Neurological disease in xeroderma pigmentosum: prospective cohort study of its features and progression.

Xeroderma pigmentosum (XP) results from biallelic mutations in any of eight genes involved in DNA repair systems, thus defining eight different genotypes (XPA, XPB, XPC, XPD, XPE, XPF, XPG and XP variant or XPV). In addition to cutaneous and ophthalmological features, some patients present with XP neurological disease. It is unknown whether the different neurological signs and their progression differ among groups. Therefore, we aim to characterize the XP neurological disease and its evolution in the heterogeneous UK XP cohort. Patients with XP were followed in the UK National XP Service, from 2009 to 2021. Age of onset for different events was recorded. Cerebellar ataxia and additional neurological signs and symptoms were rated with the Scale for the Assessment and Rating of Ataxia (SARA), the Inventory of Non-Ataxia Signs (INAS) and the Activities of Daily Living questionnaire (ADL). Patients' mutations received scores based on their predicted effects. Data from available ancillary tests were collected. Ninety-three XP patients were recruited. Thirty-six (38.7%) reported neurological symptoms, especially in the XPA, XPD and XPG groups, with early-onset and late-onset forms, and typically appearing after cutaneous and ophthalmological symptoms. XPA, XPD and XPG patients showed higher SARA scores compared to XPC, XPE and XPV. SARA total scores significantly increased over time in XPD (0.91 points/year, 95% confidence interval: 0.61, 1.21) and XPA (0.63 points/year, 95% confidence interval: 0.38, 0.89). Hyporeflexia, hypopallesthaesia, upper motor neuron signs, chorea, dystonia, oculomotor signs and cognitive impairment were frequent findings in XPA, XPD and XPG. Cerebellar and global brain atrophy, axonal sensory and sensorimotor neuropathies, and sensorineural hearing loss were common findings in patients. Some XPC, XPE and XPV cases presented with abnormalities on examination and/or ancillary tests, suggesting underlying neurological involvement. More severe mutations were associated with a faster progression in SARA total score in XPA (0.40 points/year per 1-unit increase in severity score) and XPD (0.60 points/year per 1-unit increase), and in ADL total score in XPA (0.35 points/year per 1-unit increase). Symptomatic and asymptomatic forms of neurological disease are frequent in XP patients, and neurological symptoms can be an important cause of disability. Typically, the neurological disease will be preceded by cutaneous and ophthalmological features, and these should be actively searched in patients with idiopathic late-onset neurological syndromes. Scales assessing cerebellar function, especially walking and speech, and disability can show progression in some of the groups. Mutation severity can be used as a prognostic biomarker for stratification purposes in clinical trials.

Mohs micrographic surgery for the treatment of primary cutaneous mucinous carcinoma.

Primary cutaneous mucinous carcinoma (PCMC) is a rare adnexal tumour of the skin. Clinically, it appears as a benign cyst, but it has characteristic histopathology. It is a slow-growing tumour that rarely metastasizes but is associated with significant morbidity due to its high recurrence rate. Standard practice has been to surgically remove it with a wide local excision of 1-2-cm margin. In the last decade, increasing reports of Mohs micrographic surgery (MMS) for the treatment of PCMC have been described. MMS appears to reduce recurrence rates while allowing for more conservative margins. Given the rarity of PCMC, there are no prospective randomized control trials on treatment. This is the largest case series of PCMC treated by MMS to date.

Dermatofibrosarcoma protuberans (DFSP) in children: A combined multidisciplinary approach.

Dermatofibrosarcoma protuberans (DFSP) is rare, comprising (1%-6%) of all sarcomas. The incidence is less than one per million before the age of 20. It is a locally aggressive tumor with a low risk of metastasis. We share our experience in the management of three pediatric patients with complex cases of DFSP in a combined surgical approach involving plastic and dermatologic surgery, using the slow Mohs micrographic surgery technique.

Dramatic response of metastatic cutaneous angiosarcoma to an immune checkpoint inhibitor in a patient with xeroderma pigmentosum: whole-genome sequencing aids treatment decision in end-stage disease.

"Mutational signatures" are patterns of mutations that report DNA damage and subsequent repair processes that have occurred. Whole-genome sequencing (WGS) can provide additional information to standard diagnostic techniques and can identify therapeutic targets. A 32-yr-old male with xeroderma pigmentosum developed metastatic angiosarcoma that was unresponsive to three lines of conventional sarcoma therapies. WGS was performed on his primary cancer revealing a hypermutated tumor, including clonal ultraviolet radiation-induced mutational patterns (Signature 7) and subclonal signatures of mutated DNA polymerase epsilon (POLE) (Signature 10). These signatures are associated with response to immune checkpoint blockade. Immunohistochemistry confirmed high PD-L1 expression in metastatic deposits. The anti-PD-1 monoclonal antibody pembrolizumab was commenced off-label given the POLE mutation and high mutational load. After four cycles, there was a significant reduction in his disease with almost complete resolution of the metastatic deposits. This case highlights the importance of WGS in the analysis, interpretation, and treatment of cancers. We anticipate that as WGS becomes integral to the cancer diagnostic pathway, treatments will be stratified to the individual based on their unique genomic and/or transcriptomic profile, enhancing classical approaches of histologically driven treatment decisions.

Evaluating the Diagnostic Accuracy of Reflectance Confocal Microscopy to Diagnose Skin Cancer: Protocol for a Prospective, Multicenter Study.

BACKGROUND: In the United Kingdom, 350,000 patients per year are referred to hospital clinics with suspicious moles, and approximately half undergo a biopsy to identify the 5%-10% who require further treatment. If cancer cannot be ruled out clinically and on the basis of biopsy results, the lesion is surgically removed. One type of precancerous mole, called lentigo maligna, is particularly challenging to delineate and treat. Reflectance confocal microscopy (VivaScope, Caliber Imaging & Diagnostics) is an imaging technique that can supplement dermoscopy in identifying whether a clinically suspicious mole is malignant and can better assess lentigo maligna margins for excision. It allows clinicians to visualize the skin lesion to a depth of 200 microns with subcellular resolution, described as quasi-histological, and therefore better guide more accurate diagnoses. OBJECTIVE: The aim of this paper is to describe a prospective, single blinded, multicenter study to examine patients with clinically suspicious moles or lentigo maligna to determine whether confocal microscopy can both reduce the number of unnecessary biopsies of moles and more accurately guide the surgical excision margins of lentigo maligna. METHODS: This study will prospectively recruit adults into the following two cohorts: diagnostic accuracy and margin delineation. The diagnostic accuracy cohort will assess people with clinically suspicious lesions suspected of being diagnosed with melanoma and having an equivocal finding on dermoscopy or persistent clinical suspicion despite normal dermoscopy. Diagnostic accuracy will include the sensitivity and specificity of VivaScope in comparison with the histological diagnosis as the gold standard for patients. The margin delineation cohort will assess the ability of VivaScope to accurately delineate the margins of lentigo maligna compared with that of dermoscopy alone using margins taken during Mohs micrographic surgery as the gold standard. The primary study outcomes will be the diagnostic accuracy of VivaScope for the first cohort of patients and margin agreement between VivaScope and the final pathology report for the second cohort of patients. RESULTS: Funding for this proposed research is being secured. CONCLUSIONS: The outcomes of the proposed study will indicate how many biopsies of nonmelanoma lesions, which are potentially unnecessary, could be prevented. This would reduce patient anxiety and cost to the National Health Service (NHS) in the United Kingdom. Improved margin delineation of lentigo maligna could also improve the surgical clearance rates and decrease overall cost. The results would demonstrate whether the adoption of VivaScope would potentially benefit patients and the NHS. REGISTERED REPORT IDENTIFIER: RR1-10.2196/9296.

Our experience of carbon dioxide laser ablation of angiofibromas: Case series and literature review.

Angiofibromas are one of the dermatological hallmarks of tuberous sclerosis. Various ablative treatments have been trialled and more recently topical rapamycin has been proposed. We present our experience of treatment of angiofibromas using carbon dioxide (CO2) laser ablation and provide a timely literature review. Nine patients were retrospectively identified as being treated with CO2 laser between 2009 and 2015. Three patients were male, six were female, median age at first treatment was 28 (range 15-49) years and the median number of treatments was two (range 1-17). Four of these patients could be contacted for a post-treatment telephone interview. All reported an improvement in appearance of angiofibromas following treatment and that they would recommend CO2 laser ablation to others. Three of the four reported recurrence of some lesions following treatment. The only side effect reported by one patient was transient hyperpigmentation. CO2 laser ablation appears to be a well-tolerated, efficacious treatment for angiofibromas with few long-term side effects.

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect.

Xeroderma pigmentosum (XP) is a rare DNA repair disorder characterized by increased susceptibility to UV radiation (UVR)-induced skin pigmentation, skin cancers, ocular surface disease, and, in some patients, sunburn and neurological degeneration. Genetically, it is assigned to eight complementation groups (XP-A to -G and variant). For the last 5 y, the UK national multidisciplinary XP service has provided follow-up for 89 XP patients, representing most of the XP patients in the United Kingdom. Causative mutations, DNA repair levels, and more than 60 clinical variables relating to dermatology, ophthalmology, and neurology have been measured, using scoring systems to categorize disease severity. This deep phenotyping has revealed unanticipated heterogeneity of clinical features, between and within complementation groups. Skin cancer is most common in XP-C, XP-E, and XP-V patients, previously considered to be the milder groups based on cellular analyses. These patients have normal sunburn reactions and are therefore diagnosed later and are less likely to adhere to UVR protection. XP-C patients are specifically hypersensitive to ocular damage, and XP-F and XP-G patients appear to be much less susceptible to skin cancer than other XP groups. Within XP groups, different mutations confer susceptibility or resistance to neurological damage. Our findings on this large cohort of XP patients under long-term follow-up reveal that XP is more heterogeneous than has previously been appreciated. Our data now enable provision of personalized prognostic information and management advice for each XP patient, as well as providing new insights into the functions of the XP proteins.

Macromelanosomes: their significantly greater presence in the margins of a lentigo maligna versus solar lentigo.

BACKGROUND: Macromelanosomes are melanin-containing granules characterized by their large size and spherical or ellipsoidal morphology. They are reported to be present in a variety of pigmented skin lesions, including lentigines. However, there is limited information on macromelanosomes in malignant melanocytic proliferations. The margins of a lentigo maligna/malignant melanoma in situ (LM/MMIS) and solar lentigo share morphological similarities, including lentiginous proliferation of melanocytes, increased melanin in basal cell layer keratinocytes, and solar elastosis. This may represent a potential diagnostic pitfall, particularly in small biopsies. We sought to identify whether the presence of macromelanosomes at the lesional margins of LM/MMIS may represent a morphological clue in distinguishing between these 2 entities. METHODS: Data were obtained from 2 different institutions between 2001 and 2010. 619 cases of solar lentigo and 117 cases of LM/MMIS were screened for the presence and distribution of macromelanosomes. RESULTS: 25 of 117 cases (21%) of LM/MMIS had macromelanosomes identified at the lesional margins, compared with 7 of 619 (1%) of solar lentigo cases (P < 0.0001). CONCLUSIONS: Our data demonstrate that the identification of macromelanosomes within a lentiginous melanocytic proliferation should prompt further evaluation to rule out the possibility of a contiguous LM/MMIS, particularly in a small biopsy.

An ulcerated nodule on the nose.

A 75-year-old retired nurse, originally from Barbados, presented to her general practitioner (GP) with a scaling ulcerated nodule on the left side of her nose. She was taking medication for type 2 diabetes, hypertension and glaucoma, but was otherwise well with no systemic symptoms. Her GP diagnosed a patch of eczema; however, a trial of topical steroids was not effective and she was referred to dermatology. A skin biopsy confirmed the clinical suspicion that this patient had a nodular basal cell carcinoma (BCC). BCCs account for 75% of all skin cancers; they very rarely metastasise, but can spread to invade local structures. Our patient has type VI skin. Skin cancer is rare in patients with skin type VI; however, in this group, morbidity and mortality are disproportionately high in relation to cancer incidence.

Ten cases of drug reaction with eosinophilia and systemic symptoms (DRESS) treated with pulsed intravenous methylprednisolone.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare, life-threatening, drug-induced illness characterised by a widespread polymorphic eruption, fever and multivisceral involvement. There is little published on the management of DRESS. Prompt recognition and withdrawal of the causative drug is essential, along with supportive treatment. However, the condition commonly progresses despite these measures. Oral corticosteroids are usually given but the response can be suboptimal and result in a prolonged exposure to systemic glucocorticoid. We conducted a prospective single-centre study to determine the efficacy of pulsed intravenous methylprednisolone followed by a short reducing course of oral prednisolone in ten patients with confirmed DRESS. Rash and fever responded rapidly to methylprednisolone in all patients. Compared to pre-treatment assessments, there was a significant reduction in eosinophil count at day 14 and AST level at day 90 post-treatment. One patient developed acute hepatic failure, necessitating a liver transplant, and died 4 months later. In the immediate post-treatment phase, 1 patient developed type 1 diabetes and 1 patient developed a corticosteroid-induced psychosis. Long-term follow-up on 8/10 revealed all patients to be well, although one patient had persistent pruritus. An aggressive corticosteroid regimen in the management of DRESS is associated with good clinical outcome and acceptable tolerance.