Unilateral focal palmoplantar keratoderma associated with a postzygotic variant in PIK3CA and activation of the PI3K/AKT/mTOR pathway.

Palmoplantar keratoderma (PPK) is a group of -disorders with genetic and phenotypic heterogeneity featuring skin thickening of the palms and soles. More than 60 genes involved in various biological processes are implicated in PPK. PIK3CA is an oncogene encoding p110α, and its somatic variants contribute to a spectrum of congenital overgrowth disorders, including epidermal nevi (EN). To identify the genetic basis and elucidate the pathogenesis of a patient with unilateral focal PPK. Whole-exome sequencing and Sanger sequencing combined with laser capture microdissection (LCM) were performed on genomic DNA extracted from the patient's peripheral blood and skin lesion. Skin biopsies were taken from the lesion of the patient and normal controls for immunofluorescence. Molecular docking was performed using Alphafold2-multimer. A three-year-old girl presented with unilateral focal PPK with an identified missense -variant (c.3140A>G, p.His1047Arg) in PIK3CA from affected tissue. This variant only existed in the lesional epidermis. Elevated PI3K/AKT/mTOR signalling in the affected epidermis and an increased number of Ki67-positive keratinocytes were demonstrated. Molecular docking indicated instability of the p110α-p85α dimer caused by the PIK3CA His1047Arg variant. We describe the first PPK case associated with a variant in PIK3CA, which expands the spectrum of PIK3CA-related disorders. Our study further underscores the importance of the PI3K/AKT/mTOR pathway in the homeostasis of skin keratinization.

CASTing the net wider: A case report of PLACK syndrome associated with dilated cardiomyopathy.

PLACK syndrome (OMIM 616295) is a rare genodermatosis associated with peeling skin, leukonychia, acral punctate keratosis, cheilitis, and knuckle pads and is caused by loss-of-function mutations in the CAST gene, which encodes calpastatin, a calcium-dependent protease. This case report highlights a case of PLACK syndrome presenting with the unique findings of striate hyperkeratosis on the palms as well as life-threatening cardiomyopathy. We review why CAST mutations might impact cardiac function and raise awareness of the potential association between PLACK syndrome and cardiac manifestations.

Pain Hypersensitivity in SLURP1 and SLURP2 Knock-out Mouse Models of Hereditary Palmoplantar Keratoderma.

SLURP1 and SLURP2 are both small secreted members of the Ly6/u-PAR family of proteins and are highly expressed in keratinocytes. Loss-of-function mutations in SLURP1 lead to a rare autosomal recessive palmoplantar keratoderma (PPK), Mal de Meleda (MdM), which is characterized by diffuse, yellowish palmoplantar hyperkeratosis. Some individuals with MdM experience pain in conjunction with the hyperkeratosis that has been attributed to fissures or microbial superinfection within the affected skin. By comparison, other hereditary PPKs such as pachyonychia congenita and Olmsted syndrome show prevalent pain in PPK lesions. Two mouse models of MdM, Slurp1 knock-out and Slurp2X knock-out, exhibit robust PPK in all four paws. However, whether the sensory experience of these animals includes augmented pain sensitivity remains unexplored. In this study, we demonstrate that both models exhibit hypersensitivity to mechanical and thermal stimuli as well as spontaneous pain behaviors in males and females. Anatomical analysis revealed slightly reduced glabrous skin epidermal innervation and substantial alterations in palmoplantar skin immune composition in Slurp2X knock-out mice. Primary sensory neurons innervating hindpaw glabrous skin from Slurp2X knock-out mice exhibit increased incidence of spontaneous activity and mechanical hypersensitivity both in vitro and in vivo. Thus, Slurp knock-out mice exhibit polymodal PPK-associated pain that is associated with both immune alterations and neuronal hyperexcitability and might therefore be useful for the identification of therapeutic targets to treat PPK-associated pain.

SERPINB7 Deficiency Increases Legumain Activity and Impairs the Epidermal Barrier in Nagashima-type Palmoplantar Keratoderma.

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive genodermatosis caused by loss-of-function variants in SERPINB7 and is the most prevalent form of inherited palmoplantar keratodermas among Asians. However, there is currently no effective therapy for NPPK because its pathogenesis remains unclear. In this study, Serpinb7-/- mice were generated and spontaneously developed a disrupted skin barrier, which was further exacerbated by acetone-ether-water treatment. The skin of these Serpinb7-/- mice showed weakened cytoskeletal proteins. Additionally, SERPINB7 deficiency consistently led to decreased epidermal differentiation in a three-dimensional human epidermal model. We also demonstrated that SERPINB7 was an inhibitory serpin that mainly inhibited the protease legumain. SERPINB7 bound directly with legumain and inhibited legumain activity both in vitro and in vivo. Furthermore, we found that SERPINB7 inhibited legumain in a 'protease-substrate' manner and identified the cleavage sites of SERPINB7 as Asn71 and Asn343. Overall, we found that SERPINB7 showed the nature of a cysteine protease inhibitor, and identified legumain as a key target protease of SERPINB7. Loss of SERPINB7 function led to overactivation of legumain, which might disrupt cytoskeletal proteins, contributing to the impaired skin barrier in NPPK. These findings may lead to the development of therapeutic strategies for NPPK.

Transgradient Variant of Mal De Meleda Presenting As Palmoplantar Keratoderma: A Case Report.

Mal De Meleda is a rare genetic disorder characterized by palmoplantar keratoderma, often presenting challenges in diagnosis and management. This case report discusses an 18-year-old male presenting with thickened, yellowish skin on both palms and soles, accompanied by itching and cracking. A diagnosis of the transgradiens variant of Mal De Meleda was established through clinical and histopathological examination. Treatment with oral acitretin and topical moisturizers resulted in significant improvement. This report highlights the importance of recognizing rare variants of palmoplantar keratoderma and the need for a multidisciplinary approach to diagnosis and management.

[Palmoplantar dermatoses: Diagnostic approach in primary care]. / Dermatosis palmoplantares: aproximación diagnóstica en atención primaria.

This article addresses the diagnostic challenges of palmoplantar dermatoses (PPD) within the scope of Primary Health Care (PHC). These common skin conditions, encountered in daily practice, exhibit a diverse range of symptoms and morphologies, complicating their diagnosis. They are etiologically classified into infectious inflammatory, non-infectious inflammatory, and hereditary keratodermas. While various dermatoses may affect the palms and soles, few are specific to this area. Notable examples include palmoplantar pustulosis, dyshidrosis, erythema pernio, and Bazex syndrome. Given the high prevalence of dermatological consultations in PHC, this article underscores the significance of PHC professionals' knowledge regarding these conditions. It proposes a diagnostic algorithm to facilitate their management and timely referral.

Case report of crusted scabies, brief review of its pathophysiology and latest data.

Background: Crusted scabies is a rare form of parasitic infection provoked by a massive infestation of the ectoparasite Sarcoptes scabiei varietas hominis on human skin. It is an extremely contagious type of disease and can even lead to a social stigma. In European countries like Greece, many cases remain undiagnosed for long periods, causing extreme distress in the patient's everyday life and social environment. Case Description: Herein, we present a case of an 86-year-old woman with crusted scabies in Greece, who remained undiagnosed for 5 months. Massive hyperkeratotic plaques on the extremities, and face, palmoplantar keratoderma, and numerous small erythematous papules on the torso with extreme itch were the main clinical manifestations of the patient. Dermoscopy revealed the parasite. All necessary decontamination measures were taken by personnel. Treatment was administered and a complete cure of the disease was observed. Conclusions: In this case, the use of dermoscopy has attributed to precise crusted scabies diagnosis and acute pharmacological management of the patient. Early diagnosis of such diseases not only saves patients from lethal secondary infections, but also reduces the risk of a massive scabies outbreak. We also conducted a mini-review, analyzing all recent data concerning crusted scabies macroscopic, dermatoscopic, and histological images. All new information concerning the pathophysiological mechanism of crusted scabies manifestation, updated treatment options, and potential resistance to widely-used treatments are provided.

A Case of Palmoplantar Keratoderma in the Constellation of Connective Tissue Diseases.

Overlap syndrome is a clinical challenge and brings together a wide range of treatment options for the treating physician. Addressing each and every complaint of the patient is crucial. A 50-year-old female patient presented with skin thickening, blackening, and hyperkeratosis; dysphagia; joint pain; features of myopathy; Raynaud's phenomenon; and dry mouth. Inflammatory markers were raised along with a positive antinuclear antibody (ANA) with Golgi apparatus pattern, anti-Sjögren's-syndrome-related antigen A (anti-SSA)/Ro60 3+, anti-SSA/Ro52 3+, and anti-PM/Scl 2+ antibodies that suggested overlap syndrome. Although the patient had no respiratory complaints, a unique interstitial lung disease (ILD) pattern was noted during the evaluation. Skin manifestations were puzzling, but the histopathology analyses of skin biopsies taken from two different sites revealed distinguishing features of cutaneous lupus and dermatomyositis. Treatment with hydroxychloroquine, pilocarpine, nifedipine, methotrexate, and topical tacrolimus produced a dramatic improvement in the clinical features. This case highlights subtle and florid features of different autoimmune diseases. The hyperkeratotic skin changes were the most striking feature, but the whole evaluation process unveiled many rare presentations of known autoimmune conditions that can open doors to new areas of our understanding toward connective tissue diseases (CTDs). Our case report demonstrates significant heterogeneity in the ANA patterns, ILD patterns, clinical manifestations, and treatment approaches.

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.

Acquired diffuse palmoplantar erythema with keratoderma in Chinese patients with pustular psoriasis: A predictor for IL36 receptor antagonist c.115+6T>C mutation?

Several studies have suggested that mutation of the interleukin 36 receptor antagonist gene (IL36RN) is related to generalized pustular psoriasis (GPP), and the presence of IL36RN mutation may affect the clinical manifestations and treatment responses. However, genetic testing is not routinely available in clinical practice for the diagnosis of GPP. Previously, GPP patients with acrodermatitis continua of Hallopeau (ACH) were found to have a high percentage of carrying IL36RN mutation. In this study, we reported six patients with pustular psoriasis presenting as diffuse palmoplantar erythema with keratoderma among 60 patients who carried IL36RN mutation. ACH was present in five patients and five patients had acute flare of GPP. This unique presentation may serve as a predictor for IL36RN mutation in patients with pustular psoriasis, similar to ACH.

ECFS standards of care on CFTR-related disorders: Identification and care of the disorders.

This is the third paper in the series providing updated information and recommendations for people with cystic fibrosis transmembrane conductance regulator (CFTR)-related disorder (CFTR-RD). This paper covers the individual disorders, including the established conditions - congenital absence of the vas deferens (CAVD), diffuse bronchiectasis and chronic or acute recurrent pancreatitis - and also other conditions which might be considered a CFTR-RD, including allergic bronchopulmonary aspergillosis, chronic rhinosinusitis, primary sclerosing cholangitis and aquagenic wrinkling. The CFTR functional and genetic evidence in support of the condition being a CFTR-RD are discussed and guidance for reaching the diagnosis, including alternative conditions to consider and management recommendations, is provided. Gaps in our knowledge, particularly of the emerging conditions, and future areas of research, including the role of CFTR modulators, are highlighted.

Identification of a founder variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate palmoplantar keratoderma in Southern Denmark.

Palmoplantar keratoderma (PPK) is a heterogeneous group of rare skin diseases characterized by hyperkeratosis on the palms or soles. The subtype isolated punctate PPK is caused by heterozygous variants in AAGAB. We investigated if the variant AAGAB c.370C>T, p.Arg124Ter in patients with punctate PPK in the Region of Southern Denmark represented a founder variant and estimated the age to the most recent common ancestor. We performed haplotype analysis on samples from 20 patients diagnosed with punctate PPK and the AAGAB c.370C>T, p.Arg124Ter variant. Using the Gamma Method, we calculated the years to the most recent common ancestor. We also explored the presence of the variant in other populations through literature and databases (HGMD, ClinVar, and gnomAD). Our analysis revealed a shared haplotype of 3.0 Mb, suggesting shared ancestry. The ancestral haplogroup was estimated to an age of 12.1 generations (CI: 4.9-20.3) equivalent to approximately 339 years (CI: 137-568). This study confirms that the frequently observed variant AAGAB c.370C>T, p.Arg124Ter in punctate PPK among patients in the Region of Southern Denmark is caused by a founder variant. We recommend testing for the variant as initial screening in our region and potentially for all Danish patients presenting with punctate PPK.

Spontaneous clinical remission of Nagashima-type palmoplantar keratoderma in a patient of Korean descent with a heterozygous SERPINB7 mutation.

Nagashima-type palmoplantar keratoderma (NPPK) is an autosomal recessive form of diffuse palmoplantar keratoderma (PPK) characterized by thickening and redness of palms and/or soles. In this report, we describe a female patient of Korean descent who had clinical remission of her adult-onset NPPK. To our knowledge, she is the first reported heterozygous SERBINB7 mutation carrier to present with classic NPPK who achieved spontaneous clinical remission.

Pachyonychia Congenita Project: Advancing Research and Drug Development through Collaboration.

Pachyonychia Congenita Project (PC Project) is an international patient advocacy organization dedicated to patients who suffer from pachyonychia congenita (PC). This condition is a painful and debilitating skin disorder caused by a mutation in one of five keratin genes: KRT6A, KRT6B, KRT6C, KRT16,or KRT17. Through two primary programs, namely the International Pachyonychia Congenita Consortium (IPCC) and the International Pachyonychia Congenita Research Registry (IPCRR), PC Project provides comprehensive patient support and diagnostics while uniting patients, researchers, physicians, and industry partners on a global level to advance research and drug development for meaningful treatments and, ultimately, a cure for PC.