Germline NLRP1 Mutations Cause Skin Inflammatory and Cancer Susceptibility Syndromes via Inflammasome Activation.

Inflammasome complexes function as key innate immune effectors that trigger inflammation in response to pathogen- and danger-associated signals. Here, we report that germline mutations in the inflammasome sensor NLRP1 cause two overlapping skin disorders: multiple self-healing palmoplantar carcinoma (MSPC) and familial keratosis lichenoides chronica (FKLC). We find that NLRP1 is the most prominent inflammasome sensor in human skin, and all pathogenic NLRP1 mutations are gain-of-function alleles that predispose to inflammasome activation. Mechanistically, NLRP1 mutations lead to increased self-oligomerization by disrupting the PYD and LRR domains, which are essential in maintaining NLRP1 as an inactive monomer. Primary keratinocytes from patients experience spontaneous inflammasome activation and paracrine IL-1 signaling, which is sufficient to cause skin inflammation and epidermal hyperplasia. Our findings establish a group of non-fever inflammasome disorders, uncover an unexpected auto-inhibitory function for the pyrin domain, and provide the first genetic evidence linking NLRP1 to skin inflammatory syndromes and skin cancer predisposition.

Multifocal epithelial tumors and field cancerization from loss of mesenchymal CSL signaling.

It is currently unclear whether tissue changes surrounding multifocal epithelial tumors are a cause or consequence of cancer. Here, we provide evidence that loss of mesenchymal Notch/CSL signaling causes tissue alterations, including stromal atrophy and inflammation, which precede and are potent triggers for epithelial tumors. Mice carrying a mesenchymal-specific deletion of CSL/RBP-Jκ, a key Notch effector, exhibit spontaneous multifocal keratinocyte tumors that develop after dermal atrophy and inflammation. CSL-deficient dermal fibroblasts promote increased tumor cell proliferation through upregulation of c-Jun and c-Fos expression and consequently higher levels of diffusible growth factors, inflammatory cytokines, and matrix-remodeling enzymes. In human skin samples, stromal fields adjacent to multifocal premalignant actinic keratosis lesions exhibit decreased Notch/CSL signaling and associated molecular changes. Importantly, these changes in gene expression are also induced by UVA, a known environmental cause of cutaneous field cancerization and skin cancer.

Keratose hydrogel for tissue regeneration and drug delivery.

Keratin (KRT), a natural fibrous structural protein, can be classified into two categories: "soft" cytosolic KRT that is primarily found in the epithelia tissues (e.g., skin, the inner lining of digestive tract) and "hard" KRT that is mainly found in the protective tissues (e.g., hair, horn). The latter is the predominant form of KRT widely used in biomedical research. The oxidized form of extracted KRT is exclusively denoted as keratose (KOS) while the reduced form of KRT is termed as kerateine (KRTN). KOS can be processed into various forms (e.g., hydrogel, films, fibers, and coatings) for different biomedical applications. KRT/KOS offers numerous advantages over other types of biomaterials, such as bioactivity, biocompatibility, degradability, immune/inflammatory privileges, mechanical resilience, chemical manipulability, and easy accessibility. As a result, KRT/KOS has attracted considerable attention and led to a large number of publications associated with this biomaterial over the past few decades; however, most (if not all) of the published review articles focus on KRT regarding its molecular structure, biochemical/biophysical properties, bioactivity, biocompatibility, drug/cell delivery, and in vivo transplantation, as well as its applications in biotechnical products and medical devices. Current progress that is directly associated with KOS applications in tissue regeneration and drug delivery appears an important topic that merits a commentary. To this end, the present review aims to summarize the current progress of KOS-associated biomedical applications, especially focusing on the in vitro and in vivo effects of KOS hydrogel on cultured cells and tissue regeneration following skin injury, skeletal muscle loss, peripheral nerve injury, and cardiac infarction.

Strengthening the relationship between intractable plantar keratosis and human papillomavirus.

The aim of the study was to determine the presence of human papillomavirus (HPV) in patients with intractable plantar keratosis (IPK) by comparing the histopathological findings of biopsies. A prospective, observational, and concordance study was carried out. Three different specimens were taken from each IPK. A first punch was sent for histopathological examination, and a second punch and a superficial skin scraping were both sent for HPV  polymerase chain reaction (PCR) and type determination. A total of 51 patients were included. From the histopathological examination, it was determined that 35 (68.6%) samples were diagnosed as warts and 16 (31.3%) as keratosis. However, the presence of HPV was confirmed by PCR in 49 (96.1%) and in 42 (82.4%) samples obtained by punch and superficial scraping, respectively. In the 49 PCR-positive samples, the most common HPV types were HPV1, HPV2, HPV27, HPV57, and HPV65, accounting for 81.6% of the samples. In conclusion, this study demonstrates that HPV infection and IPK lesions are very closely related. Although we cannot confirm that HPV is the cause of the development of IPK, the high prevalence of HPV observed in these lesions calls for a change to the procedures for managing IPK.

Proliferating inverted follicular keratosis of genital skin: Case series of a challenging variant.

BACKGROUND: Inverted follicular keratosis (IFK) is a benign cutaneous epithelial tumor typically presenting as a small papule on the head and neck. We have encountered deep endophytic tumors on genital skin with some characteristics of IFK but also atypical features, raising concern for squamous cell carcinoma (SCC). METHODS: Four such tumors were identified in our database. Histopathologic analysis and ancillary studies were performed. RESULTS: All patients were young women who presented with a solitary 0.5-1.0 cm lesion on the vulva, perineum, or inner buttock. Each showed a squamous proliferation arising from the epidermis, with endophytic growth that was deep and bulbous but not infiltrative. The tumor lobules contained eosinophilic keratinocytes, forming numerous squamous eddies. Small irregular spaces and dyskeratotic cells were frequently found. Nuclear pleomorphism was minimal to absent. All demonstrated wild-type p53 expression and lack of p16 block positivity. In situ hybridizations for human papillomavirus were negative. None of the three cases with follow-up data showed evidence of recurrence. CONCLUSIONS: The absence of infiltrative growth or significant pleomorphism, the presence of numerous squamous eddies, the reassuring immunoprofile, and the lack of evidence of recurrence support a variant of IFK and speak against SCC. We propose the term "proliferating IFK" to highlight the florid squamous proliferation. Recognition of this unusual variant would avoid overdiagnosis of SCC.

Dermatoscopic profiling of inverted follicular keratosis in different skin phenotypes.

BACKGROUND: Inverted follicular keratosis (IFK) is a rare benign tumour of the follicular infundibulum. Owing to its similarity to other benign and malignant cutaneous lesions, it poses a diagnostic challenge. There is limited information on the dermatoscopic characteristics of IFK and the majority of cases have been reported in patients with lighter skin types. OBJECTIVES: To describe the prevalent dermatoscopic features of IFK, especially in patients with skin of colour. METHODS: We retrospectively analysed 35 histopathologically verified cases of IFK from a single university hospital in Turkey. RESULTS: With respect to the Fitzpatrick skin phototype, 2 (6%), 12 (34%), 16 (46%) and 5 (14%) patients had Fitzpatrick skin phototypes II, III, IV and V, respectively. Clinically, the majority of IFKs were hypopigmented or nonpigmented (83%). Pink-white structureless areas (54%), ulceration (54%), a central keratin mass (43%) and blood spots on keratin mass (43%) were the most frequent dermatoscopic findings. Pigmented structures were observed as blue-grey structureless areas in 12 lesions and as blue-grey clods in 5, primarily in Fitzpatrick phototype IV and V skin. The incidence of a pink, structureless area and blood spots on ulceration was found to be statistically significantly higher in individuals with fairer skin types, while a greater prevalence of blue-grey coloration was observed in those with skin of colour (P < 0.05). CONCLUSIONS: Although our study found some distinguishing dermatoscopic findings in IFK, diagnosis is generally confirmed by histopathology, as the clinical appearance and dermatoscopic findings may not be sufficient to differentiate it from other tumours, especially squamous cell carcinoma or keratoacanthoma. The dermatoscopic characteristics of dark skin are comparable to those of pale skin; however, hyperpigmentation can be more noticeable in skin of colour.

Arsenical keratosis in China: A case report and review of the literature.

BACKGROUND: Arsenical keratosis is a precancerous dermatosis which could be induced by long-term exposure to arsenic poisoning. Arsenic is often added to traditional Chinese medicine in a non-compliant manner to increase the effectiveness of psoriasis treatment, which is often the main cause of arsenic poisoning in Chinese patients with psoriasis. OBJECTIVES: We performed a systemic review of arsenic keratosis during the past 32 years to better understand the sources, treatment, and prognosis of arsenic keratosis in China. METHODS: We searched Medline/PubMed, Embase, CNKI, and Wanfang databases for research studies published between 1992 and 2024. A total of 64 papers with 78 individual Chinese of arsenical keratosis were included in this analysis. RESULTS: Of the patients included in the analysis, 92.21% of arsenic poisoning was due to iatrogenic factors: Chinese traditional medicine. Seventy-six patients (98.70%) had skin manifestation of hyperkeratotic papules and plaques, 68 patients (88.31%) had hyperpigmentation, 43 cases (55.84%) had hypopigmentation, and only 4 had a clear indication of Mees' lines in nails. A total of 52.63% of patients presented with tumors, including squamous cell carcinoma, Bowen's disease, and basal cell carcinoma. For patients with tumors, 20 opted for surgery, 6 for radiotherapy, and 3 for PDT. All patients with only cutaneous tumors are currently well-controlled. Death occurred in one patient with metastatic squamous cell carcinoma. Keratinizing papules improved significantly in 70.59% of patients treated with Acitretin Capsules. CONCLUSIONS: In this study, arsenic sources in Chinese patients were mainly from traditional Chinese medicine, and there were no reports of exposure to water sources or occupational sources in the past 32 years. Most of the patients showed keratinizing papules and pigmentation, and more than 1/2 of the patients showed skin tumors, mainly squamous cell carcinoma. The treatments of tumors are mainly surgical treatment, PDT and radiotherapy can also be selected. The improvement in keratinizing rash was greater than 70% with acitretin capsules. Patients with this disease should be regularly followed up for early detection and timely treatment of potential malignant tumors.

Comparison of dermoscopic characteristics on toenail onychomycosis in psoriatic and non-psoriatic patients: A prospective study.

BACKGROUND: Psoriatic patients may experience the coexistence of onychomycosis (OM). However, the evaluation of OM in psoriatics has been hindered by potential clinical differences from OM in non-psoriatics. OBJECTIVE: To assess and compare dermoscopic features between toenail OM in psoriatic and in non-psoriatic patients. PATIENTS AND METHODS: Between September 2020 and September 2023, dermoscopy was conducted on 183 affected toenails by OM in psoriatics and 232 affected toenails by OM in non-psoriatics in two centres. The dermoscopic characteristics were compared using the Chi-squared test. RESULTS: Among toenail OM cases in psoriatic subjects, the most prevalent dermoscopic features included pitting (147/183, 80.33%) and subungual hyperkeratosis (118/183, 64.48%). Conversely, toenail OM in non-psoriatics was characterized by subungual hyperkeratosis (175/232, 75.43%) and nail spikes (139/232, 59.91%). Comparative analysis revealed a significantly higher occurrence of pitting (80.33% vs. 15.96%, p < .001), periungual telangiectasis (22.40% vs. 4.74%, p < .001), oil patches (12.57% vs. 0.43%,p < .001) and transverse grooves (43.72% vs. 28.45%,p < .01) in toenail OM in psoriatics. Furthermore, toenail OM in psoriatics exhibited a significantly lower frequency of yellow structureless area (13.11% vs. 42.67%, p < .001), nail spikes (43.17% vs. 59.91%, p < .01), ruin appearance of sulphur nugget (8.20% vs. 31.03%, p < .001), dotted/blocky haemorrhage (6.01% vs. 20.69%,p < .001) and partial onycholysis (32.79% vs. 46.98%, p < .01). CONCLUSIONS: Dermoscopic features of toenail OM in psoriatic and non-psoriatic patients exhibit notable differences. OM in psoriatics shows a higher frequency of pitting and periungual telangiectasis, while a lower frequency of yellow structureless areas and nail spikes under dermoscopy.

Cutaneous Horn Presentation in Porokeratotic Eccrine Ostial and Dermal Duct Nevus. A Brief Review and Case Report.

ABSTRACT: Porokeratotic eccrine ostial and dermal duct nevus is a rare adnexal hamartoma characterized by the presence of a cornoid lamella exclusively overlying eccrine acrosyringia. Different clinical presentations have been reported in the literature. Here, we report a case of a 6-year-old girl diagnosed with porokeratotic eccrine ostial and dermal duct nevus confirmed by histopathologic study. Atypical lesions are described as whitish, warty-looking neoformations located in the anterolateral region of the right hip (cutaneous horn).

Infantile anogenital digitate keratoses.

Infantile anogenital digitate keratoses (IADK) represent a distinct and under-recognized pediatric condition of the perianal area of infants, significantly more frequent in males than females. The average age of onset is 3.2 months, and it is self-remitting by 2 years of age. Perianal spiny keratoses resistant to usual topical therapies are the hallmark of IADK. We present a series of three cases of IADK seen at the dermatology clinic of the CHU Sainte-Justine to raise awareness on this pediatric condition, and to prevent invasive workup.

Morphea as an isotopic response to pigmented purpuric dermatosis and lichen striatus.

Morphea is an uncommon inflammatory and fibrosing disorder that has a polymorphous clinical presentation. We report two cases of morphea developing as an isotopic response after a preceding benign skin disease, accompanied by a review of the literature. This case series highlights the importance of return to care recommendations for benign skin conditions such lichen striatus and pigmented purpuric dermatoses due to the rare possibility of subsequent morphea development.

Eruptive syringomas associated with milia-like idiopathic calcinosis cutis.

An 11-year-old boy presented generalized eruptive syringomas (ESs) associated with multiple milia-like whitish palmar papules corresponding to dermal calcium deposits. A relationship between calcium deposits distribution to an underlying eccrine duct was noted on pathology. The observation of dermal calcium deposits and its association with generalized ESs may support a possible sweat duct origin of this uncommon and peculiar form of superficial calcinosis cutis.

Milia en plaque on the shoulder as an early manifestations of mycosis fungoides.

Milia en plaque (MEP) is an uncommon skin condition identified as retroauricular confluent milium by Boulzer and Fouqet in 1903 [1]. It can be mistaken for other dermatoses like Favre-Racouchot nodular elastosis, steatocystoma multiplex, and nevus comedonicus. Milia en plaque can either be primary or secondary and is typically benign, often triggered by dermatological procedures like cryotherapy, as reported in this journal. In some cases, MEP can arise as a secondary manifestation of other diseases, including folliculotropic mycosis fungoides (FMF). Despite this association, there are few documented cases in the literature. Herein, we present a patient in whom MEP served as the initial clinical presentation of FMF; the treatment involved oral retinoids and phototherapy. Furthermore, we highlight distinctive features of both conditions. It is important to emphasize that early diagnosis and treatment of FMF are vital for the patient's quality of life. The presence of MEP can serve as a valuable indicator for identifying it.

Mutations in SREBF1, Encoding Sterol Regulatory Element Binding Transcription Factor 1, Cause Autosomal-Dominant IFAP Syndrome.

IFAP syndrome is a rare genetic disorder characterized by ichthyosis follicularis, atrichia, and photophobia. Previous research found that mutations in MBTPS2, encoding site-2-protease (S2P), underlie X-linked IFAP syndrome. The present report describes the identification via whole-exome sequencing of three heterozygous mutations in SREBF1 in 11 unrelated, ethnically diverse individuals with autosomal-dominant IFAP syndrome. SREBF1 encodes sterol regulatory element-binding protein 1 (SREBP1), which promotes the transcription of lipogenes involved in the biosynthesis of fatty acids and cholesterols. This process requires cleavage of SREBP1 by site-1-protease (S1P) and S2P and subsequent translocation into the nucleus where it binds to sterol regulatory elements (SRE). The three detected SREBF1 mutations caused substitution or deletion of residues 527, 528, and 530, which are crucial for S1P cleavage. In vitro investigation of SREBP1 variants demonstrated impaired S1P cleavage, which prohibited nuclear translocation of the transcriptionally active form of SREBP1. As a result, SREBP1 variants exhibited significantly lower transcriptional activity compared to the wild-type, as demonstrated via luciferase reporter assay. RNA sequencing of the scalp skin from IFAP-affected individuals revealed a dramatic reduction in transcript levels of low-density lipoprotein receptor (LDLR) and of keratin genes known to be expressed in the outer root sheath of hair follicles. An increased rate of in situ keratinocyte apoptosis, which might contribute to skin hyperkeratosis and hypotrichosis, was also detected in scalp samples from affected individuals. Together with previous research, the present findings suggest that SREBP signaling plays an essential role in epidermal differentiation, skin barrier formation, hair growth, and eye function.

Loss-of-function mutations in CST6 cause dry skin, desquamation and abnormal keratosis without hypotrichosis.

Cystatin M/E (encoded by the CST6 gene) is a cysteine protease inhibitor, that exerts regulatory and protective effects against uncontrolled proteolysis mainly by directly regulating cathepsin V, cathepsin L, and legumain activities. Previous studies have suggested that CST6 may exert a regulatory role in epidermal differentiation and hair follicle formation by inhibiting the activity of respective cognate target proteases. However, until recently, studies have revealed that loss- or gain-of-function of the CST6 gene causes dry skin with hypotrichosis in humans. Here, we reported two siblings of Chinese origin with dry skin, desquamation and abnormal keratosis without hypotrichosis. By applying whole-exome sequencing, we identified homozygous loss-of-function mutation c.251G > A (p.Gly84Asp) in the CST6 gene as the underlying genetic cause. Further fluorimetric enzyme assays demonstrated the mutant cystatin M/E protein lost its inhibitory function on the protease activity of cathepsins. Moreover, the corresponding mutation in mice resulted in excessive cornification, desquamation, impaired skin barrier function, and abnormal proliferation and differentiation of keratinocytes. In conclusion, the homozygous missense mutation c.251G > A in CST6 gene resulted in dry skin, desquamation, as well as abnormal keratosis of the skin, promoting our understanding of the role of protease-antiprotease balance in human skin disorders.

Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans.

BACKGROUND: Hyperkeratosis lenticularis perstans (HLP), also known as Flegel disease, is a rare skin disease presenting with asymptomatic small hyperkeratotic papules. The lesions often appear on the dorsal feet and lower legs, and typically develop after the fourth decade of life. A genetic basis for HLP is suspected; however, so far no gene defect linked to the development of HLP has been identified. OBJECTIVES: We aimed to identify the genetic cause of HLP. METHODS: For mutational analysis we studied a cohort of five patients with HLP using next-generation sequencing (NGS). We used DNA -extracted from fresh skin biopsies alongside ethylenediamine tetraacetic acid (EDTA) blood samples from two patients, and formalin-fixed -paraffin-embedded skin biopsy material from three patients. In addition, immunofluorescence staining of HLP lesions from four patients was investigated. RESULTS: In all samples from the five patients with HLP we identified by NGS rare variants in the SPTLC1 gene. In four patients we detected small deletions/frameshift variants and in one patient a splicing variant, predicted to disturb the splicing process. In blood samples the detected variants were heterozygous with an allele frequency of 49% and 50%, respectively. In skin biopsies the allele frequency was within the range of 46-62%. Immunofluorescence staining revealed reduced SPTLC1 protein levels in skin of patients. CONCLUSIONS: Our findings suggest that pathogenic variants in the SPTLC1 gene are the underlying genetic cause of HLP. Of note, the identified variants were either frameshift- or splicing variants probably leading to nonsense-mediated mRNA decay and thus reduced SPTLC1 protein levels. We conclude that diminished SPTLC1, the key enzyme in sphingolipid biosynthesis, leads to the development of HLP, which highlights the sphingolipid pathway as a new therapeutic target.

Pitted keratolysis.

Pitted keratolysis (PK) is a common superficial bacterial skin infection confined to the stratum corneum. It is clinically characterized by multifocal, discrete, pits or crater-like punched-out lesions, commonly over the pressure-bearing aspects of the foot. It is asymptomatic and associated with malodour. The surface is often moist and macerated. The diagnosis of PK is often clinical and diagnostic procedures are usually unnecessary. Lifestyle modifications form the cornerstone of the management of PK. It responds well to topical antimicrobials.

Preliminary evaluation of penile papule dermatoses with reflectance confocal microscopy in children.

BACKGROUND: Owing to their similar appearance, lichen striatus (LS), lichen nitidus (LN), juvenile xanthogranuloma (JXG), and molluscum contagiosum (MC) on the penis often lead to misdiagnosis and missed diagnosis, especially in children. In vivo evaluation of penile dermatoses with reflectance confocal microscopy (RCM) is helpful in the diagnosis of these ambiguous lesions in children. METHODS: We recruited 12 patients with LS, nine with LN, seven with JXG, and nine with MC and evaluated the characteristics and distinguishing features of the four kinds of papule dermatoses on the penis using RCM. RESULTS: The four dermatoses all had unique RCM features. LS generally showed focally destroyed dermal papillary rings, with numerous mononuclear cell clusters aggregated inside the papillary rings, and highly refractive clumps were observed. For LN, the dermal papillary rings were completely destroyed and arranged in a solitary, enlarged, cavity-like structure, in which round cells, particulate matter structures, and plump cellular structures were aggregated; the adjacent skin was completely normal. In JXG, the dermal papillary rings were significantly dilated, and the superficial dermis was filled with different-sized large bright ring cells; smaller, refractive, roundish structures; and particulate matter. For MC, the normal structures completely disappeared; the lesions were arranged in a crater-shaped structure; and a mass-like substance formed by the aggregation of multiple, uniform, roundish structures was observed within the crater. CONCLUSION: RCM allows for real-time visualization of major key diagnostic and distinguishing features of four papule dermatoses, LS, LN, JXG, and MC, on the penis in children.

Treponema spp. spirochetes and keratinopathogenic fungi isolated from keratomas in donkeys.

Keratoma is an aberrant keratin mass thought to originate from epidermal horn-producing cells interposed between the stratum medium of the hoof wall and the underlying third phalanx. The cause is unknown, although the presence of keratomas is frequently associated with chronic irritation, focal infection, or trauma. A total of 167 donkeys with keratomas were presented in this study. The diagnosis of a keratoma was based on clinical signs, radiography, and histopathologic examination. Surgical excision was attempted on all donkeys with lameness unless euthanasia was advised. Histopathologic examination, including Giemsa, periodic acid Schiff, and Young's silver special histochemical stains, was performed and showed the presence of fungal hyphae and spirochete bacteria within the degenerate keratin. Polymerase chain reaction (PCR) for treponeme bacteria was performed on 10 keratoma lesions and 9 healthy pieces of hoof (controls). All healthy donkey tissues were negative for the 3 recognized digital dermatitis (DD) treponeme phylogroups, whereas 3 of 10 (30%) donkey keratoma samples were positive for one of the DD treponeme phylogroups. Routine fungal culture and PCR for fungi were performed on 8 keratoma lesions and 8 healthy pieces of hoof (controls). Keratinopathogenic fungi were detected in 1 of 8 (12.5%) keratomas, while only non-keratinopathogenic, environmental fungi were detected in 8 control healthy hoof samples. This is the first time the DD treponemes phylogroup and keratinopathogenic fungi have been detected in keratomas. Further studies are required to assess the significance of this finding.

Aquagenic wrinkling of the palms in a cohort of Greek children diagnosed with cystic fibrosis: Associated clinical parameters.

BACKGROUND: Aquagenic wrinkling of the palms (AWP) is an excessive and early palmar wrinkling occurring after brief immersion to water (BIW), and has been reported as a frequent finding among Cystic Fibrosis (CF) patients. OBJECTIVES: To investigate any associations of CF patients presenting AWP with other disease characteristics and explore the pathomechanism of AWP phenomenon. METHODS: We evaluated AWP in CF patients and assessed the AWP parameters of palmar wrinkling, oedema, papules, pruritus and pain at 3, 7 and 11 min after a BIW test with other disease characteristics. Statistical analyses explored the associations of AWP with genotype, lung function, pancreatic insufficiency, hyperhidrosis, personal and family history of atopy and sweat chloride levels. RESULTS: One hundred CF patients (mean age 10.4 years) were included in the analysis. The genotypic distribution was ΔF508/ΔF508: 47%, ΔF508/other: 41% and other/other: 12%. Statistically significant associations of Kaplan-Meier curves of the AWP parameters with various disease characteristics and personal/family history were detected. Wrinkling was associated with history of atopy, hyperhidrosis and levels of sweat chloride test. The time to presentation of oedema and the appearance of papules were associated with history of hyperhidrosis and age at diagnosis. Finally, time to appearance of pruritus was related to history of atopy and of hyperhidrosis. Regarding TEWL regression analysis showed significant associations with age at diagnosis (p = 0.024), sweat chloride test levels (p = 0.005), history of hyperhidrosis (p = 0.033), history of atopy (p = 0.002) and hepatic-pancreatic involvement (p = 0.027). CONCLUSIONS: The existence of a statistically significant association between AWP and the history of hyperhidrosis, atopy, sweat chloride levels and hepatic-pancreatic function in CF patients was detected. A strong association between AWP and CF was detected. AWP after BIW could be elicited easily and possibly can be used as an initial screening tool to diagnose an individual with symptoms and signs that raise the likelihood of CF.