seven NTS patients from five different families allowed us to identify two known and three novel mutations all creating premature termination codons. We developed a monoclonal antibody giving a strong signal for LEKTI in the stratum granulosum of normal skin and demonstrated absence of the protein in NTS epidermis. Immunoblot analysis revealed presence of full length LEKTI and of LEKTI cleavage fragments in normal hair roots, whereas in NTS hair roots LEKTI and its cleavage products were completely missing. Transglutaminase1 activity was present throughout almost the entire suprabasal epidermis in NTS, whereas in normal skin it is restricted to the stratum granulosum. In contrast, immunostaining for transglutaminase3 was absent or faint. Moreover, comparable with the altered pattern in psoriatic skin the epidermis in NTS strongly expressed the serine proteinase inhibitor SKALP/elafin and the anti-microbial protein human β-defensin 2. These studies demonstrate LEKTI deficiency in the epidermis and in hair roots at the protein level and an aberrant expression of other proteins, especially transglutaminase1 and 3, which may account for the impaired epidermal barrier in NTS.