Germline pathogenic variants (GPVs) in RB1 are associated with the pediatric-onset intra-ocular malignancy retinoblastoma and typically present in infancy as multi-focal or bilateral disease. Survivors of retinoblastoma are at high risk for developing subsequent malignant neoplasms (SMNs); indeed, these are the leading cause of death for individuals cured of their retinoblastoma. With the exception of sarcomas, typically occurring at the site of antecedent radiation therapy for the original retinoblastoma diagnosis, and melanoma, little is known of other SMNs in retinoblastoma survivors. Here, we describe a unique case of pancreatic adenocarcinoma (PDAC) in a patient with a RB1 GPV who was diagnosed with retinoblastoma as an infant. At age 57, he was diagnosed with PDAC. Sequence analysis of the PDAC revealed the acquisition of a somatic second-hit in RB1 in the PDAC. Multispectral immunofluorescence analyses of the PDAC tumor illustrated selective loss of the RB protein in the tumor that was accompanied by the continued expression of p16ink4a, encoded by the CDKN2A gene. In PDAC, CDKN2A loss is a common early event that contributes to carcinogenesis. This case may suggest that PDAC is a rare late component of RB1-associated tumor predisposition and illustrates that biallelic loss of RB1 is an alternative mechanism by which the RB1-pathway can be disrupted in PDAC independent of CDKN2A inactivation.

The European Reference Network on Genetic Tumour Risk Syndromes (ERN GENTURIS) established in 2017 and connecting more than 50 European expert centres improves access to diagnosis, treatment, and the provision of high-quality healthcare for patients with rare genetic tumour risk syndromes (hereditary cancer), no matter where they live in Europe.

Cancer remains a leading cause of death in children/adolescents. Approximately 8–18% of children/adolescents with cancer have an underlying pediatric Genetic Cancer Risk (p-GCR). P-GCR clinics offer surveillance aimed at improving survival outcomes. Yet children/adolescents require more than surveillance protocols to support holistic health. A multidisciplinary model of care (MoC), including Advanced Practice Nurses (APN) is needed. Yet a MoC and formal description of the APN is lacking in p-GCR clinics. To explore existing evidence of holistic, multidisciplinary approaches to care for children/adolescents and families with a p-GCR; to identify how Advanced Practice Nurses (APN) contribute to care delivery in p-GCR services. A scoping review was conducted in three databases: MEDLINE (Ovid), Embase (Ovid) and CINAHL Complete. JBI methodology for conducting and reporting scoping reviews was used to search MEDLINE, Embase and CINAHL Complete. Gray and white literature was considered from 1991 to 2023. Thirty two studies met inclusion criteria. Thirteen aspects of a MoC in p-GCR were identified including: clinic scope, clinic locality, clinicians involved, care coordination, clinic activity, geography, centralisation of care, psychosocial aspects, shared decision making, education, referrals, transition to adult services and research. There were 10 APN roles described that supported the service/organisation and the delivery of holistic care to children/adolescents with a p-GCR. Using a systematic approach, this review identified how services provide care to children/adolescents with a p-GCR and the APN role in these services. A multidisciplinary MoC with dedicated care coordination can enable child and family centred care with a holistic healthcare approach.

Hybrid neurofibroma/schwannoma tumors (HNS) represent a still underrecognized, yet clinically and diagnostically significant entity within the spectrum of schwannomatosis (SWN). While classical schwannomas have been well known for decades, HNS have only recently been described as a distinct histological pattern, composed of intermixed features typical of both schwannomas and neurofibromas. Differentiating HNS from pure neurofibroma (Nf) is critical, as misclassification may lead to an incorrect diagnosis of neurofibromatosis type 1 rather than SWN. The distinction of hybrid tumors (more precisely HNS) is especially important in SWN forms outside the neurofibromatosis type 2 (NF2) spectrum (NF2-SWN), where major diagnostic criteria are less well defined, making histological differentiation even more significant. At the molecular level, HNS frequently show alterations in the genes NF2, LZTR1, and SMARCB1, often accompanied by characteristic losses of chromosome 22q. In addition, recurrent somatic mutations have been identified in genes such as ERBB2, RET, KMT2A, and CTNNA3. Methylation profiling classifies HNS within the schwannoma spectrum, supporting the hypothesis that they may be a morphological variant rather than a distinct entity, although this has not yet been conclusively confirmed. Histologically, HNS are characterized by a combination of mostly schwannoma-associated Antoni A patterns, collagen-rich neurofibroma-like areas, lymphocytic infiltrates, and, in some cases, plexiform growth. Given the diagnostic challenges, artificial intelligence-based image analysis, such as whole-slide imaging and radiomics, may offer valuable tools for more accurate identification of these tumors in the future. Initial studies in related fields have shown that such approaches can even surpass human-level accuracy. Nevertheless, an accurate histological and, if necessary, molecular evaluation remains essential—particularly for the correct classification as SWN and for ensuring appropriate genetic counseling to affected individuals.

In patients with Familial Adenomatous Polyposis (FAP), large desmoid tumors can develop all over the body. However, the most frequent presentation is as large intra-abdominal masses, usually located in the mesentery of the small bowel. From there, they tend to grow and invade both the abdominal wall and/or the retroperitoneal structures. This can cause life-threatening complications such as recurrent abdominal sepsis with fistulation and damage to vital organs. In selected patients, the only option may be radical resection and replacement by intestinal transplantation (ITx). We aimed to review all the current literature on ITx for FAP-related desmoids and provide an update from the largest single-center experience (2007–2024). All patients undergoing ITx for FAP-related desmoid were included. Between 2007 and 2024, 166 ITx was performed in 158 patients at Addenbrooke’s Hospital, Cambridge, UK. Of these, 20 (12%) were for desmoid associated with FAP (10 modified multivisceral transplants, 8 isolated ITx and 2 liver-containing grafts). The five-year all-cause patient survival was 92%, median follow-up was 4.3 years. As the patients presented with very advanced disease, many technical challenges were faced such as: extensive ureteric involvement, abdominal wall fistulation, management of previously formed ileo-anal pouches and extra-abdominal recurrences. Graft selection was another evolving issue, as foregut resection- versus sparing techniques require careful preoperative risk stratification due to increased long-term cancer risk in FAP patients. For certain patients with advanced FAP/desmoid disease, ITx can allow for a radical resection with excellent survival and functional outcomes. However, there is a high degree of initial morbidity associated with the operation and patients should be appropriately counselled. Graft selection and degree of native organ resection requires a careful balanced discussion.

Deciphering the spectrum and founder disease-causing variants (DCVs) in specific populations can shape and facilitate the diagnostic process of Lynch Syndrome (LS). The aim of this report was to comprehensively update on the genetic landscape of LS in the ethnically diverse Israeli-Jewish population. The cohort included 1080 carriers from 588 families; some from underrepresented, understudied Israeli ethnic groups recruited from 8 genetic institutes and high-risk clinics throughout the country. Variant classification was performed according to the American College of Medical Genetics criteria. A total of 157 DCVs were identified, 12 are reported here for the first time, and 9 reclassified. MSH2 DCVs were identified in 286 families (49%). Most DCVs (125/157, 80%) were noted in one or two families only. Sixteen DCVs, each detected in ≥ 5 families, and accounted for LS in 378/588 (64%) families. Constitutional mismatch repair deficiency (CMMRD) was diagnosed in 7 families. Twenty-five carriers (2.3%) had an additional DCV or risk alleles in another cancer susceptibility gene. In conclusion, MMR gene variant distribution in Israel is diverse. MSH2 is most commonly mutated due to founder DCVs. Though the 16 prevalent LS-associated DCVs were frequently detected in our cohort, none of them is frequently reported in the general population. These data should facilitate variant interpretation, spouse and cascade testing.

Hereditary Hemorrhagic Telangiectasia (HHT) is an autosomal vascular dysplasia characterized by the presence of mucocutaneous telangiectasia and arteriovenous malformations in solid organs. The Curaçao criteria and/or detection of ALK1, ENG, and SMAD4 gene mutations are used for diagnosis. Juvenile Polyposis Syndrome (JPS) is diagnosed according to the number and localization of juvenile polyps, and family history of JPS. Both entities have a low prevalence. Mutation of SMAD4 leads to a combined syndrome of these two conditions called HHT-JPS Overlap Syndrome. We aim to describe the clinical characteristics associated with this condition focusing on long term follow up and review of the literature. A cross-sectional descriptive study of HHT-JPS cases from an HHT Institutional Registry was designed. Patients were eligible for this case series if they fulfilled both HHT and JPS diagnostic criteria and/or mutation on SMAD4. A comprehensive review was conducted on the clinical phenotype associated with HHT and its gastrointestinal involvement. Fourteen patients from eleven families in 788 previously HHT-diagnosed patients met the inclusion criteria. The ages ranged between 25 and 70 years old and 12 were females. In addition to the typical signs/symptoms of HHT, two distinct phenotypes were observed. Nine patients predominantly exhibited initially upper, while five showed predominantly initially lower gastrointestinal involvement. Numerous musculoskeletal and cardiovascular anomalies were also identified. The observed phenotypic diversity, particularly in gastrointestinal involvement, underscores the need for tailored clinical approaches. Comprehensive assessments identified associated musculoskeletal and cardiovascular anomalies, emphasizing the systemic nature of HHT-JPS.

Familial adenomatous polyposis (FAP) predisposes individuals to duodenal adenomas. This study describes the histopathological features of endoscopic and surgical specimens from the duodenum, as well as genotype-phenotype associations. All known FAP patients were included from the Danish Polyposis Register. FAP patients were defined as having more than 100 cumulative colorectal adenomas and/or having a known germline pathogenic variant in the APC gene. Endoscopic procedures, histopathology, and genetics were evaluated. Of 500 FAP patients, 70.6% underwent esophagogastroduodenoscopy (EGD) at least once. Of these, 59.2% presented with detectable duodenal adenomas. The most severe morphology was tubular in 62.7% patients, tubulovillous in 25.4%, and villous in 12.0%, while the most severe dysplasia was low-grade in 67.5% patients, high-grade in 25.4%, and 6.7% had adenocarcinoma. In 6.2% of FAP patients, duodenal resection was recommended, including 29% with duodenal adenocarcinoma. The risk of duodenal surgery was 1.31 per 1,000 person-years (median age: 53 years). The predominant reason for surgery was extensive polyposis (67.7%). Of the patients who underwent duodenal resection, a median of six (IQR: 4-8) EGDs were performed within five years prior to surgery, but 67.6% and 83.9% never underwent a duodenal polypectomy or endoscopic mucosa resection, respectively. Of note, seventeen of 500 patients (3.4%) developed duodenal adenocarcinoma, of which 47% were advanced at diagnosis. Genetic evaluations revealed various pathogenic variants in the APC gene, with no strong genotype-phenotype association. The prevalence of duodenal adenomas and cancer in FAP warrants vigilant endoscopic surveillance. Nevertheless, the need for duodenal surgery persists and should together with endoscopic practice be monitored in national registers.

Telomerase Reverse Transcriptase (TERT) encodes the telomerase reverse transcriptase enzyme and is the most frequently mutated gene in patients with telomeropathies. Heterozygous variants impair telomerase activity by haploinsufficiency and pathogenic variants are associated with bone marrow failure syndrome and predisposition to acute myeloid leukaemia. Owing to their rarity, telomeropathies are often unrecognised and misdiagnosed. Herein, we report a novel TERT gene variant, c.2605G > A p.(Asp869Asn) in a family with hereditary aplastic anaemia. This report emphasises the importance of routine deep genetic screening for rare TERT variants in patients with a family history of cytopenia or aplastic anaemia, which could identify clinically inapparent telomere disorders.