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The article explores shared clinical features and successful therapeutic interventions in CARD14-associated papulosquamous eruption (CAPE), a condition caused by gain-of-function variants in the CARD14 gene. The study retrospectively analyzed 22 individuals from 16 families with CARD14 variants, showing variable responses to biologic treatments like ustekinumab, risankizumab, and bimekizumab. The research highlights the need for personalized treatment approaches for CAPE patients and suggests that early biologic intervention may lead to more sustained improvements. Further studies are needed to optimize treatment strategies for this rare condition. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

Olmsted syndrome (OS) is a rare congenital skin disorder, typically characterized by symmetrical, severe palmoplantar and periorificial keratoderma, often accompanied by alopecia, and onychodystrophy, with varying degrees of pruritus and pain. Gain-of-function variants of the transient receptor potential cation channel subfamily V member 3 (TRPV3) were described as a cause of OS. Here, we report an atypical case of OS caused by a novel mutation in the TRPV3 gene that has not been described before in OS. The patient presented with disabling, bilateral palmoplantar keratoderma, and subsequently developed squamous cell carcinoma on the right sole. Genetic analysis identified a novel heterozygous p.Val306Met missense mutation in the exon 8 of TRPV3. Our findings expand the phenotypic spectrum of TRPV3-related OS and underscore the need for vigilant long-term monitoring of these patients. [ABSTRACT FROM AUTHOR]

Case: Vohwinkel syndrome is a rare, inherited condition marked by defective keratinization. The disorder may feature digital constriction bands (pseudoainhum) which can lead to autoamputation. Surgical excision is the only treatment of pseudoainhum; however, it is fraught with recurrence. We present a 10-year-old boy with pseudoainhum of the right long and small fingers at the distal interphalangeal joints. He underwent 180-degree band excision and z-plasty. Conclusion: Since establishing care 8 years ago, he has undergone treatment of 5 constriction bands with only 1 recurrence. We believe this success can at least be partially attributed to the technique described by Upton. [ABSTRACT FROM AUTHOR]

This article discusses a case study of a 2-year-old female patient from Turkey with Mal de Meleda (MDM), a rare form of palmoplantar keratoderma. The patient presented with hyperkeratotic plaques on her palms and soles, which gradually extended to the dorsum of her hands and feet. The article describes the clinical characteristics of MDM, including hyperhidrosis, perioral erythema, and nail dystrophies. A novel mutation in the SLURP1 gene, which is associated with MDM, was identified in the patient. The article emphasizes the need for genetic counseling for affected individuals and their families. [Extracted from the article]

Introduction • Palmoplantar keratoderma is an abnormal thickening of the skin on the palms of the hands and soles of the feet. The classification of palmoplantar keratoderma depends on the clinical characteristics and whether it is hereditary or acquired. The traditional approach tries to soften and minimize skin thickness. The usual treatment choices include emollients, keratolytics like salicylic acid or urea, antifungal cream or pills, as well as topical retinoids/calcipotriol and systemic retinoids. However, the persistent use of such medications frequently exhausts the patients because the problem returns as soon as the local applications are discontinued. Methods • The case was recorded in the dermatological department of Dr DY Patil HMC & RC. A 27-year-old female patient prediagnosed with Palmoplantar Keratoderma was treated with individualized homeopathic medicine (iHOM) between 25th February 2021 to 22nd July 2021. During the follow-up visits outcome was assessed. To assess whether the changes were due to homeopathic medicine a modified Naranjo criteria was performed. Based on the totality of symptoms, individualized homeopathic medicine Petroleum 30C was given. Results • The patient was successfully treated for palmoplantar keratoderma with homeopathic Petroleum 30C over five months. Cracks and thickening of skin on the palms and soles resolved completely with no pain and itching. Conclusion • Individualized homeopathic treatment of palmoplantar keratoderma is possible and offers a gentle, non-invasive alternative to pharmaceutical use. [ABSTRACT FROM AUTHOR]

This article discusses the use of tildrakizumab, an interleukin (IL) inhibitor, for the treatment of recalcitrant pityriasis rubra pilaris (PRP). PRP is a rare skin disorder with no approved biologic treatments in Australia. The article presents three cases of PRP that were successfully treated with tildrakizumab, resulting in significant improvements in symptoms and minimal adverse effects. Tildrakizumab is considered a promising therapeutic option for PRP, and further studies are needed to determine its optimal use. [Extracted from the article]

Reactive arthritis(ReA), a form of arthritis occurring post-infection, manifests with antecedent infection symptoms, arthritis, and extra-articular manifestations, categorizing it as spondyloarthritis. "Keratoderma blennorrhagicum" (characterized by pustular hyperkeratosis on palms and soles, resembling pustular psoriasis) represents the most typical skin manifestation of ReA, occurring in acute or chronic phases. Severe lesions necessitate systemic disease modifying antirheumatic drugs (DMARDs) or biologic therapies. This article reports a case of ReA with sacroiliitis and widespread pustular eruptions following a urinary tract infection. Treatment with sulfasalazine and thalidomide significantly improved sacroiliitis, but the skin rash remained persistent and recurring. Subsequent use of adalimumab and secukinumab resulted in worsening skin rash, prompting a switch to tofacitinib, leading to a remarkable improvement in pustular eruptions after 20 days of treatment. This case demonstrates successful application of tofacitinib in treating severe keratoderma blennorrhagicum refractory to conventional DMARDs and biologics, offering insights into JAK inhibition for challenging rheumatic diseases with skin involvement. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The article discusses non-pachyonychia congenita conditions found in the International Pachyonychia Congenita Research Registry. Pachyonychia congenita is a rare disorder with specific clinical features, and genetic testing is crucial for an accurate diagnosis. The registry has identified other rare skin disorders with similar phenotypes, such as Clouston syndrome, Olmsted syndrome, and striate palmoplantar keratoderma, caused by different gene variants. Genetic testing is emphasized for accurate diagnosis and appropriate clinical management of these conditions. [Extracted from the article]

The article in Experimental Dermatology discusses a case study of a 12-year-old boy with palmoplantar keratoderma and woolly hair, which are associated with a variant in the DSP gene. The boy showed symptoms such as hyperkeratosis on his feet and fingers, as well as abnormal hair characteristics. Genetic testing revealed a variant in the DSP gene, leading to a reduction in desmoplakin protein expression. The study highlights the importance of genomic investigations in carriers of this variant to understand the associated phenotype. [Extracted from the article]

The article published in the British Journal of Dermatology discusses a case of progressive symmetric erythrokeratodermia (PSEK) caused by a loss-of-function variant in the KLF4 gene. The patient, a 16-year-old woman, exhibited erythema and hyperkeratosis on her hands and feet since birth, with lesions spreading to other parts of her body. The study highlights the genetic and phenotypic heterogeneity of PSEK and identifies KLF4 as a novel gene associated with this condition. [Extracted from the article]

Connexin hemichannels (HCs) expressed at the plasma membrane of mammalian cells are of paramount importance for intercellular communication. In physiological conditions, HCs can form gap junction (GJ) channels, providing a direct diffusive path between neighbouring cells. In addition, unpaired HCs provide conduits for the exchange of solutes between the cytoplasm and the extracellular milieu, including messenger molecules involved in paracrine signalling. The synergistic action of membrane potential and Ca2+ ions controls the gating of the large and relatively unselective pore of connexin HCs. The four orders of magnitude difference in gating sensitivity to the extracellular ([Ca2+]e) and the cytosolic ([Ca2+]c) Ca2+ concentrations suggests that at least two different Ca2+ sensors may exist. While [Ca2+]e acts as a spatial modulator of the HC opening, which is most likely dependent on the cell layer, compartment, and organ, [Ca2+]c triggers HC opening and the release of extracellular bursts of messenger molecules. Such molecules include ATP, cAMP, glutamate, NAD+, glutathione, D-serine, and prostaglandins. Lost or abnormal HC regulation by Ca2+ has been associated with several diseases, including deafness, keratitis ichthyosis, palmoplantar keratoderma, Charcot–Marie–Tooth neuropathy, oculodentodigital dysplasia, and congenital cataracts. The fact that both an increased and a decreased Ca2+ sensitivity has been linked to pathological conditions suggests that Ca2+ in healthy cells finely tunes the normal HC function. Overall, further investigation is needed to clarify the structural and chemical modifications of connexin HCs during [Ca2+]e and [Ca2+]c variations. A molecular model that accounts for changes in both Ca2+ and the transmembrane voltage will undoubtedly enhance our interpretation of the experimental results and pave the way for developing therapeutic compounds targeting specific HC dysfunctions. [ABSTRACT FROM AUTHOR]

Ichthyosis hystrix (Curth-Macklin ichthyosis) is an ultrarare autosomal dominant non-syndromic inherited ichthyosis belonging to the group of keratinopathic ichthyosis characterized by common histology pattern of epidermolytic hyperkeratosis. It is inherited either as an autosomal dominant or sporadic variety. We report the case of a 10-year-old male child with hyperkeratotic scales all over the body in blaschkoid pattern for 1.5 years of age with predominant involvement of flexures and relative sparing of face and scalp. There was no history of similar complaints in any family member. The case is being reported on account of rarity of the disease, that too with a very rare sporadic presentation. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Acral amelanotic melanomas (AAMs), a rare subset of melanomas located on acral sites such as the palms, soles, and subungual areas, are diagnostically challenging due to their lack of typical pigmentation and often benign clinical appearance. Misdiagnosis is common, leading to delays in treatment and potentially worse outcomes. This systematic review aims to synthesise evidence on cases of AAM initially misdiagnosed as other conditions, to better understand their clinical and epidemiological characteristics, diagnostic pitfalls, and management strategies. Methods: A comprehensive search of the MEDLINE/PubMed, EMBASE, and SCOPUS databases was conducted up to March 2024. Case reports and small case series of AAMs initially misdiagnosed as other conditions were included. Data on patient demographics, clinical presentation, and diagnostic methods were collected and analyzed. Results: Of the 152 records identified, 26 cases from 23 articles met the inclusion criteria. A demographic analysis revealed that the gender distribution appears to be perfectly balanced, with an age range of 38 to 91 years. Misdiagnoses included non-healing ulcers or traumatic lesions (37.5%), benign proliferative lesions (29.2%) and infectious lesions (20.8%). The foot was the most affected site (53.8%). Notably, a histological evaluation was performed in 50% of cases involving the upper extremities, in contrast to only 7.1% of cases involving the foot and 0% of cases of the heel. This discrepancy suggests a reluctance to perform biopsies in the lower extremities, which may contribute to a higher misdiagnosis rate in these areas. Conclusions: The underutilization of biopsy in the diagnosis of lower extremity lesions contributes significantly to the misdiagnosis and delay in treatment of AAMs. Especially when the clinical assessment and dermoscopy are inconclusive, biopsies of suspicious lesions are essential. Immunohistochemistry and markers such as PRAME are critical in differentiating melanoma from other malignancies such as clear cell sarcoma. This review highlights the need for increased vigilance and a proactive diagnostic approach to increase early detection rates and improve prognostic outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND: Lichen nitidus is an infrequent dermatosis and especially prevalent in the pediatric population, although it also affects adults. It is typically characterized by papules with a smooth or umbilicated surface located on the extremities, trunk, and genitals. However, it exhibits various clinical manifestations that may vary according to location and subtype, making its diagnosis in these cases a challenge for the dermatologist. CLINICAL CASE: A 60-year-old female patient with a 9-month history of generalized, pruritic and some purpuric lesions, associated with keratoderma-type palmoplantar involvement. A biopsy was taken from one of the lesions located on the left forearm, compatible with generalized lichen nitidus. CONCLUSIONS: It is important to know the clinical varieties of this dermatosis, especially the generalized form. In these cases, the identification of typical lichen nitidus lesions in some body segments, central palmar involvement, and histological findings are key. [ABSTRACT FROM AUTHOR]

Background: Changes in skin, hair, and nails may be initial manifestations of an underlying thyroid hormone deficiency. Symptomatic treatment of cutaneous manifestations without treatment of underlying hypothyroidism contributes to long-term morbidity in patients. Aims and Objectives: The aim of the study was to study the cutaneous manifestations and demographic profile of patients with hypothyroidism. Materials and Methods: We conducted a hospital-based cross-sectional study of 200 patients presenting with cutaneous changes in primary hypothyroidism for a period of 18 months. A detailed history, clinical examination, and relevant investigations were performed. Results: Out of 200 patients, cutaneous manifestations were more prevalent in the age group between 30 and 49 years. The ratio of male to female was 1.0:6.4. A family history of hypothyroidism was present in 34.5% of patients. The most common cutaneous features were alteration in skin texture (53.0%), dry skin (48.5%), generalized pruritus (42.5%), urticaria (17%), followed by pigmentation of the skin (34.5%), out of which vitiligo was 9.0%, melasma was 5.5%, and others were 20.0%. Other changes include xerosis (32.5%), eczematous disorder (13%), acquired palmoplantar keratoderma (11.5%), and brittle nails (3.5%). 39.5% had hair changes, out of which diffuse hair loss was 17.5%, coarse hair wa s 12%, alopecia areata was 4.5%, and lateral loss of eyebrows was 4.5%. Changes in the oral cavity and mucous membrane were present in 3.0% of the patients, which included lip vitiligo (1.5%), oral lichen planus (1%), and oral candidiasis (0.5%). Menstrual abnormalities were present in 50.84% of females. The percentage of hypothyroid patients who complained of easy fatigability, facial puffiness, cold intolerance, weight gain, constipation, neck swelling, hoarseness of voice, increased sleeping pattern, and non-pitting edema of feet were 38.5%, 36.5%, 26.0%, 23.5%, 17.0%, 9%, 8%, 7.5%, and 6.5%, respectively. Conclusion: Based on our study, it can be concluded that the presence of certain skin conditions, such as alteration in skin texture, dry skin, generalized pruritus, urticaria, skin pigmentation, and diffuse hair loss, may indicate the possibility of hypothyroidism. These cutaneous manifestations may occur earlier than the diagnosis of hypothyroidism through biochemical testing. Therefore, it is important to consider the possibility of hypothyroidism when examining patients with these skin conditions. [ABSTRACT FROM AUTHOR]

Pachyonychia congenita (PC) is a group of rare hereditary disorders, characterised by hypertrophic nails and palmoplantar keratoderma (PPK), particularly localised to the pressure areas of the feet. At a molecular level, it is caused by mutations in genes encoding KRT6A, KRT6B, KRT6C, KRT16, or KRT17. To identify the underlying gene mutation in a Chinese family with PC presenting with disabling palmoplantar keratoderma and subsequent associated acral melanoma. Genomic DNA was extracted from peripheral blood samples of three available individuals in the Chinese family, which included the patient and his two unaffected sisters. The index patient presented with severe palmoplantar keratoderma as well as a newly diagnosed acral malignant melanoma (MM). Whole-exome sequencing (WES) was carried out with amplification of exon 1 of KRT16 by polymerase chain reaction (PCR). PCR products were then sequenced to identify potential mutations. We identified the proline substitution mutation p.Arg127Pro (c.380G>C) in our patient's 1A domain of KRT16. The same mutation was not found in his sisters or unrelated healthy controls. The mutation (p.Arg127Pro (c.380G>C)) in KRT16 has been reported in Dutch patients with PC. However, it is the first such report of a patient with a PC of Chinese origin. In addition, the acral MM occurred under the background of genetic PPK caused by KRT16 mutation in this patient. [ABSTRACT FROM AUTHOR]

Palmoplantar keratoderma (PPK) is a multi-faceted skin disorder characterized by the thickening of the epidermis and abrasions on the palms and soles of the feet. Among the genetic causes, biallelic pathogenic variants in the FAM83G gene have been associated with PPK in dogs and humans. Here, a novel homozygous variant (c.794G>C, p.Arg265Pro) in the FAM83G gene, identified by whole exome sequencing in a 60-year-old female patient with PPK, is reported. The patient exhibited alterations in the skin of both hands and feet, dystrophic nails, thin, curly and sparse hair, long upper eyelid eyelashes, and poor dental enamel. FAM83G activates WNT signalling through association with ser/thr protein kinase CK1α. When expressed in FAM83G−/− DLD1 colorectal cancer cells, the FAM83GR265P variant displayed poor stability, a loss of interaction with CK1α and attenuated WNT signalling response. These defects persisted in skin fibroblast cells derived from the patient. Our findings imply that the loss of FAM83G-CK1α interaction and subsequent attenuation of WNT signalling underlie the pathogenesis of PPK caused by the FAM83GR265P variant.

Abstract Keratoderma climactericum is characterized by palmoplantar hyperkeratosis developing after the onset of menopause. Although rare, keratoderma climactericum can profoundly impact quality of life and may be refractory to prescription‐strength topical steroids and keratolytics. We report a 52‐year‐old female with a 1‐year history of palmoplantar keratoderma. She had a medical history of generalized anxiety disorder and had reached menopause 2 years before presentation. Previously failed treatments included clotrimazole 1% cream twice daily, triamcinolone 0.1% cream twice daily, and betamethasone 0.05% cream mixed with tazarotene 0.1% cream twice daily. She was diagnosed with keratoderma climactericum, and conjugated oestrogen 0.625 mg/g cream twice daily was initiated. After 4 weeks, she had dramatically reduced erythema and hyperkeratosis of her bilateral palms and soles. No adverse effects to treatment were reported. Although the utility of topical oestrogen for keratoderma climactericum has been debated, our case provides further evidence for its efficacy and safety.

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

This article discusses two cases of erythrodermic pityriasis rubra pilaris (PRP) that showed a rapid and significant response to treatment with tildrakizumab. PRP is a rare skin condition characterized by scaly plaques and palmoplantar keratoderma. The usual treatments for PRP, such as retinoids and immunosuppressants, can take several months to show results and may have adverse effects. However, these cases demonstrate that tildrakizumab, a biologic therapy, can lead to a fast clearance of lesions in patients with PRP. This information provides additional therapeutic options for the treatment of PRP, especially when a quick resolution of symptoms is needed. [Extracted from the article]

Background: Hereditary palmoplantar keratodermas (hPPKs) comprise a heterogeneous group of skin disorders characterized by persistent palmoplantar hyperkeratosis. Loss‐of‐function variants in a serine peptidase inhibitor, SERPINA12, have recently been implicated in autosomal recessive diffuse hPPK. The disorder appears to share similarities with another hPPK associated with protease overactivity, namely Nagashima‐type PPK (NPPK) caused by biallelic variants in SERPINB7. Objectives: The aim of this study was to enhance the understanding of the clinical and genetic characteristics of serine protease‐related hPPKs caused by variants in SERPINA12 and SERPINB7. Methods: Whole‐exome sequencing (WES) was performed for hPPK patients. Haplotype analysis was completed for the patients with identified recessive SERPINA12 variants and their available family members. In addition, the current literature of SERPINA12‐ and SERPINB7‐related hPPKs was summarized. Results: The phenotype of SERPINA12‐related hPPK was confirmed by reporting three new SERPINA12 patients, the first of European origin. A novel SERPINA12 c.1100G>A p.(Gly367Glu) missense variant was identified confirming that the variant spectrum of SERPINA12 include both truncating and missense variants. The previously reported SERPINA12 c.631C>T p.(Arg211*) was indicated enriched in the Finnish population due to a plausible founder effect. In addition, SERPINA12 hPPK patients were shown to share a similar phenotype to patients with recessive variants in SERPINB7. The shared phenotype included diffuse transgradient PPK since birth or early childhood and frequent palmoplantar hyperhidrosis, aquagenic whitening and additional hyperkeratotic lesions in non‐palmoplantar areas. SERPINA12 and SERPINB7 hPPK patients cannot be distinguished without genetic analysis. Conclusions: Recessive variants in SERPINA12 and SERPINB7 leading to protease overactivity and hPPK produce a similar phenotype, indistinguishable without genetic analysis. SERPINA12 variants should be assessed also in non‐Asian patients with diffuse transgradient PPK. Understanding the role of serine protease inhibitors will provide insights into the complex proteolytic network in epidermal homeostasis. [ABSTRACT FROM AUTHOR]

Background: Data on the treatment of palmoplantar psoriasis (PP) are very limited as these patients are often excluded from clinical trials. Moreover, this form of psoriasis is often resistant to treatment, making its clinical management complex. Methods: Primary endpoint was to evaluate the clinical and demographic characteristics and the drug survival of both biological and non‐biological drugs in a population affected by PP. Secondary endpoint was to highlight any differences between the hyperkeratotic and pustular variant. We analyzed data from 233 psoriasis patients with palmoplantar involvement, with or without chronic plaque psoriasis. We performed a drug‐survival analysis with the aid of Kaplan‐Meier survival and a multivariate analysis to highlight the influence of certain variables on treatment persistence using a Cox regression model. Results: The drug‐survival analysis revealed that biologic drugs compared to non‐biologic drugs are associated with a higher persistence in treatment (59.73 vs. 43.56%); in particular, anti‐IL23 drugs were found to be the drugs with the best drug‐survival overall (67.94% of patients at 60 months are still on these drugs). Furthermore, our multivariate analysis shows that when compared with biological drugs, non‐biological drugs are associated with an increased risk of treatment discontinuation (HR = 1.95 [95% CI: 1.41–2.68], P = 0.001). Conclusions: Our study confirms the difficulty of treating PP and shows that biologic drugs are associated with longer persistence in treatment than non‐biologics in both PP's variants, not because of their higher effectiveness but because of their better safety profile. [ABSTRACT FROM AUTHOR]

Carvajal syndrome (MIM605676) is a cardiocutaneous disease with non-epidermolytic palmoplantar keratosis (PPK), hair anomalies (woolly hair or hypotrichosis) and dilated cardiomyopathy (DCM). Autosomal recessive inherited mutations in the desmoplakin (DSP) gene are causative for this disorder. Cardiac involvement may lead to heart failure and sudden cardiac death. Since this may require pacemaker and heart transplantation, early diagnosis and cardiologic screening is of great importance. We present a diagnostic case with typical but also hidden symptoms of Carvajal syndrome and its clinical follow up. A skin biopsy showed hyperkeratosis, acanthosis and "acantholysis of the desmosomal-type" as defined by hypereosinophilic epidermal keratinocytes, widening of the intercellular spaces and partial loss of the intercellular bridges in the suprabasal layers. Vesiculation, blistering, crusting and stronger inflammation were absent. We would like to point out the importance of a diagnostic skin biopsy and discuss the histologic differential diagnoses of acantholysis of the desmosomal-type. [ABSTRACT FROM AUTHOR]

Pachyonychia Congenita (PC) is a rare genetic disorder characterised by excessive keratinisation of the skin, nails, and mucous membranes, leading to thickened nail beds and skin on pressure points, notably on the soles of the feet. A 10-year-old girl came to the Outpatient Department (OPD) with her 38-year-old mother. Both of them had same complaints regarding their nails and callous formation over soles. They both had thickened nail plates with thickened pressure points on sole [Table/Fig-1a-c,2a-c]. In PC, oral manifestations are found but on the day of visit they didn’t have any lesion in mouth. Both of them had difficulty and pricking sensation during walking. Both of them had anorexia due to the heinous presentation of the nails. They had taken lots of medicines for the conditions of nails but of no use. Other family members were not affected. Dyskeratosis congenita, pterygium inversum unguis, and onycholysis can be differential diagnosis. The final diagnosis is PC type I. In [Table/Fig-1a-c,2a,b], onychodystrophy can be seen clearly. In [Table/Fig-2c], plantar keratoderma can be seen, which are the cardinal features for the diagnosis of PC.

Laila Tsaqilah,1 Keshia Amalia Mivina Mudia,1 Hermin Aminah Usman,2 Hartati Purbo Dharmadji,1 Risa Miliawati Nurul Hidayah,1 Erda Avriyanti1 1Department of Dermatology and Venereology, Faculty of Medicine, Universitas Padjadjaran–Dr. Hasan Sadikin General Hospital, Bandung, West Java, Indonesia; 2Department of Anatomical Pathology, Faculty of Medicine, Universitas Padjadjaran–Dr. Hasan Sadikin General Hospital, Bandung, West Java, IndonesiaCorrespondence: Laila Tsaqilah, Department of Dermatology and Venereology, Faculty of Medicine, Universitas Padjadjaran–Dr. Hasan Sadikin General Hospital, Jl. Pasteur 38, Bandung, West Java, 40161, Indonesia, Tel +6282284474849, Email lailazuardy@gmail.comAbstract: Acquired palmoplantar keratoderma (PPK) is a non-hereditary hyperkeratosis of the palms and soles that is caused by various factors, including chemotherapeutic agents. The purpose of this case report is to present a rare case of acquired PPK caused by the chemotherapeutic agent capecitabine. A 54-year-old female complained of painful erythematous plaques on her palms and soles with history of consuming capecitabine. Physical examination revealed scaly erythematous plaques on the palmoplantar surface and knuckle pads on both hands. Histopathological features showed hyperkeratosis, acanthosis, vasodilatation, and perivascular lymphocytic infiltration. Therefore, the patient was diagnosed with acquired PPK due to capecitabine. The dose of capecitabine was reduced and the patient was administered topical corticosteroid and emollient. Improvement of skin lesions was strongly observed after discontinuation of capecitabine. The underlying cause of PPK should be identified to determine the appropriate treatment. Dose reduction or drug discontinuation is the mainstay therapy for patients with acquired PPK caused by chemotherapeutic agents.Keywords: capecitabine, chemotherapy, palmoplantar keratoderma

This article discusses two cases of palmoplantar keratoderma, a skin condition characterized by thickened and hardened skin on the palms and soles. The patients presented with linear distribution of verrucous and keratotic plaques on their hands, feet, and other areas of the body. Genetic analysis revealed pathogenic variants in the HRAS gene, which is associated with various skin disorders. The article suggests that the clinical presentation of HRAS-associated nevus (HAN) can vary widely, from isolated linear palmoplantar keratoderma to widespread lesions covering the skin in a mosaic pattern. [Extracted from the article]

This article discusses a case of lichenoid dermatosis on the feet of an 83-year-old woman. The patient presented with hyperkeratotic plaques on the left heel, onychodystrophy of the toenails, and other skin and mucosal lesions. The diagnosis was determined to be hypertrophic lichen planus based on clinical findings and histopathology. Treatment with clobetasol ointment and methotrexate resulted in notable improvement. The article also provides information on lichen planus and its variants, as well as other conditions that may present with similar symptoms. [Extracted from the article]

Abstract Papillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disease that presents clinically with palmoplantar keratoderma and periodontitis and results in early‐onset dental loss. PLS management is difficult. We report a 30‐year‐old female with PLS who had unfavourable response to topical keratolytic creams, oral isotretinoin and narrow‐band ultraviolet‐B (NB‐UVB) phototherapy but showed significant clinical improvement to adalimumab.

Abstract Background Ectodermal dysplasia syndactyly syndrome 1 (EDSS1) is a rare hereditary disorder characterized by defects in teeth, hair, and nails in association with a fusion of the digits. Genetically, the disease phenotypes are caused by homozygous and compound heterozygous variants in NECTIN4 gene. Objective The main objective of the study was to identify the pathogenic sequence variant(s) for family screening and identification of carriers. Methods In the present study, the authors have investigated a large consanguineous family of Pakistani origin segregating autosomal recessive EDSS1. All the coding exons of the NECTIN4 gene were directly sequenced using gene-specific primers. Results The affected individuals presented the classical EDSS1 clinical features including sparse hair, hypoplastic nails with thick flat discolored nail plates, peg-shaped, conical, and widely spaced teeth with enamel hypoplasia, proximal cutaneous syndactyly of fingers and toes. Sequence analysis of the coding region of the NECTIN4 identified a novel nonsense variant [c.163C>T; p.(Arg55*)] in exon-2 of the gene. Computational analysis of protein structure revealed that the variant induced premature termination at Arg55 located in Ig-like V-loop region leading to loss of Ig-C2 type domains and transmembrane region, and most likely Nectin-4 function will be lost. Study limitation Gene expression studies are absent that would have strengthened the findings of computational analysis. Conclusion The present study expanded the phenotypic and mutation spectrum of the NECTIN4 gene. Further, the study would assist in carrier testing and prenatal diagnosis of the affected families.

This article discusses a case of atypical epidermolytic palmoplantar keratoderma (EPPK), a rare hereditary skin condition. The patient, an 8-year-old boy, presented with diffuse hyperkeratosis on his palms, soles, and other areas of his body. Genetic analysis revealed a mutation in the KRT1 gene, which is associated with EPPK and other skin conditions. Ultrastructural analysis of the patient's skin showed abnormal keratin structures, suggesting that atypical EPPK is a minimal phenotypic variant of epidermolytic ichthyosis (EI). The study also suggests that non-genetic factors and inflammatory cytokines may contribute to the development of these skin diseases. [Extracted from the article]

This article explores the genetic and clinical aspects of autosomal recessive congenital ichthyosis (ARCI) caused by mutations in the NIPAL4 and PNPLA1 genes. The study investigates potential treatments for ARCI, including anti-interleukin therapy for cytokine dysregulation and pruritus. The authors conducted a retrospective analysis of patients with these gene mutations and evaluated their response to specific treatments. The results showed varying effects, highlighting the need for further research in this area. The article also includes a table summarizing the genetic variants and clinical features of twelve patients with different forms of ichthyosis and palmoplantar keratoderma. The study was conducted as part of the European Reference Network-SKIN subthematic group Ichthyosis and Palmoplantar Keratoderma and received ethical approval. [Extracted from the article]

Background: Palmoplantar keratodermas (PPK) represents a group of skin disorders characterized by excessive epidermal thickening of palms and soles. They are classically divided into inherited and acquired groups. Dermoscopy is a non-invasive procedure that can aid in the clinical diagnosis of PPK. Objectives: To study the clinical features and dermoscopic patterns of PPK caused by various dermatological conditions. Methods: Ninety-eight patients with various types of PPK were included in this cross-sectional observational study after obtaining informed consent. Symptoms, general systemic findings, and dermatological manifestations were recorded. The dermoscopic examination was performed by a single observer using Heine Delta 20+ and FotoFinder Medicam 1000. Diagnostically challenging cases were biopsied for histopathological examination. SPSS (Statistical Package for Social Sciences) version 20 [IBM SPSS statistics (IBM Corp. Armonk, NY, USA released 2011)] was used to perform statistical analyses. The chi-square test was applied to examine statistical associations between qualitative variables. The level of significance was set at 5%. Results: Out of 98 cases with PPK, 93 were acquired, and 5 were inherited. The commonest dermoscopy pattern included palmoplantar psoriasis (n = 48), showing a background light red color with yellow diffused white scales with regular dotted and glomerular vessels, followed by palmoplantar eczema (n = 39) (light red color with yellow patchy white background, yellow scales, and patchy dotted vessels). Light red/dull red background with diffuse white scaling and regular linear, dotted, or glomerular vessels were significantly in favor of palmoplantar psoriasis, while a yellow background, diffuse yellow scaling, patchy dotted vessels, and yellow crust were more in favor of palmoplantar dermatitis. Pityriasis rubra pilaris (PRP) (n = 3) showed a light red background, diffused white scales, and dotted and linear vessels with patchy distribution. Lichen planus (n = 2) revealed a light red color with a yellow background, diffused and peripheral white scales, and irregular linear (radial) and dotted vessels. Wickham’s striae were found on palms. Tinea manuum with pedis (n = 1) showed a dull red background and diffused white and yellow scales with the localization of the scales in the skin furrows. PPK secondary to ichthyosis vulgaris (n = 3) revealed a light red background with diffused white and yellow patchy scaling and regular linear and patchy glomerular vessels. Greither’s disease showed a light red color with a yellow background, a diffused white scale pattern, and multiple dotted vessels arranged in an irregular pattern. Erythrokeratodermia variabilis showed a background color of light red and diffused white scales in a crisscross pattern. Conclusions: Dermoscopy can reveal characteristic but not pathognomonic dermoscopic patterns that can be useful in the clinical diagnosis of various types of PPK. More studies with larger sample sizes may help validate these findings and identify new patterns. [ABSTRACT FROM AUTHOR]

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Introduction. Despite the availability of effective biologic therapies for psoriasis, there is no gold-standard treatment for nonpustular palmoplantar psoriasis (ppPsO). Methods. G-PLUS, a phase IIIb, double-blind, placebo-controlled, multicentre clinical trial, randomised adults with moderate-to-severe nonpustular ppPsO and limited plaque psoriasis (Psoriasis Area and Severity Index (PASI) ≥3 but <10) to guselkumab (an interleukin-23p19 blocker) or placebo. Placebo participants were crossed over to receive guselkumab at week (Wk) 16. The primary efficacy endpoint was the proportion of participants achieving palmoplantar PASI (ppPASI) 75 response at Wk16; clinical, biomarker, and quality-of-life endpoints were assessed through Wk48 and safety through Wk56. Results. At Wk16, ppPASI75 response was achieved by 35.9% of the guselkumab participants compared with 28.2% in the placebo group, resulting in a 7.7% difference in response rates (95% confidence interval: −11.5 and 24.7), which was not statistically significant (p = 0.533). More pronounced numerical improvements favouring guselkumab were observed for more stringent efficacy endpoints, such as Wk16 palmoplantar Investigator's Global Assessment (ppIGA) 0/1 response (guselkumab 34.6% vs. placebo 15.4%). Through Wk48, further improvements were observed in ppPASI75 response (55.1% and 64.1%) and ppIGA 0/1 response (42.3% and 48.7%) for the guselkumab and placebo-crossover groups, respectively. Dermatology Life Quality Index responses showed comparable trends at both timepoints. Safety and pharmacodynamic findings were consistent with the established profile for guselkumab. Serum biomarker levels were significantly reduced with guselkumab and correlated with the baseline PASI score but not the ppPASI score. Conclusion. Although the primary endpoint was not met, analysis of stringent secondary endpoints and post hoc analyses showed numerical improvements favouring guselkumab at Wk16. There were no new safety signals. Further studies are warranted to better understand the impact of guselkumab treatment in patients with ppPsO. This trial is registered with NCT03998683. [ABSTRACT FROM AUTHOR]

Background: Palmoplantar keratoderma (PPK) is a heterogeneous group of hereditary or acquired disorders characterised by excessive epidermal thickening of the palms and soles. Proper knowledge about the aetiology of the disease and clinico-demographic profile helps in planning management and predicting outcomes. Aims and Objective: To determine the prevalence of different dermatoses and describe their clinico-histological correlation in acquired palmoplantar keratoderma. Materials and Methods: An institution-based cross-sectional study conducted after obtaining Ethics-Committee permission and consent from participants. Patients of any age or gender presenting with acquired PPK were recruited. The calculated sample size was 67 by using the prevalence rate (p) of 22.2%, allowable error (L) of 10%, the confidence level of 95% (z = 1.96), and an infinite population size of 20,000. Patients were evaluated by taking demographic and clinical data in a pre-designed case record form, necessary laboratory investigations and histopathological examination that wereevaluated by three blinded experts. The pooled data were analysed with statistical software. Results: Among the 67 participants, Psoriasis was diagnosed clinically in 39 (58.2%) and histologically in 7 (10.4%), Lichen planus (LP) clinically in 16 (23.9%) and histologically in 9 (13.4%), Pityriasis rubra pilaris (PRP) in 8 (11.9%) patients clinically and 7 (10.4%) histologically and Hyperkeratotic eczema (HKE) in 4 (6%) clinically and 43 (64.2%) histopathologically. There was very poor inter-rater agreement (Kappa = 0.148, SE 0.0047, 95% CI 0.057 to 0.24). The clinico-pathological correlation was found to be agreeable in 17.9% Psoriasis, 56.2% LP and 87.5% PRP. HKE was commonly misdiagnosed as Psoriasis in 65.1% of patients. Conclusion: Hyperkeratotic lesions of the palm and sole often present with overlapping clinical features and a skin biopsy has to be done to aid in diagnosis. Limitation: Stratification of the clinical expertise of clinicians was done during the analysis. [ABSTRACT FROM AUTHOR]

Palmoplantar pustulosis (PPP) is a stubborn skin disease involving repeated aseptic small pustules on the palms and soles of the feet, which is triggered and exacerbated by metals and dental focal infections. There are few reports of an exacerbation of PPP symptoms after orthognathic surgery. The patient is a 40-year-old female who consulted an orthodontist at our hospital, complaining of a protruding maxilla and malocclusion. Under the diagnosis of skeletal prognathism, she underwent surgery for jaw deformity. Although no allergic symptoms were observed during the orthodontic treatment prior to surgery, postoperative scaling on the palms and soles of her feet worsened, and itching was observed on the skin, especially on the titanium plate used to secure the bone fragments. Under the diagnosis of metal allergy, treatment with steroids and vitamin D ointment failed to improve the condition, so surgery was performed to replace the metal plate with a non-metallic absorbable plate in the third postoperative month. Afterwards, the pruritus resolved, and erythema and scale on the palms and soles nearly disappeared. In the present case, though, oral bacterial infection, a past history of smoking, and stress from surgery were also considered to be possible causes of PPP exacerbation, and we concluded that one of the causes of PPP exacerbation was metal allergy from the plates or screws used to fix the bone fragments. [ABSTRACT FROM AUTHOR]

Eccrine Syringofibroadenoma (ESFA) is an infrequent benign adnexal cutaneous lesion distinguished by hyperplastic epithelium and differentiation into eccrine ducts, displaying diverse clinical presentations. In the present case, a 48-year-old Chinese female patient exhibited a decade-long history of palmoplantar erythema, which clinically resembled Dyshidrotic Eczema. Histological examination suggested the presence of ESFA. Ultimately, considering both the clinical manifestations and histological outcomes, the patients received a diagnosis of reactive ESFA. [ABSTRACT FROM AUTHOR]

Introduction: The involvement of palms and soles is variable among disease entities belonging to autoimmune bullous diseases (AIBD). We present our own clinical-laboratory experience concerning presentations of skin lesions on palms and soles in the pemphigus diseases group, pemphigoid diseases group, epidermolysis bullosa acquisita (EBA), and lichen planus pemphigoides (LPP) and discuss the pertinent literature. Methods: Lesions on palms and soles were assessed retrospectively on the basis of just photographic archives from the beginning of 2014 to March 2023. We comparatively evaluated 462 Slavic patients with AIBD. Results: Palmoplantar involvement was observed in only 21 patients with AIBD (12 females and 9 males). There was no statistically significant difference between palmoplantar involvement in the pemphigus diseases group compared to the pemphigoid diseases group and no statistically significant difference between the pemphigus diseases group compared to the subepithelial AIBD. Discussion: Nevertheless, particularly in LPP and EBA, and occasionally in pemphigus diseases and pemphigoid diseases groups of AIBD, localization on palms and soles may be diagnostically important at the clinical level. [ABSTRACT FROM AUTHOR]

Ectodermal dysplasias (ED) encompass a collection of conditions wherein the development of two or more structures derived from the ectoderm exhibits abnormal patterns. One example of such a rarity within the spectrum of ectodermal dysplasias is hidrotic ectodermal dysplasia, also known as Clouston syndrome. This particular variant is distinguished by a triad of clinical characteristics, which encompass partial-to-complete alopecia, nail dystrophy, and palmoplantar hyperkeratosis. It stands as a scarcely encountered autosomal-dominant inherited disorder, resulting from a mutation in the GJB6 gene that encodes the gap junction protein connexin 30. We hereby document the case of a forty-five-year-old Jordanian woman who presented with alopecia affecting the scalp, eyebrows, and eyelashes, in addition to nail dystrophy. Interestingly, she did not manifest palmoplantar keratoderma. It is worth mentioning that several members of her extended family also manifested similar clinical features. Subsequent genetic testing conclusively established the diagnosis of Clouston syndrome. In light of this diagnosis, comprehensive counseling was extended to the patient. [ABSTRACT FROM AUTHOR]

Congenital skin disorders are a class of complex genetic diseases that are difficult to diagnose and treat. We developed trio whole-exome sequencing-plus (WES-plus) for detecting de novo mutations and evaluated the use of traditional Chinese medicine (TCM) for treating congenital skin disorders. In this study, we successively performed panel-based next-generation sequencing (NGS) and Trio WES-plus in a child with frequent large blisters. Panel-based NGS revealed no pathogenic mutations. Trio WES-plus for resequencing based on cutaneous keratosis of the palms and feet detected a missense mutation (c.1436T>A, p.Ile479Asn) in the coding region of KRT1 in the child but not in his parents. Following prenatal diagnosis, a healthy second baby without the mutation was born. The disease symptoms of epidermolytic palmoplantar keratoderma (EPPK) application were improved by TCM and Western medicine. Our study revealed the pathogenicity of a de novo mutation in human KRT1, which expands the mutation spectrum of EPPK. Trio WES-plus is useful for diagnosing genetic diseases and providing genetic guidance from prenatal diagnosis to treatment. [ABSTRACT FROM AUTHOR]

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disease that affects men and women of all ages, including children. PRP is characterized by follicular and palmoplantar hyperkeratosis and salmon-colored scaling plaques. The exact pathogenesis of PRP is still unknown; most PRP cases are acquired, but some cases may show a familial occurrence, often associated with a mutation in the CARD14 gene. Due to the rarity of PRP, treatment recommendations are based mainly on case reports, small case series and expert opinions and still represent a major therapeutic challenge, especially in children. A growing number of reports on treatment with biologicals, particularly anti-TNFα, has been published. However, an involvement of the IL-23/Th17 axis in both psoriasis and PRP pathogenesis may suggest that this pathway may be a potential therapeutic target. Here, we present three pediatric patients with PRP successfully treated with risankizumab. All patients exhibited a severe course of PRP and lack of response to conventional therapy, including acitretin, cyclosporine and phototherapy. A single dose of 75 mg risankizumab resulted in almost complete clearance of skin lesions in case 1 and 2 at week 4. In patient 3, clear skin was achieved after the second administration of risankizumab (150 mg). All patients continue the treatment with risankizumab, and no adverse effects have been reported up to the present time. Our study demonstrates that risankizumab, an IL-23 blocker, shows good efficacy and safety among pediatric patients with PRP. [ABSTRACT FROM AUTHOR]

Introduction: We evaluated the anti-interleukin-36 receptor antibody spesolimab in patients with moderate-to-severe palmoplantar pustulosis (PPP). Methods: This phase IIb trial comprised a loading dose period to week (W) 4, then maintenance dosing to W52. Patients were randomised 2:1:1:1:2 to subcutaneous spesolimab 3000 mg to W4 then 600 mg every 4 weeks (q4w), spesolimab 3000 mg to W4 then 300 mg q4w, spesolimab 1500 mg to W4 then 600 mg q4w, spesolimab 1500 mg to W4, 300 mg q4w to W16 then 300 mg every 8 weeks (q8w), or placebo switching to spesolimab 600 mg q4w at W16. The primary efficacy endpoint was percentage change from baseline in Palmoplantar Pustular Area and Severity Index (PPP ASI) at W16. Secondary endpoints included a Palmoplantar Pustular Physician's Global Assessment (PPP PGA) score of 0/1. Safety (including adverse events [AEs], local tolerability) was assessed. Results: 152 patients were treated. The primary endpoint was not met; mean differences for spesolimab versus placebo ranged from − 14.6% (95% confidence interval [CI]: − 31.5%, 2.2%) to − 5.3% (95% CI: − 19.1%, 8.6%); none reached significance. At W16, 23 (21.1%) and two (4.7%) patients in the combined spesolimab and placebo groups, respectively, achieved PPP PGA 0/1 (mean difference 16.4%; 95% CI: 3.8%, 25.7%), increasing to 59 (54.1%; combined spesolimab) and 12 (27.9%; placebo switch to spesolimab) patients at W52. Non-Asian patients had significant improvements in the primary endpoint (mean difference − 17.7%; nominal P = 0.0394) and PPP PGA 0/1 at W16 with spesolimab versus placebo. Rates of AEs and AE-related discontinuations were similar for spesolimab and placebo. Local tolerability events and injection-site reactions were more frequent with spesolimab than placebo. Conclusion: The primary objective to demonstrate a non-flat dose–response relationship and proof-of-concept was not achieved; improvements with spesolimab occurred in secondary endpoints and in non-Asian patients, indicating potential modest benefits. Spesolimab was generally well tolerated (ClinicalTrials.gov NCT04015518). Plain Language Summary: A clinical trial of spesolimab for patients with palmoplantar pustulosis. Palmoplantar pustulosis (PPP) is a painful, difficult-to-treat skin disease that is found on patients' palms and the soles of their feet. In this clinical trial, we studied an injected medicine called spesolimab for treating patients with PPP. Patients were split into five groups; four groups received different doses of spesolimab and one received placebo (an injection without spesolimab). After 16 weeks, patients receiving placebo switched to spesolimab. We measured the body area affected by PPP and how severe PPP was at week 16. Patients' doctors also assessed skin affected by PPP. At 16 weeks of treatment, there was no significant difference between spesolimab and placebo in terms of the PPP-affected area and severity. However, more patients had clear or almost clear skin with spesolimab than placebo. Among non-Asian patients, more showed an improvement in their PPP with spesolimab than with placebo; this was not the case with Asian patients. Patients taking spesolimab or placebo reported side effects, of which the most common were colds, aches and headaches. More patients receiving spesolimab reported a reaction at the injection site compared with placebo. We monitored patients for up to 1 year, and results remained similar. We showed that spesolimab may have a modest effect on the body area affected by PPP, as well as the severity of PPP, and did not seem to cause more side effects than placebo, except for reactions at the injection site. [ABSTRACT FROM AUTHOR]