PTEN hamartoma tumor syndrome (PHTS) encompasses a group of inherited disorders caused by germline mutations in the PTEN gene, which functions as a tumor suppressor. We report the case of a 10-year-old girl presenting with neck swelling. Initial ultrasound revealed nodular changes in the thyroid gland. Laboratory results indicated a euthyroid state, with normal calcitonin levels. However, thyroid scintigraphy demonstrated markedly pathologic findings, including cold, nonfunctioning nodules, raising suspicion for an underlying neoplastic or syndromic cause. This prompted further investigation through biopsy and molecular analysis, which confirmed a pathogenic PTEN mutation, establishing the diagnosis of PHTS.

PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germlinePTENvariants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenicPTENvariants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects ~ 1/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates forPTEN-related disorder. Compared with carriers of other cancer-related gene variants and noncarriers,PTENvariant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.

This publication presents in two parts a comprehensive comparison of the manyfold salivary gland and cutaneous adnexal tumors, investigating both striking similarities and discrepancies with respect to clinical aspects, terminology, (immune)-histology, and molecular pathology. Part I has presented basic embryology/histology and overlapping topographical aspects, followed by a first series of related tumor entities. In this second part, a further series of histologically analogous/similar tumor entities are compared, comprising secretory and microsecretory carcinoma, sialadenoma and syringocystadenoma papilliferum, adenoidcystic carcinoma, mucinous and mucoepidermoid tumors, lymphoepithelial tumors, sebaceous tumors, and further rare related tumor groups. Finally, in a synoptic comparison, general features are summarized: While tumors with follicular differentiation are lacking in salivary glands, tumors with acinar and oncocytic differentiation are lacking in the skin. In general, salivary tumors have a higher proportion of malignancy, are on average larger, are frequently more difficult to resect due to a more complex topography, and, hence, show a higher propensity for recurrence and metastases, on average with a poorer prognosis. Multifocality with or without link to hereditary tumor syndromes is not infrequent in cutaneous lesions, but is very rare in salivary tumors.

Background . Neurofibromatosis type 1 (NF1) is a genetic disorder that is characterized by multiple light brown patches of skin (café-au-lait spots) and neurofibromas. It can lead to an increased risk of malignant tumors, cognitive impairment, and skeletal abnormalities. NF1 is caused by heterozygous mutations in the NF1 gene, and identifying the specific mutation can form the basis for pathogenetic treatment of tumor syndrome. Several studies indicate that patients with the NF1 in-frame deletions tend to have a milder form of the disease that is characterized by the absence of neurofibromas. the purpose of the study was to identify in-frame deletions in the NF1 gene in patients from the Republic of Bashkortostan as well as to characterize the clinical symptoms of NF1 in this group of patients. Material and Methods . An analysis of outpatient records of NF1 patients from the Republic of Bashkortostan was conducted, along with an objective clinical examination of the patients and DNA sequencing to identify in-frame deletions in the NF1 gene. Twenty-six patients (12 females and 14 males) aged 3 to 69 years were studied. Results . The retrospective analysis of outpatient records and examination of NF1 patients showed the NF1 incidence of 1:7403.6 people. Two in-frame deletions in the NF1 gene were identified in 6 patients with NF1 from 3 unrelated families: NF1:NM_000267.3:exon21:c.2674_2679del:p. S892_K893del; NF1:NM_000267.3:exon27:c.3526_3528delAGA:p.Arg1176del. The clinical manifestations of NF1 in patients with identified mutations and their comparative characteristics with all NF1 patients in the Republic were described. In the general group of NF1 patients from the Republic, a rarer detection of neurofibromas and malignant tumors, optic nerve gliomas, and cognitive impairment was revealed. Conclusion . In patients with NF1 from the Republic of Bashkortostan with in-frame deletions in the NF1 gene, no brain cysts or tumors, plexiform neurofibromas, and optic nerve gliomas were detected. Although the mutations we identified have not previously been described in the scientific literature, our analysis of clinical features is consistent with the findings of other authors regarding the presence of phenotypic correlations with in-frame deletions.

The intrinsic muscles of the hand (IMH) include the thenar muscles, hypothenar muscles, lumbrical muscles, dorsal interosseous muscles (DIOM), and ventral interosseous muscles (VIOM). The thenar muscles consist of the abductor pollicis brevis (APB), opponens pollicis (OPP), flexor pollicis brevis (FPB), and adductor pollicis (ADP). The hypothenar muscles comprise the abductor digiti minimi (ADM), flexor digiti minimi (FDM), and opponens digiti minimi (ODM). Numerous anatomical variants of the IMH exist - including the accessory abductor digiti minimi (aADM), adductor hypothenar muscle, extensor digitorum brevis manus (EDBM), lumbrical muscle (LM) variants, and accessory flexor digitorum superficialis of the index finger. Although these variants are common, they can cause symptoms, especially in nerve compression syndromes such as carpal tunnel syndrome (CTS) from median nerve (MN) compression or Guyon's canal syndrome from ulnar nerve (UN) compression. Knowledge of these variants and their imaging characteristics facilitates understanding of related pathologies and contributes to improved therapeutic management. These muscle variants are diagnosed using high-resolution ultrasound (US) and magnetic resonance imaging (MRI).This review provides a comprehensive overview of the normal anatomy of the IMH, their anatomical variants, and their imaging features. High-resolution US is the primary modality for studying the IMH, while high-field 3T MRI offers excellent spatial resolution and contrast.Understanding the anatomy and anatomical variants of the IMH is essential for accurately assessing both normal and pathological conditions using US and MRI. · Variants of the intrinsic hand muscles can be reliably diagnosed by ultrasound and high-resolution MRI.. · Accessory abductor digiti minimi (aADM) may cause compression of the ulnar nerve within the Guyon's canal.. · Extensor digitorum brevis manus (EDBM) can mimic a dorsal pseudotumoral soft-tissue mass.. · Variants of the lumbrical muscles may compress the median nerve within the carpal tunnel.. · Accessory flexor digitorum superficialis indicis can simulate a tumor or cause carpal tunnel syndrome.. · Bouredoucen H, Boudabbous S, Poletti P et al. Imaging of the intrinsic muscles of the hand - part I: high-resolution ultrasound and 3T MRI appearance of symptomatic anatomical variants. Rofo 2025; DOI 10.1055/a-2761-4259.

Sirolimus to treat chronic uveitis in PTEN hamartoma tumor syndrome: experience of a target therapy customized on specific disease pathway.

ABSTRACTPTEN hamartoma tumour syndrome (PHTS), a rare disease caused by germline heterozygous PTEN variants, is associated with multi-organ/tissue overgrowth, autism spectrum disorder and increased cancer risk. Phenotypic variability in PHTS is partly due to diverse PTEN variants and the protein's multifaceted functions. PTEN is primarily a phosphatidylinositol(3,4,5)trisphosphate (PIP3) phosphatase regulating PI3K/AKT signalling but also maintains chromosomal stability through nuclear functions such as double-stranded (ds)DNA damage repair. Here, we show that PTEN-R173C, a pathogenic variant frequently found in PHTS and somatic cancer, has elevated PIP3 phosphatase activity that effectively regulates canonical PI3K/AKT signalling. However, PTEN-R173C is unstable and excluded from the nucleus. We generated Pten+/R173C mice which developed few tumours during their lifetime, aligning with normal PI3K/AKT signalling. However, they exhibited lymphoid hyperplasia, macrocephaly and brain abnormalities, associated with impaired nuclear functions of PTEN-R173C, demonstrated by reduced dsDNA damage repair. We integrated PHTS patient data with our mouse model results, and propose that defective nuclear functions of PTEN variants can predict the onset of PHTS phenotypes and that late-onset cancer in these individuals may arise from secondary genetic alterations, facilitated by compromised dsDNA repair.

The combination of disease manifestations, the familial burden, and varying penetrance of endocrine tumor syndromes (ETSs) is unique. This review aimed to portray and summarize available data on psychosocial outcomes in patients with ETSs and explore gaps and opportunities for future research and care. Literature was systematically searched for articles on psychosocial outcomes in patients with multiple endocrine neoplasia (MEN), von Hippel-Lindau (VHL), and pathogenic variants (PVs) in succinate dehydrogenase (SDHx) genes via PubMed, PsychInfo, and Embase. Study quality was assessed using the CASP and STROBE appraisal tools. In total, 36 studies were found with fluctuating levels of evidence, of which five included pediatric patients. Overall, studies showed a considerable impact of ETSs on psychosocial outcomes such as quality of life (QoL), anxiety, and depression. Maladaptive coping, as well as social and financial restraints, were associated with poorer psychosocial outcomes. Surveillance protocols had ambivalent effects, both creating a sense of control and serving as a constant reminder of having an ETS. Parathyroid disease was associated with adverse psychosocial effects in MEN1. In MEN2A, gastrointestinal symptoms and having affected offspring were associated with poorer psychosocial outcomes. In MEN2B, pain was reported to interfere with daily life. Studies regarding VHL reported a wide range of experiences in patients and family members. Only a few studies were found for patients with PVs in SDHx genes, mainly describing effects due to the manifestation of disease or paraganglioma. Psychosocial outcomes and possible underlying factors seem different for each ETS. More research is needed to address psychosocial outcomes in children with an ETS.

Familial non-medullary, follicular cell-derived thyroid neoplasms represent a genetically diverse and under-recognized group of tumors arising from follicular epithelial cells. These familial thyroid tumors are subclassified into syndromes where thyroid tumors represent the major disease manifestation and syndromes with a predominance of non-thyroid neoplasms. Among the latter group, germline mutations in the DICER1 and PTEN genes are increasingly implicated in syndromic forms of follicular-derived thyroid disease. DICER1 syndrome and PTEN-hamartoma tumor syndrome, encompassing Cowden syndrome and related entities, confer a high organ-specific predisposition to benign and malignant thyroid lesions. Both syndromes demonstrate distinctive clinicopathologic patterns, including early-onset thyroid follicular nodular disease, multifocal follicular adenomas, and increased risk for thyroid malignancies. Recognizing clinical, anatomical, and histomorphological clues when evaluating thyroid specimens (particularly bilateral nodules, multinodularity, histologically distinct neoplasms, multiple adenomatous nodules, macrofollicular pattern, oncocytic features, unusual adenoma subtypes, young male gender, or early presentation) can prompt genetic evaluation. Here, we review the molecular pathogenesis, clinical features, histologic spectrum, and diagnostic strategies associated with familial follicular cell-derived thyroid tumors caused by DICER1 and PTEN germline alterations. Increased awareness of these entities by pathologists and clinicians is critical to ensure timely diagnosis, risk-appropriate surveillance, and cascade testing in affected families.

GsMTx-4 reduces mechanical allodynia in a model of schwannomatosis-related pain.

Targeted RNA sequencing of thyroid tumors from individuals with PTEN hamartoma tumor syndrome reveals a unique transcriptome with a predominantly RAS-like expression profile.

ABSTRACT Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome caused by pathogenic variants in the NF1 gene. Beside tumor formation, patients often have sleep disturbances, suggesting circadian involvement. Previous NF1 studies have implicated MAPK pathway, cAMP-PKA, calcium signaling, and ALK in circadian regulation, and shown disrupted rhythms in murine astrocytes lacking NF1. However, whether human Schwann cells show rhythmic gene expression remains unknown, although impaired rhythms may contribute to tumorigenesis. In this study, we analyzed normal human Schwann cells and NF1-derived malignant peripheral nerve sheath tumors (MPNST) for rhythmic gene expression. Cultured cells were synchronized via serum shock, and mRNA levels of core clock and associated genes (e.g. ARNTL, JUN, TGFA, CLOCK, VEGFA, MYC) were quantified at defined intervals. We observed rhythmic core clock gene expression in normal Schwann cells, demonstrating intrinsic circadian oscillations in peripheral glia. In contrast, MPNST lacked rhythmicity in core clock genes, instead showing de novo rhythmic expression of oncogenes and growth factors like MYC and VEGFA. Thus, loss of clock gene rhythmicity (desynchronization) and emergence of rhythmic oncogene expression (synchronization) in NF1-associated MPNST further our understanding of peripheral glial physiology and tumorigenesis. These insights suggest that chronotherapeutic strategies may be beneficial for NF1-associated MPNST.

Objective. To evaluate the clinical efficacy of follow-up of healthy carriers of pathogenic germline variants associated with hereditary tumor syndromes and to determine the impact of personalized screening programs on early diagnosis of breast cancer. Material and methods. A prospective study included 986 participants who underwent genetic testing in the Loginov Moscow Clinical Scientific Center in 2018—2024. Among the participants, 551 people are healthy carriers of mutations (group A), 435 — patients with previously diagnosed malignant neoplasms (group B). Persons with germline mutations in BRCA1, BRCA2, CHEK2, PALB2, ATM, STK11 and TP53 genes were included. Monitoring was performed every 6 months, it included specialist consultations, mammography or magnetic resonance imaging, ultrasound examination of the mammary glands and pelvic organs. The primary outcome was the stage of detected breast cancer in mutation carriers compared to patients in whom disease has been diagnosed outside the screening program. Results. In healthy carriers of the mutations (group A, 551 people in total), 57 (10.3%) cases of cancer (predominantly breast cancer — 56 cases) have been detected during follow-up. Tumors were diagnosed at the stage I—II in 94.7% of the subjects, at the stage III — in 3.5%, cases of stage IV were not registered. Similar stages were revealed in 69.4% of the group B patients, the proportion of advanced stages (III—IV) amounted to 22%. BRCA1 c.5366dupC (p.Gln1777ProfsTer74) variant was the most frequent mutation. The proportion of triple-negative subtypes reached about 40% in both groups. Conclusion. Personalized follow-up and screening programs for the carriers of pathogenic germline variants ensure predominant early breast cancer detection and form an effective prevention model for high genetic risk groups.

(1) Background: Globe-sparing radiotherapy is widely utilised in the treatment of uveal melanoma, but often results in complications requiring vitreoretinal intervention. The outcomes of secondary vitrectomy remain unclear. A multidisciplinary approach involving vitreoretinal and ocular oncology specialists is essential to managing complications. (2) Methods: We reviewed 1794 patients treated with radiotherapy for uveal melanoma between 2012 and 2022. In total, 70 patients underwent secondary vitrectomy after primary radiotherapy treatment. The outcomes included overall tumour control and visual outcome. (3) Results: Complications requiring vitrectomy were more common after proton-beam radiotherapy than plaque brachytherapy (5.4% versus 3.0%). Common indications included vitreous haemorrhage (39%) and retinal detachment/toxic tumour syndrome (31%). The affected tumours were larger, more often ciliary body in origin, and associated with a worse prognosis. Vitrectomy patients had higher rates of enucleation (9% versus 3%), metastasis (16% versus 6%), and visual decline (average 0.60 LogMAR), with limited visual improvement (≥3-line gain in 13%). Proton-beam patients had worse outcomes than plaque brachytherapy patients. (4) Conclusions: Vitreoretinal complications after uveal melanoma radiotherapy are rare, but timely treatment by those with experience may enable patients to keep their eye in situations where enucleation would be the only alternative. Patients and clinicians must understand the risks of complications to make informed decisions about treatment plans, with vitreoretinal surgeons and ocular oncologists key to outcomes.

Parathyroid carcinoma (PC) is a rare malignancy of the parathyroid glands, accounting for only a minute fraction of all cancers worldwide. Although uncommon, it poses significant diagnostic and therapeutic challenges because its clinical features often resemble those of benign primary hyperparathyroidism (PHPT). This review summarizes current understanding of PC, integrating recent advances in epidemiology, genetics, diagnostics approaches and management. The global incidence is estimated at 3–6 new cases per 10 million people annually, affecting men and women equally and typically presenting around the fifth decade of life. Genetic alterations play a central role in pathogenesis. Mutations in CDC73 with consequent loss of parafibromin function are the most characteristic finding, especially in the hereditary hyperparathyroidism–jaw tumor (HPT-JT) syndrome. Other hereditary conditions such as multiple endocrine neoplasia types 1 and 2 (MEN1 and MEN2) or isolated familial hyperparathyroidism may also involve the parathyroid glands, though carcinoma remains rare in these syndromes. Additional molecular abnormalities, such as alterations in RB1, TP53, BRCA2, and CCND1, and activation of PI3K/AKT-/mTOR and MAPK pathways - have been linked to tumor progression. The cornerstone of treatment is early, complete en bloc resection, offering the best chance of cure. For recurrent or metastatic disease, therapy focuses on controlling hypercalcemia using cinacalcet, denosumab, and, in selected cases, adjuvant radiotherapy. Early recognition, genetic testing, and multidisciplinary care are crucial for improving long-term outcomes in this rare but challenging endocrine malignancy.

Neuroendocrine neoplasms have heterogeneous morphological features and varying clinical manifestations, which in turn influences their therapeutic approach. Histologically, based on cell morphology, they can be divided into neuroendocrine tumors and neuroendocrine carcinomas. Clinically, they are subdivided into functioning (in the presence of a specific tumor syndrome) and nonfunctioning (in cases where only general, nonspecific symptoms are observed). One of the most common clinical manifestations of functioning neuroendocrine tumors is carcinoid syndrome, caused by the tumor’s secretion of multiple hormonal amines and peptides, primarily serotonin. In most cases, these tumors are relatively indolent. However, as the disease slowly progresses, patients may experience delayed complications such as carcinoid heart disease, mesenteric fibrosis, malnutrition, and vitamin deficiencies. Carcinoid syndrome can also rapidly worsen to a life-threatening complication known as a carcinoid crisis. Given the multifaceted and insidious nature of carcinoid syndrome, effective treatment relies on the indispensable role of a multidisciplinary team consisting of gastroenterologists, endocrinologists, radiologists, oncologists, nuclear medicine physicians, surgeons, cardiologists, and nutritionists.

PTEN hamartoma tumor syndrome (PHTS) is a cancer predisposition disorder caused by germlinePTENvariants, yet its full clinical spectrum remains poorly defined due to reliance on highly selected cohorts. Accordingly, PHTS is underrecognized and its prevalence underestimated. Leveraging genomic and electronic health record data from 414,830 participants in the All of Us (AoU) Research Program, we identified 55 individuals with pathogenic or likely pathogenicPTENvariants, the majority of whom lacked a prior PHTS diagnosis, underscoring underrecognition in the general population. PHTS affects ∼1/7500 individuals in this US cohort, which is about 26-folds higher than historical estimates forPTEN-related disorder. Compared with carriers of other cancer-related gene variants and noncarriers,PTENvariant carriers exhibited the highest cancer prevalence and significantly younger ages at first cancer diagnosis. Phenotype enrichment revealed expected overgrowth-related features as well as previously unreported associations, including adenotonsillar hypertrophy, sleep apnea, acanthosis nigricans, and extreme obesity, suggesting broader systemic involvement than classically appreciated. Variant spectra were consistent across the population-based and clinically-ascertained PHTS cohorts. These findings demonstrate that PHTS is more prevalent, more heterogeneous, and more often undiagnosed than current clinical practice reflects, emphasizing the value of population-scale genomics for comprehensive characterization and earlier detection of PHTS.

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic disorder caused by germline pathogenic variants in the PTEN tumor suppressor gene. Everolimus, an oral mTORC1 inhibitor, is approved for the treatment of tuberous sclerosis complex-related tumors; however, evidence for its efficacy in PHTS remains limited. A recent randomized controlled trial (RCT) reported safety and efficacy findings, but the composite primary efficacy endpoint did not reach statistical significance. We conducted a sensitivity analysis of this RCT to further evaluate the efficacy of everolimus in PHTS. Five statistical approaches were applied: analysis of covariance and four linear mixed-effects models. Outcomes included the composite neurocognitive score as a primary endpoint and multiple secondary neurocognitive and behavioral measures. Across all analysis approaches, everolimus did not significantly improve the composite neurocognitive score compared with placebo. However, several secondary outcomes showed consistent benefits. Fine motor function assessed by the Purdue Pegboard Test (left hand) demonstrated sustained improvement over placebo across models. Social functioning, assessed by the total score (higher values indicating better functioning) of the reverse-coded Social Responsiveness Scale, second edition, improved over time, with significant differences observed at 6months in the everolimus group. Several additional secondary endpoints showed consistent trends favoring everolimus. Although the composite primary endpoint did not demonstrate significant improvement, sensitivity analyses identified potential benefits of everolimus in motor and social domains in individuals with PHTS. These results are consistent with the original trial findings and provide further support for investigating everolimus as a therapeutic option in this population.

Purpose: Zollinger-Ellison syndrome (ZES) is the most frequent, functional, malignant pancreatic neuroendocrine tumor syndrome (pNET), which is due to ectopic secretion of gastrin by a pNET/NET (i.e., gastrinomas) resulting in severe, refractory acid-peptic disease (ulcer, GERD). ZES has several unique management features, which lead to a number of unresolved controversies. Areas covered: Whereas both medical and surgical controversies exist, they have not been examined in detail for some time. This review contains an analysis of a number of the main current, medical controversies that are unresolved in ZES patients, including insights into the basis of these controversies and possible insights into their resolution from recent studies in patients with gastrinomas or from recent studies in other pNET syndromes or other neuroendocrine tumors (NETs). These include the following: controversies in the long-term control of acid secretion and acid antisecretory drug side-effects; controversies related to the difficulty in making the diagnosis of ZES; nonsurgical MEN1/ZES controversies related to the management of gastric carcinoids (Type II); nonsurgical MEN1/ZES controversies related to whether genotype-phenotype correlations exist in MEN1 patients including MEN1/ZES patients; nonsurgical MEN1/ZES controversies related to the roles of imaging/tumor localization in MEN1 patients for gastrinomas/pNETs in their initial/follow-up management; controversies related to the role of non-surgical tumor ablation for treatment of ZES/gastrinomas; and controversies related to medical treatment selection for advanced, metastatic disease in patients with ZES/gastrinomas/other malignant pNETs. Conclusions: In this paper, the basis for the development of each of these unique ZES-related controversies is discussed and insights into progress that could lead to their resolution are reviewed.

Genetic tumor risk syndromes (genturis) contribute substantially to the overall cancer burden and provide opportunities for early detection, prevention, and individualized treatment. Yet, many affected individuals remain undiagnosed due to restrictive testing criteria and challenges in variant interpretation. This review summarizes recent advances in the diagnostic evaluation of genturis. We trace the evolution from single-gene testing to multigene panel testing, highlighting gains in diagnostic yield alongside the growing prevalence of uncertain and incidental findings. We then describe emerging functional approaches such as RNA sequencing and proteomics that generate molecular evidence to refine variant classification. Next, we outline how long-read sequencing overcomes technical limitations in complex genomic regions. Finally, we discuss practical aspects of clinical implementation, including reporting practices, workflow integration, and professional education, and propose strategies to improve diagnostic accuracy, efficiency, and equitable access to testing.