Detection of PTCH1 Copy-Number Variants in Mosaic Basal Cell Nevus Syndrome.

Basal cell nevus syndrome (BCNS) is an inherited disorder characterized mainly by the development of basal cell carcinomas (BCCs) at an early age. BCNS is caused by heterozygous small-nucleotide variants (SNVs) and copy-number variants (CNVs) in the Patched1 (PTCH1) gene. Genetic diagnosis may be complicated in mosaic BCNS patients, as accurate SNV and CNV analysis requires high-sensitivity methods due to possible low variant allele frequencies. We compared test outcomes for PTCH1 CNV detection using multiplex ligation-probe amplification (MLPA) and digital droplet PCR (ddPCR) with samples from a BCNS patient heterozygous for a PTCH1 CNV duplication and the patient's father, suspected to have a mosaic form of BCNS. ddPCR detected a significantly increased PTCH1 copy-number ratio in the index patient's blood, and the father's blood and tissues, indicating that the father was postzygotic mosaic and the index patient inherited the CNV from him. MLPA only detected the PTCH1 duplication in the index patient's blood and in hair and saliva from the mosaic father. Our data indicate that ddPCR more accurately detects CNVs, even in low-grade mosaic BCNS patients, which may be missed by MLPA. In general, quantitative ddPCR can be of added value in the genetic diagnosis of mosaic BCNS patients and in estimating the recurrence risk for offspring.

Medulloblastoma and other neoplasms in patients with heterozygous germline SUFU variants: A scoping review.

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

Acquisition of Drug Resistance in Basal Cell Nevus Syndrome Tumors through Basal to Squamous Cell Carcinoma Transition.

Although basal cell carcinomas arise from ectopic Hedgehog pathway activation and can be treated with pathway inhibitors, sporadic basal cell carcinomas display high resistance rates, whereas tumors arising in patients with Gorlin syndrome with germline Patched (PTCH1) alterations are uniformly suppressed by inhibitor therapy. In rare cases, patients with Gorlin syndrome on long-term inhibitor therapy will develop individual resistant tumor clones that rapidly progress, but the basis of this resistance remains unstudied. In this study, we report a case of an SMO inhibitor-resistant tumor arising in a patient with Gorlin syndrome on suppressive SMO inhibitor for nearly a decade. Using a combination of multiomics and spatial transcriptomics, we define the tumor populations at the cellular and tissue level to conclude that Gorlin tumors can develop resistance to SMO inhibitors through the previously described basal to squamous cell carcinoma transition. Intriguingly, through spatial whole-exome genomic analysis, we nominate PCYT2, ETNK1, and the phosphatidylethanolamine biosynthetic pathway as genetic suppressors of basal to squamous cell carcinoma transition resistance. These observations provide a general framework for studying tumor evolution and provide important clinical insight into mechanisms of resistance to SMO inhibitors for not only Gorlin syndrome but also sporadic basal cell carcinomas.

Whole-Exome Sequencing Identified Two Novel Pathogenic Mutations in the PTCH1 Gene in BCNS.

Basal cell nevus syndrome (BCNS, OMIM 109400) is a familial cancer syndrome characterized by the development of numerous basal cell cancers and various other developmental abnormalities, including epidermal cysts of the skin, calcified dural folds, keratocysts of the jaw, palmar and plantar pits, ovarian fibromas, medulloblastomas, lymphomesenteric cysts, and fetal rhabdomyomas. BCNS shows autosomal dominant inheritance and is caused by mutations in the patched 1 (PTCH1) gene and the suppressor of the fused homolog (SUFU) gene. In a few cases, variants of patched 2 (PTCH2) have been found in patients who met the criteria for BCNS. In an investigation of 11 Hungarian families who fulfilled the diagnostic criteria for BCNS, whole-exome sequencing (WES) and multiplex ligation-dependent probe amplification (MLPA) identified two novel pathogenic variants (c.2994C>A; p.Cys998Ter and c.814_818del; p.Asn272SerfsTer11), one recently identified variant (c.1737_1745del p.Val580_Val582del), and three recurrent disease-causing variants of the PTCH1 gene with a diagnosis rate of 63.6%. Disease-causing variants were not found for the SUFU and PTCH2 genes. These applied methods could not fully elucidate the genetic background of all the BCNS cases that we investigated. To uncover the missing heritability of BCNS, whole-genome sequencing or an epigenetic approach might be considered in the future.

18F-FDG PET/CT and Whole-Body Bone Scan Findings in Gorlin-Goltz Syndrome.

Gorlin-Goltz syndrome (basal cell nevus syndromes) is an uncommon, autosomal dominant inherited disorder characterized by developing basal cell carcinomas from a young age. Other distinct clinical features include keratocystic odontogenic tumors, dyskeratotic palmar and plantar pitting, and skeletal abnormalities. Clinicopathological findings of the syndrome are very diverse, and many symptoms manifest during a certain period of life. We present the compelling whole-body bone scan and 18F-FDG PET/CT findings in a 32-year-old man with odontogenic keratocyst, early-onset basal cell carcinoma, multiple ectopic calcifications in extremities, calcified falx cerebri, spinal scoliosis, macrocephaly, and ocular hypertelorism.

SUFU-associated Gorlin syndrome: Expanding the spectrum between classic nevoid basal cell carcinoma syndrome and multiple hereditary infundibulocystic basal cell carcinoma.

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

Pediatric Cutaneous Oncology: Genodermatoses and Cancer Syndromes.

Skin cancers represent the most common malignancy worldwide. In children, the diagnosis of skin cancer is rare and raises the possibility of an underlying genetic predisposition. Recent molecular advances have increased understanding of certain genetically determined regulatory pathways that constantly protect the skin from atypical cell growth and cancer. Knowledge about these underlying gene defects aids a dermatologist's ability to recommend confirmatory genetic testing and provides potential targets for future therapies. In this review, we outline genetic conditions important to dermatologists that are associated with skin cancer development and review the current approaches to the management of these patients.

Molecular Mechanisms and Targeted Therapies of Advanced Basal Cell Carcinoma.

Among human cutaneous malignancies, basal cell carcinoma is the most common. Solid advances in unveiling the molecular mechanisms of basal cell carcinoma have emerged in recent years. In Gorlin syndrome, which shows basal cell carcinoma predisposition, identification of the patched 1 gene (PTCH1) mutation was a dramatic breakthrough in understanding the carcinogenesis of basal cell carcinoma. PTCH1 plays a role in the hedgehog pathway, and dysregulations of this pathway are known to be crucial for the carcinogenesis of many types of cancers including sporadic as well as hereditary basal cell carcinoma. In this review, we summarize the clinical features, pathological features and hedgehog pathway as applied in basal cell carcinoma. Other crucial molecules, such as p53 and melanocortin-1 receptor are also discussed. Due to recent advances, therapeutic strategies based on the precise molecular mechanisms of basal cell carcinoma are emerging. Target therapies and biomarkers are also discussed.

Patient and caregiver perspectives on delayed childhood Gorlin syndrome diagnoses.

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

Advances in Management and Therapeutics of Cutaneous Basal Cell Carcinoma.

Basal cell carcinoma (BCC), the most common cancer in humans, is a malignant neoplasm of cells derived from the basal layer of the epidermis. Tumor characteristics such as histologic subtype, primary versus recurrent tumor, anatomic location, size, and patient attributes determine the risk level and acceptable treatment options. Surgical options offer histologic confirmation of tumor clearance. Standard excision provides post-treatment histologic assessment, while Mohs micrographic surgery (MMS) provides complete margin assessment intraoperatively. Additional treatment options may be employed in the correct clinical context. Small and low-risk BCCs, broad field cancerization, locally-advanced disease, metastatic disease, cosmetic concerns, or morbidity with surgical approaches raise consideration of other treatment modalities. We review herein a range of treatment approaches and advances in treatments for BCC, including standard excision, MMS, electrodesiccation and curettage, ablative laser treatment, radiation therapy, targeted molecular therapies, topical therapies, field therapies, immunotherapy, and experimental therapies.

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).

Decoding a gene expression program that accompanies the phenotype of sporadic and basal cell nevus syndrome-associated odontogenic keratocyst.

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

An investigation of metabolic disturbances, including urinary stone disease, hypothyroidism, and osteoporosis in basal cell nevus syndrome.

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

Development of a targeted gene panel for the diagnosis of Gorlin syndrome.

Gorlin syndrome is a rare autosomal dominant disease caused by mutations in the PTCH1, PTCH2, and SUFU genes. Each symptom of the disease has a different time point of onset, which makes early diagnosis based solely on symptoms challenging. In this study, a gene panel was developed to overcome the challenges in the diagnosis of Gorlin syndrome and allow diagnosis using a single test. A custom panel was generated for four genes associated with Gorlin syndrome: PTCH1, PTCH2, SMO, and SUFU. Twenty-seven samples from 12 patients with Gorlin syndrome and three asymptomatic blood relatives of the patients were examined. This panel was highly reliable with a high Q30 quality score, on-target ratio, and coverage. The panel was time- and cost-efficient and enabled the detection of more mutations than whole-exome sequencing for the same patient. Pathogenic mutations in both PTCH1 and PTCH2 were detected in five of the 12 patients with Gorlin syndrome who were diagnosed based on clinical symptoms. Using this panel, the same mutation was identified in the patients and their blood relatives. In summary, this panel facilitated the highly reliable genetic diagnosis of Gorlin syndrome at a low cost, using only blood samples.

Novel recurrence risk stratification of odontogenic keratocysts: A systematic review.

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

Oral and Maxillofacial Surgeon's Perspective on Gorlin-Goltz Syndrome - A Report of Two Cases.

Rationale: Gorlin-Goltz syndrome (GGS) is an autosomal dominant disorder and is associated with multisystem involvement, multiple cysts, neoplasms and other developmental anomalies. The purpose of the study was to highlight the incidental findings of GGS and to lay emphasis on its early diagnosis. Patient Concerns: Two patients complaining of pain, swelling and at times pus discharge from the oral cavity were reported with a coincidental finding of odontogenic keratocysts and positive family history. Diagnosis: Upon thorough examination, a diagnosis of GGS was made. Treatment: The patients were managed by enucleation and chemical cauterisation using Carnoy's solution and were maintained on follow-up semi-annually. Outcomes: Both patients showed no signs of recurrence post six months follow-up. Lessons: The role of an oral and maxillofacial surgeon is of utmost importance in the early diagnosis of this syndrome to render good quality of life to these patients.