JEADV clinical practice最新文献

Mosaicism due to postzygotic mutations is more common than considered before the era of massive parallel sequencing. In the clinical dermatologic practice, it is important to recognize skin lesions and syndromes caused by genetic mosaicism, to initiate genetic testing and counsel the patient and families regarding prognosis and risk of transmission to the offspring. Precise diagnosis and identification of the dysregulated pathway are also the basis for therapeutic interventions. Here we address the questions why, when, and how to perform genetic testing for mosaic skin conditions.

In this overview, the following 12 different categories of cutaneous mosaicism are considered: (1) Discrimination between monoallelic and biallelic mosaicism in autosomal dominant traits; (2) Segmental versus disseminated mosaicism in autosomal dominant disorders. (3) Simple segmental versus superimposed mosaicism in autosomal dominant disorders. (4) Lethal mutations surviving in a mosaic; (5) Isolated segmental biallelic monoclonal mosaicism; (6) Autosomal recessive mosaicism; (7) Revertant mosaicism in autosomal dominant disorders; (8) Revertant mosaicism in autosomal recessive disorders; (9) Epigenetic mosaicism in X-linked dominant, male-lethal traits; (10) Epigenetic mosaicism in X-linked, nonlethal traits; (11) Mosaicism in polygenic disorders; (12) Hypothetical epigenetic mosaicism in an autosomal dominant trait. Future research may show whether this classification is useful and complete.

A mosaic is an individual composed of two or more genetically different cell lines originating from one homogeneous zygote. This short but precise definition, based on a genetic concept applicable to all pluricellular living organisms, has a great impact on human skin diseases, as it is the hallmark of a great number of human diseases with extremely variable presentations. The skin is a privileged organ for the study of mosaicism because the skin lesions are visible, readily accessible to gene testing and may be associated with internal lesions in organs embryologically related to the skin structures affected by mosaicism.

Overall, every skin lesion caused by a postzygotic pathogenic variant is considered a mosaic lesion. In a broad sense, every skin nevus or even tumoral lesion, regardless of age of appearance and clinical expression (including both patterned and non-patterned lesions), is the result of mosaicism, with different mosaic mechanisms involved, ranging from lethal mutations occurring during embryonic development to second-hit mutations in nonlethal dominant genes causing tumor-prone syndromes. The genetic concept of mosaicism thus provides an explanation for the pathogenesis of both rare and common skin diseases. In a more restricted sense, the group of mosaic conditions encompasses skin lesions that most often appear at birth or in infancy, and follow fixed embryonic patterns or reflect the migration of cell clones during embryonic development.

During the past decades, theories based on observation were formulated, mainly proposed by Prof. Rudolf Happle. Advances in genetic testing have corroborated most of Happle's hypotheses, and many laboratories worldwide are now able to document, at the molecular level, the mutational origin of the vast majority of skin mosaic conditions. While some preliminary studies have demonstrated the potential of targeted therapies acting at different levels in mosaic skin conditions, it is expected that in the future, most mosaic conditions will be treatable with targeted drugs administered orally or topically.

This Special Issue of JEACP is dedicated to Cutaneous Mosaicism and is authored by some of the most reputed European experts in the field. It offers an overview of the basic mechanisms of cutaneous mosaicism, the clinical approach to mosaic disorders and reviews the most important groups of mosaic skin conditions. I hope our readers will enjoy the outstanding work carried out by our contributors.

The author declares no conflicts of interest.

Epidermal nevi (EN) arise from postzygotic variants in ectoderm-derived cell lines, such as keratinocytes and cells forming adnexa. EN may be present alone without any associated abnormality or be part of a syndrome. In this review, we will discuss about the clinical and genetics of the main types of EN and related syndromes.

Superficial vascular anomalies are mosaic disorders and are mostly sporadic. They result from activating post-zygotic mutations involving genes that belong to two main signalling pathways: the PIK3CA-AKT-mTOR pathway and the RAS-MAK-kinases pathway. More rarely, some conditions may be hereditary, and mosaic clinical manifestations result from the second hit mechanism; in those cases, the pathogenic variant leads to a loss-of-function; the capillary malformation-arteriovenous malformation syndrome (CM-AVM) is related to pathogenic variants in RASA1 or EPHB4; the PTEN hamartoma and tumour syndrome (PHTS) results from PTEN pathogenic variants [1].

Superficial vascular anomalies are listed in the ISSVA classification [2]. Several guidelines for management of various types of vascular anomalies are already published by different teams, and it is not our aim herein to add a further opinion [1-4]. The overall management of cutaneous mosaic disorders described by Kinsler et al. feats perfectly well those of vascular origin [5]. Diagnosis relies first on clinical manifestations that can be enough to make it out. However, in some instances, further investigations may be necessary: imaging such as US Doppler, Magnetic resonance imaging and angiography, histopathology and genetics. Investigations will be specifically performed depending on the complete clinical assessment conclusions. Genetics is not always mandatory and frequently not enough to confirm a diagnosis. A single lesion may be related to different pathogenic variants. This is the case of venous malformations that can result from either TEK or PIK3CA mutations [6, 7]. As another example, soft tissue angiomatosis, which is characterized by specific clinical, imaging and histopathological features, will be defined as PHTS hamartoma of soft tissue (PHOST) in the context of PHTS, and Fibro-adipose vascular anomaly (FAVA) when isolated with an identified somatic PIK3CA pathogenic variant [8]. On the other hand, a single pathogenic variant may lead to different types of lesions or syndromes: PIK3CA will be responsible for isolated venous and lymphatic malformations, combined syndromes such as Congenital Lipomatous Overgrowth Vascular Epidermal skeletal anomalies syndrome (CLOVES) or megalencephaly-capillary malformation (M-CAP) [9]. Therefore, identified genetic variants always need to be confronted with clinical manifestations as well as imaging or histopathological features, if necessary, to reach an accurate diagnosis. Even more, some clinical presentations may be highly evocative of a specific syndrome, but the expected pathogenic variant fails to be identified in some instances. In the CM-AVM syndrome characterized by numerous small round pale pink capillary malformations with a pale halo, central nervous system screening may be considered to se

Acquired haemophilia A (AHA) is a rare condition due to neutralizing antibodies against Factor VIII and can result in severe bleeding manifestations. The association of AHA with bullous pemphigoid (BP) is rare, most frequently observed in the elderly, and has been attributed to cross-reactive antibodies targeting Factor VIII and BPAG2 protein. The diagnosis of AHA requires specific investigations, and treatment involves urgent haemostasis and intensive immunosuppression. Managing both conditions simultaneously is challenging due to the risk of severe bleeding and treatment-related complications including infections. Early diagnosis and treatment are crucial to improve outcomes in these patients.

A 66-year-old woman with a history of metastatic colon adenocarcinoma and sarcoidosis presented with a 4-month history of widespread ulcerated, hyperkeratotic, verrucous plaques with violaceous borders on the face, trunk and limbs, measuring up to 5 cm (Figure 1a). She had recently undergone home renovations due to water damage. She reported no systemic symptoms. Skin biopsy and culture revealed broad-based budding yeast forms consistent with Blastomyces dermatitidis (Figure 1b), confirming disseminated cutaneous blastomycosis. Chest X-ray showed no pulmonary involvement. Oral itraconazole was initiated, leading to significant clinical improvement.

Blastomycosis is a systemic fungal infection endemic to parts of North America. This case highlights the importance of including blastomycosis in the differential diagnosis of verrucous nodules or ulcers, particularly in patients with relevant travel or environmental exposure in endemic regions such as Southern Quebec, where incidence has been rising.

Lorena Alexandra Mija: writing – original draft preparation. Elio Kechichian and Carolina Lucena Fernandes: conceptualisation, methodology, supervision.

All patients in this manuscript have given written informed consent for participation in the study and the use of their deidentified, anonymized, aggregated data and their case details (including photographs) for publication. Ethical Approval: not applicable.

The authors declare no conflicts of interest.