Nevoid Basal Cell Carcinoma Syndrome Research Articles

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

Nevoid basal cell carcinoma syndrome (NBCCS) is a rare genodermatosis caused by germline mutations in genes of the Sonic Hedgehog pathway (SHH) and characterized by early onset of multiple basal cell carcinoma (BCC). Although skin tumors 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.140 skin tumors from NBCCS and 140 control BCC tumors 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 to immunohistochemical and molecular analysis.Thirty-three tumors among the exploratory cohort were classified as BFH and were exclusively detected in NBCCS patients. Histopathological criteria that were significantly different from BCC were: a small size (<1.5mm), connection to a hair follicle, arborescent organoid architecture, lack of cytologic atypia, 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 tumors to BCC.Our study confirms the high prevalence of BFH representing up to 24% of skin tumors 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.

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.

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

BackgroundTo demonstrate and analyze the 18F-FDG positron emission tomography/computed tomography (PET/CT) findings in this rare nevoid basal cell carcinoma syndrome (NBCCS).Case presentationA 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.ConclusionsIt is important to recognize this syndrome on 18F-FDG PET/CT because of different diagnoses and therapeutic consequences.

Skin cancer-associated genodermatoses in skin of color patients: a review.

Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients.

Clinical versus molecular diagnosis of Gorlin syndrome: Relevance of diagnostic criteria depends on the age of patients.

Gorlin Syndrome (GS) is an autosomal dominant disorder characterised by a predisposition to basal cell carcinoma and developmental defects, and caused by pathogenic variants in PTCH1 or SUFU genes. To ascertain the efficiency of molecular screening in a cohort of patients with a suspicion of GS and to describe patients' clinical and genetic characteristics. 110 patients with a suspicion of GS, addressed to the Genetic Department of Bichat University Hospital for molecular screening were studied. Patients' clinical and paraclinical data were collected and analysed according to Evan's diagnosis criteria, and compared to molecular information. Among 110 probands, only 56% fulfill Evan's diagnosis criteria. 75% of patients who fulfill those criteria carry a PTCH1/SUFU pathogenic variation. We compared clinical and paraclinical data of 54 probands carrying a PTCH1/SUFU mutation with 56 probands without identified mutation. Among patients carrying a pathogenic variation in PTCH1 or SUFU genes, 30 years of age appears to be the cut off age after which all patients have a clear clinical GS. Indeed, after 30 years, all patients carrying a PTCH1/SUFU mutation fulfill the diagnosis criteria of Evans (82% meet the clinical criteria, and we reach 100% with complementary exams such as X-rays and ultrasound). Before 30 years of age, only 37% of mutated patients fulfilled the clinical diagnosis criteria's and we only reach 62% with simple complementary exams. Furthermore, we report 22 new mutations in PTCH1. Molecular screening of patients with GS who do not fulfill Evan's diagnostic criteria should only be offered in first intention to patients under 30 years of age. After 30 years, a careful clinical examination and complementary radiological exams should be enough to eliminate the diagnosis of GS among patients who do not fulfill diagnostic criteria.

Attention to Quality of Life in Patients With Gorlin Syndrome

Attention to Quality of Life in Patients With Gorlin Syndrome

Assessment of Mammalian Target of Rapamycin Pathway Activation in Basal Cell Carcinoma as a New Therapeutic Approach.

Targeting the mammalian target of rapamycin (mTOR) pathway represents a potentially novel approach to treat basal cell carcinoma (BCC), but activation of this pathway has not been well described in human BCCs. The purpose of this study was to assess whether mTOR pathway activation occurs in BCCs (both sporadic and syndromic) and report a case of a patient with Gorlin syndrome (GS) whose clinically suspicious BCCs responded to mTOR inhibition through topical sirolimus treatment. After Stanford Institutional Review Board Approval, archived BCCs from patients with GS (n = 25), sporadic BCCs (n = 35), and control tissues were subjected to immunohistochemical analysis for the activation of mTOR pathway, and immunohistochemical staining intensity was evaluated by a dermatopathologist. BCCs (compared with normal skin) had elevated levels of eIF4EBP1 ( Padjusted = 0.0336), which is downstream of mTOR. a serine/threonine kinase Phospho-(AKT), which interacts with mTOR, was also significantly elevated (perinuclear: Padjusted < 0.0001; cytoplasmic: Padjusted = 0.0021). When off-label topical 1% sirolimus was used on a pediatric patient with GS, we noted reduction of new BCC development and decreased size of existing neoplasms clinically suspicious for BCCs. This treatment was well tolerated after 2 years of continuous use, with no other treatments needed during this period. Topical sirolimus is a promising therapeutic candidate against both sporadic and GS-associated BCC. Multicenter, prospective studies are needed to understand the efficacy and safety of topical mTOR inhibitors in BCC treatment, and ascertain whether the immunohistochemical markers downstream of mTOR could have predictive value in identifying BCCs most likely to respond to topical mTOR inhibitors, such as sirolimus.

Update on Cancer Predisposition Syndromes and Surveillance Guidelines for Childhood Brain Tumors.

Tumors of the central nervous system (CNS) comprise the second most common group of neoplasms in childhood. The incidence of germline predisposition among children with brain tumors continues to grow as our knowledge on disease etiology increases. Some children with brain tumors may present with nonmalignant phenotypic features of specific syndromes (e.g., nevoid basal cell carcinoma syndrome, neurofibromatosis type 1 and type 2, DICER1 syndrome, and constitutional mismatch-repair deficiency), while others may present with a strong family history of cancer (e.g., Li-Fraumeni syndrome) or with a rare tumor commonly found in the context of germline predisposition (e.g., rhabdoid tumor predisposition syndrome). Approximately 50% of patients with a brain tumor may be the first in a family identified to have a predisposition. The past decade has witnessed a rapid expansion in our molecular understanding of CNS tumors. A significant proportion of CNS tumors are now well characterized and known to harbor specific genetic changes that can be found in the germline. Additional novel predisposition syndromes are also being described. Identification of these germline syndromes in individual patients has not only enabled cascade testing of family members and early tumor surveillance but also increasingly affected cancer management in those patients. Therefore, the AACR Cancer Predisposition Working Group chose to highlight these advances in CNS tumor predisposition and summarize and/or generate surveillance recommendations for established and more recently emerging pediatric brain tumor predisposition syndromes.

NF2-related Schwannomatosis and Gorlin Syndrome

NF2-related Schwannomatosis and Gorlin Syndrome

Novel PTCH1 Mutation Causes Gorlin-Goltz Syndrome.

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. 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. 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. 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.

Imaging approaches for the diagnosis of genetic diseases affecting the female reproductive organs and beyond.

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.