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This review aims to provide an overview of neoplastic lesions associated with genetic diseases affecting the female reproductive organs. It seeks to enhance our understanding of the radiological aspects in diagnosing genetic diseases including hereditary breast and ovarian cancer syndromes, Lynch syndrome, Peutz-Jeghers syndrome, nevoid basal cell carcinoma syndrome, and Swyer syndrome, and explores the patterns and mechanisms of inheritance that require elucidation. Additionally, we discuss the imaging characteristics of lesions occurring in other regions due to the same genetic diseases. [ABSTRACT FROM AUTHOR]

Gorlin–Goltz syndrome (GGS) is a rare hereditary disease characterized by multiple basal cell carcinomas, odontogenic keratocyst (OKCs) and musculoskeletal malformations. Pathogenesis of the syndrome is attributed to abnormalities in the long arm of chromosome 9 (q22.3–q31) and mutations in the human patched gene (PTCH1 gene). Here, we report a rare case of an incidental finding of GGS in an 18-year-old male patient presenting multiple OKCs, calcification of the falx cerebri, and bifid rib. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is the most common skin cancer, for which there are multiple treatment options, including the gold standard Mohs micrographic surgery (MMS), surgical excision, electrodesiccation and curettage, radiation therapy, cryosurgery, and photodynamic therapy (PDT). While PDT is currently approved for treating actinic keratosis, it has been used off-label to treat BCC patients who may not tolerate surgery or other treatment modalities. We present a review of the efficacy of these modalities and describe important considerations that affect the usage of PDT and MMS. ALA-PDT and MAL-PDT are both efficacious treatment options for lower-risk BCC that can serve as non-invasive alternatives to surgical excision with favorable cosmetic outcomes in patients unsuitable to undergo surgery. In particular, PDT may be considered an adjuvant for the prevention and treatment of BCC lesions in patients with some genetic syndromes such as Gorlin syndrome, and in combination with surgical excision in lesions presenting in certain locations. Limitations to PDT include lack of margin control to prevent recurrence, pain, and cost of certain photosensitizers. Future studies should investigate the role of PDT as adjunctive therapy, standardization of protocols, and causes and ways to address recurrence following PDT treatment. [ABSTRACT FROM AUTHOR]

Background: Gorlin-Goltz's syndrome (GGS) is an extremely rare autosomal dominant disorder showing a high penetrance and variable expressivity. Gorlin-Goltz's syndrome is an infrequent multisystemic disease, which is usually characterized by numerous basal cell carcinomas, odontogenic keratocysts (OKCs), and musculoskeletal malformations along with neurological, ophthalmic, endocrine, and genital manifestations. There are also multiple manifestations in the domain of ENT and patient may primarily present to an ENT clinician with one of the diverse clinical involvements. Case presentation: We report one such infrequent case of a 24-year-old male patient who presented with an oroantral fistula at our tertiary health care center and was diagnosed to have Gorlin-Goltz's syndrome. The diagnosis was made in our patient by the presence of 4 major and 2 minor criteria. Conclusion: Early diagnosis and management of GGS helps to prevent long-term sequelae including malignancy and oro-maxillofacial deformation. The constellation of symptoms of such rare disorders should be promptly recognized and a high index of suspicion should be maintained. This case report is an appraisal of the diagnosis and management of GGS from an otolaryngological perspective and is being reported here for extreme rarity and clinical interest. [ABSTRACT FROM AUTHOR]

Background: Gorlin-Goltz syndrome is a rare autosomal dominant disorder resulting from PTCH1 gene mutation and presents with variable clinical manifestations. The co-occurrence of medulloblastoma and cardiac fibroma in Gorlin-Goltz syndrome is extremely rare. The present article discusses a patient diagnosed with Gorlin-Goltz syndrome and concurrent medulloblastoma and cardiac fibroma. Case presentation: A 19-month-old boy transferred to our hospital after a radiological finding of posterior fossa lesion and hydrocephalus. A pericardial mass was noted after persistent arrhythmias. Both tumors were excised for definitive management. The histopathological sections were diagnostic of desmoplastic nodular medulloblastoma, WHO grade 4 and cardiac fibroma. Molecular and genetic investigations confirmed a pathogenic variant of PTCH1 gene, suggestive of autosomal dominant Gorlin-Goltz syndrome. Conclusion: Co-occurrence of medulloblastoma and cardiac fibroma is extremely rare and poses a management dilemma. Genetic counseling and antenatal screening are of utmost importance to early detect and manage patients with Gorlin-Goltz syndrome. [ABSTRACT FROM AUTHOR]

Introduction: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant condition characterized by the development of odontogenic keratocyst (OKC), basal cell carcinomas and palmar–plantar pits among other conditions. Reports about Latin American population are scarce. Objective: To analyze the clinical, radiographic, histopathologic and inherited features of odontogenic keratocyst and palmar pits in three Chilean families with nevoid basal cell carcinoma syndrome. Material and methods: After histopathologic diagnosis of OKC, notified consent was requested and evaluation of the affected patients and their families was done. Results: Two families appeared to have only one affected adolescent, and both of them were considered de novo cases. In the third family, three affected members participated in this study, with an autosomal dominant presentation. All affected patients had OKC and palmar pits. Basal cell carcinomas were present only among adult patients. All examined patients were from Latin American ethnic groups. Conclusions: Patients with NBCCS had single or multiple OKCs that were located more frequently in the mandibular area. One family had autosomal dominant inheritance and the other two families were de novo cases. None of the three teenage patients had basal cell carcinomas. [ABSTRACT FROM AUTHOR]

Recent genetic sequencing studies in large series' of predominantly childhood medulloblastoma have implicated loss-of-function, predominantly truncating, variants in the ELP1 and GPR161 genes in causation of the MBSHH subtype specifically. The latter association, along with a report of an index case with some features of Gorlin syndrome has led to speculation that GPR161 may also cause Gorlin syndrome. We show that these genes are associated with relatively low absolute risks of medulloblastoma from extrapolating lifetime risks in the general population and odds ratios from the population database gnomAD. The projected risks are around 1 in 270–430 for ELP1 and 1 in 1600–2500 for GPR161. These risks do not suggest the need for MRI screening in infants with ELP1 or GPR161 variants as this is not currently recommended for PTCH1 where the risks are equivalent or higher. We also screened 27 PTCH1/SUFU pathogenic variant-negative patients with Gorlin syndrome for GPR161 and found no suspicious variants. Given the population frequencies of 0.0962% for GPR161 and 0.0687% for ELP1, neither of these genes can be a cause of Gorlin syndrome with an unexplained population frequency far lower at 0.0021%. [ABSTRACT FROM AUTHOR]

The vast majority of skin cancers can be classified into two main types: melanoma and keratinocyte carcinomas. The most common keratinocyte carcinomas include basal cell carcinoma (BCC) and squamous cell carcinoma (SCC). Multiple familial syndromes have been identified that can increase the risk of developing SCC, BCC, and/or melanoma. The major syndromes include oculocutaneous albinism for SCC, basal cell nevus syndrome for BCC, familial atypical multiple mole-melanoma syndrome, and hereditary breast and ovarian cancer syndrome for melanoma. In addition, familial syndromes that can predispose individuals to all three major skin cancers include xeroderma pigmentosum and Li–Fraumeni syndrome. This review highlights the epidemiology, risk factors, pathogenesis, and etiology of the major and minor syndromes to better identify and manage these conditions. Current investigational trials in genomic medicine are making their way in revolutionizing the clinical diagnosis of these familial syndromes for earlier preventative measures and improvement of long-term prognosis in these patients. [ABSTRACT FROM AUTHOR]

Basal cell nevus syndrome (BCNS), or Gorlin syndrome, is a rare autosomal dominant disorder caused by mutations in the tumor suppressor gene PTCH1 with complete penetrance and variable expressivity characterized by a broad spectrum of developmental anomalies and a predisposition to neoplasms. Herein, we report a novel de novo splice site mutation in the PTCH1 gene related to mild developmental delay and autistic traits in a 4-year-old male patient. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) data coming from the Levantine coast of the Mediterranean Sea are limited. The study aimed to primarily analyze the demographic, clinical, pathological, and prognostic characteristics of BCC in this region of the world and secondarily identify features associated with high-risk, recurrent, or multiple BCCs. Patients with at least one diagnosis of BCC registered in the pathology department between January 2015 and December 2019 were included in this analytical retrospective single-center cohort study. Patients with basal cell nevus syndrome were excluded. Patients' characteristics and pathological features were collected through file check for a first analysis. Risk factors and evolution were sought through a phone call interview for the second analysis. The first analysis included 506 BCCs corresponding to 365 patients with a mean age of 65 ± 15 years, twenty-two (6%) were less than 40 years old, 180 (49.3%) were women, and 85 (23.3%) had two or more BCCs. The second analysis included 279 BCCs corresponding to 205 patients. Periorificial and infiltrative BCCs were more frequent in men. Periorificial tumors were more frequently nodular or infiltrative and were associated with recurrence. Tumors with perineural involvement were histologically never nodular nor superficial. Recurrence was more frequent in BCCs having periorificial location, a size larger than 2 cm, or an infiltrative subtype. Multiple BCCs were more frequent in patients with light skin type or familial history of skin cancer. High-risk BCCs were more common in patients with low sun exposure. [ABSTRACT FROM AUTHOR]

Medulloblastoma (MB) is a rapidly growing malignant solid tumor that arises from stem cells located in the subependymal germinal matrix or outer granular layer of the cerebellum. It represents 15 to 30% of pediatric brain tumors and less than 1% of primary brain tumors. The reason for the high incidence of MB in children compared to adults is the embryonic origin of the tumor. In typical cases, MB manifests as a solitary lesion in the fourth ventricle or in the cerebellar parenchyma; cases of synchronous multifocal and disseminated MB are quite rare in patients without familial tumor syndromes. To date, only 7 cases in adults and a single pediatric case with Gorlin syndrome have been described previously. Here, the authors report a new case of synchronous multifocal classic cerebrospinal histologically confirmed MB in a 10-year-old male patient revealed by bilateral decreased visual acuity without any other localizing neurological signs. The authors will proceed with a review of the current literature regarding this rare entity. [ABSTRACT FROM AUTHOR]

Background: Gorlin syndrome, also known as Gorlin-Goltz syndrome (GGS) or basal cell nevus syndrome (BCNS) or nevoid basal cell carcinoma syndrome (NBCCS), is an autosomal dominant familial cancer syndrome. It is characterized by the presence of numerous basal cell carcinomas (BCCs), along with skeletal, ophthalmic, and neurological abnormalities. It is essential to anticipate the diagnosis by identifying the pathology through the available diagnostic tests, clinical signs, and radiological manifestations, setting up an adequate treatment plan. Main body: In the first part, we searched recent databases including MEDLINE (PubMed), Embase, and the Cochrane Library by analyzing the etiopathogenesis of the disease, identifying the genetic alterations underlying them. Subsequently, we defined what are, to date, the major and minor clinical diagnostic criteria, the possible genetic tests to be performed, and the pathologies with which to perform differential diagnosis. The radiological investigations were reviewed based on the most recent literature, and in the second part, we performed a review regarding the existing jawbone protocols, treating simple enucleation, enucleation with bone curettage in association or not with topical use of cytotoxic chemicals, and "en bloc" resection followed by possible bone reconstruction, marsupialization, decompression, and cryotherapy. Conclusion: To promote the most efficient and accurate management of GGS, this article summarizes the clinical features of the disease, pathogenesis, diagnostic criteria, differential diagnosis, and surgical protocols. To arrive at an early diagnosis of the syndrome, it would be advisable to perform radiographic and clinical examinations from the young age of the patient. The management of the patient with GGS requires a multidisciplinary approach ensuring an adequate quality of life and effective treatment of symptoms. [ABSTRACT FROM AUTHOR]

A number of case/family reports have proposed PTCH2 as a putative Gorlin Syndrome (GS) gene, but evidence to support this is lacking. We assessed our cohort of 21 PTCH1/SUFU negative GS families for PTCH2 variants and assessed current evidence from reported cases/families and population data. In our PTCH1/SUFU variant negative GS cohort (25% of total), no pathogenic or likely pathogenic PTCH2 variants were identified. In addition, none of the previously published PTCH2 variants in GS families/cases could be considered pathogenic or likely pathogenic using current guidelines. The absence of clear pathogenic variants in GS families and the high frequency of Loss-of-function (LoF) variants in the general population, including the presence of homozygous LoF variants without a clinical phenotype, mean that it is untenable that PTCH2 is a GS gene. PTCH2 should not be included in panels for genetic diagnosis of GS. [ABSTRACT FROM AUTHOR]

Growing evidence has revealed that circular RNAs (circRNA) play critical roles in cancer progression. Here, we examined the function of a novel circRNA, Circ_0005795, in basal cell carcinoma (BCC) and explored the possible molecular mechanism. Nodular BCC and adjacent non-tumor tissues derived from 30 patients and 2 BCC cell lines were applied to analyze gene expression. Circ_0005795 loss- and gain-of-function were constructed to investigate BCC progression. Nuclear and cytoplasmic fractionation and luciferase assay were carried out to determine cellular localization and molecular interaction of Circ_0005795. Circ_0005795 expression was significantly elevated in BCC tissues and cells. Knockdown of Circ_0005795 dramatically reduced cell viability, colony formation, and anti-apoptotic protein levels, while increased caspase-3 activity. Circ_0005795 located in cytoplasm, which exerted its tumor-promoting effect through targeting and sponging miR-1231 in BCC cells. In summary, Circ_0005795 works as an oncogene in BCC, which might be used as a promising biomarker and a potential therapeutic target for BCC diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is a tumor predisposition condition, the cardinal features of which emerge in adolescence or adulthood. Using statistical optimization, this study proposes NBCCS criteria with improved sensitivity in children less than 18 years of age. Earlier detection may lead to improved surveillance and prevention of sequelae. A survey eliciting medical history was completed by, or on behalf of, individuals with NBCCS. Based on these findings, criteria for suspicion of NBCCS in children were suggested using information from a Bernoulli naïve Bayes classifier relying on the human phenotype ontology. The sensitivity and specificity of the existing and proposed diagnostic criteria were also assessed. Participants (n = 48) reported their first signs of NBCCS appeared at a median age of 8 months, but by our retrospective analysis, they did not fulfill the current diagnostic criteria until a median age of 7 years. This study delineates the early-onset features of NBCCS and proposes criteria that should prompt consideration of NBCCS. Additionally, we demonstrate a method for quantitatively assessing the utility of diagnostic criteria for genetic disorders. [ABSTRACT FROM AUTHOR]

Introduction: Sonidegib is approved to treat locally advanced basal cell carcinoma (laBCC) in the USA, EU, Switzerland, and Australia and metastatic basal cell carcinoma (mBCC) in Switzerland and Australia in patients not amenable to surgery or radiotherapy. Vismodegib is approved to treat patients with mBCC, recurrent laBCC, or those not candidates for surgery or radiation. There is no head-to-head trial comparing Hedgehog inhibitors. We describe time to onset and severity of adverse events (AEs) in two studies reporting cumulative AE incidence every treatment cycle: the sonidegib phase 2 BOLT study and the expanded-access, open-label vismodegib study. Methods: This analysis included patients with histologically confirmed laBCC or mBCC from BOLT who received sonidegib 200 mg once daily (QD) and patients from the vismodegib study who received vismodegib 150 mg QD. Cumulative occurrence of AEs and median time to AE onset were calculated on 30-day cycles for sonidegib and 28-day cycles for vismodegib. AEs were graded for severity using the Common Terminology Criteria for Adverse Events. Only common (at least 15% incidence) AEs were analyzed in this study. Results: Over 18 treatment cycles, the most common all-grade AEs for sonidegib and vismodegib were muscle spasm (54.4% vs 70.6%; P = 0.0236), alopecia (49.4% vs 58.0%; no significant difference [NS]), and dysgeusia (43.0% vs 70.6%; P = 0.0003); incidences of diarrhea, nausea, fatigue, and weight decrease were 31.6% vs 25.2% (NS), 39.2% vs 19.3% (P = 0.0032), 32.9% vs 19.3% (P = 0.0429), and 30.4% vs 16.0% (P = 0.0217), respectively. Sonidegib-treated patients had more delayed median time to onset for all AEs than vismodegib-treated patients, except fatigue and weight decrease (NS). Most AEs reported were grade ≤ 2. Conclusion: This post hoc analysis suggests lower overall incidence and slower onset of certain AEs in patients treated with sonidegib compared with vismodegib. In the absence of head-to-head comparisons, the relevance of these findings needs further studies to provide conclusive evidence. [ABSTRACT FROM AUTHOR]

Gorlin syndrome (MIM 109,400), a cancer predisposition syndrome related to a constitutional pathogenic variation (PV) of a gene in the Sonic Hedgehog pathway (PTCH1 or SUFU), is associated with a broad spectrum of benign and malignant tumors. Basal cell carcinomas (BCC), odontogenic keratocysts and medulloblastomas are the main tumor types encountered, but meningiomas, ovarian or cardiac fibromas and sarcomas have also been described. The clinical features and tumor risks are different depending on the causative gene. Due to the rarity of this condition, there is little data on phenotype-genotype correlations. This report summarizes genotype-based recommendations for screening patients with PTCH1 and SUFU-related Gorlin syndrome, discussed during a workshop of the Host Genome Working Group of the European branch of the International Society of Pediatric Oncology (SIOPE HGWG) held in January 2020. In order to allow early detection of BCC, dermatologic examination should start at age 10 in PTCH1, and at age 20 in SUFU PV carriers. Odontogenic keratocyst screening, based on odontologic examination, should begin at age 2 with annual orthopantogram beginning around age 8 for PTCH1 PV carriers only. For medulloblastomas, repeated brain MRI from birth to 5 years should be proposed for SUFU PV carriers only. Brain MRI for meningiomas and pelvic ultrasound for ovarian fibromas should be offered to both PTCH1 and SUFU PV carriers. Follow-up of patients treated with radiotherapy should be prolonged and thorough because of the risk of secondary malignancies. Prospective evaluation of evidence of the effectiveness of these surveillance recommendations is required. [ABSTRACT FROM AUTHOR]

Gorlin syndrome (GS) is an autosomal dominant genetic disorder involving Patched 1 (PTCH1) mutations. The PTCH1 is a receptor as well as an inhibitor of hedgehog (Hh) to sequester downstream Hh pathway molecules called Smoothened (SMO). PTCH1 mutations causes a variety of GS conditions including falx calcification, odontogenic keratocytes and basal cell carcinomas (BCC). Because PTCH1 is a major driver gene of sporadic BCC, GS patients are characteristically prone to BCC. In order to elucidate the pathological mechanism of BCC-prone GS patients, we investigated keratinocytes derived from GS patient specific iPS cells (G-OFiPSCs) which were generated and reported previously. We found that keratinocytes derived from G-OFiPSCs (GKCs) have increased expression of Hh target molecules. GKCs were irradiated and those cells showed high resistance to UV induced apoptosis. BCL2, known as anti-apoptotic molecule as well as Hh target, significantly increased in GKCs. Several molecules involved in DNA repair, cell cycle control, senescence, and genotoxic stress such as TP53, BRCA1 and GADD45A increased only in GKCs. GKCs are indicated to be resistant to UV irradiation by upregulating molecules which control DNA repair and genotoxic even under DNA damage caused by UV. The anti-apoptotic properties of GKCs may contribute BCC. [ABSTRACT FROM AUTHOR]

Objectives: To provide a systematic review of the literature on studies comparing the immunoprofile of nevoid basal cell carcinoma syndrome (BCNS)–associated and sporadic odontogenic keratocysts (OKCs), in order to identify markers that could accurately distinguish the two OKC subtypes. Materials and methods: We searched MEDLINE/Pubmed, Web of Science, EMBASE via OVID, and grey literature for publications until December 28th, 2019, that compared the immunohistochemical expression of the two OKC subtypes. The studies were qualitatively assessed using the Critical Appraisal Tool for Case Series (Joana Briggs Institute). Sensitivity and specificity, positive and negative likelihood ratio, diagnostic odds ratio and area under the curve, and pooled estimates were calculated, using a random-effects model. Results: Seventy-one studies were qualitatively analyzed; 61 markers were evaluated in one study and 32 in ≥ 2 studies. Twenty-five studies reported differential expression of 29 markers in the form of higher number of positive cells or greater staining intensity usually in BCNS-associated OKCs. Meta-analysis for bcl-2, Cyclin D1, CD56, CK18, p53, and PCNA showed that none of those markers is distinguishable between BCNS-associated and sporadic OKCs, in a 95% confidence interval. The risk of bias was high in 34 studies, moderate in 22, and low in 15. Conclusions: The present systematic review and meta-analysis uncovered that, although several immunohistochemical markers might characterize the OKC phenotype, they cannot discriminate between the BCNS-associated and sporadic OKCs. Clinical relevance: This study highlighted the requirement for additional screening for markers by immunohistochemistry, preferentially coupled to alternative diagnostic applications such as genomics technologies. [ABSTRACT FROM AUTHOR]

Although surgery represents the treatment of choice for the majority of basal cell carcinomas, different therapies are required to treat the advanced ones. Vismodegib and sonidegib are the two oral Smoothened (Smo) inhibitors approved for the treatment of advanced basal cell carcinoma. Clinical detection of subclinical basal cell carcinoma during and after vismodegib treatment could be difficult, requiring the use of dermoscopy and reflectance confocal microscopy as noninvasive diagnostic methods. We report the case of a 62-year-old woman with a locally advanced basal cell carcinoma successfully treated with vismodegib in which dermoscopy and reflectance confocal microscopy showed their superiority in detecting subclinical recurrent basal cell carcinoma developed on scar tissue after complete regression of the tumor. [ABSTRACT FROM AUTHOR]

Scalp is a common site for skin tumors mainly squamous cell carcinoma and basal cell carcinoma. It is always challenging to reconstruct the scalp defect following tumor excision. Conventional methods of skin grafting or rotation flap is not always feasible for large scalp defect. This paper presents the author's experience in 3 patients of scalp tumors in which conventional methods were not sufficient to reconstruct the defect, hence pedicled latissimus dorsi flap was used considering the flap size to cover the defect and reach needed for the pedicled flap. In all the 3 cases latissimus dorsi myocutaneous was able to reach the defect site and cover the large scalp defect area; thereby serving as an alternative to free flap which is technically more challenging, skill based and less feasible in normal surgical settings. [ABSTRACT FROM AUTHOR]

Purpose: To investigate the incidence rate of hereditary disease in patients with medulloblastoma. Methods: The genetic reports of 129 patients with medulloblastoma from January 2016 to December 2019 were retrospectively analyzed. A panel sequence of 39 genes (Genetron Health) were used for all patients to evaluate the tumor subgroup. Four genes (TP53, APC, PTCH1, SUFU) were screened to routinely rule out germline mutation. Results: Five patients (3.9%) were found with hereditary disease, and all belonged to the sonic hedgehog (SHH) subgroup. Two patients were retrospectively diagnosed with Gorlin–Goltz disease with germline PTCH1 and SUFU mutations. One patient (PTCH1 mutation) accepted whole craniospinal irradiation and had scalp nevoid basal cell carcinoma 5 years later. The other patient (SUFU mutation) accepted chemotherapy and had local tumor relapse 1 year later. Three patients were diagnosed with Li–Fraumeni syndrome and carried the TP53 mutation; all three patients died. One of the patients had bone osteosarcoma, while all three had early tumor relapse. Conclusion: Patients with SHH medulloblastoma should routinely undergo genetic testing. We propose that whole genome, whole exome sequence, or custom-designed panel-targeted exome sequencing should be performed. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is mainly characterised by multiple basal cell carcinomas (BCCs) caused by PTCH1, PTCH2, and SUFU. However, clinical and genetic data on Asian NBCCS patients are limited. We aimed to analyse the clinical phenotypes and genetic spectrum of Korean patients with NBCCS. Fifteen patients with NBCCS at Seoul National University Hospital were included, and their clinical data were analysed. Whole-exome sequencing and/or multiplex ligation-dependent probe amplification using peripheral blood were performed to identify genetic causes. Genetic analysis revealed that 73.3% (11/15) of the patients carried 9 pathogenic variants, only in the PTCH1 gene. Variants of uncertain significance (VUS) and likely benign were also detected in 2 (13.3%) and 2 (13.3%) patients, respectively. BCCs were found in the majority of the cases (93.3%) and the number of BCCs increased with age (ρ = 0.595, P = 0.019). This study revealed that PTCH1 pathogenic variants were the main cause of NBCCS in Korean patients. As BCCs are commonly detected, a periodic dermatologic examination is recommended. Finally, our results support the addition of genetic screening to the existing criteria for NBCCS diagnosis. [ABSTRACT FROM AUTHOR]

An understanding of genetics and genomics is increasingly important for all clinicians. Next-generation genomic sequencing technologies enable sequencing of the entire human genome in short timescales, and are increasingly being implemented in health care systems. Clinicians across all medical specialties will increasingly use results generated from genomic testing to inform their clinical practice and provide the best quality of care for patients. These innovations are already transforming the diagnostic pathways for rare genetic diseases, including skeletal dysplasias, with an inevitable impact on the traditional roles of diagnosticians. This article covers the fundamentals of human genetics, mechanisms of genetic variation and the technologies used to investigate the genetic basis of disease, with a specific focus on skeletal dysplasias and the potential impact of genomics on paediatric radiology. [ABSTRACT FROM AUTHOR]

Treatment of choice for nodular basal-cell carcinomas (BCCs) is complete excision, implying that small lesions are of minor concern. Metastasis is very rare (< 1%). However, locally advanced basal-cell carcinomas (laBCCs), which are ineligible for surgery or radiation, are a therapeutic challenge. First-generation Smoothened (SMO) inhibitors (vismodegib, sonidegib) have been approved for treatment, but common side effects limit their use. Numerous new compounds are being investigated in clinical trials as potential therapeutic alternatives, among them second-generation SMO inhibitors, other Hedgehog signaling pathway inhibitors, immune-checkpoint inhibitors and intralesional modalities such as oncolytic viruses. Neoadjuvant treatment regimens open another field. This article deals with the clinical management of laBCCs, based on the description of an illustrative case from our department featuring multiple extensive lesions of the scalp. In this short review we will discuss therapeutic options and implications for the future. Some of the new strategies might potentially evolve as alternatives in the management of genodermatoses such as basal-cell carcinoma syndrome, if proven effective and safe. [ABSTRACT FROM AUTHOR]

Introduction: Although non-melanoma skin cancers (NMSCs) are associated with a very low mortality risk, they have been reported to have a major impact on patients' health-related quality of life (HRQoL). Vismodegib is a therapy for patients who are affected by locally advanced basal cell carcinoma (BCC) or metastatic BCC who are ineligible for surgery and/or radiotherapy. The aim of the present clinical study was to assess the long-term efficacy of vismodegib after its withdrawal by evaluating the recurrence rate of advanced BCC, assessing also patients' HRQoL after 3 and 6 months from drug withdrawal. Methods: A retrospective study was performed to analyze patients with advanced and/or multiple BCCs that had been treated with vismodegib (150 mg daily) at the Non-Melanoma Skin Cancer Unit of the University of Naples Federico II (Italy) and had obtained a complete regression in 6 months. At the end of the 6-month treatment cycle, patients that reported total remission of the skin tumor were visited monthly in order to assess their therapeutic response. Moreover, to assess the specific impact of vismodegib on HRQoL, DLQI was administered before vismodegib treatment (baseline), at the end of the therapy cycle (6 months), as well as after 3 and 6 months from vismodegib discontinuation. Results: Thirty-five patients (27 male, 8 female), with a complete regression of their advanced BCC after vismodegib treatment, were included in the study. The duration of treatment for all patients was 6 months as set by study inclusion criteria. A BCC recurrence rate of 31% (11/35) was reported after a 6-month follow-up. The average reported Dermatology Life Quality Index (DLQI) score increased from a value of 0 at the end of the 6-month vismodegib treatment to a mean value of 2.4 after 3 months from drug withdrawal and 3.6 after 6 months from treatment discontinuation. Conclusion: The results of this exploratory analysis of vismodegib withdrawal are consistent with a substantial link between treatment response and patients' HRQoL. Furthermore, 11 out of 35 (31%) patients that reported a complete remission of the disease after 6 months of vismodegib treatment reported BCC recurrence. These data highlight the importance of continuous follow-up and perhaps different regimens of treatment, such as an alternate dose regimen to maintain disease control and reduce the adverse events as previously described in the literature. [ABSTRACT FROM AUTHOR]

The consensus panel for 2017 classification argued that there was some evidence in support for reclassifying the cyst in 2005 including aggressive growth, post-operative recurrence, the rare reports of a solid variants of OKC, and mutations in the PTCH gene, but the evidence was not sufficient to support this reclassification as a tumour at present. Odontogenic keratocyst (OKC) - reverting back from tumour to cyst: Keratocystic odontogenic tumour (KCOT) - a cyst to a tumour. Sir, In continuation to our publication, B Keratocystic odontogenic tumour (KCOT) - a cyst to a tumour. [Extracted from the article]

Basal cell carcinoma (BCC) environment consists of stromal and inflammatory cells which produce variety of cytokines, chemokines and growth factors that may affect tumor behavior. One of the cytokines suggested to be involved in the pathogenesis of BCC is IL-6, which is the upstream element of IL-6/JAK/STAT3 pathway. The correlation between polymorphisms of the genes related to this pathway and cancer risk/prognosis have been previously investigated in several neoplasia, but available data concerning BCC are scarce. In the present study, rs1800795 (-174 G/C) IL-6 gene polymorphism and two polymorphisms in the STAT3 gene, namely rs2293152 (intron 11, C/G) and rs4796793 (-1697, C/G) were assessed in relation to the BCC risk and clinical course. Additionally, IL-6 serum level was assessed in relation to IL-6 genotype and clinical variables. The study included 254 unrelated patients with BCC and of mean age 70.39 ± 11.43 (69.83 ± 12.32 women, 71.03 ± 10.31 men) and 198 healthy, unrelated age- and sex-matched volunteers. IL-6 and STAT3 polymorphisms were analyzed using polymerase chain reaction with sequence-specific primers (SSP-PCR). Serum concentration of IL-6 was measured using the ELISA test. We have found that the presence of C allele in rs1800795 IL-6 gene polymorphism was associated with increased risk of BCC (aOR 1.86; 95% CI 1.22–2.84; p = 0.004). The presence of CC genotype in STAT3 rs2293152 polymorphism was associated with increased BCC risk in recessive model analysis (aOR 3.94; 95% CI 1.59–9.77; p = 0.003). In contrast, the presence of GC genotype in overdominant model was associated with decreased risk of BCC (aOR = 0.24; 95% CI 0.12–0.49; p < 0.0001). The presence of C allele in STAT3 rs2293152 polymorphism was associated with increased risk of BCC (aOR 1.31; 95% CI 1.01–1.69; p = 0.04). The presence of GG genotype in STAT3 rs4796793 polymorphism was associated with increased BCC risk in recessive model analysis (aOR 3.66; 95% CI 1.33–10.10; p = 0.012). The presence of G allele in STAT3 rs4796793 polymorphism was associated with increased risk of BCC (aOR 1.59; 95% CI 1.01–2.49; p = 0.04). IL-6 serum level positively correlated with the tumor size. [ABSTRACT FROM AUTHOR]

Introduction: Non-melanoma skin cancer (NMSC) is the most common type of human tumor, with an estimated five million new cases each year. NMSC has been described as having a major impact on the health-related quality of life of the patient. Vismodegib is a hedgehog pathway inhibitor therapy for patients who are affected by locally advanced basal cell carcinoma (laBCC) and metastatic basal cell carcinoma and are ineligible for surgery and/or radiotherapy. The objective of this study was to assess treatment-emergent adverse events reported by patients with advanced BCC who were undergoing hedgehog pathway inhibitor therapy with vismodegib, and to quantify their health-related quality of life using the Dermatology Life Quality Index (DLQI) questionnaire. Methods: Patients with advanced and/or multiple basal cell carcinomas treated with vismodegib at the Non-Melanoma Skin Cancer Unit of the University of Naples Federico II (Italy) were consecutively enrolled. Each patient was evaluated every month until the end of the treatment cycle to assess adverse events related to the drug and the patient's quality of life. Results: 48 patients (35 males and 13 females) with advanced BCC were included in the study. Muscle spasms, alopecia, and dysgeusia were the most frequently reported adverse events. 41 patients completed the DLQI questionnaire at the baseline visit and after 6 months of treatment. The average reported DLQI score decreased from a mean value of 5.7 at the baseline visit to 0.4 after 6 months of treatment. Conclusion: This is the first study to demonstrate a significant change in patient health-related quality of life from baseline to 6 months after hedgehog pathway inhibitor therapy initiation using the DLQI test. Interestingly, patients with BCC in visible areas such as the face or neck presented an overall DLQI score that was higher than that of patients with BCC located on the trunk and legs at the baseline visit, but the DLQI scores of these two groups were almost the same after 6 months of vismodegib therapy. [ABSTRACT FROM AUTHOR]

We describe association of olfactory bulb and olfactory tract abnormalities in a child with acrocallosal syndrome caused by kinesin family membrane 7 (KIF7) mutation in sonic hedgehog pathway. The child also had fontanellar bone in the anterior fontanelle, short sagittal suture, sagittal synostosis, hippocampal malrotation and Joubert malformation. Fontanellar bone has been described in GLI3 mutation and mutant mice models but has not been reported in KIF7 mutation. We briefly review the role of sonic hedgehog pathway and its components KIF7 and GLI3 in forebrain and olfactory system development and also describe olfactory system abnormality in a child with GLI3 mutation. [ABSTRACT FROM AUTHOR]

Objectives: Genetic variants in the hedgehog signaling pathway and VDR gene are involved in inflammatory responses and neoplastic transformation. Current study investigated whether single-nucleotide polymorphisms in the hedgehog pathway genes PTCH1, GLI1, SMO, and VDR contribute to susceptibility to odontogenic cystic lesions, odontogenic keratocysts, or inflammatory radicular cysts. Material and methods: Current study examined polymorphisms of PTCH1 (rs357564) and PTCH1 insertion (IVS1-83), GLI1 (rs2228224, rs2228226), SMO (rs2228617), and VDR (rs2228570, rs731236, rs7975232). A case-control study was conducted on 41 keratocyst cases, 43 radicular cyst cases, and control group of 93 healthy individuals without cystic lesions, radiographically confirmed. Single-nucleotide polymorphisms were assessed by real-time and TaqMan SNP genotyping assays, while PTCH1 insertion 18 bp IVS1-83 polymorphism was determined by PCR. Results: The difference in genotype distribution between keratocyst cases and control group was observed for PTCH1 IVS1-83 and GLI1 rs2228224 polymorphism (p = 0.022, p = 0.030, respectively). Homozygous mutant GG genotype within GLI1 rs2228224 is associated with increased susceptibility for odontogenous keratocysts, with adjusted odds ratio of 4.098 (confidence interval of 1.482–11.328, p = 0.007). Conclusion: GLI1 rs2228224 and PTCH1 polymorphisms could predispose to odontogenic keratocysts. Clinical relevance: Variants in hedgehog signaling pathway genes, such as GLI1 and PTCH1, and vitamin D receptor gene, might be considered as molecular risk factors in odontogenic cystic lesions and potential targets for novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Basal cell carcinoma (BCC) is the most commonly diagnosed malignancy in humans, and as such it poses a significant healthcare burden. The majority of BCC cases are amenable to cure by surgical extirpation. However, until recently there have been no good treatment options for a significant minority of advanced BCC cases, including locally advanced BCC and metastatic BCC. The introduction of a novel class of drugs, the Hedgehog pathway inhibitors, into clinical practice has ushered in a new treatment algorithm for the treatment of difficult BCC cases. In this review we present the latest available evidence and discuss areas for further research in this rapidly evolving field. [ABSTRACT FROM AUTHOR]

Aims: The aim of this study was to compare the clinical and demographic features of 62 patients presenting sporadic odontogenic keratocysts (OKCs) or OKCs associated with nevoid basal cell carcinoma syndrome (NBCCS). In conjunction with this, we also evaluated the immunohistochemical expression of Shh, Ptch1, Ptch2, Smo, Gli1, Gli2 and Gli3 proteins in 86 OKCs. By doing this, we add to the understanding of the biology of this type of lesion, providing tools that will help facilitate the early diagnosis of NBCCS in those patients where the first manifestation is that of OKCs.Methods: This is a retrospective study; patients were classified into two groups: group 1 which consisted of those who were not affected by NBCCS (49 patients and 57 OKCs) and group 2 which consisted of those who were diagnosed with NBCCS (13 patients and 29 OKCs). The clinical and demographic features were studied and the immunohistochemical expression of Sonic Hedgehog proteins (Shh, Ptch1, Ptch2, Smo, Gli1, Gli2, and Gli3) was analyzed in all samples.Results: There was an increase in the expression of three proteins in the syndromic OKC, when compared to that of sporadic cysts. Shh and Gli1 showed higher cytoplasmic expression, while Smo revealed stronger nuclear and cytoplasmic expressions.Conclusion and clinical relevance: Our findings suggest that the expression patterns of important Shh pathway proteins can represent valuable markers for early diagnosis of NBCCS-associated OKCs, as the major criterion for the diagnosis of NBCCS is currently based on the late appearance of basal cellular carcinomas. Thus, standardizing a new diagnostic tool for diagnosis of NBCCS could be of great importance in the identification of therapeutic targets. We therefore suggest, as based on our findings, that OKCs showing high expression of Shh, Smo, and Gli1 are potentially associated with NBCCS. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disease characterized by the development of multiple jaw keratocysts and basal cell carcinomas (BCC) and accompanied by diverse phenotypes. The establishment of diagnosis lies on the identification of a heterozygous germline pathogenic variant in the patched homolog 1 gene (PTCH1). PTCH1 has alternative splicing and selective initial coding exon, leading to three types of encoding proteins (PTCHL, PTCHM and PTCHS). The expression of each protein in NBCCS remains ambiguous, especially the importance of the first two exons in translation. Here, we report a Chinese NBCCS family of a novel PTCH1 heterozygous mutation (IVS 2, c.394+1G>T, g.10652G>T) identified by genomic sequencing and reverse-transcription-PCR as aberrant splicing. To the best of our knowledge, this is the first report of NBCCS with a splicing site mutation in intron 2 resulting in exon 2 skipping. Our finding suggests that exon 2 plays an important role in the development of NBCCS and further speculates that the role of longer isoforms PTCHL and PTCHM is crucial in NBCCS, while that of short isoform PTCHS might be dispensable. [ABSTRACT FROM AUTHOR]

Abstract: The latest (4th) edition of the World Health Organization (WHO) Classification of Head and Neck Tumours, published in January 2017, has reclassified keratocystic odontogenic tumour as odontogenic keratocyst. Therefore, odontogenic keratocysts (OKCs) are now considered benign cysts of odontogenic origin that account for about 10% of all odontogenic cysts. OKCs arise from the dental lamina and are characterised by a cystic space containing desquamated keratin with a uniform lining of parakeratinised squamous epithelium. The reported age distribution of OKCs is considerably wide, with a peak of incidence in the third decade of life and a slight male predominance. OKCs originate in tooth-bearing regions and the mandible is more often affected than the maxilla. In the mandible, the most common location is the posterior sextant, the angle or the ramus. Conversely, the anterior sextant and the third molar region are the most common sites of origin in the maxilla. OKCs are characterised by an aggressive behaviour with a relatively high recurrence rate, particularly when OKCs are associated with syndromes. Multiple OKCs are typically associated with the nevoid basal cell carcinoma syndrome (NBCCS), an autosomal dominant multisystemic disease. Radiological imaging, mainly computed tomography (CT) and, in selected cases, magnetic resonance imaging (MRI), plays an important role in the diagnosis and management of OKCs. Therefore, the main purpose of this pictorial review is to present the imaging appearance of OKCs underlining the specific findings of different imaging modalities and to provide key radiologic features helping the differential diagnoses from other cystic and neoplastic lesions of odontogenic origin.Key Points: • Panoramic radiography is helpful in the preliminary assessment of OKCs.• CT is considered the tool of choice in the evaluation of OKCs.• MRI with DWI or DKI can help differentiate OKCs from other odontogenic lesions.• Ameloblastoma, dentigerous and radicular cysts should be considered in the differential diagnosis.• The presence of multiple OKCs is one of the major criteria for the diagnosis of NBCCS. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome, or basal cell nevus syndrome (Gorlin syndrome), is a rare autosomal dominantly inherited disorder that is characterized by development of basal cell carcinomas from a young age. Other distinguishing clinical features are seen in a majority of patients, and include keratocystic odontogenic tumors (formerly odontogenic keratocysts) as well as dyskeratotic palmar and plantar pitting. A range of skeletal and other developmental abnormalities are also often seen. The disorder is caused by defects in hedgehog signaling which result in constitutive pathway activity and tumor cell proliferation. As sporadic basal cell carcinomas also commonly harbor hedgehog pathway aberrations, therapeutic agents targeting key signaling constituents have been developed and tested against advanced sporadically occurring tumors or syndromic disease, leading in 2013 to FDA approval of the first hedgehog pathway-targeted small molecule, vismodegib. The elucidation of the molecular pathogenesis of nevoid basal cell carcinoma syndrome has resulted in further understanding of the most common human malignancy. [ABSTRACT FROM AUTHOR]

After obtaining specific surgical and interdisciplinary expertise (tumor board), in some cases, alternative approaches to surgical excision are required since an R0 resection cannot be reliably achieved due to advanced stage of the tumor, cosmetic changes after surgery, or multiple BCC lesions [[5], [9]]. Therefore, oral treatment with sonidegib (capsule 200 mg; Odomzo®) once a day for 6 months was administered for the treatment of the periocular BCC and for preventing potential further recurrent BCCs. Personalized medicine in the treatment of periocular tumors: targeted treatment and use of immune checkpoint inhibitors. [Extracted from the article]

The present study was conducted to address the molecular pathogenesis underlying the progression of basal cell carcinoma (BCC) in a nevoid basal cell carcinoma syndrome (NBCCS) patient. We analyzed infiltrative BCCs that invaded the subcutaneous tissue of the scalp and penetrated the skull in a 61-year-old Japanese female. Whole-exome sequencing validated by Sanger sequencing was applied to assess the subcutaneously infiltrative BCCs. Differences in genetic alterations between the superficial and infiltrative BCCs were also examined. Of particular note, the infiltrative BCCs showed a nonsense mutation, c.943C>T, resulting in p.Q315X in the large tumor suppressor 1 ( LATS1) gene, as well as the loss of the wild-type allele of LATS1 (6q25.1), thus indicating that the LATS1 gene was biallelically disrupted. In contrast, no alterations in the LATS1 gene were observed in the superficial BCCs. Additionally, a loss of heterozygosity analysis revealed that the distal region of chromosome 6q where LATS1 locates was deleted in a heterozygous manner. The present results imply that the biallelic disruption of LATS1 is a progressive factor of the infiltrative BCCs observed in this NBCCS patient and suggest that the Hippo pathway is a potential therapeutic target in cases of infiltrative BCC. [ABSTRACT FROM AUTHOR]

The article presents a case study of a 40-year-old male patient who was presented in a hospital with painful mandibular swelling. Findings of examinations reveal unilateral posterior mandibular swelling with purulent discharge, multiple skin lesions, and multiple multilobular radiolucent lesions. He was diagnosed with Gorlin-Goltz syndrome or as nevoid basal cell carcinoma syndrome (NBCCS) and was treated through multiple surgical operations.

Hedgehog (Hh) is first described as a genetic mutation that has 'spiked' phenotype in the cuticles of Drosophila in later 1970s. Since then, Hh signaling has been implicated in regulation of differentiation, proliferation, tissue polarity, stem cell population and carcinogenesis. The first link of Hh signaling to cancer was established through discovery of genetic mutations of Hh receptor gene PTCH1 being responsible for Gorlin syndrome in 1996. It was later shown that Hh signaling is associated with many types of cancer, including skin, leukemia, lung, brain and gastrointestinal cancers. Another important milestone for the Hh research field is the FDA approval for the clinical use of Hh inhibitor Erivedge/Vismodegib for treatment of locally advanced and metastatic basal cell carcinomas. However, recent clinical trials of Hh signaling inhibitors in pancreatic, colon and ovarian cancer all failed, indicating a real need for further understanding of Hh signaling in cancer. In this review, we will summarize recent progress in the Hh signaling mechanism and its role in human cancer. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS) is characterized by basal cell carcinoma, skeletal abnormalities, benign tumors including ovarian fibroma, and various other phenotypic expressions. Ovarian fibromas in NBCCS before puberty are very rare. We report a 6-year-old prepubescent girl with NBCCS showing skeletal abnormalities, medulloblastoma, and ovarian fibromas. The patient was referred to our hospital owing to abdominal distension. On admission, a huge elastic hard tumor was palpable and computed tomography showed a huge tumor of the left ovary. We performed a left salpingo-oophorectomy and diagnosed the tumor as a benign fibroma. Further examination of the computed tomography images showed skeletal abnormalities. In addition, the patient had a history of medulloblastoma at the age of 4 years. Therefore, we diagnosed NBCCS. A genetic examination indicated a novel 1 bp deletion in exon 18 (c.3055delG). Sequence analysis of exon 18 using DNA from the ovarian tumor revealed a mutant allele (c.3055delG) dominant to the wild-type allele, thus suggesting loss of heterozygosity in the PTCH1 gene, which is known to be associated with NBCCS. Conclusion On the basis of our experience, physicians treating pediatric ovarian tumors should be aware that such huge benign ovarian tumors may be a phenotype of NBCCS, as shown in our patient. In addition, genetic examination focusing on the PTCH1 gene might be important for diagnosis of NBCCS in pediatric patients. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the use of enucleation and chemical cauterization in the management of odontogenic keratocyst (OKC) of the jaw. This study involves the retrospective review of 32 patients (20 males and 12 females) with 34 biopsy proven odontogenic keratocysts. All patients received a combination of enucleation and chemical cauterization with every time freshly prepared Carnoy's solution (absolute alcohol 6 mL, chloroform 3 mL, glacial acetic acid 1 mL, ferric chloride 0.1 gm/mL). None of these patients were diagnosed with basal cell nevus syndrome. Four of these patients did not give the follow up and were not included in the study. A total of 30 biopsy proven OKC were resolved with this treatment method. Post-operative follow up consists of clinical and radiographic examination. Follow up time ranged from a minimum of 2 years to a maximum of 5 years. Mean follow up was of 2.8 years. Recurrence rate of 5.8% was observed. Hence, concluded that the combination of enucleation and chemical cauterization may offer patients improved therapy in the management of odontogenic keratocysts of the jaws. [ABSTRACT FROM AUTHOR]

Nevoid basal cell carcinoma syndrome (NBCCS, Gorlin syndrome) is an autosomal dominant condition with a wide range of manifestations, including multiple basal cell carcinomas, medulloblastoma, odontogenic keratocysts (OKC) and skeletal abnormalities. Children with NBCCS also have a predisposition for secondary cancers after exposure to ionising radiation. In children undergoing imaging for posterior fossa mass and/or maxillofacial cysts, certain additional findings can raise the possibility of NBCCS. Making the diagnosis can significantly impact patient management, especially for children with medulloblastoma. [ABSTRACT FROM AUTHOR]