Junctional epidermolysis bullosa (JEB) is one of the four major types of EB caused by genetic variants in the genes coding the proteins of the lamina lucida. All patients with this major type of EB present syndromic hypoplastic amelogenesis imperfecta (AI), with either a pits and fissures or generalized hypoplastic phenotype. Severe forms of AI are associated with compromised oral health-related quality of life (QoL) mostly due to poor dental aesthetics, dentofacial anomalies, and oral pain. To present the comprehensive dental treatment of a patient with JEB and AI from the age of 20 months until the age of 18 years, including complex orthodontics and digital oral rehabilitation. A male patient with intermediate JEB (homozygous c.3228+1G>A LAMB3 variant) has been under the care of the special care dentistry clinic of the University of Chile since the age of 20 months. His complex dental needs include structural enamel abnormalities in primary and permanent dentition (hypoplastic generalized AI), severe dental crowding with maxillary compression, Class III skeletal pattern, agenesia (#45), and gingivitis. Pediatric dental care included oral hygiene education and preventive strategies (prophylaxis and fluoride applications), maintaining the dentition free of caries. Due to AI, severe tooth sensitivity hindered proper oral hygiene and required early rehabilitation with temporary polycarbonate and metallic crowns. At the age of 16, the patient began orthodontic treatment. A maxillary expansion was performed with two consecutive mini-implant assisted rapid palate expansion (MARPE) bonded to four mini-implants in the palate. After finishing orthodontic treatment metallic multibrackets (duration 19 months), a definitive oral rehabilitation based on digital smile design with feldspathic crowns of all anterior teeth and premolars was performed. Patients with severe generalized hypoplastic syndromic AI associated with JEB benefit from long-term preventive oral care. Complex orthodontic techniques, such as MARPE, and multibrackets can be successfully. Digital smile design provides a definitive oral rehabilitation technique improving oral function, aesthetics, and QoL.

Epidermolysis bullosa (EB) is an inherited disorder of skin fragility, caused by mutations in a large number of genes associated with skin integrity and dermal-epidermal adhesion. Skin fragility is manifested by a decrease in resistance to external mechanical influences, the clinical signs of which are the formation of blisters, erosions and wounds on the skin and mucous membranes. EB is a multisystemic disease and characterized by a wide phenotypic spectrum with extracutaneous complications in severe types, besides the skin and mucous membranes, with high mortality. More than 30 clinical subtypes have been identified, which are grouped into four main types: simplex EB, junctional EB, dystrophic EB and Kindler syndrome. To date, pathogenic variants in 16 different genes are associated with EB and encode proteins that are part of the skin anchoring structures or are signaling proteins. Genetic mutations cause dysfunction of cellular structures, differentiation, proliferation and apoptosis of cells, leading to mechanical instability of the skin. The formation of reduced proteins or decrease in their level leads mainly to functional disorders, forming mild or intermediate severe phenotypes. Absent protein expression is a result of null genetic variants and leads to structural abnormalities, causing a severe clinical phenotype. For most of the genes involved in the pathogenesis of EB, certain relationships have been established between the type and position of genetic variant and the severity of the clinical manifestations of the disease. Establishing an accurate diagnosis depends on the correlation of clinical, genealogical and immunohistological data in combination with molecular genetic testing. In general, the study of clinical, genetic and ultrastructural changes in EB has significantly expanded the understanding of the natural history of the disease and supplemented the data on genotype-phenotype correlations, promotes the search and study of epigenetic and non-genetic disease modifier factors, and also allows developing approaches to radical treatment of the disease. New advances of sequencing technologies have made it possible to describe new phenotypes and study their genetic and molecular mechanisms. This article describes the pathogenetic aspects and genes that cause main and rare syndromic subtypes of EB. Буллезный эпидермолиз (БЭ) – наследственное нарушение, вызывающее хрупкость кожи, обусловленную изменениями генов, отвечающих за целостность кожи и дермо-эпидермальную адгезию. Хрупкость кожи проявляется снижением устойчивости к внешним механическим воздействиям, клинические признаки которой – образование пузырей, эрозий и ран на коже и слизистых оболочках. Для БЭ характерен широкий фенотипический спектр, при тяжелых типах, кроме кожи и слизистых, отмечаются мультисистемность поражения и развитие внекожных осложнений, высокая летальность. Выделено более 30 клинических подтипов БЭ, сгруппированных в четыре основных типа: простой, пограничный, дистрофический БЭ и синдром Киндлера. На сегодняшний день БЭ обусловливают патогенные варианты в 16 различных генах, которые кодируют белки, входящие в состав крепящих структур кожи, и сигнальные белки. Генетические дефекты в этих генах служат причиной нарушения функции клеточных структур, процессов дифференцировки, пролиферации и апоптоза клеток, приводя к механической неустойчивости кожи. Образование укороченных белков или уменьшение их количества обуславливает в основном функциональные нарушения, формируя легкие или среднетяжелые фенотипы. При нулевых генетических вариантах, вследствие которых экспрессия белка утрачивается полностью, возникают структурные нарушения, влекущие тяжелую клиническую картину. Для большинства вовлеченных в патогенез БЭ генов обнаружены определенные связи между характером и локализацией генетических де- фектов с тяжестью клинических проявлений заболевания. Установление точного диагноза зависит от корре- ляции клинических, генеалогических и иммуногистологических данных в сочетании с молекулярно-генетиче- ским исследованием. В целом изучение клинических, генетических и ультраструктурных изменений при БЭ значительно расширяет понимание естественного течения заболевания и пополняет данные о корреляциях генотип-фенотип, способствует поиску и изучению эпигенетических и негенетических факторов-модификато- ров заболевания, а также разработке подходов к радикальному лечению заболевания. Новые возможности технологий секвенирования позволили описать новые фенотипы и изучить их генетические и молекулярные механизмы. В настоящей статье описаны патогенетические аспекты и гены, вызывающие классические и ред- кие синдромальные подтипы БЭ.

Kidney-urinary tract (KUT) manifestations cause substantial morbidity in patients with junctional epidermolysis bullosa (JEB), but the spectrum of disease severity and the clinical course have been poorly characterized. To examine in a large cohort of patients with intermediate JEB the KUT manifestations, diagnostic and therapeutic procedures, genotype-phenotype correlations, and outcomes as a basis for recommendations, prognosis, and management. In this retrospective, longitudinal case series study, 99 patients with a diagnosis of JEB based on clinical and genetic findings who were treated in a single dermatology department in Freiburg, Germany, were assessed during an 18-year period (January 1, 2003, to December 31, 2021). Clinical, laboratory, and molecular genetic parameters were extracted from patients' medical records. Clinical characteristics, natural history, management of KUT manifestations, and genotype-phenotype correlations of intermediate JEB. Of the 183 patients with JEB, 99 (54%) had intermediate JEB and were included in this cohort. The cohort included 49 female patients and 50 male patients. None of 49 female patients and 15 of 50 male patients had KUT involvement affecting different levels of the urinary tract, resulting in a prevalence of 30% for males; thus, the overall prevalence was 15%. The mean age at onset of KUT manifestations was 6.9 years (range, first weeks of life to 20 years; age was not available for 1 patient). Median follow-up after diagnosis of KUT involvement was 13 years (range, 3 months to 54 years). Patients with laminin 332 or integrin β4 deficiency had at least 1 missense or splice site genetic variant, leading to residual expression of laminin 332 or integrin α6β4, respectively. Severity of KUT complications did not correlate with the extent of skin involvement but with the affected protein. Physicians and patients with JEB should be aware of the risk for KUT involvement in intermediate JEB, and physicians should apply interdisciplinary and individualized diagnostic and therapeutic procedures for management of these complications. Because this disorder is so rare, multicenter studies are required to make general recommendations.