BIODERMA Congress Reports ESPD 2023

Speakers: John McGrath, Cristina Has and Angela Hernández-Martín

Report written by Prof. Ivelina Yordanova

New genodermatosis discoveries

John McGrath

Professor John McGrath, head of St John's Institute of Dermatology, King's College, London, professor of molecular dermatology and lead of the Genetic Skin Disease Group, presented the latest discoveries in the field of new genetic mutations and previously undescribed genodermatoses. He said that discovering the genetic basis of inherited skin diseases is fundamental to improving diagnostic accuracy and genetic counseling. Over the past decade the advent of next‐generation sequencing (NGS) technologies has accelerated diagnostic discovery and precision. The number of discoveries increased from approximately 40 disease‐associated genes prior to the identification of CYBB in 1986 to having over 1000 disease genes documented in the Online Mendelian Inheritance in Man (OMIM) database is currently available. One of the major promises of the genomic medicine era has been to give patients with inherited diseases accurate clinical diagnoses based on individual gene and mutation data. Implicit to this is the consideration of the relationship between individual genotypes and their associated clinical phenotypes. Of the 166 new disease–gene associations for inherited skin diseases discovered using NGS approaches between 2009 and 2019, there was an approximately even split between autosomal dominant and autosomal recessive conditions (51·2% vs. 47·0%, respectively), with the autosomal dominant conditions also divided approximately equally into dominant and de novo dominant inheritance. Other studies have similarly demonstrated the relative over‐representation of genes underlying autosomal recessive disorders reflecting the more straightforward filtering of homozygous or compound heterozygous variants compared with the identification of single and clearly pathogenic heterozygous variants for autosomal dominant diseases. From a clinical standpoint, the recognition of multiple molecular diagnoses can have important implications for genetic counseling, allowing more precise management and estimates of familial recurrence risk.

Genodermatoses: what can we treat?

Cristina Has

Prof. Cristina Has is a professor at the Department of Dermatology of the University of Freiburg in Germany, Head of the Molecular Dermatology Laboratory with a focus of interest on Epidermolysis bullosa and other genetic skin disorders. Her clinical activity includes general and pediatric dermatology, and genodermatoses. With her group, she has identified new genes and characterized large cohorts of patients with genodermatoses, established genotype-phenotype correlations and explored the underlying disease mechanisms. In the session today she presented what can we treat genodermatoses.

Due to the lack of effect and high toxicity of the treatment of some genodermatoses with classic drugs such as systemic retinoids, methotrexate and cyclosporine, we are turning our attention to new biological drugs, monoclonal antibodies blocking various molecules of the skin inflammation cascade. In addition to discovering genetic-clinical correlations, we are increasingly looking for pathogenetically-based therapeutic options targeting primary or reactive dysregulation. It turns out that different genetic defects lead to and trigger different tissue or system reactions related to skin inflammation and releasing of inflammatory cytokines - TNF alpha, IL-1, IL-17, IL-6, etc. The use of various biological molecules for treatment, significantly improves the quality of life of patients with genodermatoses and their families. As examples, she therefore indicated cases of a very good therapeutic effect achieved as a result of treatment of Epidermolysis bullosa dystrophica pruriginosa, which has a Th2 immune profile with biological drugs for the treatment of atopic dermatitis from the group of JAK kinase inhibitors - upadacitinib, baricitinib, tofacitinib and anti IL-4 - Dupilumab. Prof. Has presented a case of successful treatment of a patient with recessive dystrophic epidermolysis bullosa with Dupilumab in two different dosage regimens 200 mg/2 weeks and 300 mg/4 weeks. She also said that the drug losartan has an antifibrotic effect in cases of recessive dystrophic epidermolysis bullosa by reducing blistering, reducing esophageal strictures and restenosis, but not in all patients it has an effect. A change in the treatment model /paradigm/ of keratinization diseases, which have a complex immune profile related to an allergic response, similar to atopic dermatitis and psoriasis with predominance of IL-17 was shown. In fact, in the group of ichthyoses, the established primary genetic defects in the barrier structure of the stratum corneum lead to impairment of the protective function of the skin and an increase in its permeability to allergens, bacteria and viruses. This further increases skin inflammation. Due to this fact, a remarkable effect with reduction of erythema and pruritus was shown in the treatment of patients with Netherton's syndrome with anti-IL-17, anti-IL-12/23, anti-TNF alpha. Prof. Has presented cases of 6 children with Netherton's syndrome under 6 years of age successfully treated for erythema and pruritus with Dupilumab at a dose of 300 mg/4 weeks.

The result of systemic therapy with Gentamicin inducing protein expression in patients with specific stop codon mutations such as epidermolysis bullosa, Nagashima type palmoplantar keratosis, congenital hypotrichosis simplex of the scalp, was shown. The results of a Phase III clinical study approved by the EMA in the treatment of wounds in patients with junctional and dystrophic epidermolysis bullosa with Oleogel S10 - birch bark extract, were presented. Prof. Has also presented the current status of gene therapy in epidermolysis bullosa - ex vivo gene and stem cell therapy and in vivo gene therapy for dystrophic epidermolysis bullosa awaiting FDA approval.

Clinical practice and Genetics: a match made in heaven

Angela Hernández-Martín

Dr. Ángela Hernández-Martín, Senior Consultant in Department of Dermatology, Hospital del Niño Jesús, Madrid, Spain, secretary of the Spanish Group of Pediatric Dermatology, co-authored numerous chapter textbooks (including Bolognia ́s General Dermatology Textbook, Harper ́s Pediatric Dermatology Textbook, last editions) with main areas of interests keratinization disorders and neurocutaneous diseases, presented clinico-genetic correlations in ichthyoses and in particular several rare cases of ichthyosis with confetti.

Neonatal skin signs suggesting genodermatoses

Maya El-Hachem

Today we attended a remarkable session on neonatal dermatology. The session was chaired by Dr. Maya El Hachem, a pediatric dermatologist at Bambino Gezu Children's Hospital in Rome.

She gave a very didactic lecture on "Neonatal skin signs suggesting genodermatoses". The group of keratinopathic ichthyoses was presented, which occurs with symptoms of congenital erythroderma and desquamation. Netherton's syndrome is characterized by congenital erythroderma, sparse hair, trichorexis invagina, atopic diathesis, and an elevated level of immunoglobulin E. It is associated with a complete absence of the LECTI protein, which is due to a mutation in the SPINK5 gene. Desquamation and hyperkeratosis in the neonatal period are signs of ichthyoses, representing a group of genodermatoses characterized by congenital damage to keratinization. An example of the most severe ichthyosis is Harlequin-ichthyosis. Restrictive dermopathy is a rare genodermatosis due to ZMPSTE 24, more rarely to LMNA mutation. This disease is characterized by an extremely poor prognosis, resulting in early neonatal death. Clinical signs are fetal transfer, intrauterine fetal retardation, thin rigid skin with lacerations in the folds, facial dysmorphism, and joint ankyloses. Incontinentia pigmenti is a genetic disease associated with a mutation of NEMO gene located on the X-chromosome.

Mosaicism due to lionization is common here. It affects only the female sex, it is fatal for the male and characterized by diffusely located vesicles along Blashko's lines, which subsequently turn into hyperkeratotic lesions, healing with postlesional linear hypopigmentation. It is associated with extracutaneous signs. Epidermolysis bullosa congenita is a clinically and genetically heterogeneous group of genodermatoses characterized by skin and mucosal blistering after minimal trauma. They are inherited in an autosomal dominant or recessive manner. There are 4 main variants - simplex, junctional, dystrophic and Kindler syndrome. All EB subtypes are caused by mutations in 16 genes encoding total of 13 proteins of the dermo-epidermal membrane zone structure. Skin atrophy and poikiloderma are typical of Kindler syndrome. Tuberous sclerosis is an autosomal-dominant disease characterized by multiple dysplastic organ lesions and neuropsychiatric symptoms. Mutations are present in 70% of patients and 2/3 have occurred daily. Congenital giant melanocytic nevi are associated with genetic mutations in the NRAS gene, which disrupt the normal differentiation and proliferation of melanoblasts. Patients with this diagnosis should be followed up by MRI for neuromelanosis. Clinical and dermatoscopic follow-up should be performed. In conclusion, neonatal skin manifestations can predict a wide and heterogeneous group of genodermatoses. Diagnostic tests, including molecular genetic testing, should be performed as early as possible. Multidisciplinary management is mandatory to ensure adequate care. Genetic counseling should be provided for the parents and psychological support should be provided.

Erythroderma in the newborn

Iria Neri

The second presentation in this short session was on neonatal erythroderma and was presented by Dr. Iria Neri. Erythroderma is a persistent generalized skin erythema affecting at least 90% of the skin surface. Neonatal erythroderma can appear already during birth or in the first 4 weeks after it. Depending on the degree of epidermal disturbance, erythroderma can cause serious complications such as electrolyte imbalance, hypoalbuminemia, dehydration, temperature instability, infections that could even lead to sepsis. In the neonatal period, erythroderma can be a manifestation of a number of congenital conditions. Dr. Neri presented the 6-step approach to the diagnosis of the relevant genodermatosis, published in 2022 in JEADV. Neonatal erythroderma is also rare - only 74 cases were identified in a 30-year period. Diagnosis is often a challenge for clinicians and is usually delayed due to the nonspecific nature of clinical signs. Clinical clues and diagnostic tests can be of great importance in making the final diagnosis. Three are the most common diseases occurring with neonatal erythroderma, accounting for 64% of cases. These are the ichthyoses, Netherton syndrome and Omenn syndrome. Omenn syndrome is characterized by the following clinical signs: pachydermal thickening of the skin, alopecia. Parents are usually consanguineous. Extracutaneous signs include severe growth failure, lymphadenopathy, diarrhea, infections, hepatosplenomegaly. The term Collodion baby describes a number of syndromes, in 75% of cases it is represented by autosomal recessive congenital ichthyoses, in 10% - self-healing Collodion baby and in 15% - other keratinizing diseases. In conclusion, neonatal erythroderma is rare, in the neonatal period it may be the first manifestation of many diseases whose typical clinical phenotype may appear later.

The last day of the Congress of the European Association of Pediatric Dermatology 06/05/2023 in Malaga was full of new information about the latest clinical studies in the field of pediatric dermatology. We are now in the golden years of pediatric dermatology for the treatment of a number of childhood widespread and rarer childhood diseases. The reason is that we live in the era of biologicals, which have rapidity of action and high efficiency. Targeted therapies have almost minimal risk of organ damage. The opportunities for gene therapies in genodermatoses are increasing. We are still working with conventional systemic treatment. The choice of therapy requires an in-depth knowledge of the benefits and risks of each drug in patients, each of whom is an individual case.

An exceptional lecture was given by Dr. Lisa Weibel, head of the Department of Pediatric Dermatology at the University Children's Hospital Zurich, on the topic "Skin manifestations of systemic diseases". Dr. Weibel has two medical specialty - in pediatrics and dermatology, making her an exceptional specialist in the field of pediatric dermatology.

 The skin is not an isolated organ, it participates in all processes that occur in the human body. When examining a child, we must look closely at the skin and skin appendages, fingernails and toenails, hair, where we may find some signs of internal, sometimes life-threatening diseases. She provided an in-depth review of skin manifestations in genetic disorders, conditions associated with developmental abnormalities, infectious diseases, immunologic inflammatory diseases, and childhood malignancies. Nail patella syndrome is an autosomal-dominant inherited genetic disorder characterized by progressive nail dystrophy from infancy, starting initially in the fingers and subsequently affecting the toes, presenting with severe dystrophy , hypoplasia and longitudinal striae or splitting of the nail plates. Nail dystrophy is the first sign that may lead to suspicion of nail patella syndrome, characterized by dysplastic or missing patella, glaucoma and impaired renal function in 30-50% and terminal renal failure in 15% of cases. Erythropoietic protoporphyria, inherited in an autosomal recessive manner, results in the absorption of visible light by protoporphyrin, leading to capillary damage. Indications for this disease can be skin manifestations in the child's preschool age, expressed in painful swellings and erythema of the hands, ears, nose, covered with crusts after sunny days. Mild liver damage is usually found in the disease, in 5% - liver failure. Degos disease or malignant atrophic papulosis is an extremely rare disorder in which small and medium sized arteries become blocked (occlusive arteriopathy), restricting the flow of blood to affected areas. Degos disease usually causes characteristic skin lesions that may last for a period of time ranging from weeks to years - "porcelain" shining atrophic papules on the eyelids, enlarged nail folds capillaries. Children diagnosed with this disease may develop complications due to impairment of internal organs. Similar papules can also form in patients with Dermatomyositis, but a different histopathological picture there is established. Acute leukemia is not a rare disease in children and is always characterized by high fever and erythematous macules on the body. The diagnosis is confirmed immunohistochemically, by taking a skin biopsy and must be made in time in order to start a specific treatment which is a bone marrow transplant. With long-term use of Levamisole for the treatment of nephrotic syndrome in childhood, in some cases, circulating autoantibodies (antinuclear, antiphospholipid and anticytoplasmic) are formed, which lead to necrotizing vasculitis and vasculopathy, manifested clinically as purpura of the ears, nose and auricles. These skin changes always resolve spontaneously when treatment with Levamisole is discontinued. The appearance of ecthyma-like necrotic changes on the skin of the torso immediately after birth is a sign of congenital Langerhans histiocytosis. In the presence of epidermolysis of the skin at birth, as well as the appearance of bullae and desquamation of the palms and soles, in addition to congenital epidermolysis bullosa, epidermolytic ichthyosis and SSSS syndrome, we must also think about congenital syphilis and perform the relevant serological tests. In congenital syphilis, mucosal involvement is observed in up to 60% of cases. The presence of cutaneous granulomas from infancy is associated with primary immunodeficiency diseases. Oculocutaneous albinism, bleeding diathesis, Crohn's-like enteropathy and pulmonary fibrosis are associated with Hermansky-Pudlak syndrome, which is a very rare autosomal recessive genodermatosis. A skin manifestation of Hodgkin's Lymphoma, which represents 7% of childhood neoplasias affecting the age of 14-19 years, is persisting pruritus (eczema) in 20-50% of cases. When eczema started at this age, it is appropriate to refer patients for MRI and CT of the lung, where enlarged mediastinal lymph nodes can be detected. Evaluation of multiple atypical cafe-au-lait-spots. When they are typical and combined with axillary freckling, it is Neurofibromatosis 1. When they are atypically located, they are associated with increased tumor formation in early childhood. When the spots are hypopigmented, signs of Fanconi anemia type D1 should be looked for, because these patients carry a genetically high risk for the development of solid tumors - medulloblastoma, Wilms' tumor, neuroblastoma, acute leukemia, before the age of 5 years. Strict tumor screening is required in these patients. The management of small patients with skin manifestations of life-threatening diseases requires a multidisciplinary approach and collaboration between dermatologists, rheumatologists, pediatricians, neurologists, oncologists, immunologists and endocrinologists.