Nevoid Basal Cell Carcinoma Syndrome Research Articles

Gorlin-Goltz Syndrome: A Comprehensive Analysis of the Clinical, Genetic and Therapeutic Manifestations of a Rare and Complex Disease

Gorlin-Goltz syndrome, also known as basal cell nevus syndrome or nevoid basal cell carcinoma syndrome, is a rare and heterogeneous genetic disease with a varied clinical presentation involving multiple systems and organs. This comprehensive review aims to provide an in-depth understanding of this syndrome from a medical and scientific perspective. Gorlin-Goltz syndrome is characterized by an inherited predisposition to the formation of skin and skeletal tumors, as well as the development of jaw cysts, cleft palates, facial deformities, ocular malformations and other anomalies. At the genetic level, this syndrome is linked to mutations in the PTCH1 gene, which regulates the hedgehog signaling pathway, playing a crucial role in the regulation of cell growth and differentiation. Early and accurate diagnosis of Gorlin-Goltz syndrome is essential to prevent serious complications, such as advanced basal cell carcinomas and facial disfigurement. Molecular diagnostic strategies and therapeutic options, including reconstructive surgery, hedgehog pathway inhibitor therapy, and multidisciplinary patient management will be addressed. This review will also explore the psychological and social impact on patients and their families, as well as advances in genetic and therapeutic research that may open new perspectives for the management and prevention of this complex disease. Ultimately, detailed knowledge of Gorlin-Goltz syndrome is essential to improve the quality of life of those affected and to promote future research in this evolving field.

A novel de novo canonical splice site mutation in the PTCH1 gene in a male patient with mild psychomotor retardation and autistic traits: a case report

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

Odontogenic keratocyst in the mandible of a 7‐year‐old child: A case report and literature review

AbstractOdontogenic keratocysts (OKCs) are one of the most frequently encountered cystic diseases of the jaw in clinical practice. Although OKC has been reported as a manifestation of nevoid basal cell carcinoma syndrome (Gorlin syndrome) in many pediatric patients, there have been few reports of OKC occurring in isolation. Herein, we report the case of a relatively large OKC in the mandibular body of a 7‐year‐old girl who was treated conservatively using cystectomy and open wound surgery, and the permanent teeth were unaffected. Regular check‐ups, including radiographic examinations, starting in childhood may contribute to the early detection of lesions in the maxillofacial region.

Incidence and Prevalence of 73 Different Genodermatoses: A Nationwide Study in Sweden.

This retrospective registry-based cohort study aimed to estimate the incidence and prevalence of genodermatoses in the Swedish population and to analyse associated healthcare usage. Patients diagnosed with genodermatoses were identified from the patient registry of Sahlgrenska University Hospital (Gothenburg, Sweden) between 2016 and 2020. Clinical data from medical records were used to verify diagnoses recorded in the National Patient Registry (NPR). The NPR was then searched for International Classification of Diseases, Tenth Revision (ICD-10) codes Q80-82 and Q84 from 2001 to 2020. The local cohort included 298 patients with 36 unique genodermatosis diagnoses. Verification of these diagnoses in the NPR showed positive predictive values of over 90%. The NPR search yielded 13,318 patients with 73 unique diagnoses, including ichthyoses (n = 3,341; 25%), porokeratosis (n = 2,277; 17%), palmoplantar keratodermas (n = 1,754; 13%), the epidermolysis bullosa group (n = 1011; 7%); Darier disease (n = 770; 6%), Hailey-Hailey disease (n = 477; 4%) and Gorlin syndrome (n = 402; 3%). The incidence and prevalence of each diagnosis were calculated based on the nationwide cohort and are reported. A total of 149,538 outpatient visits were registered, a mean of 4.6 visits per patient. This study provides a valuable resource for the epidemiology of genodermatoses by reporting on the incidence and prevalence of 73 different genodermatoses.

LB1763 Combinatorial BRD9 and SMO targeting synergistically suppress UV-induced BCC tumor burden in a murine model of Gorlin syndrome (GS)

LB1763 Combinatorial BRD9 and SMO targeting synergistically suppress UV-induced BCC tumor burden in a murine model of Gorlin syndrome (GS)

Hedgehog-Related Mutation Causes Bone Malformations with or without Hereditary Gene Mutations.

The hedgehog (Hh) family consists of numerous signaling mediators that play important roles at various stages of development. Thus, the Hh pathway is essential for bone tissue development and tumorigenesis. Gorlin syndrome is a skeletal and tumorigenic disorder caused by gain-of-function mutations in Hh signaling. In this review, we first present the phenotype of Gorlin syndrome and the relationship between genotype and phenotype in bone and craniofacial tissues, including the causative gene as well as other Hh-related genes. Next, the importance of new diagnostic methods using next-generation sequencing and multiple gene panels will be discussed. We summarize Hh-related genetic disorders, including cilia disease, and the genetics of Hh-related bone diseases.

Establishment of induced pluripotent stem cells derived from patients and healthy siblings of a nevoid basal cell carcinoma syndrome family.

It is known that a nevoid basal cell carcinoma syndrome (NBCCS) is characterized by a combination of developmental abnormalities and a predisposition to form various tumors. Although it is possible to create disease models via gene editing, there are significant potential problems with this approach such as off-target mutations and differences in SNPs. On the other hand, since disease families share common SNPs, research using iPSCs derived from both patients and healthy siblings of the same disease family is very important. Thus, establishment of induced pluripotent stem cells derived from patients and healthy siblings of the same NBCCS family will be of great importance to study the etiology of this disease and to develop therapeutics. In this study, we generated hiPSCs using peripheral blood mononuclear cells derived from the patients and healthy siblings of familial NBCCS with the novel mutation in PTCH1_c.3298_3299insAAG in the feeder- and serum-free culture conditions using SeVdp. In addition, disease-specific hiPSCs such as those expressing the PTCH1_c.3298_3299insAAG mutation could be powerful tools for revealing the genotype-phenotype relationship and pathogenicity of NBCCS.

Performance of the eHealth decision support tool, MIPOGG, for recognising children with Li-Fraumeni, DICER1, Constitutional mismatch repair deficiency and Gorlin syndromes

BackgroundCancer predisposition syndromes (CPSs) are responsible for at least 10% of cancer diagnoses in children and adolescents, most of which are not clinically recognised prior to cancer diagnosis. A variety...

Headache as the presenting manifestation of Gorlin-Goltz syndrome with diastematomyelia: A case report.

Gorlin-Goltz syndrome (GGS) is an autosomal dominant multisystemic disease with high penetrance. Headache heralding GGS has been previously reported but without discussing potential sources. We report a patient with headache and a novel association (diastematomyelia), which helped with the diagnosis. A 46-year-old woman presented with persistent holocranial headache. On examination, countless hyperpigmented basal cell nevi over the face, pits over the palmar/plantar surface, and palmar and plantar keratosis were observed. A magnetic resonance imaging (MRI) of the spinal cord revealed diastematomyelia. Diagnosis of GGS was finally made. Headache and diastematomyelia should be included in the clinical picture of GGS.

Gorlin-Goltz Syndrome: A Case Report and Literature Review with PTCH1 Gene Sequencing.

Gorlin-Goltz syndrome, also known as nevoid basal cell carcinoma syndrome, is an autosomal dominant disease characterized by multisystemic developmental defects caused by pathogenic variants such as patched-1 ( PTCH1 ) gene variants and/or SUFU gene variants. The presence of either two main criteria or one major and two minor criteria are required for the diagnosis of Gorlin-Goltz syndrome. Recently, a major criterion for molecular confirmation has also been proposed. In this article, we report the case of an 80-year-old male who was admitted at our department for multiple brown-to-black papules and plaques on the entire body. He was diagnosed with Gorlin-Goltz syndrome with clinical, radiologic, and pathologic findings. While the diagnosis was made based on the clinical findings in general, confirmation of the genetic variants makes an ideal diagnosis and suggests a new treatment method for target therapy. We requested a genetic test of PTCH1 to ideally identify the molecular confirmation in the hedgehog signaling pathway. However, no pathogenic variants were found in the coding region of PTCH1, and no molecular confirmation was achieved.

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.

BG12 A case of severe gastrointestinal bleeding while on vismodegib therapy

Abstract We report the case of a 50-year-old woman, with a history of Gorlin syndrome on vismodegib therapy, who presented with two episodes of upper gastrointestinal bleeding (UGIB) in the absence of other risk factors. Gorlin syndrome is a rare disorder characterized by multiple basal cell carcinomas (BCCs) secondary to a mutation in PTCH1. Mutations in PTCH1 lead to dysregulation of the hedgehog signalling pathway and subsequent abnormal proliferation. Vismodegib is a systemic hedgehog inhibitor that has been shown to be effective in treating advanced BCCs and Gorlin syndrome. Our patient acquired multiple BCCs which excision, photodynamic therapy and topical chemotherapy agents failed to control. Therefore, a decision to commence vismodegib was made. During treatment with vismodegib, she had a perforated gastrointestinal ulcer and required an emergency laparotomy. Vismodegib was stopped, but over the next few years, her BCCs progressed again to an excess of 50 BCCs, including large plaques of carcinoma measuring up to 12 cm in diameter. Vismodegib was restarted with a high-dose proton–pump inhibitor cover, as recommended by the gastroenterology team, and her BCCs were largely resolved. However, a second bleed occurred approximately 1 year after restarting treatment. Gastroscopies undertaken following these episodes were largely normal, showing mild, nonerosive duodenitis only, and Helicobacter pylori testing was negative. Given the lack of pre-existing risk factors and temporal relation to vismodegib therapy, the decision was made to suspend the drug. To our knowledge, this is the first case reported in the literature of UGIB associated with vismodegib. A separate case has reported colonic mucosal changes in a patient with chronic diarrhoea on vismodegib. The hedgehog protein and RNA expression have been found to be present in the gastrointestinal endothelium and mesenchyme. Evidence suggests the hedgehog pathway activation in gastrointestinal lining is involved in the wound-healing response, endothelial turnover and activation of mesenchymal immune responses. Therefore, inhibition of the hedgehog pathway via vismodegib could potentially impair the essential maintenance of the gastrointestinal endothelium. We postulate that this mechanism could have led to the presentation in our patient, through endothelial damage exposure of vessels leading to gastrointestinal bleeding. Treatment options for BCC in our patient are now limited. Vismodegib is one of the few therapies that has been shown to induce remission of symptoms and reduce disease burden. We present this case to raise awareness of this potential adverse event.

H07 Papyri and sarcophagi: a tour of dermatology in Ancient Egypt

Abstract Long before medicine was demystified by the Renaissance, Enlightenment and modern thinkers with whom we are most familiar, the skin and its diseases were pondered on by the Ancient Egyptians. Through their writings and remains, modern scholars are able to assemble a picture of what dermatological conditions ailed the Egyptians and how they were contemporaneously perceived. The Ebers Papyrus (c. 1550 Bc), the largest record of Ancient Egyptian medicine, is noted for its vivid descriptions of lesions and grisly details of treatments. Some of the conditions mentioned therein are straightforwardly identified from their descriptions, whereas others are open to interpretation. Recent DNA evidence has also shed light on this topic, causing scholars to re-evaluate the presence of various conditions, such as leprosy and tuberculosis, in different parts of the ancient world. The Egyptians are perhaps most famed for the preservation of bodies through the process of mummification, which provides us with a unique glimpse into the nature of skin disease in the ancient world. Mummified skin tends to be shrunken, deeply pigmented and brittle. Even so, nails, hair and epidermal ridging are preserved. Prolonged rehydration and staining can reveal the stratum corneum, keratinocytes, melanin, collagen and elastic fibres, along with adnexal structures and subcutaneous tissue. Mummies with identifiable dermatological disease include Ramses V (d. 1145 Bc), whose face, neck, shoulders, lower abdomen and scrotum bear the marks of smallpox. The diagnosis was later confirmed by electron microscopy, which identified the variola viral corpuscle in his skin. Skin tumours have also been found in mummified remains, as have syndromic features of diseases, which predispose to multiple dermatological malignancies, such as Gorlin–Goltz syndrome, which is suspected in two fraternal mummies from around 3000 Bc. One specimen from c. 1300 Bc was identified as having a venous ulcer, which was subsequently confirmed when histology demonstrated perivascular haemosiderin deposition. Other tentative diagnoses have been made on appearance alone, including pustular dermatosis, impetigo and pemphigus foliaceus. Too often do we perceive medical history as starting in earnest during the last few centuries. The Ancient Egyptians have bequeathed to us a wealth of information, both historical and archaeological, which, combined with modern techniques, has allowed us to peer through the millennia into a dermatological world that can feel simultaneously alien and familiar. This presentation/poster will showcase what we understand of this world and what future research might hold in store.

H19 The bronze diabetic

Abstract Many works of art throughout the centuries have not only garnered intrigue, but also debate among physicians relating to a possible medical diagnosis depicted by the artist. Representation of both anatomy and disease with the use of votive offerings and forms of grotesque art is well recognized. Such work was particularly prevalent in pieces produced during the Hellenistic Age and includes statuettes, anatomical replicas, coins and other art work. Diseases such as acromegaly, Gorlin syndrome, lymphoedema, neurofibromatosis and ophthalmic disorders, among others, have been represented in such pieces. It had been thought by the suppliants that in presenting these offerings to the Gods, particularly Asclepius, the Greek god of medicine and son of Apollo, they could be cured from their ailments. An example of an artistic piece representing an individual with disease is that of a small bronze statuette described as a ‘Statue of an Emaciated Man’ and housed at the Dumbarton Oaks Research Library and Collection, Washington DC. It is a small bronze statue measuring at just 11.5 × 5 × 8.3 cm, and is thought to date from around the first century Bc to the first century Ad. It depicts a gaunt young man sitting atop a bench with his left hand held limply and an apparently swollen right foot. It has been suggested that this individual could have suffered from lead poisoning. However, lead neuropathy is typically symmetrical and emaciation is uncommon. A more common source of lead poisoning in ancient times was wine drinking, as lead was used both as a sweetener and preservative. In addition, occupational exposure was common as lead was used widely in pottery, painting, lead smelting and glass ceramics. A disease that could explain the three features of emaciation, wrist drop and a swollen foot is diabetes mellitus. Diabetes had been recognized in Egyptian manuscripts dating back to 1500 Bc commenting on ‘honey urine’. Diabetes has been well documented during the Hellenistic Age with Apollonius of Memphis in 250 Bc being credited for coining the term ‘diabetes’. Insulin insufficiency can cause emaciation mainly through ketosis. The neuropathy of diabetes mellitus can affect single nerves, and a radial nerve palsy resulting in a wrist drop has been recognized. The appearance of an apparent swollen foot could be due to a Charcot joint, which is a result of repetitive microtrauma-induced complications of polyneuropathy. In conclusion, we believe this statuette represents features consistent with diabetes mellitus and is a ‘bronze diabetic’.

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.

SYNCHRONOUS ODONTOGENIC MYXOMA AND ODONTOGENIC KERATOCYSTS IN NEVOID BASAL CELL CARCINOMA SYNDROME: A CASE REPORT

Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. An 11-year-old girl was referred for evaluation due to a lack of eruption of teeth 14 and 15. Her past medical history and physical examination were unremarkable. Imaging exams showed well-defined pericoronal radiolucencies associated with teeth 14 and 37, as well as an additional radiolucent lesion affecting the right mandibular body. Microscopic analyses of both pericoronal lesions proved to be odontogenic keratocysts (OKC). The additional mandibular lesion showed a proliferation of spindle and stellate cells in a predominantly myxoid stroma and numerous concentric basophilic calcifications, consistent with odontogenic myxoma (OM). The patient was referred for genetic counseling and the diagnosis of NBCCS was made. To the best of our knowledge, this represents the second case of synchronous OKC and OM in a patient with NBCCS. Nevoid basal cell carcinoma syndrome (NBCCS) is a hereditary condition characterized by a wide range of developmental abnormalities and a predisposition to neoplasms. An 11-year-old girl was referred for evaluation due to a lack of eruption of teeth 14 and 15. Her past medical history and physical examination were unremarkable. Imaging exams showed well-defined pericoronal radiolucencies associated with teeth 14 and 37, as well as an additional radiolucent lesion affecting the right mandibular body. Microscopic analyses of both pericoronal lesions proved to be odontogenic keratocysts (OKC). The additional mandibular lesion showed a proliferation of spindle and stellate cells in a predominantly myxoid stroma and numerous concentric basophilic calcifications, consistent with odontogenic myxoma (OM). The patient was referred for genetic counseling and the diagnosis of NBCCS was made. To the best of our knowledge, this represents the second case of synchronous OKC and OM in a patient with NBCCS.

Базальноклеточный рак на фоне синдрома Горлина – Гольца: клинические особенности и возможности терапии

Gorlin-Goltz syndrome is a rare hereditary disorder characterised by multiple congenital abnormalities and cancer predisposition – basal cell cancer (BCC) and medulloblastoma. BCC develops in most patients throughout their life. The number of BCCs varies from a few to several thousand. In this paper we describe the diagnostic features for Gorlin-Goltz syndrome and treatment options for BCC associated with this hereditary disease. We analysed our clinical experience and presented data on patients with multiple BCC related to Gorlin-Goltz syndrome who were referred to N.N. Blokhin National Medical Research Center of Oncology from 2012 to 2023 (n = 10)

DIAGNOSIS OF GORLIN-GOLTZ SYNDROME: CLINCIAL CASE REPORT

The diagnosis of Gorlin-Goltz syndrome involves clinical, radiographic, and histopathological aspects. Computed tomography contributes to the evaluation of the characteristics, to the extension of cystic lesions, and to the diagnosis of signs, such as calcifications in the falx cerebri. A 22-year-old male presented a complaint of halitosis. Upon extraoral examination, a slight increase in volume in the lower third of the right face, suggestive of a cystic lesion in the soft tissue, and a scar on the skin of the nasolabial region, were noted. Tomographic imaging revealed hypodense lesions involving impacted teeth, two in the maxilla (with extension to the maxillary sinuses) and two in the mandible. The intraosseous lesions underwent biopsy, and the histopathological findings were consistent with keratocysts. Intracranial calcifications were also detected. Additionally, an anatomical alteration of the incisive foramen and nasal cavity was identified. Basal cell carcinomas were not observed. The patient is undergoing follow-up. The diagnosis of Gorlin-Goltz syndrome involves clinical, radiographic, and histopathological aspects. Computed tomography contributes to the evaluation of the characteristics, to the extension of cystic lesions, and to the diagnosis of signs, such as calcifications in the falx cerebri. A 22-year-old male presented a complaint of halitosis. Upon extraoral examination, a slight increase in volume in the lower third of the right face, suggestive of a cystic lesion in the soft tissue, and a scar on the skin of the nasolabial region, were noted. Tomographic imaging revealed hypodense lesions involving impacted teeth, two in the maxilla (with extension to the maxillary sinuses) and two in the mandible. The intraosseous lesions underwent biopsy, and the histopathological findings were consistent with keratocysts. Intracranial calcifications were also detected. Additionally, an anatomical alteration of the incisive foramen and nasal cavity was identified. Basal cell carcinomas were not observed. The patient is undergoing follow-up.

Artículo traducido] Sonidegib para el tratamiento del carcinoma basocelular avanzado en práctica clínica real: estudio nacional multicéntrico

BackgroundBasal cell carcinoma (BCC) is the most prevalent cancer. A minority of BCCs have an aggressive behaviour (laBCC) and may require hedgehog pathway inhibitors such as sonidegib as its treatment. ObjectiveTo describe the use of sonidegib in a large number of patients and provide more data on its real-life efficacy and safety profile. MethodsWe conducted a retrospective and multicentric study that included patients treated with sonidegib. Epidemiological, effectiveness and safety data were collected. ResultsA total of 82 patients with a mean age of 73.9 years were included. Ten patients had Gorlin syndrome. Median treatment duration was 6 months. Median follow-up duration was 34.2 months. Globally, 81.7% of the patients showed clinical improvement (52.4% partial response and 29.3% complete response), 12.2% clinical stability and 6.1% disease progression. There was no statistically significant difference in clinical improvement between the 24 h and 48 h sonidegib posology. After 6 months of treatment, 48.8% of the patients discontinued sonidegib. Prior vismodegib treatment and recurrent primary BCC were associated with a poorer response to sonidegib. At 6 months of treatment, 68.3% of the patients experienced at least one adverse effect. ConclusionSonidegib shows good effectiveness and acceptable safety profile in usual clinical practice.

Bifurcated rib as major diagnostic criteria of Gorlin syndrome in paediatric patient: a rare case report

Background: Bifurcated rib or Bifid rib is considered to be an anatomical overgrowth anomaly of the chest wall, forming a forked sternal end. Diagnosis of this condition is generally an incidental finding on imaging or post-mortem examination. Most of the cases were asymptomatic and established as part of Gorlin syndrome. Here we describe a rare case of chest wall deformity in a paediatric patient, and our approach for this case with limited cost and resources. Case Presentation: A 5-year-old boy, presented at orthopedic outpatient clinic with complaint of a painless lump in his upper left chest. No significant history of infection, malignancy or any congenital syndromes. Chest imaging revealed a bifid left 4th rib at the sternal end. Conclusion: There is currently no data on the best approach to managing bifid ribs. In addition, genetic testing for susceptible genes should be strongly considered. In this situation with limited cost and resources, we suggest close monitoring with regular follow-ups for the patient as the best approach, including detection of any other diagnostic criteria of Gorlin syndrome, to ensure better prognosis and quality of life for this patient.