Search

Background: One of the hereditary syndromes associated with multiple early‐onset basal cell carcinomas (BCCs) is basal cell nevus syndrome (BCNS), of which a minority is caused by germline SUFU mutations. Germline SUFU mutations show a spectrum of phenotypes, of which multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC) is one. Patients with MHIBCC develop multiple basaloid skin tumors from middle age onwards. Methods: Three patients presenting with an MHIBCC phenotype were tested for a germline SUFU mutation. Skin biopsies were assessed by two dermatopathologists. Results: Our study adds three new pathogenic SUFU variants, including a mosaic, to the current literature. Literature suggests a spectrum of phenotypes of patients carrying the same SUFU mutation, which ranges from the MHIBCC phenotype, to BCNS, to patients that develop life‐threatening brain tumors. This last risk is significantly higher in germline SUFU mutation carriers when compared to BCNS patients carrying germline PTCH1 mutations. Conclusions: Germline SUFU mutation carriers should be recognized as a distinct group of patients carrying specific health risks, independent of meeting the BCNS criteria. Phenotypic prediction based on the specific SUFU mutation seems unfeasible. It is of utmost importance that the less apparent MHIBCC phenotype is recognized, to provide (second generation) germline SUFU mutation carriers appropriate healthcare. [ABSTRACT FROM AUTHOR]

Treatment with Hedgehog Inhibitors in Gorlin‐Goltz syndrome (GGS) yields favourable objective clinical responses, yet secondary resistance and class‐related toxicity restrict treatment duration. This study aims to review current data on GGS patients undergoing vismodegib therapy, focusing on treatment duration, clinical outcomes and schedule modifications. A systematic search of the PubMed database was conducted for English articles from 1993 to 2023, identifying 31 papers suitable for inclusion. A total of 351 patients, with a mean age of 52 years, were analysed. The average treatment duration was 9.3 months for patients who discontinued treatment, and 25.1 months for those who continued vismodegib at the time this study was published. Vismodegib achieved a complete response rate of 44%. Treatment interruption predominantly occurred due to side effects (69.1%) and secondary resistance (9.1%). The use of alternative regimens, although not compromising efficacy, may enhance treatment compliance. Further investigations are warranted to ascertain the optimal treatment regimen and timeline for GGS patients. Schedule modifications offer promise in ameliorating side effects and facilitating long‐term treatment. [ABSTRACT FROM AUTHOR]

In 2002, heterozygous suppressor of fused variants (SUFU+/−) in the germline were described to have a tumor suppressor role in the development of pediatric medulloblastoma (MB). Other neoplasms associated with pathologic germline SUFU+/− variants have also been described among patients with basal cell nevus syndrome (BCNS; BCNS is also known as Gorlin syndrome, nevoid basal cell carcinoma [BCC] syndrome or Gorlin‐Goltz syndrome; OMIM 109400), an autosomal‐dominant cancer predisposition syndrome. The phenotype of patients with germline SUFU+/− variants is very poorly characterized due to a paucity of large studies with long‐term follow‐up. As such, there is a clinical need to better characterize the spectrum of neoplasms among patients with germline SUFU+/− variants so that clinicians can provide accurate counseling and optimize tumor surveillance strategies. The objective of this study is to perform a scoping review to map the evidence on the rate of medulloblastoma and to describe the spectrum of other neoplasms among patients with germline SUFU+/− variants. A review of all published literature in PubMed (MEDLINE), EMBASE, Cochrane, and Web of Science were searched from the beginning of each respective database until October 9, 2021. Studies of pediatric and adult patients with a confirmed germline SUFU+/− variant who were evaluated for the presence of any neoplasm (benign or malignant) were included. There were 176 patients (N = 30 studies) identified with a confirmed germline SUFU+/− variant who met inclusion criteria. Data were extracted from two cohort studies, two case‐control studies, 18 case series, and eight case reports. The median age at diagnosis of a germline SUFU+/− variant was 4.5 years where 44.4% identified as female and 13.4% of variants were de novo. There were 34 different neoplasms (benign and malignant) documented among patients with confirmed germline SUFU+/− variants, and the most common were medulloblastoma (N = 59 patients), BCC (N = 21 patients), and meningioma (N = 19 patients). The median age at medulloblastoma diagnosis was 1.42 years (range 0.083–3; interquartile range 1.2). When data were available for these three most frequent neoplasms (N = 95 patients), 31 patients (32.6%) had neither MB, BCC nor meningioma; 51 patients (53.7%) had one of medulloblastoma or BCC or meningioma; eight patients (8.4%) had two of medulloblastoma or BCC or meningioma, and five patients (5.3%) had medulloblastoma and BCC and meningioma. This is the first study to synthesize the data on the frequency and spectrum of neoplasms specifically among patients with a confirmed germline SUFU+/− variant. This scoping review is a necessary step forward in optimizing evidence‐based tumor surveillance strategies for medulloblastoma and estimating the risk of other neoplasms that could impact patient outcomes. [ABSTRACT FROM AUTHOR]

Gorlin‐Goltz syndrome (GGS) is an autosomal dominant multisystemic disease with high penetrance. Headache heralding GGS has been previously reported but without discussing potential sources. We report a patient with headache and a novel association (diastematomyelia), which helped with the diagnosis. A 46‐year‐old woman presented with persistent holocranial headache. On examination, countless hyperpigmented basal cell nevi over the face, pits over the palmar/plantar surface, and palmar and plantar keratosis were observed. A magnetic resonance imaging (MRI) of the spinal cord revealed diastematomyelia. Diagnosis of GGS was finally made. Headache and diastematomyelia should be included in the clinical picture of GGS. [ABSTRACT FROM AUTHOR]

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome, is characterized by an aberrant activation of the hedgehog (Hh) pathway, most cases being caused by PTCH1 mutations. However, certain features such as multiple hereditary infundibulocystic basal cell carcinomas (MHIBCC), sclerotic fibromas, childhood medulloblastoma or meningioma may be relatively specific to a SUFU mutation. We present two patients with MHIBCC, along with a more complex cutaneous and extracutaneous phenotype. MHIBCC syndrome and BCNS may share clinical features and, indeed, both syndromes probably represent different degrees of upregulation in the Hh pathway. [ABSTRACT FROM AUTHOR]

In spite of the syndrome also being known as "focal dermal hypoplasia", dermal hypoplasia is not a I sine que non i diagnostic requisite.[11] However, focal dermal hypoplasia occurs in 95% of individuals with the syndrome. Keywords: focal dermal hypoplasia; Goltz syndrome; Goltz-Gorlin syndrome EN focal dermal hypoplasia Goltz syndrome Goltz-Gorlin syndrome 993 997 5 12/01/22 20221201 NES 221201 INTRODUCTION Goltz syndrome is an ectodermal and mesodermal genodermatosis, which was described in the literature in detail in two papers in the early 1960s.[[1]] Although examples of the condition had been presented previously in several publications,[3], [4], [5], [6], [7], [8], [9] Gorlin and Goltz were the first and the last author in both papers, so the syndrome is also known as the Goltz-Gorlin syndrome. Focal dermal hypoplasia, Goltz syndrome, Goltz-Gorlin syndrome It should not be mistaken, however, with the Gorlin-Goltz syndrome (nevoid basal cell carcinoma syndrome; basal cell nevus syndrome), which was also described by these two authors around the same time. [Extracted from the article]

Optical Coherence Tomography (OCT) is a useful non‐invasive diagnostic tool for diagnosing and monitoring treatment of basal cell carcinomas. We describe the use of OCT in a patient with Basal Cell Naevus Syndrome. Through measuring tumour depth on OCT, management of individual tumours was triaged accordingly using 0.4 mm tumour depth as a cut‐off for surgical and non‐surgical management. OCT has potential to reduce unnecessary excisions and associated morbidity in this population of patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to identify all clinical, radiological, histopathological, and immunohistochemical features associated with recurrence of odontogenic keratocysts (OKCs) in the literature and formulate a recurrence risk stratification based on these findings. A search was performed in PubMed/Medline, Scopus, Web of Science, Google Scholar and Cochrane databases for clinical and laboratory studies reporting on clinico‐pathological features that led to OKC recurrences for the period 2000 to 2020. Twenty‐three studies were identified and analyzed qualitatively. A total of 2064 OKCs were included of which 439 OKCs were recurrent with a mean follow‐up period of 46.7 months. Significantly associated parameters with OKC recurrence included age (variable age categories), large (>4 cm), multilocular lesions with cortical perforation, association with dentition, presence of daughter cysts, and epithelial budding. Immunohistochemical markers including high Ki67 index and AgNOR count were also implicated. A recurrence risk stratification was formulated based on these findings. Although the level of evidence from the included studies was low, there was considerable evidence that the clinico‐pathological parameters identified were linked with higher OKC recurrence. The surgeon, radiologist, and pathologist should aim to identify these features when making a diagnosis so as to determine the appropriate management regime and prevent recurrences. [ABSTRACT FROM AUTHOR]

Background: Ovarian sex cord‐stromal tumors (OSCTs) are rare ovarian tumors that can develop from sex cord, stromal cells, or both. OSCTs can be benign or malignant. Bilateral and/or unilateral ovarian fibromas, a type of OSCT of the stromal cells, have been reported in individuals diagnosed with nevoid basal cell carcinoma syndrome (NBCCS). Calcified ovarian fibromas have been reported in 15–25% of individuals diagnosed with NBCCS while 75% of those cases occur bilaterally. The average age at diagnosis of OSCT/ovarian fibromas in patients with NBCSS is in the second to third decade compared with age 50 in the general population. Ovarian tumors are rare in pediatric populations. Methods: The patient is a 5‐year‐old female diagnosed with bilateral ovarian fibromas at age 4. Multigene panel for the patient and subsequent targeted molecular evaluation of parents were completed. Histological evaluations on the surgically resected ovaries were performed for microscopic characterization of fibromas. Results: Germline testing identified de novo heterozygous novel likely pathogenic variants in PTCH1 gene, exon 12 deletion, and an SMARCA4 splicing variant c.2002‐1G > A. Microscopic examination of bilateral tumors was consistent with an ovarian fibroma. Conclusions: To our knowledge, this is the first report of bilateral benign ovarian fibroma in a child with a diagnosis of nevoid basal cell carcinoma syndrome (NBCCS) with a potential predisposition to Rhabdoid Tumor Predisposition Syndrome (RTPS). [ABSTRACT FROM AUTHOR]

Background/Objectives: Basal cell nevus syndrome (BCNS) is an autosomal dominant skin cancer predisposition syndrome associated with abnormal mineral metabolism, a risk factor for urinary stone disease (USD). However, no research investigating the association between BCNS and USD or other manifestations of abnormal mineral metabolism has been conducted. The objective of this study is to investigate the association between BCNS and conditions associated with disordered mineral metabolism including USD, hypothyroidism, and osteoporosis and compare them to prevalence in the general population to elucidate potential unknown manifestations of the condition. Methods: This retrospective study examined medical records of adult and pediatric patients with confirmed BCNS from the Mayo Clinic database from 1 January 1995 to 12 January 2020. Records were surveyed for evidence of USD and other comorbidities potentially related to BCNS. The studied cohort included 100 adult patients and 5 pediatric patients. Results: A total of 105 patients were included in this analysis, 10 of whom experienced confirmed USD, representing a prevalence of 10%. Six adult patients were identified with a diagnosis of osteoporosis, representing a prevalence of 6%. Thirteen adult patients were identified with a diagnosis of hypothyroidism, representing a prevalence of 13%. Conclusions: This study identified a prevalence of USD in BCNS patients comparable to estimates of national prevalence, indicating that known abnormalities in mineral metabolism likely do not increase the incidence of USD in BCNS patients. Additional findings included increased prevalence of hypothyroidism and decreased prevalence of osteoporosis in the BCNS cohort compared to national averages. [ABSTRACT FROM AUTHOR]

Basal cell nevus syndrome, also known as Gorlin‐Goltz syndrome, is a rare autosomal dominant disorder caused by mutations in the hedgehog signaling pathway, mainly in PTCH1. This pathway is involved in embryogenesis and tumorigenesis, and the loss of function of PTCH1 protein produces an aberrant increase in the hedgehog signaling pathway activity. Basal cell nevus syndrome is characterized by tumor predisposition, particularly with the development of multiple basal cell carcinomas at an early age, along with odontogenic keratocysts, palmoplantar pits, skeletal abnormalities, and an increased risk of medulloblastoma. Diagnosis is clinical, with gene mutation analysis confirming the suspicion. The striking phenotypic variability of the syndrome may lead to a delayed diagnosis, making it an uncommon but important entity to recognize. A high index of suspicion and an early diagnosis is crucial for prevention, surveillance, and the prompt establishment of multidisciplinary medical care. [ABSTRACT FROM AUTHOR]

Background: Odontogenic keratocyst is characterized by local aggressive behavior and a high recurrence rate, as well as its potential to develop in association with the basal cell nevus syndrome. The aim of this study was to decode the gene expression program accompanying odontogenic keratocyst phenotype. Methods: 150‐bp paired‐end RNA‐sequencing was applied on six sporadic and six basal cell nevus syndrome‐associated whole‐tissue odontogenic keratocyst samples in comparison to six dental follicles, coupled with bioinformatics and complemented by immunohistochemistry. Results: 2654 and 2427 differentially expressed genes were captured to characterize the transcriptome of sporadic and basal cell nevus syndrome‐associated odontogenic keratocysts, respectively. Gene ontologies related to "epidermis/skin development" and "keratinocyte/epidermal cell differentiation" were enriched among the upregulated genes (KRT10, NCCRP1, TP63, GRHL3, SOX21), while "extracellular matrix organization" (ITGA5, LOXL2) and "odontogenesis" (MSX1, LHX8) gene ontologies were overrepresented among the downregulated genes in odontogenic keratocyst. Interestingly, upregulation of various embryonic stem cells markers (EPHA1, SCNN1A) and genes committed in cellular reprogramming (SOX2, KLF4, OVOL1, IRF6, TACSTD2, CDH1) was found in odontogenic keratocyst. These findings were highly shared between sporadic and basal cell nevus syndrome‐associated odontogenic keratocysts. Immunohistochemistry verified SOX2, KLF4, OVOL1, IRF6, TACSTD2/TROP2, CDH1/E‐cadherin, and p63 expression predominantly in the odontogenic keratocyst suprabasal epithelial layers. Conclusion: The odontogenic keratocyst transcriptomic profile is characterized by a prominent epidermal and dental epithelial fate, a repressed dental mesenchyme fate combined with deregulated extracellular matrix organization, and enhanced stemness gene signatures. Thus, we propose a developed epidermis‐like phenotype in the odontogenic keratocyst suprabasal epithelial cells, established in parallel to a significant upregulation of marker genes related to embryonic stem cells and cellular reprogramming. [ABSTRACT FROM AUTHOR]

Multiple basal cell carcinomas (mBCC) are encountered in few genetic diseases such as Gorlin syndrome, xeroderma pigmentosum and Bazex-Dupré-Christol syndrome. PTCH mutations and deletions in patients with typical nevoid basal cell carcinoma syndrome and in patients with a suspected genetic predisposition to basal cell carcinoma: a French study. Multiple basal cell carcinomas revealing a biallelic MUTYH gene mutation in a 39-year-old male patient. [Extracted from the article]

Basal cell carcinoma (BCC) is the most common cutaneous malignancy in the world, and the incidence of pulmonary metastasis is exceedingly rare. We present a case of middle‐aged male with findings consistent with BCC with metastasis to the lungs managed with surgical resection and the use of targeted therapy using the hedgehog pathway inhibitor with improvement. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) may be challenging to differentiate from basaloid squamous cell carcinoma (bSCC), both clinically and histologically. BCC constitutes one of the most common tumours and metastatic behaviour is extremely rare. In contrast, bSCC is a rare entity with an increased propensity for distant metastasis. If these conditions develop into inoperable metastatic disease, the therapeutic alternatives are different, but the use of PD‐1 inhibitors may be a valid option for both. Here, we report a case with complex histology with a component initially classified as bSCC with lung metastases and treated with the PD‐1 inhibitor cemiplimab resulting in radiological and clinical responses. Re‐examination of the lung biopsy using routine histomorphology in combination with immunohistochemical staining for cytokeratin 14, cytokeratin17 and BerEp4 has, however, revealed a histopathological pattern of BCC, which is in concordance with a similar analysis of the cutaneous primary tumour in the face that the patient underwent surgery for more than 5 years earlier. [ABSTRACT FROM AUTHOR]

Hedgehog pathway inhibitors, vismodegib and sonidegib, are the recommended systemic treatment for locally advanced basal cell carcinoma (laBCC) patients.1,2 However, patients' adherence and compliance to Hedgehog inhibitors are often poor due to the high frequency of adverse events (AEs).1-3 We conducted a real-world, multicentre, retrospective study aimed at evaluating the clinical determinants of complete response (CR) in laBCC patients receiving vismodegib. Twenty-four patients (53.3%) were males, a solitary BCC was present in 24 (53.3%) patients, and BCCs were located on the head/neck region in 86.7% of patients with a median diameter of the target lesion of 3.0 cm (0.3-35.0 cm). Patient demographic, tumour characteristics, treatment variables and treatment-related AEs (TRAEs) were recorded. [Extracted from the article]

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants., (© 2024 Japanese Dermatological Association.)

Modestly deregulated SHH has been previously associated with the genesis of benign BFH.7,8 Tumour-suppressor gene syndromes generally follow Knudson two-hit model, where biallelic gene inactivation leads to tumour growth. Nevoid basal cell carcinoma syndrome (NBCS, Gorlin syndrome) (OMIM #109400) is a rare autosomal-dominant but most common hereditary form of basal cell cancer (BCC). [Extracted from the article]

The diagnostic trends of Gorlin syndrome (GS) in the pediatric population are not well understood. In an international survey conducted by the Gorlin Syndrome Alliance, 118 individuals who were diagnosed with GS when aged 18 years and under provided information about their diagnosis. Oral surgeons and dermatologists were the most commonly reported physicians involved in diagnosis for 48.3% and 28% of cases, respectively. For 50% of children, the diagnosis was made within a year from presenting sign(s), while 27% report over 4 years to receive GS diagnosis. Of individuals who reported >4 years between presenting signs and diagnosis, 81.3% attributed the delay to insufficient medical team knowledge and 65.6% attributed to lack of personal awareness that presenting signs were related to GS, emphasizing the need for patient and physician education of GS for prompt diagnosis. [ABSTRACT FROM AUTHOR]

Background: Severe asthma is a complex disease. Transcriptomic profiling has contributed to understanding the pathogenesis of asthma, especially type‐2 inflammation. However, there is still poor understanding of non‐type‐2 asthma, and consequently, there are limited treatment options. Objective: The aim of this study was to identify differentially expressed genes (DEGs) and pathways in endobronchial biopsies associated with inflammatory phenotypes of severe asthma. Methods: This cross‐sectional study examined endobronchial biopsies from 47 adults with severe asthma (neutrophilic asthma (NA) n = 9, eosinophilic asthma (EA) n = 22 and paucigranulocytic asthma (PGA) n = 16) and 13 healthy controls (HC). RNA was extracted and transcriptomic profiles generated (Illumina Humanref‐12 V4) and analysed using GeneSpring GX14.9.1. Pathway identification using Ingenuity Pathway Analysis. Results: NA had the most distinct profile, with signature of 60 top‐ranked DEGs (FC >±2) including genes associated with innate immunity response, neutrophil degranulation and IL‐10 signalling. NA presented enrichment to pathways previously linked to neutrophilic inflammation; dendritic cell maturation, Th1, TREM1, inflammasome, Th17 and p38 MAPK, as well as novel links to neuroinflammation, NFAT and PKCθ signalling. EA presented similar transcriptomic profiles to PGA and HC. Despite the higher proportion of bacterial colonization in NA, no changes were observed in the transcriptomic profiles of severe asthma culture positive compared with severe asthma culture negative. Conclusions & Clinical Relevance: NA features a distinct transcriptomic profile with seven pathways enriched in NA compared to EA, PGA and HC. All those with severe asthma had significant enrichment for SUMOylation, basal cell carcinoma signalling and Wnt/β‐catenin pathways compared to HC, despite high‐dose inhaled corticosteroids. These findings contribute to the understanding of mechanistic pathways in endobronchial biopsies associated with NA and identify potential novel treatment targets for severe asthma. [ABSTRACT FROM AUTHOR]

Background: Digital clubbing is a well‐known clinical sign characterized by thickening of the distal phalanges of the fingers and toes. Unilateral clubbing occurs less frequently. A previous report showed for the first time two cases of unilateral clubbing as a clinical manifestation of lower limb venous malformation. The objective of the present study is to describe a series of 13 patients with a low‐flow vascular malformation where a clubbing‐like unilateral digital thickening is also observed. Methods: All patients were retrospectively included after reviewing clinical photographs from a vascular malformations database. Results: A total of 13 patients with low‐flow vascular malformations were included in this study. The mean age at diagnosis was 11 years (range 5–26 years) with a female predominance (nine patients). The most frequent vascular malformation collected was a blue rubber bleb nevus syndrome in four patients, followed by common venous malformations in three patients. All patients characteristically exhibited a clubbing‐like digital thickening. Seven patients had foot involvement and six patients hand involvement. Conclusions: Although the number of cases is limited, our study is the first series of cases where a clubbing‐like digital thickening is described in patients with a low‐flow vascular malformation. The unilateral presence of clubbing or pseudoclubbing should lead to the suspicion of an underlying vascular malformation. [ABSTRACT FROM AUTHOR]

However, these correlations are still unclear because the likelihood of developing chronic diseases or malignancies is generally higher in patients above the age of 50.1-3,4 The clinical diagnosis of SK could pose a diagnostic challenge. About a third of these have been reported in patients with personal history of malignancies; 12 of these 18 cancer-related SK patients (66.6%) were male, with a mean age of 72.4 years (range 54-85). Spiny keratoderma (SK) of the palms and soles is an infrequent palmoplantar keratoderma, of unknown aetiology, characterised by multiple isolated keratotic plugs, arising from the palms, soles, or both.1-3 It is distinct in two different types: an autosomal dominant benign form, with onset in childhood, and an acquired form, typically starting in the second half of life. [Extracted from the article]

Itraconazole is as an anti‐fungal agent with the ability to inhibit the Hedgehog signalling pathway, which makes it a candidate drug that can be repurposed for the treatment of basal cell carcinomas (BCCs). We present a case of metastatic BCC, treated with oral itraconazole 100 mg twice daily, that resulted in sustained partial regression of metastatic pulmonary nodules. A systematic review on the clinical outcomes of BCCs treated with itraconazole highlights that current evidence for its clinical application remains limited and that this is the first case report where itraconazole monotherapy has achieved favourable response in metastatic BCC. [ABSTRACT FROM AUTHOR]

Basal Cell Nevus Syndrome (BCNS) is an autosomal dominant inherited disease caused by PTCH1 (9q22.3‐q31) germline mutations. Skin manifestations are mainly characterized by hyperkeratosis of the palms and soles, palmoplantar pits and a strong predisposition to develop multiple basal cell carcinomas (BCCs). Recently, it has been hypothesized that basaloid follicular hamartomas (BFH) could be included in BCNS skin features. We present three pediatric cases of GS with BCCs and BFHs. Clinical, dermoscopic and immunohistochemical tools are reported. [ABSTRACT FROM AUTHOR]

Basal cell nevus syndrome (also known as Gorlin Syndrome; MIM109400) is an autosomal dominant disorder characterized by recurrent pathological features such as basal cell carcinomas and odontogenic keratocysts as well as skeletal abnormalities. Most affected individuals have point mutations or small insertions or deletions within the PTCH1 gene on human chromosome 9, but there are some cases with more extensive deletion of the region, usually including the neighboring FANCC and/or ERCC6L2 genes. We report a 16‐year‐old patient with a deletion of approximately 400,000 bases which removes only PTCH1 and some non‐coding RNA genes but leaves FANCC and ERCC6L2 intact. In spite of the small amount of DNA for which he is haploid, his phenotype is more extreme than many individuals with longer deletions in the region. This includes early presentation with a large number of basal cell nevi and other skin lesions, multiple jaw keratocysts, and macrosomia. We found that the deletion was in the paternal chromosome, in common with other macrosomia cases. Using public databases, we have examined possible interactions between sequences within and outside the deletion and speculate that a regulatory relationship exists with flanking genes, which is unbalanced by the deletion, resulting in abnormal activation or repression of the target genes and hence the severity of the phenotype. [ABSTRACT FROM AUTHOR]

Gardner syndrome with odontogenic sinusitis is rare but should be suspected in patients with multiple osteomas of the skull and facial bones, excess teeth, impacted teeth, and odontomas. Early diagnosis and treatment of GS may improve prognosis. [ABSTRACT FROM AUTHOR]

(c) Histopathology: Shows an infundibulocystic basal cell carcinoma characterized by a relatively well-circumscribed neoplasm showing cystic areas as well as a cleft in the adjacent dermis (hematoxylin-eosin stain original magnification ×10) gl The patient's mother was a 77-year-old woman with a medical history of a single facial nodular BCC, a frontobasal meningioma, and a mandibular plexiform ameloblastoma. Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (GS), is a tumor predisposing disorder with an autosomal dominant inheritance.1,2 It is caused by mutations in the hedgehog pathway, being I PTCH1 i the most commonly affected gene. Many other syndromes are also associated with the development of multiple facial papules and solid organ neoplasias and should be considered in the differential diagnosis (Table 2).2,10 Patients with I SUFU i mutations also seem to develop less odontogenic keratocysts when compared with patients harboring I PATCHED i mutations. [Extracted from the article]

Aim: To gain insight in the actual ratio of recurrent odontogenic keratocysts (OKCs) occurring in the tooth‐bearing area as compared to the posterior region of the mandible in order to come up with reliable data to base upon a rational treatment policy. Material and Methods: We searched MEDLINE, Web of Science, Scopus, Cochrane Library and Google Scholar databases for studies reporting on the location of recurrent mandibular OKCs. Risk Difference with a confidence interval of 95% of having the lesion in the tooth‐bearing area versus the posterior region was the effect measure. P value for the summary effect of <0.05 was considered statistically significant. Results: The 1411 records retrieved were reduced to 13 studies to be qualitative/quantitative assessed. The pooled values showed that the difference in the clinical risk of having recurrent OKCs in the posterior region of the mandible and in the tooth‐bearing area of the maxilla is of 7% (CI: −0.08, 0.22; P = 0.36), the posterior region being more susceptible to develop a recurrent OKC. Conclusions: The recurrence rate of OKCs in the posterior mandible is not significantly higher than of those located in the tooth‐bearing part of the mandible; however, there is no reason to follow a more aggressive treatment policy for OKCs in the tooth‐bearing area. [ABSTRACT FROM AUTHOR]

The article offers information on Gorlin–Goltz syndrome (also named Nevoid Basal Cell Carcinoma Syndrome, NBCCS) is a rare autosomal-dominant disease with estimated prevalence. Topics include the most common features of NBCCS patients are multiple basal cell carcinomas (BCCs), odontogenic keratocysts (OKCs), and multiple development abnormalities.

Basal cell nevus syndrome (BCNS) is an autosomal dominant condition caused most often by a loss‐of‐function mutation in the Patched‐1 (PTCH1) gene. It is characterized by the development of varied benign and malignant tumors, including numerous cutaneous basal cell carcinomas (BCCs). The PTCH1 gene is integral in hair follicle development and loss of function mutation may lead to BCCs with an infundibulocystic histopathology in BCNS patients. Few studies have described the histopathological features of BCCs in BCNS. The recognition of these histopathologic features by dermatologists, dermatopathologists, and others caring for children will allow earlier and more effective identification of BCNS. We performed a retrospective analysis of 25 BCCs in 11 patients aged 5 to 19 years with BCNS and evaluated the histopathologic features on hematoxylin‐eosin‐stained sections. Our study found that 80% of BCCs in BCNS patients occurred on the head and neck with 64% of the specimens demonstrating infundibulocystic differentiation. Infundibulocystic differentiation is a common finding in BCCs found in BCNS. The finding of cutaneous neoplasms consistent with BCC with infundibulocystic differentiation in children is common in pediatric patients with BCNS and can be considered to be an early marker of the disorder, prompting further clinical investigation. [ABSTRACT FROM AUTHOR]

The presence of a spectrum of follicular differentiated tumors ranging from benign trichoepitheliomas to infundibular BCC, and eventually nodular BCCs, suggests that some trichoepitheliomas underwent the malignant transformation into BCCs. Dear Editor, CYLD cutaneous syndrome (CCS) is a rare autosomal dominant genetic syndrome characterized by multiple tumor formation of the skin appendages in the head and neck region because of a heritable heterozygous pathogenic variant (PV) in the I CYLD i gene.1 Multiple familial trichoepithelioma (MFT) is a clinical phenotype of CSS where patients typically present with numerous trichoepitheliomas on the center of the face, especially the nasolabial folds.2 Trichoepitheliomas share clinical and histological similarities with infundibulocystic variants of basal cell carcinomas (BCC) and therefore pose a diagnostic challenge in some patients.2,3 Further complicating this, the medical literature has described the malignant transformation of benign trichoepitheliomas to malignant BCCs.1 A Caucasian gentleman in his 40s had several punch biopsies on the centrofacial region which demonstrated basaloid tumors with features of trichoepithelioma and focal areas suggestive of transformation to basal cell carcinoma of infundibulocystic type (Fig. [Extracted from the article]

Dear Editor, Dermoscopy has a high accuracy for diagnosing basal cell carcinoma (BCC); however, few studies have histologically evaluated its accuracy of margin assessment.1,2 Previous studies included selected subtypes, and accuracy was based on "bread-loaf" sections, examining <1% of the peripheral margin.1,2 In the present study, we evaluated dermoscopy accuracy of distinct BCC subtypes with Mohs micrographic surgery (MMS) allowing 100% histological margin assessment. To determine dermoscopic accuracy, tumors were divided into two groups: Accurate dermoscopy: lateral margins cleared on the first MMS stage (71.7%), and Inaccurate dermoscopy: >1 stage to clear margins. [Extracted from the article]

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant genetic disorder. It is commonly caused by mutations in PTCH1 and chiefly characterized by multiple basal cell carcinomas (BCCs) developing prior to the age of 30 years. In rare cases, NBCCS presents with a late onset of BCC development. Objective: To investigate BCC tumorigenesis in two brothers, who showed characteristic features of NBCCS but developed their first BCCs only after the age of 40 years. Two other siblings did not show signs of NBCCS. Results: We obtained blood samples from four siblings and nine BCCs from the two brothers with NBCCS. Whole exome sequencing and RNA sequencing revealed loss of heterozygosity (LOH) of PTCH1 in eight out of nine tumours that consistently involved the same haplotype on chromosome 9. This haplotype contained a germinal splice site mutation in PTCH1 (NM_001083605:exon9:c.763‐6C>A). Analysis of germline DNA confirmed segregation of this mutation with the disease. All BCCs harboured additional somatic loss‐of‐function (LoF) mutations in the remaining PTCH1 allele which are not typically seen in other cases of NBCCS. This suggests a hypomorphic nature of the germinal PTCH1 mutation in this family. Furthermore, all BCCs had a similar tumour mutational burden compared to BCCs of unrelated NBCCS patients while harbouring a higher number of damaging PTCH1 mutations. Conclusions: Our data suggest that a sequence of three genetic hits leads to the late development of BCCs in two brothers with NBCCS: a hypomorphic germline mutation, followed by somatic LOH and additional mutations that complete PTCH1 inactivation. These genetic events are in line with the late occurrence of the first BCC and with the higher number of damaging PTCH1 mutations compared to usual cases of NBCCS. [ABSTRACT FROM AUTHOR]

Background: Nevoid basal cell carcinoma syndrome (NBCCS) is a neurocutaneous disease, characterized by tumorigenesis and developmental anomalies due to aberrant sonic hedgehog (Shh) signaling. Patients with NBCCS typically appear calm and carefree, suggesting that a specific personality in these patients may be associated with an enhanced hedgehog pathway. Our study aimed to determine the personality type in these patients. Methods: We enrolled 14 mentally normal patients with genetically confirmed NBCCS (seven males and seven females; mean age = 25.2 years) and 20 controls (10 males and 10 females; mean age = 27.9 years). The patients were assessed with the Japanese version of the Temperament and Character Inventory, based on the seven‐dimensional model of temperament and character, and their clinical symptoms were evaluated. The amygdala volumes of six patients with NBCCS were measured using magnetic resonance imaging with image‐processing software. Results: Patients with NBCCS scored significantly lower on harm avoidance (0.89) than controls (1.00; P = 0.0084). Moreover, patients with NBCCS and developmental malformations such as rib anomalies, who may have experienced Shh signaling enhancement from the prenatal period, scored significantly lower on harm avoidance (0.80 [P = 0.0031]). The left amygdala volume was also significantly reduced in patients with NBCCS (P = 0.0426). Conclusions: Patients with NBCCS who experienced increased Shh signaling from the prenatal period showed significantly lower harm avoidance related to serotonin. The left amygdala volume was significantly reduced in these patients. Our results indicate that Shh signaling may influence the human personality. [ABSTRACT FROM AUTHOR]

Aim: Follistatin-like-1 (FSTL-1) is considered to be a novel cytokine, and it is associated with metabolic diseases. However, it is necessary to investigate further the association of FSTL-1 with metabolic syndrome (MetS) and insulin resistance (IR). We performed a cross-sectional study to investigate the associated of circulating FSTL-1 with the MetS.Materials and Methods: A cross-sectional study was performed in 487 Chinese people, including 231 control subjects and 256 patients with MetS. Bioinformatics analysis was used to determine the protein and pathways associated with FSTL-1. The protein and protein interaction (PPI) network was constructed and analysed. Serum FSTL-1 concentrations were determined by an ELISA assay. The association of FSTL-1 with MetS components and IR was assessed.Results: Serum FSTL-1 levels were markedly higher in patients with newly diagnosed MetS than in controls (7.5 [5.6-9.2] vs 5.8 [5.0-7.7] μg/L, P < .01). According to bioinformatics analysis, the top high-degree genes were identified as the core genes, including SPARCL1, CYR61, LTBP1, IL-6, BMP2, BMP4, FBN1, FN1 CHRDL1 and FSTL-3. These genes are mainly enriched in pathways including TGF-ß, AGE-RAGE signalling pathway in diabetic complications, and Hippo signalling pathways; in basal cell carcinoma, cytokine-cytokine receptor interaction and in amoebic and Yersinia infections. Furthermore, serum FSTL-1 levels were positively associated with fasting plasma glucose (FPG), waist circumference (WC), blood pressure, triglyceride levels and visceral adiposity index (VAI). We found that serum FSTL-1 levels were markedly associated with MetS and IR by binary logistic regression analysis.Conclusions: We conclude that FSTL-1 may be a novel cytokine related to MetS and IR. [ABSTRACT FROM AUTHOR]

Background: Among the various types of basal cell carcinoma, the sclerodermiform variant has a high risk of recurrence and local invasiveness. A systematic description of the dermatoscopic features associated with specific body localization is lacking. Objectives: To describe the clinical and dermoscopic features of sclerodermiform basal cell carcinoma (BCC) according to localization in the body confronting with superficial and nodular types. Methods: Clinical and dermoscopic images of sclerodermiform, nodular and superficial BCCs were retrospectively evaluated to study the location in the various body districts, maximum diameter, clinical appearance of the lesion, features of edges and presence or absence of specific dermatoscopic criteria of BCCs. Results: We examined 291 histopathologically proven BCCs showing that in nodular BCCs, classical arborizing vessels were more frequently found in the body macro‐area (trunk and limbs; n = 46, 97.9%) than in the head/neck area (n = 43, 82.7%); within sclerodermiform BCCs, short arborizing vessels were found more frequently in the head/neck district (n = 35, 49.3%) than in the body (n = 6, 23.1%; P‐value 0.02); within nodular BCCs, multiple blue‐grey dots and globules were more frequently found on the trunk (n = 23, 48.9%) than in the head/neck district (n = 12, 23.1%; P‐value 0.01). In sclerodermiform BCCs, ulceration was found more frequently in the head/neck district (n = 38, 53.5%) than in the body (n = 4, 15.4%; P‐value > 0.01), and in superficial BCCs, ulceration was found more frequently in the head/neck district (n = 5, 38.5%) than in the body (n = 8, 9.8%; P‐value 0.02). Conclusion: Our study shows that superficial BCC are found frequently in the head/neck district dermoscopically characterized by ulceration and arborizing vessels; nodular BCCs are more frequently found in the body than in the head/neck district, and the dermoscopic pattern is characterized by the combination of three features: (i) classical arborizing vessels, (ii) multiple blue‐grey dots and (iii) globules. Instead, sclerodermiform BCC is preferentially located in areas at high–moderate risk of recurrence; if pink‐white areas and/or fine arborizing vessels are seen, clinicians should consider this diagnosis. Furthermore, location‐specific dermatoscopic criteria have been described. [ABSTRACT FROM AUTHOR]

These findings suggested that the tumour did not experience ultraviolet-induced mutagenesis which was typical of BCC, and instead, accumulated cell cycle-related mutations. Because solitary BCC on the palms and soles in patient without NBCCS is rare, we performed whole exome sequencing to confirm that the tumour was genetically compatible with BCC. Basal cell carcinoma (BCC) is the most frequent skin tumour and generally occurs on the hair-bearing skin of sun-exposed areas. [Extracted from the article]

Background: Antitumor immune response affects tumor growth. The effect of antitumor immune response on recurrence has been poorly studied in basal cell carcinoma (BCC). Objectives: To investigate the effects of the peritumoral immune infiltrate on BCC recurrence. Methods: A total of 30 BCC patients without recurrence and 29 BCC patients with recurrence were included in this retrospective study. Non‐recurrent tumor samples as well as primary and recurrent tumor samples from the recurrent group were stained immunohistochemically with anti‐CD4, CD8, CD25, FOXP3, CD68, CD163, and CD1a antibodies. Immune infiltrates were semiquantitatively evaluated. Results: BCC tumor microenvironment was rich in CD4+ cells. CD163 expression was higher than CD68. In primary tumors of the recurrent group, CD8 expression was significantly lower than CD4 expression. CD1a expression was lower in primary tumors of the recurrent group than in nonrecurrent tumors. Conclusions: Our results suggest the existence of an immunosuppressive microenvironment in BCC. Lower CD8+ T‐cell numbers and sparsity of dendritic cells in primary tumors of recurrent patients suggest further immunosuppression in the tumor microenvironment and an increase in recurrence risk. This is the first study that evaluates and compares tumor immune microenvironments of primary and recurrent BCC lesions with several markers and investigates the role of antitumor immunity on BCC recurrence. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) have well‐established dermatoscopic criteria that make them relatively easy to recognize on a clinical basis. However, even with the addition of dermatoscopy, a morphologic overlap between the two tumours does exist. Objectives: To analyse the dermatoscopic morphology of clinically and dermatoscopically misclassified BCCs and SCCs, to identify factors causing the erroneous clinical interpretation and, therefore, minimize the morphologic overlap between BCC and SCC. Methods: Retrospective study including histopathologically diagnosed BCCs or SCCs that had been clinically inversely diagnosed. Their dermatoscopic images were blindly evaluated for the presence of predefined criteria. Descriptive statistics were performed and univariate and multivariate predictors were calculated. Results: A total of 68 cases were included, 41 of which were BCCs and 27 SCCs. Most tumours in both groups were non‐pigmented, ulcerated and displayed a polymorphous vascular pattern. The presence of erosions was positively associated to BCC (5.2‐fold higher odds, P = 0.05), whereas scales/keratin masses were positively associated to SCC (3.7‐fold higher odds, P = 0.07), although marginally not statistically significant. Conclusions: Clinically misclassified BCCs and SCCs are usually non‐pigmented ulcerated tumours. Erosions and keratin masses/scales are more robust criteria as compared to vascular structures for the differential diagnosis between BCC and SCC. [ABSTRACT FROM AUTHOR]

Sonidegib and vismodegib are hedgehog pathway inhibitors (HhIs) approved for the treatment of advanced basal cell carcinoma (BCC). Until recently, vismodegib was the only targeted treatment available for patients with locally advanced BCC (laBCC) in cases where surgery and radiotherapy are inappropriate. Sonidegib has recently been approved and now presents an alternative treatment option. The clinical differences between the two HhIs in patients with laBCC are unclear, as no head‐to‐head randomized controlled trials are or will be initiated. Moreover, there were important differences in the designs of their pivotal studies, BOLT (sonidegib) and ERIVANCE (vismodegib), and these differences complicate evidence‐based analysis of their relative efficacy and safety profiles. In this paper, a group of clinical experts in the management of laBCC summarizes the clinical and pharmacological profiles of sonidegib and vismodegib based on published data and their own clinical experience. One key difference between the two pivotal studies was the criteria used to assess BCC severity. ERIVANCE (a single‐arm phase II trial) used the conventional Response Evaluation Criteria in Solid Tumors (RECIST), while the more recent double‐blind randomized BOLT trial used the stringent modified RECIST. A preplanned analysis adjusted the outcomes from BOLT with RECIST‐like criteria, and this enabled the experts to discuss relative efficacy outcomes for the two treatments. Centrally reviewed objective response rate (ORR) for vismodegib was 47.6% (95% CI: 35.5–60.6) at 21‐month follow‐up using RECIST. After adjusting with RECIST‐like criteria, the ORR for sonidegib according to central review at 18‐month follow‐up was 60.6% (95% CI: 47.8–72.4). Both treatments were associated with similar patterns of adverse events. Sonidegib and vismodegib share the same efficacy and tolerability profiles, but their pharmacokinetic profiles show several differences, such as volume of distribution and half‐life. Further studies are needed to understand how these differences may impact clinical practice. [ABSTRACT FROM AUTHOR]

Background: Historically, persons with albinism (PWA) were thought to develop squamous cell carcinoma (SCC) more frequently than basal cell carcinoma (BCC). Recent evidence suggests BCCs in PWA are more common than initially hypothesized. Objective: To characterize the presentation of BCC in PWA. Methods: Fifty‐four PWA with lesions suspicious for non‐melanoma skin cancer sought care at Tanzanian dermatologic clinics from 2017 to 2019. Demographic and clinical presentation data were recorded. Histologic analysis of each sample was completed. Results: The majority of PWA were female (53.7%), with a mean age of 34.6 ± 14.9 years and a mean duration of disease of 0.70 ± 0.73 years. Physician description of histologically proven BCC included ulceration (41.7%), erythema (16.7%), and scale (16.7%). Lesions were most commonly located on the trunk (47.1%) and face (41.2%). Histologic analysis demonstrated 30.2% of lesions were BCC, 26.4% SCC, and 17% Bowen's disease. Limitations: Patient population was limited to those visiting clinics, and data were limited by accuracy of the medical record. Conclusions: Basal cell carcinoma occurs at a higher rate than SCC in our population, suggesting BCC in PWA is underdiagnosed. It is important to recognize BCC early in PWA to avoid large disease burden and high rates of morbidity and mortality. [ABSTRACT FROM AUTHOR]

The patched tumor suppressor gene (PTCH1) encodes a receptor, which is a key component of the hedgehog signalling pathway. Mutations in PTCH1 are implicated in the development of sporadic basal cell carcinomas (BCC), as well as those in Gorlin Syndrome. Rarely, BCCs may develop in a linear pattern along lines of Blaschko due to cutaneous mosaicism. In cases in which there are other features of Gorlin syndrome, genomic analysis has demonstrated lesional mutations in the Hedgehog signalling pathway. Causative mutations, however, have not been firmly demonstrated in the cases of linear and segmental BCCs in otherwise healthy individuals. Herein, we report a case of a 31 year‐old Caucasian woman with linear development of multiple superficial BCCs in a Blaschkoid distribution without other characteristic findings of Gorlin syndrome. Genomic analysis of lesional skin by whole‐exome sequencing identified a novel heterozygous mutation PTCH1: NM_000264.3, Exon 15, c.2336‐2337insGGTAGGA, p.Asp779Glufs*13 in PTCH1, shared by two discrete samples within the lesion, while no mutations were found in the non‐lesional skin or peripheral blood. Given the young age of our patient and linear distribution of BCCs on non‐sun exposed skin, our findings suggest segmental mosaicism. The patient was treated with topical 5% imiquimod with histologically confirmed clearance of BCCs in 2 months. [ABSTRACT FROM AUTHOR]

Little guidance on management of basal cell nevus syndrome in children exists. We report a case series of four patients diagnosed with BCNS in early childhood, in whom several highly suspicious lesions were biopsied, but several smaller and questionably concerning lesions were treated with therapies that are more tolerable for children, including topical imiquimod, 5‐fluorouracil, cryotherapy, or touch electrodessication following topical anesthetic cream. These therapies were well tolerated, and all residual or persistent lesions were subsequently biopsied and found to be benign. This approach is often preferable for pediatric BCNS patients, in whom concerning lesions can be identified clinically and managed compassionately. However, any lesion that exhibits growth, bleeding, or symptoms should be biopsied for definitive diagnosis. [ABSTRACT FROM AUTHOR]

Nonmelanoma skin cancers (NMSCs), which are primarily composed of squamous cell carcinoma (SCC), basal cell carcinoma (BCC) and sebaceous carcinoma, are the most common skin tumours and have an increasing incidence[1] and a high mortality rate. Therefore, in this study, we measured B7x expression in various skin hyperplasias to determine the value of B7x as a new marker for some skin tumours. [Extracted from the article]

Background: Radiographic imaging is often used to determine basal cell carcinoma (BCC) extension and invasion and to define a surgical plan. However, imaging modalities may overestimate tumor invasion and lead to unnecessarily aggressive treatment. Methods: A 77‐year‐old woman was seen with a growing BCC of the scalp with MRI imaging indicative of calvarial diploic space invasion. The patient underwent Mohs surgery followed by a parietal craniectomy. Results: Contrary to the MRI findings, histological evaluation of the cortical parietal calvarium and the diploic space did not demonstrate BCC. Conclusions: Surgeons should be wary of diploic space changes in the absence of cortical erosion demonstrated in MRI as it may not explicitly indicate tumor invasion. Biopsy of the diploe is necessary in such cases to determine the surgical course and to avoid morbidity associated with calvarium removal. [ABSTRACT FROM AUTHOR]

Background: Basal cell carcinomas (BCCs) have previously been treated off‐label with ingenol mebutate (IM). Ablative fractional laser (AFL) may improve efficacy of IM by increasing drug uptake in the tumour. Optical coherence tomography (OCT) and reflectance confocal microscopy (RCM) detect BCC non‐invasively. Our aim was to investigate BCC response and tolerability after combined AFL and IM treatment of low‐risk BCCs. Methods: Twenty patients with histologically verified superficial (n = 7) and nodular (n = 13) BCCs were treated with combined fractional CO2‐laser (10 600 nm) and IM 0.015% or 0.05%, the concentration depending on anatomical location. BCC response was evaluated clinically, by OCT and RCM at day 29 and 90 after first treatment, and histologically at day 90. Treatment was repeated at day 29 if BCC persisted. Local skin reactions (LSRs) were assessed using LSR scale at all visits. Results: At day 29, 18/20 patients received a second treatment due to residual BCC detected clinically, by OCT or RCM. OCT and RCM presented subclinical BCCs in five of 20 cases (25%). At day 90, overall histological cure rate was 70%, corresponding to clinical (65%) and OCT/RCM (60%) cure rates, and agreement between evaluation methods was substantial (kappa ≥ 0.796, P < 0.0001). Clearance rates were similar for sBCCs and nBCCs (P = 0.354) and for lesions treated with IM 0.015% and 0.05% (P = 0.141). LSRs were tolerable, but scarring was observed in the majority of cleared patients. Conclusion: Two treatments of combined AFL and IM show potential to treat low‐risk BCCs with acceptable tolerability. OCT and RCM show promise to detect subclinical BCCs at short‐term follow‐up. [ABSTRACT FROM AUTHOR]