Oral Smoothened Inhibitors for Gorlin Syndrome: A Clinical Review.

BACKGROUND: Although smoothened inhibitors (SMOi) have demonstrated efficacy in the management of basal cell carcinoma (BCC), no guidelines are available on how to utilize SMOi in the treatment of Gorlin syndrome (GS). OBJECTIVE: Assess the clinical response to SMOi in GS, provide practical guidance for clinicians, and identify areas for future research. METHODS: Alongside a comprehensive search of Medline and Google Scholar for systemic therapies related to Gorlin Syndrome (GS), expert opinion was specifically sought to provide detailed guidance on the use of SMOi in the management of GS. RESULTS: Intermittent dosing of SMOi and daily dosing had similar efficacy. Intermittent dosing resulted in better compliance with therapy. However, lack of tolerability limited long-term use of SMOi. LIMITATIONS: There are few studies solely on the use of SMOi in GS. Included studies often had a subgroup of GS patients. CONCLUSION: While the adverse events of SMOi, such as vismodegib and sonidegib, may result in their discontinuation during treatment of GS, intermittent dosing may improve compliance. Further research is needed to identify dosing strategies that minimize tumor burden while mitigating side effects to achieve maximum compliance.

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.

18F-FDG PET/CT findings in nevoid basal cell carcinoma syndrome: a systematic review and a new case report.

BACKGROUND: To demonstrate and analyze the 18F-FDG positron emission tomography/computed tomography (PET/CT) findings in this rare nevoid basal cell carcinoma syndrome (NBCCS). CASE PRESENTATION: A 71-year-old woman with the left invasive breast cancer was treated with hormone therapy for six months and underwent the 18F-FDG PET/CT examination for efficacy evaluation. 18F-FDG PET/CT revealed the improvement after treatment and other unexpected findings, including multiple nodules on the skin with 18F-FDG uptake, bone expansion of cystic lesions in the bilateral ribs, ectopic calcifications and dilated right ureter. She had no known family history. Then, the patient underwent surgical excision of the all skin nodules and the postoperative pathology were multiple basal cell carcinomas. Finally, the comprehensive diagnosis of NBCCS was made. The patient was still in follow-up. Additionally, we have summarized the reported cases (n = 3) with 18F-FDG PET/CT from the literature. CONCLUSIONS: It is important to recognize this syndrome on 18F-FDG PET/CT because of different diagnoses and therapeutic consequences.

Conservative management of multiple odontogenic keratocysts in a child with nevoid basal cell carcinoma syndrome: A case report.

BACKGROUND: Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant multisystemic disorder characterized by the presence of multiple odontogenic keratocysts (OKC), which are a hallmark feature of the syndrome. The treatment of these OKC poses challenges due to their high recurrence rates and the myriad of management options available. CASE REPORT: We describe here a case of NBCCS diagnosed in an 11-year-old girl who presented with multiple OKC in the jaws. Chest and cranial radiographs showed no abnormalities in the ribs and the cerebral falx, respectively. Cephalometric analysis indicated mandibular retrusion, a skeletal class II relationship, and a convex profile. The treatment approach involved a personalized strategy tailored for each cyst, comprising marsupialization followed by enucleation. This approach aimed to minimize surgical trauma and to reduce the risk of recurrence. The patient underwent regular follow-up appointments, demonstrating successful outcomes with no signs of recurrence or de novo OKC observed over a 32-month period. CONCLUSION: Clinicians should consider lesion characteristics and patient cooperation when determining treatment strategies for the optimization of outcomes for children and adolescents with NBCCS and multiple OKC.

Case report: A novel PTCH1 frameshift mutation leading to nevoid basal cell carcinoma syndrome.

A patient presenting with several basal cell carcinomas, pigmented nevi, and developmental defects was diagnosed with nevoid basal cell carcinoma syndrome. Gene panel sequencing and Sanger sequencing were used to identify a novel heterozygous frameshift mutation, c.1312dupA:p.Ser438Lysfs, in exon 9 of PTCH1. I-Tasser and PyMol analyses indicated that the mutated protein patched homolog 1 (PTCH1) lacked 12 transmembrane domains and the intracellular and extracellular rings of ECD2 compared with the wild-type protein, resulting in a remarkably different structure from that of the wild-type protein. This case extends our knowledge of the mutation spectrum of NBCCS.

Novel PTCH1 Mutation Causes Gorlin-Goltz Syndrome.

OBJECTIVE: To analyse the aetiology and pathogenesis of Gorlin-Goltz syndrome (GS; also known as nevoid basal cell carcinoma syndrome [NBCCS] or basal cell nevus syndrome [BCNS]) in a Chinese family. METHODS: Whole-exome sequencing (WES) was performed on genomic DNA samples from the subjects in a family, followed by the investigation of pathogenesis via bioinformatic approaches and conformational analysis. RESULTS: A novel heterozygous non-frameshift deletion patched 1 (PTCH1) [NM_000264: c.3512_3526del (p.1171_1176del)] was identified by WES and further validated by Sanger sequencing. Bioinformatic and conformational analysis showed that the mutation caused altered PTCH1 protein structure, which may be related to functional abnormalities. CONCLUSION: This study expands the mutation spectrum of PTCH1 in GS and facilitates the early diagnosis and screening of GS. PTCH1 [c.3512_3526del (p.1171_1176del)] may cause structural abnormalities and functional disabilities, leading to GS in families.

Sustained Suppression of Gorlin Syndrome-Associated Basal Cell Carcinomas with Vismodegib or Sonidegib: A Case Series.

Nevoid basal-cell carcinoma syndrome (Gorlin syndrome) is characterized by numerous cutaneous basal cell carcinomas mediated by mutations in the hedgehog pathway. Vismodegib or sonidegib represent promising treatment options. We identified 10 Gorlin patients who were treated with sonidegib (n = 6) or vismodegib (n = 4) between March 2012 and March 2022. We analyzed the activity, toxicity, and duration of the response to oral hedgehog inhibitors. The number of new tumors that developed prior to treatment or after treatment as well as the time of response and durability of responses were assessed. All patients achieved a complete remission. With a 30.7 ± 48.4-month median follow-up, the drug treatment significantly reduced the number of new basal cell cancers from a mean of 28.3 ± 24.6 prior to treatment to a mean of 1.4 ± 2.0 during treatment (p = 0.0048). The median time to develop a new basal cell cancer was 47.3 months. Three patients eventually developed localized recurrences. After resection, ongoing treatment suppressed the development of additional lesions. One patient developed numerous new drug-resistant basal cell cancers and died of acute leukemia. Six patients required treatment modifications for toxicity. Sustained hedgehog inhibitor treatment can suppress the progression of both new and existing basal cell carcinomas for an extended period. Drug administration schedule adjustments improved tolerance without altering efficacy, potentially contributing to a prolonged response duration.

Basaloid follicular hamartoma syndrome: acquired sporadic variant with hypothyroidism, hypohidrosis and alopecia, a rare case.

Basaloid follicular hamartoma is a rare benign malformation of hair follicles, characterised clinically as generalised or localised multiple brown papules mostly on face, scalp and trunk. It may be congenital or acquired with or without any associated disease. Histologically it is composed of epithelial proliferation of basaloid cells with radial disposition enclosed in a fibrous stroma. It is of important consideration because it can be mistaken for basal cell carcinoma both clinically and histologically. Here we report the case of a 51-year-old female with acquired, generalised basaloid follicular hamartomas associated with alopecia, hypothyroidism and hypohidrosis which is an extremely rare disease.

Comparison of the effectiveness of 5-Fluorouracil and modified Carnoy's solution in reducing the recurrence of odontogenic keratocyst.

Introduction: Odontogenic keratocysts (OKC) has a high potential for recurrence. Resection is currently the only fool-proof method to ensure that recurrence does not occur; however, it drastically affects the patient's function and aesthetics. Application of modified Carnoy's solution (MCS) as an adjunct to reduce the recurrence rate is currently in vogue. 5- Flurouracil (5-FU) is an anti-metabolite that has been used in the treatment of basal cell carcinoma and is relatively safer than MCS. The present study aims to compare the effectiveness of 5-UC and MCS in reducing the recurrence rate in OKC.. Material and methods: A total of 42 OKCs were enucleated followed by application of MCS (control group, n = 21) or 5-FU dressing (study group, n = 21) following enucleation. Pain, swelling, temporary and permanent paresthesia paresthesia, bone sequestrum formation, osteomyelitis and recurrence in both groups were evaluated at periodic intervals up to 12 months post-surgery. Results: There was no significant difference in terms of pain, or swelling in both groups. Permanent paresthesia and recurrence rates were higher in patients treated with MC but the difference was not statistically significant. Conclusion: 5-FU is an easy-to-use, feasible, biocompatible and cost-effective alternative for MCS in the management of OKCs. Treatment with 5-FU, therefore, reduces the risk of recurrence and also the post-surgical morbidity associated with other treatment procedures.

Cardiac Fibroma with Asymptomatic Ventricular Arrhythmia in an Adolescent with Gorlin's Syndrome.

Nevoid basal cell carcinoma syndrome (NBCCS), also referred to as Gorlin's syndrome, is an autosomal dominant inherited condition that predisposes affected individuals to various tumors such as cardiac fibromas. Though technically benign, cardiac fibromas may result in malignant arrhythmias and sudden death. The pertinent literature pertaining to pediatric cases of cardiac fibromas and their clinical features were reviewed. We present the case of an asymptomatic teenage with de novo NBCCS who was diagnosed with both NBCCS and cardiac fibroma later in life. The patient was noted to have clinically significant ventricular arrhythmias that were eliminated with tumor resection. There are no established best practice guidelines for the management of cardiac fibromas in patients with NBCCS. Given the risk of sudden arrhythmic death, the presence of ventricular arrhythmias should prompt strong consideration of tumor resection.

Clinical, radiographic, pathological and inherited characteristics of odontogenic keratocyst in nevoid basal cell carcinoma syndrome: a study in three Chilean families.

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.

PTCH1 mutant small cell glioblastoma in a patient with Gorlin syndrome: A case report.

Gorlin syndrome or nevoid basal cell carcinoma syndrome is a rare genetic disease characterized by predisposition to congenital defects, basal cell carcinomas and medulloblastoma. The syndrome results from a heritable mutation in PATCHED1 (PTCH1), causing constitutive activation of the Hedgehog pathway. The present study described a patient with Gorlin syndrome who presented early in life with characteristic basal cell carcinomas and later developed a small cell glioblastoma (GBM), World Health Organization grade IV, associated with a Patched 1 (PTCH1) N97fs*43 mutation. Comprehensive genomic profiling of GBM tissues also revealed multiple co-occurring alterations including cyclin-dependent kinase 4 (CDK4) amplification, receptor tyrosine-protein kinase 3 (ERBB3) amplification, a fibroblast growth factor receptor 1 and transforming acidic coiled-coil containing protein 1 (FGFR1-TACC1) fusion, zinc finger protein (GLI1) amplification, E3 ubiquitin-protein ligase (MDM2) amplification and spectrin α chain, erythrocytic 1 (SPTA1) T1151fs*24. After the biopsy, imaging revealed extensive leptomeningeal enhancement intracranially and around the cervical spinal cord due to leptomeningeal disease. The patient underwent craniospinal radiation followed by 6 months of adjuvant temozolomide (150 mg/m2) with good response. She was then treated with vismodegib for 11 months, first combined with temozolomide and then with bevacizumab, until disease progression was noted on MRI, with no significant toxicities associated with the combination therapy. She received additional therapies but ultimately succumbed to the disease four months later. The current study presents the first documentation in the literature of a primary (non-radiation induced) glioblastoma secondary to Gorlin syndrome. Based on this clinical experience, vismodegib should be considered in combination with standard-of-care therapies for patients with known Gorlin syndrome-associated glioblastomas and sonic hedgehog pathway mutations.

Case report of bilateral ovarian fibromas associated with de novo germline variants in PTCH1 and SMARCA4.

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).

PTCH1-null induced pluripotent stem cells exclusively differentiate into immature ectodermal cells with large areas of medulloblastoma-like tissue.

Nevoid basal cell carcinoma syndrome (NBCCS) is an autosomal dominant disorder with an increased incidence of tumors, such as basal cell carcinomas and medulloblastomas. The PTCH1 gene, responsible for NBCCS, suppresses the hedgehog signaling pathway, which is recognized as one of the important pathways in tumorigenesis and, thus, is a therapeutic target in cancer. In the present study, we generated PTCH1-/- induced pluripotent stem cells (iPSCs) from NBCCS patient-derived iPSCs (PTCH1+/-) by gene editing. The proliferation of PTCH1-/- iPSCs was accelerated due to the activation of the hedgehog signaling pathway. When PTCH1-/- iPSCs were subcutaneously injected into immunodeficient mice, the resulting teratomas almost exclusively contained immature ectodermal lineage cells expressing medulloblastoma markers, and the percentages of the area occupied by medulloblastoma-like tissue were larger in PTCH1-/- teratomas than in PTCH1+/- teratomas. In contrast, in PTCH1+/+ teratomas, medulloblastoma-like tissue positive for all of these medulloblastoma markers was not observed. The present results indicate the importance of PTCH1 in medulloblastoma formation and the suitability of these gene-edited iPSCs and PTCH1-/- teratomas as models for the formation of tumors, such as medulloblastomas and Hh-related tumors.

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Nevus-like basal cell carcinoma syndrome (NBCCS) is a rare autosomal dominant disease characterized by the occurrence of multiple maxillofacial keratocysts, basal cell carcinoma, child medulloblastoma, and various skeletal and soft tissue dysplasia. In 2020, a patient with NBCCS dominated by facial basal cell carcinoma was admitted to Xiangya Hospital of Central South University. The patient was an elderly woman. Ten years ago, the systemic mass appeared, especially on the face, but it was not treated. Later, these masses gradually increased in volume and number, and showed invasive properties. The nasal mass was broken and suppurated, seriously affecting the patient's life quality. The patient came to the hospital to improve the symptoms. Staphylococcus aureus and Providencia rettgeri were cultured in the patient's nasal secretions. Nasal sinus enhanced MRI showed that the subcutaneous soft tissue of the right cheek and the anterolateral mucosa of the left nasal cavity were invaded, indicating multiple malignant skin lesions. After admission, local anesthesia was performed and some masses were removed. Pathological examination of the mass showed basal cell carcinoma. After general anesthesia, multiple masses were resected. The postoperative pathological examination showed that multiple basal cell carcinoma invaded the deep dermis near subcutaneous fat layer. Combined with the results of clinical and immunohistochemical examination, the patient was diagnosed as NBCCS. There were no clear tumor thrombus in the vessel and no nerve invasion. No recurrence or new tumor was found after 1 year follow-up. The incidence rate of NBCCS is low and clinical symptoms are different. The patient's life quality is poor and the patient needs long-term individualized treatment.

Dental and orthodontic follow-up in nevoid basal cell carcinoma syndrome patient with odontogenic keratocystic tumors.

OBJECTIVES: Nevoid Basal Cell Carcinoma Syndrome (NBCS) is a rare genetic condition affecting multiple organs including the maxillofacial and dental region. The surgical removal of the odontogenic keratocystic tumors (OKT), the high rate of recurrence leads to a iatrogenic tooth loss requiring dental care. The aim of this study is therefore to describe the dental and orthodontic management, and to assess the impact of surgery on facial growth and oral development. METHODS: A retrospective study including 14 patients with GGS, followed at the Necker Enfants Malades Hospital. The study was carried out on the medical files and photographic records RESULTS: Patients developed on average 5.5 OKT (range: 1 to 11) and 1.7 recurrences (range:0 to 9) during the follow-up. The mean age at diagnosis of first OKT was 11.23 years (range: 6.75 to 16). KOTs were more frequently localized at the mandibular (30.9%) and maxillary molar level (25.1%). Forty-seven impacted teeth were extracted during the OKT removal. Eight patients out of 12 presented a class III skeletal relationship. The remaining ones had a skeletal class II associated with a hyperdivergent typology. Almost all patients had dental impactions with ectopic positions of the succedaneums tooth. At the inter-arch level, all patients needed orthodontic care, 3 patients did not begin their orthodontics. Orthodontic treatments began with an orthopedic phase followed by braces for the majority in 8 patients. Two patients had to undergo orthognathic surgery. Impacted teeth were treated by traction or extraction with further rehabilitation. CONCLUSION: The objective is not to simply compensate the iatrogenic hypodontia generated by the surgical procedure but to take into consideration the maxillofacial phenotype, skeletal characteristics and numerous intra- and inter-arch dental anomalies for a healthy oral management.