Nevoid Basal Cell Carcinoma Syndrome Research Articles

Phase 2 Trial of Topical Application of the Hedgehog Inhibitor Patidegib in Patients With Gorlin Syndrome.

Patients with Gorlin (basal cell nevus) syndrome (GS) have numerous phenotypic abnormalities due to over-activity of the hedgehog (HH) signaling pathway, most commonly due to a heritable mutation in the PTCH1 gene, which encodes a major inhibitor of this pathway. HH inhibitors (HHi) taken orally can reverse some of the manifestations, most prominent of which is the development of numerous cutaneous basal cell carcinomas (BCCs). In order to improve the benefit:risk ratio, we have developed a gel containing a small cyclopamine-derived molecule that can be applied topically in expectation that this mode of delivery can reduce the burden of BCCs without producing the systemic adverse effects that cause patients to stop treatment with oral HHis. This study attempts to determine whether or not Patidegib Topical Gel, 2% or 4%, can accumulate in high enough concentrations to have local anti-BCC efficacy but not so high that systemic drug levels produce the adverse effects that are typical of oral HHi treatment. We conducted a small, randomized, double blinded Phase 2A trial at two sites in the United Kingdom to assess the clinical and molecular efficacy and adverse effects of 6 months of twice daily application of Patidegib Topical Gel to the entire face as well as to treatment-targeted surgically-eligible BCCs at other anatomical sites. Post hoc analyses suggested that Patidegib Topical Gel reduced the number of new surgically-eligible BCCs and the level of HH signaling with minimal adverse effects. Patidegib Topical Gel warrants further clinical development.

Use of Anti-PD1 Blockade After Hedgehog Inhibitors or as First-Line Therapy for Gorlin Syndrome

This case series examines treatment with anti–programmed cell death 1 (PD1) immunotherapy for patients with basal cell nevus syndrome.

Gorlin-Goltz syndrome- report of a case with review of literature

Gorlin-Goltz syndrome- report of a case with review of literature

Telehealth in a Pediatric Patient with Nevoid Basal Cell Carcinoma Syndrome

During COVID19, telemedicine was adapted by many practices to serve patients with a variety of health conditions including those affected by cancer. Here we report an 11-year-old patient who went to her dentist where a routine panorama x-ray showed multiple jaw keratocysts. Because jaw keratocysts can be identified with a hereditary predisposition to basal cell cancer and other tumors, she was referred for genetics. She was seen in 2021 where telehealth was the primary modality for visits. The hospital’s secure video platform was used to gather medical history and counsel the mother on genetic testing for nevoid basal cell carcinoma syndrome(NBCCS). While in the past genetic testing was often thousands of dollars, the genetic testing company offered a patient pay option of $250. Two days later, the patient presented to the cancer center to have her blood drawn and a fifteen-minute physical exam was performed which identified macrocephaly, and palmar pits. Of note the mother asked about numerous pinpoint lesions around the patient’s ocular region. Genetic testing was positive for a pathogenic variant in PTCH1 c.454_455del. The patient was referred to pediatric dermatology where over fifty basal cells were diagnosed and started treatment with imiquimod and efudex. She also was referred to cardiology and gynecology given reports of individuals with cardiac fibromas and gynecologic ovarian tumors. The patient is now 14 going into her freshman year of high school and is doing well. This case highlights how telehealth offers a holistic approach to patient care.

Recurrence rate of the odontogenic keratocysts patient cohort in a UK regional maxillofacial surgery unit

AbstractBackgroundDespite the benign nature of odontogenic keratocyst (OKC), the reported recurrence rates range from 3% to 60% depending on the treatment modality. Surgical enucleation alone is often insufficient to prevent recurrence, thus adjunctive therapies have been adopted. The aim of this study was to determine the recurrence rate of OKC, both sporadic and those associated with naevoid basal cell carcinoma syndrome based on the treatment modality.Materials and MethodsTwo hundred patients diagnosed and treated between 2012 and 2021 for OKC were identified, from which 72 were excluded because of inadequate clinicopathological data. Forty‐four (34.3%) patients were cases of syndromic and 84 (65.5%) sporadic OKC.ResultsThe most common surgical procedure was enucleation alone (45%) followed by enucleation and removal of the associated tooth (28.1%). Carnoy's solution was the most used adjunctive method (14.7%). The overall recurrence rate of sporadic OKC in our study was 18.7% which was in line with the 16.6% reported by Al‐Moraissi et al. in their systematic review.ConclusionsSyndromic cases were statistically significantly more likely to recur at the same site of the surgery than sporadic cases (p < 0.05) with a recurrence rate of 52% (23 out of 44). Overall, adjunctive treatments to enucleation alone are associated with a lower recurrence rate but no one method eliminates recurrence.Practical ImplicationsIncisional biopsy and diagnosis of OKC can better tailor definitive treatment. Syndromic OKC is associated with a higher recurrence rate, and adjunctive treatments to enucleation alone help in reducing recurrence rate.

Nevoid basal cell carcinoma syndrome: a rare case report

Nevoid basal cell carcinoma syndrome: a rare case report

Understanding and managing locally advanced basal cell carcinoma: insights into pathogenesis, therapeutic strategies, and the role of hedgehog pathway inhibitors.

Understanding and managing locally advanced basal cell carcinoma (BCC) is crucial given its substantial prevalence and potential for local tissue destruction. While BCC typically exhibits low metastatic potential, its high incidence underscores the need for enhanced therapeutic strategies. Locally advanced BCC presents unique challenges, often necessitating aggressive interventions to prevent disfigurement and functional impairment. The emergence of hedgehog pathway inhibitors (HHIs) offers promising therapeutic avenues by targeting aberrant hedgehog signaling, a key driver in BCC pathogenesis. Thus, elucidating the pathogenesis of locally advanced BCC and exploring the role of HHIs are critical endeavors in effectively managing this prevalent carcinoma. Epidemiologically, BCC primarily affects individuals with fair skin and chronic sun exposure, with an increasing incidence noted among younger age groups. Risk factors include UV radiation exposure, familial history of skin cancer, immunosuppression, and genetic syndromes such as basal cell nevus syndrome and xeroderma pigmentosum. Pathogenetically, BCC arises from cells in the skin's epidermis, with hedgehog pathway activation being a primary genetic driver, involving mutations in PTCH1 and SMO. Resistance to hedgehog inhibitors may occur due to genetic changes, complicating treatment strategies. BCC is characterized by low immunogenicity, which hinders immune response and contributes to treatment challenges. Enhanced understanding of the epidemiology, risk factors, and pathogenesis of locally advanced BCC, along with the development of targeted therapeutic approaches such as hedgehog pathway inhibitors, is essential for effectively managing this prevalent carcinoma and improving patient outcomes.

Early Diagnosis and Management of Gorlin-Goltz Syndrome: Case Report

Early Diagnosis and Management of Gorlin-Goltz Syndrome: Case Report

Inherited Basaloid Neoplasms Associated With SUFU Pathogenic Variants.

Germline SUFU pathogenic variants (PVs) have previously been associated with basal cell nevus syndrome (BCNS) and multiple infundibulocystic basal cell carcinoma syndrome; however, a broader spectrum of cutaneous findings in patients with SUFU PVs has not been well delineated. To define the clinical and histopathologic spectrum of cutaneous findings in patients with germline SUFU PVs. This case series was conducted in multiple US academic dermatology, medical genetics, and medical oncology clinics between July 2014 and July 2022. The study included patients with confirmed germline SUFU PVs who were evaluated by a dermatologist. The analysis took place from March to September 2023. Histopathologic evaluation of skin biopsies with or without immunohistochemical staining, and targeted next-generation sequencing (NGS) on tumor specimens. All 5 patients were women. The mean (range) age at presentation was 50.2 (31-68) years, with skin manifestations initially appearing in the fourth to sixth decades of life. None had keratocystic odontogenic tumors. A total of 29 skin pathology specimens from the 5 patients were reviewed; of these, 3 (10.3%) were diagnosed as basaloid follicular hamartomas (BFHs), 10 (34.5%) classified as infundibulocystic basal cell carcinomas (iBCCs), 6 (20.7%) classified as nodular basal cell carcinomas (nBCCs), and 1 (3.4%) as infiltrative basal cell carcinoma (BCC). Targeted NGS studies on tumor specimens suggest that an increased number of UV-signature variants is associated with basal cell carcinomas compared with more indolent basaloid follicular hamartomas. Patients with germline SUFU PVs may present with multiple indolent basaloid neoplasms in addition to conventional basal cell carcinomas, typically appearing in the fourth to sixth decades of life. Although there are overlapping clinical manifestations, these findings help to differentiate the clinical syndrome associated with SUFU PVs from PTCH1 BCNS. Awareness of the clinicopathologic spectrum of SUFU-associated basaloid neoplasms is important for dermatologists and dermatopathologists because many (although not all) of these lesions are indolent and do not require aggressive surgical treatment. Importantly, because SUFU lies downstream of the protein smoothened, vismodegib and other smoothened inhibitors are unlikely to be effective therapies in this subset of patients.

Clinicopathological and molecular spectrum of patients with germline SUFU mutations: A case series.

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. Three patients presenting with an MHIBCC phenotype were tested for a germline SUFU mutation. Skin biopsies were assessed by two dermatopathologists. 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. 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.

Brain morphological analysis in mice with hyperactivation of the hedgehog signaling pathway.

Hedgehog signaling is a highly conserved pathway that plays pivotal roles in morphogenesis, tumorigenesis, osteogenesis, and wound healing. Previous investigations in patients with Gorlin syndrome found low harm avoidance traits, and increased volumes in the cerebrum, cerebellum, and cerebral ventricles, suggesting the association between brain morphology and the constitutive hyperactivation of hedgehog signaling, while the changes of regional brain volumes in upregulated hedgehog signaling pathway remains unclear so far. Herein, we investigated comprehensive brain regional volumes using quantitative structural brain MRI, and identified increased volumes of amygdala, striatum, and pallidum on the global segmentation, and increased volumes of the lateral and medial parts of the central nucleus of the amygdala on the detail segmentation in Ptch heterozygous deletion mice. Our data may enhance comprehension of the association between brain morphogenic changes and hyperactivity in hedgehog signaling.

Re-evaluation of the concept of basaloid follicular hamartoma associated with naevoid basal cell carcinoma syndrome: a morphological, immunohistochemical and molecular study

Naevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog pathway (SHH) and is characterised by early onset of multiple basal cell carcinomas (BCCs). Although skin tumours with follicular differentiation, notably basaloid follicular hamartoma (BFH), have been reported in NBCCS, their relations with BCC are poorly defined. In this context, the aim of this study was to clarify morphological, immunohistochemical ​and molecular features of BFH arising in a context of NBCCS.A total of 140 skin tumours from NBCCS and 140 control BCC tumours were reviewed, blinded to clinical data and classified as BCC or BFH. The morphological characteristics of these two groups were then compared. Twenty cases were submitted for immunohistochemical and molecular analysis. Thirty-three tumours among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were as follows: a small size (<1.5 mm), connection to a hair follicle, arborescent organoid architecture, lack of cytologic atypia and infundibulocystic differentiation. Immunohistochemical analysis confirmed activation of the SHH pathway in these lesions. Targeted next-generation sequencing suggested that MYCN and GLI2/3 amplifications and TP53 mutations might be involved in progression of these follicular tumours to BCC.Our study confirms the high prevalence of BFH representing up to 24% of skin tumours in NBCCS and potentially being BCC precursors.

Reticulate acropigmentation of Kitamura in a case of Gorlin-Goltz syndrome − coincidence or association?

Gorlin-Goltz syndrome also known as nevoid basal cell carcinoma syndrome (NBCCS) is a rare, complex hereditary disorder characterized by phenotypic developmental anomalies and postnatal tumors especially basal cell carcinomas (BCCs) and medulloblastomas. It is inherited as autosomal dominant disorder with inactivating mutation in PTCH 1 gene. Reticulate acropigmentation of Kitamura, a rare pigmented genodermatosis has not been described in the literature in association with NBCCS and may be a new finding. Considering the rarity of the disease and its wide clinical spectrum and complications, it is of paramount importance to identity these atypical presentations of the syndrome at an early stage for holistic approach, early intervention, monitoring of basal cell carcinoma, and genetic counselling.

Navigating the maze: A comprehensive journey in the management of odontogenic Keratocyst

This case report describes the intricate management of an odontogenic keratocyst (OKC) associated with a mandibular tooth. Formerly known as keratocystic odontogenic tumor, OKC is a benign intraosseous lesion with diverse manifestations that occurs either as a solitary entity or as multiple lesions within the same individual. Often linked to nevoid basal cell carcinoma syndrome (NBCCS), OKC presents a unique challenge requiring meticulous diagnosis and treatment. In this case, a 71-year-old male with significant mandibular swelling sought treatment after a failed endodontic procedure. Detailed clinical and radiographic evaluations revealed an extensive radiolucent lesion affecting teeth 45 to 36. The treatment involved a multidisciplinary approach, including endodontic therapy and surgical enucleation with bone curettage. The patient exhibited successful healing and bone formation during a one-year follow-up, emphasizing the significance of comprehensive management strategies for OKCs. This case underscores the importance of early diagnosis, collaboration between specialties, and long-term follow-up in ensuring optimal outcomes for patients with OKCs associated with mandibular teeth.

Surgical management of ovarian fibromas in young patients with Gorlin syndrome: a case series and review of the literature

Surgical management of ovarian fibromas in young patients with Gorlin syndrome: a case series and review of the literature

Gorlin-Goltz Syndrome with Multiple OKC in a 10-Year-Old Child: A Case Report

Gorlin-Goltz syndrome is rare multi-system disease, which is, characterized by neoplasms and other developmental abnormalities. 1 It is a hereditary condition inherited as an autosomal dominant trait and caused by abnormalities in the PTCH1 (Patched1) gene which is traced to the long arm of chromosome 9q22.3-q31. It is characterized by the triad of multiple baso-cellular epitheliomas, odontogenic keratocysts (OKC) in the jaws and skeletal anomalies. Early diagnosis and treatment are important for long-term prognosis of the syndrome by reducing the severity of cutaneous carcinomas and deformities due to jaw cyst. Current case discusses a 10-year-old child suffering from Gorlin-Goltz syndrome, this case report emphasizes on early diagnosis and prompt treatment of such case. Keywords OKC, Gorlin-Goltz syndrome, Multi nodular radiolucency

Intrauterine growth in chromatinopathies: A long road for better understanding and for improving clinical management.

Chromatinopathies are a heterogeneous group of genetic disorders caused by pathogenic variants in genes coding for chromatin state balance proteins. Remarkably, many of these syndromes present unbalanced postnatal growth, both under- and over-, although little has been described in the literature. Fetal growth measurements are common practice in pregnancy management and values within normal ranges indicate proper intrauterine growth progression; on the contrary, abnormalities in intrauterine fetal growth open the discussion of possible pathogenesis affecting growth even in the postnatal period. Among the numerous chromatinopathies, we have selected six of the most documented in the literature offering evidence about two fetal overgrowth (Sotos and Weaver syndrome) and four fetal undergrowth syndromes (Bohring Opitz, Cornelia de Lange, Floating-Harbor, and Meier Gorlin syndrome), describing their molecular characteristics, maternal biochemical results and early pregnancy findings, prenatal ultrasound findings, and postnatal characteristics. To date, the scarce data in the literature on prenatal findings are few and inconclusive, even though these parameters may contribute to a more rapid and accurate diagnosis, calling for a better and more detailed description of pregnancy findings.

MDB-25. ESTABLISHING A NOVEL CEREBELLAR ORGANOID MODEL FOR INVESTIGATING HEREDITARY PREDISPOSITION TO CHILDHOOD BRAIN CANCER

Abstract During the development of the central nervous system, pools of progenitor cells undergo proliferation and subsequent differentiation into mature neurons, establishing a functional neuronal network. However, an imbalance in these processes, characterized by excessive proliferation and loss of differentiation, can lead to tumor formation in pediatric patients. In the developing cerebellum, medulloblastomas of the Sonic Hedgehog (SHH) group arise from excessive proliferation of granule neuron progenitor cells (GNPs) driven by SHH signaling, accompanied by hindered differentiation into mature granule neurons. Genetic predisposition accounts for nearly 40% of all pediatric SHH-medulloblastomas, but the development of humanized models to study these predisposition genes has been lacking. To address this gap, we created an ATOH1-driven EGFP reporter iPSC line to generate reliable cerebellar organoids focused on the development of the granule cell lineage. Our cerebellar organoid protocol yielded homogeneous organoids with robust activation of the ATOH1-EGFP reporter around day 30. Through bulk transcriptomics analysis at day 30, we observed pronounced expression of GNP markers, followed by increased expression of markers associated with mature granule neurons by day 60. Furthermore, by aligning the single-nuclei RNA sequencing (snRNAseq) data of day 60 cerebellar organoids with our human cerebellar development snRNAseq atlas, we identified various cerebellar cell types, including GNPs, mature granule neurons, Purkinje cells, interneurons, as well as glutamatergic and GABAergic neurons. Using this protocol, we examined the development of cerebellar organoids in models of hereditary predisposition to childhood cancer. Using a Gorlin syndrome model, we found that PTCH1HET organoids are larger in size than their isogenic control counterparts, while a model for ELP1HET hereditary predisposition showed no change in size compared with control organoids. These organoid models will allow us to uncover novel molecular mechanisms of hereditary predisposition using human cells.

Case Report of Gorlin-Goltz Syndrome

Gorlin-Goltz syndrome, also known as basal cell nevus syndrome. This condition is characterized by various clinical manifestations, including multiple cutaneous lesions and other systemic abnormalities. We present the case of a 32-year-old man with no significant medical history who was referred to our institution for evaluation of multiple budding lesions. Clinical examination revealed three lesions in the upper right nasolabial fold, one in the lower right cheek, one in the left nasolabial fold, and additional suspect lesions on the chin, right temple, and right cheek. This case underscores the importance of recognizing the diverse manifestations of Gorlin-Goltz syndrome, which can aid in early diagnosis and management of this inherited disorder. Further investigation and long-term follow-up are essential for understanding the progression and management of this condition.

Gorlin Syndrome-Associated Basal Cell Carcinomas Treated with Vismodegib or Sonidegib: A Retrospective Study.

Nevoid basal cell carcinoma syndrome (NBCCS), also known as Gorlin syndrome (GS), is a genetic disorder characterized by the development of multiple cutaneous BCCs due to mutations in the hedgehog signaling pathway. The use of hedgehog pathway inhibitors-vismodegib and sonidegib-has emerged as a promising therapeutic strategy for managing BCCs in individuals with GS. In a retrospective study conducted between March 2012 and January 2024, a cohort of 16 Gorlin syndrome patients who received treatment with either sonidegib or vismodegib were analyzed. The primary objectives of the study were to evaluate the efficacy, safety profile, and duration of response to oral hedgehog inhibitors in this patient population. The study assessed various parameters, including the number of new BCCs that developed before and after treatment initiation, the duration and sustainability of treatment responses, as well as the incidence of adverse effects associated with hedgehog inhibitor therapy. The findings of the study revealed that sustained treatment with hedgehog inhibitors could effectively suppress the progression of both new and existing BCCs. Furthermore, the results indicated that sonidegib exhibited superior efficacy and safety compared to vismodegib in the treatment of BCCs in individuals with GS. Notably, adjustments to the administration schedule of sonidegib were found to improve tolerability without compromising therapeutic efficacy, potentially leading to prolonged durations of treatment response and disease control.