Challenges in the Diagnosis and Management of Giant Porokeratosis: A Case Report.

Porokeratosis encompasses a diverse group of dermatoses, both acquired and genetic, marked by a keratinization disorder. Porokeratosis of Mibelli (PKM) presents as solitary plaques or multiple papules/macules with central atrophy and raised hyperkeratotic borders. Here, we present a case of giant porokeratosis (GPK), a rare form often considered a morphological variant of PKM, with unique clinical and histopathological aspects. Our case involves a 29-year-old patient with a 15 × 10 cm irregular plaque on the dorsal aspect of the right hand. The patient was previously prescribed various topical treatments (retinoids, calcineurin inhibitors, and combinations of corticosteroids with vitamin D3 analogs) and systemic retinoids without improvement before presenting to our department. Due to the high risk of neoplastic transformation and the unavailability of imiquimod, the patient was recommended topical 5-fluorouracil treatment. The trajectory of the lesion under treatment revealed a favorable evolution, and the patient was subjected to regular monitoring every three months to assess the ongoing progress. Recognizing GPK as a high-risk variant is crucial for dermatologists, and it requires a personalized approach. Regular monitoring is advised to detect potential malignant transformations promptly. Future research holds promise for diagnostic advancements, refined treatment modalities, and a deeper understanding of the molecular mechanisms underlying malignancy in porokeratosis.

A novel heterozygous frameshift mutation in the KRT6A gene responsible for an uncommon phenotype of pachyonychia congenita: One case report and review of literature.

Pachyonychia congenita is an uncommon autosomal dominant skin disorder characterized by hypertrophic nail dystrophy, palmoplantar keratoderma, oral leukokeratosis, and cutaneous cysts. And fissured tongue is rarely reported in patients with pachyonychia congenita. The disease is primarily associated with mutations in five keratin genes, namely KRT6A, KRT6B, KRT6C, KRT16 or KRT17. Herein we report a 9-year-old Chinese girl who has thickened nails, keratinized plaques, and fissured tongue since birth. To investigate the underlying genetic cause, whole-exome sequencing and Sanger sequencing were performed in this patient and her family members. We identified a candidate variant c.1460-2_1460del (p.S487Lfs*21) in the KRT6A gene (NM_005554.4) by whole-exome sequencing. Sanger sequencing revealed the absence of the mutation in both parents, indicating that it is a de novo variant. Thus, the novel heterozygous frameshift mutation c.1460-2_1460del (p.S487Lfs*21) within exon 9 of KRT6A was identified as the genetic cause of the patient. Our study identified a rare de novo heterozygous frameshift mutation in the KRT6A gene in a patient with pachyonychia congenita presenting fissured tongue. Our findings expand the KRT6A gene mutation spectrum of Pachyonychia congenita, and will contribute to the future genetic counseling and gene therapy for this disease.

The Depressiveness, Quality of Life and NEO-FFI Scale in Patients with Selected Genodermatoses.

Background: Dermatological conditions extend beyond physical symptoms, profoundly impacting the psychological well-being of patients. This study explores the intricate relationship between depressive symptoms, quality of life (QoL), and personality traits in individuals diagnosed with specific genodermatoses. Methods: The study cohort comprised 30 patients with genodermatoses treated at the dermatology clinic, and a healthy control group. Standardized survey questionnaires: The Dermatology Life Quality Index (DLQI), Beck's Depression Inventory (BDI), and NEO Five-Factor Inventory (NEO-FFI) were employed for assessments. Results: The findings indicate a significantly elevated risk of severely or very severely reduced QoL in the study group compared to matched controls (OR = 22.2, 95% CI: 2.7-184.8). Specifically, individuals with ichthyosis exhibited a staggering 131-fold higher risk of diminished QoL compared to the control group. Furthermore, the prevalence of depression was higher in the study group than in the control group (36.7% vs. 10%; p = 0.0086). A detailed analysis revealed that patients with low or average agreeableness exhibited a notably higher incidence of depression compared to those with high agreeableness (100% or 75% vs. 28.6%; p = 0.0400). Similarly, individuals with high levels of neuroticism had a significantly higher incidence of depression compared to those with average or low levels of neuroticism (rates: 66.7% vs. 9.1% or 0%, respectively; p = 0.0067). Conclusions: The study underscores a substantial correlation between genodermatoses and the mental health of affected individuals, underscoring the imperative consideration of psychological factors in the management of hereditary skin disorders. Our study's primary limitation is the small sample size, stemming from difficulties in recruiting participants due to the rare nature of the studied conditions.

Strategy for the optimization of read-through therapy for junctional epidermolysis bullosa with COL17A1 nonsense mutation.

The read-through therapy suppresses premature termination codons and induces read-through activity consequently restoring missing proteins. Aminoglycosides are widely studied as read-through drugs in different human genetic disorders including hereditary skin diseases. Our previous work revealed that aminoglycosides have effect on COL17A1 nonsense mutations and represent a therapeutic option to alleviate disease severity. However, the amount of restored type XVII collagen (C17) in C17 deficient junctional epidermolysis bullosa (JEB-C17) keratinocytes was less than 1% relative to normal keratinocytes and was achieved only after high dose gentamicin treatment, which induced deep transcriptional changes. Therefore, in this study, we designed a strategy for the read-through therapy to challenge with aminoglycosides limitation factors in clinical use and the chronic inflammation in JEB-C17 patients. We developed TRID-C5 containing low dosage of aminoglycosides, CC-90009, NMDI-14, melatonin and apocynin that was able to induce about 20% of missing C17 without cell toxicity and effect on in vitro wound closure. TRID-C5 significantly induced COL17A1 expression and reverted the proinflammatory phenotype of JEB-C17 keratinocytes. Evaluation of this drug cocktail regarding its stability, penetration and efficacy as a topical treatment remains to be determined. TRID-C5 might represent an improved therapeutic strategy for JEB and for other genetic skin disorders.

Lipoid proteinosis: A rare genodermatosis with multisystemic manifestations-A case report.

Lipoid proteinosis (LP) is a rare autosomal recessive genodermatosis, which is characterized by the deposition of amorphous hyaline material in various tissues, including the mucosa, visceral organs, and skin. We report a case of a 11-year-old girl born to consanguineous parents presented with multisystemic manifestations of the disorder. The patient presented with progressive skin lesions evolving from blisters to papules, distinctive beaded papules along eyelid margins, hoarseness of voice, impaired speech, hair loss, and a painful jaw swelling. Clinical examination revealed waxy skin, atrophic scars, and keratotic plaques. Histopathology report revealed amorphous hyaline eosinophilic material deposition. This case report highlights the multisystemic manifestations of LP and the importance of early diagnosis and management.

[Focal dermal hypoplasia associated with pathogenic PORCN gene variant in postzygotic, unilateral mosaic form]. / Fokale dermale Hypoplasie durch pathogene Variante im PORCN-Gen in postzygotischer, unilateraler Mosaik-Konstellation.

We report a case of a 29-year-old woman with subtle partial erythematous, partial hyperpigmented streaks along the Blaschko's lines on the right side of the body since early childhood. Primary DNA results of the skin and blood assay diagnosed focal dermal hypoplasia in mosaic form. The postzygotic mutation in the PORCN gene was only detectable in the affected skin and not in the blood assay. This article illustrates that clinically very discrete hypopigmentation and poikiloderma along Blaschko lines should raise awareness for robust diagnostic analysis in order to recognize this variable multisystem disease and to ensure an appropriate search for extracutaneous abnormalities and human genetic counseling, ideally before pregnancy. Careful correlation of clinical, histological, and genetic features along with close multidisciplinary cooperation of specialists from the fields of human genetics, dermatology, pediatrics, orthopedics and ophthalmology is crucial for final diagnosis, assessment of the prognosis and targeted genetic counseling of affected individuals.

Self-reported clinical features and treatment effectiveness of Papillon-Lefèvre syndrome patients from five Latin American countries: A cross-sectional online survey study.

BACKGROUND/OBJECTIVES: Most studies about Papillon-Lefèvre syndrome (PLS) are limited to case reports and patients of the same nationality. This study aimed to determine the self-reported prevalence of signs, symptoms and treatment effectiveness in PLS patients from five Latin American countries. METHODS: An online survey was conducted among adult and paediatric patients from Mexico, Argentina, Colombia and Brazil. Data were collected using multiple-choice, open-ended and image-chooser questions on demographics, signs and symptoms, perceived treatment effectiveness and quality of life. RESULTS: Seventeen patients (10 males and 7 females) aged 4-47 years were surveyed. All had palmoplantar hyperkeratosis. Other affected sites were the feet and hand dorsum (82.35%), Achilles tendon (88.24%), forearms (58.82%), legs (29.41%) and glutes (23.53%). They frequently presented hyperhidrosis and nail pitting. Four had a history of delayed umbilical cord separation. All used topical treatments, with moderate effectiveness; half used oral retinoids, perceived as highly effective. Most reported decreased quality of life and walking difficulties. CONCLUSIONS: The study's results align with prior research on PLS, but reveal new insights, including the impact on patients' quality of life and a history of delayed umbilical cord separation. These findings warrant consideration in future research and patient care.

Incontinencia pigmenti. progresión clínica y diagnóstico de un caso / Incontinentia pigmenti. clinical progression and diagnosis of a case

Resumen La incontinencia pigmenti(IP) es una genodermatosis infrecuente ysistémica del neuroectodermo que involucra la piel, el sistema nervioso central, los ojos y los dientes, entre otros. Los signos clínicos dermatológicos constituyen el principal criterio diagnóstico, debido a que suelen ser los primeros en manifestarse. Se describen cuatro estadios característicos de la enfermedad según las lesiones cutáneas predominantes. No obstante, su pronóstico depende de los signos y síntomas extracutáneos. El diagnóstico se centra en criterios clínicos, histopatológicos y/o genéticos. Visto que no existe una terapéutica específica, la atención médica de esta enfermedad es multidisciplinaria y sintomática, y debe acompañarse del asesoramiento genético a los afectados y sus familiares. Presentamos el caso de una niña, nacida a término completo, quien presentó un cuadro clínico compatible con incontinencia pigmenti, del cual detallamos su progresión clínica, diagnóstico y seguimiento.

Abstract Incontinentiapigmenti is a rare and multisystemic,neuroectodermal genodermatosis that involves the skin, central nervous system, eyes and teeth, among others. Dermatological clinical signs are the main diagnostic criteria because they are usually the first to manifest. Four characteristic stages of the disease are described according to the predominant skin lesions. Nonetheless, prognosis depends on extracutaneous clinical signs and symptoms. Diagnosis is based on clinical, histopathological and/or genetic criteria. Considering there is no specific treatment available, the management of this disease is multidisciplinary and symptomatic, and must be accompanied by genetic counseling for those affected and their families. We present in a full-tern newborn femalethat presented with a clinical picture compatible with incontinentiapigmenti, and we will detail the clinical progression, diagnosis, and follow-up.

Dyschromatosis symmetrica hereditaria: A clue to early diagnosis of Aicardi-Goutières syndrome.

A 6-year-old female with a history of Aicardi-Goutières syndrome (AGS) presented to dermatology clinic with hypopigmented and hyperpigmented macules and patches consistent with dyschromatosis symmetrica hereditaria (DSH). Previous genetic workup demonstrated a de novo, heterozygous mutation in the adenosine deaminase acting on RNA 1 (ADAR) gene. While the co-occurrence of AGS and DSH has previously been described in mutations of the ADAR gene, our case highlights the potential association between these disorders that may aid in earlier future diagnosis of AGS.

Defective monocyte plasticity and altered cAMP pathway characterize USB1-mutated poikiloderma with neutropenia Clericuzio type.

Poikiloderma with neutropenia (PN) Clericuzio type (OMIM #604173) is a rare disease with areas of skin hyper- and hypopigmentation caused by biallelic USB1 variants. The current study was spurred by poor healing of a perianal tear wound in one affected child homozygous for c.266-1G>A (p.E90Sfster8) mutation, from a family reported previously. Treatment with G-CSF/CSF3 or GM-CSF/CSF2 transiently increased neutrophil/monocytes count with no effect on wound healing. Analysis of peripheral blood revealed a lack of non-classical (CD14+/- CD16+ ) monocytes, associated with a systemic inflammatory cytokine profile, in the two affected brothers. Importantly, despite normal expression of cognate receptors, monocytes from PN patients did not respond to M-CSF or IL-34 in vitro, as determined by cytokine secretion or CD16 expression. RNAseq of monocytes showed 293 differentially expressed genes, including significant downregulation of GATA2, AKAP6 and PDE4DIP that are associated with leucocyte differentiation and cyclic adenosine monophosphate (cAMP) signalling. Notably, the plasma cAMP was significantly low in the PN patients. Our study revealed a novel association of PN with a lack of non-classical monocyte population. The defects in monocyte plasticity may contribute to disease manifestations in PN and a defective cAMP signalling may be the primary effect of the splicing errors caused by USB1 mutation.

Pachyonychia Congenita: A Research Agenda Leading to New Therapeutic Approaches.

Pachyonychia congenita (PC) is a dominantly inherited genetic disorder of cornification. PC stands out among other genodermatoses because despite its rarity, it has been the focus of a very large number of pioneering translational research efforts over the past 2 decades, mostly driven by a patient support organization, the Pachyonychia Congenita Project. These efforts have laid the ground for innovative strategies that may broadly impact approaches to the management of other inherited cutaneous and noncutaneous diseases. This article outlines current avenues of research in PC, expected outcomes, and potential hurdles.

X-linked genodermatoses from diagnosis to tailored therapy.

Background: Genodermatoses are rare heterogeneous genetic skin diseases with multiorgan involvement. They severely impair an individual's well-being and can also lead to early death. Methods: During the progress of this review, we have implemented a targeted research approach, diligently choosing the most relevant and exemplary articles within the subject matter. Our method entailed a systematic exploration of the scientific literature to ensure a compre-hensive and accurate compilation of the available sources. Results: Among genodermatoses, X-linked ones are of particular importance and should always be considered when pediatric males are affected. Regardless of other syndromic forms without prevalence of skin symptoms, X-linked genodermatoses can be classified in three main groups: keratinization defects, pigmentation defects, and inflammatory skin diseases. Typical examples are dyskeratosis congenita, keratosis follicularis spinulosa decalvans, hypohidrotic ectodermal dysplasia, chondrodysplasia punctata, hypohidrotic ectodermal dysplasia, incontinentia pigmenti, chronic granulomatous disease, CHILD syndrome and ichthyosis. In this field, genetic diagnosis of the specific disease is important, also considering that numerous clinical trials of orphan drugs and genetic therapies are being proposed for these rare genetic diseases. Conclusions: Thus, this chapter starts from clinical to molecular testing and ends with a review of all clinical trials on orphan drugs and gene therapy for genodermatoses.

[Hereditary epidermolysis bullosa in children]. / L'épidermolyse bulleuse héréditaire chez les enfants.

Hereditary epidermolysis bullosa (HES) is a heterogeneous group of rare genetic disorders characterized by localized or generalized fragility of the skin and/or mucous membranes, varying greatly in severity from one form to another and even within a subgroup. Skin wounds can be a source of pain, pruritus and discomfort from birth. Progression varies from patient to patient and from form to form. Specific care must be provided from the neonatal period onwards, and throughout life, to aid healing and limit complications. Nurses are at the heart of skin care for HES patients, and must be familiar with the main principles, while adapting to the individual.

Retrospective study of efficacy and adverse events of immune checkpoint inhibitors in 22 xeroderma pigmentosum patients with metastatic or unresectable cancers.

Background: Xeroderma pigmentosum (XP), a rare disease with defects in DNA repair genes, has >1,000-fold increased risk of ultraviolet-induced skin cancers. Immune checkpoint inhibitors (ICIs) are used for treating cancers with large numbers of mutations but may also promote adverse events (AEs). Deficient DNA repair in XP patients may lead to increased numbers of mutations, leading to enhanced efficacy of cancer response or, alternatively, to increased AE in response to ICI. We sought to compare the efficacy and AE of ICI in XP patients with metastatic or unresectable cancers to that of ICI-treated patients in the general population. Methods: In this retrospective study, we reviewed medical records of XP patients treated in the United States and in London (UK). We also reviewed published reports of ICI-treated XP patients and patients in the general population. Results: Metastatic or unresectable cancers in all 22 (100%) XP patients showed regression or remission in response to ICI. The types and frequencies of AE in XP patients were similar to those reported among ICI-treated patients in the general population. However, two XP patients had concurrent additional cancers that did not respond to ICI, two XP patients had cancer recurrence or progression after initial response, and eight XP patients developed new skin cancers during or after ICI treatment. Conclusion: In this retrospective study with small sample size, XP patients demonstrated positive responses to ICI and the treatment was well tolerated but some patients developed new skin cancers while being treated. ICIs can be considered in treating metastatic or unresectable cancers in XP patients.

Severe Hypernatremia as Presentation of Netherton Syndrome.

Netherton syndrome is a rare, multisystem, autosomal recessive genodermatosis characterized by a triad of manifestations: congenital ichthyosis, immune dysregulation, and scalp anomalies. We report the case of a 1-month-old male infant evaluated for failure to thrive and feeding difficulties. At birth, the infant was admitted to intensive care for severe hypernatremia (natremia 186 mg/dL). Upon entering the ward, the general conditions were poor. He presented with diffuse erythrodermia. A dermatological evaluation showed evidence of "invaginated trichuriasis," a typical sign of Netherton syndrome. Netherton syndrome is caused by a genetic mutation causing loss of function of the SPINK5 gene it encodes for the LEKTI protein, normally expressed in epithelia. Loss of LEKTI induces severe skin barrier defect. The history of the disease is characterized by serious potential complications in the first months of life, such as the risk of hypernatremic dehydration induced by high skin permeability, recurrent and/or severe infections, and growth retardation.