Cell-free DNA fragmentomics and second malignant neoplasm risk in patients with PTEN hamartoma tumor syndrome.

Individuals with PTEN hamartoma tumor syndrome (PHTS) harbor pathogenic germline PTEN variants that confer a significantly increased lifetime risk of various organ-specific cancers including second primary malignant neoplasms (SMNs). Currently, there are no reliable biomarkers that can predict individual-level cancer risk. Despite the highly promising value of cell-free DNA (cfDNA) as a biomarker for underlying sporadic cancers, the utility of cfDNA in individuals with known cancer-associated germline variants and subclinical cancers remains poorly understood. We perform ultra-low-pass whole-genome sequencing (ULP-WGS) of cfDNA from plasma samples from patients with PHTS and cancer as well as those without cancer. Analysis of cfDNA reveals that patients with PHTS and SMNs have distinct cfDNA size distribution, aberrant genome-wide fragmentation, and differential fragment end motif frequencies. Our work provides evidence that cfDNA profiles may be used as a marker for SMN risk in patients with PHTS.

Utilizing PTEN immunohistochemistry as a screening test for Cowden syndrome.

OBJECTIVES: Cowden syndrome (CS) is a multisystem disease with an elevated lifetime risk of internal malignancy. We aim to assess the role of PTEN immunostain as a screening test for CS in a variety of common CS-associated neoplasms, with a particular focus on cutaneous tumors. METHODS: We retrospectively searched for patients meeting criteria for CS and/or demonstrating germline PTEN mutation from 2008 to 2022. We then performed PTEN immunostains on tumors of these patients as well as control cases. RESULTS: Our study included 30 patients with CS who had a total of 25 CS-associated malignancies (13 thyroid, 8 breast, and 4 endometrial carcinomas). Specifically, there were 11 patients with biopsy-confirmed CS-associated cutaneous neoplasms, including 1 patient with multiple trichilemmomas and 3 with multiple sclerotic fibromas. In total, 45 CS-associated tumors (6 trichilemmomas, 7 sclerotic fibromas, 5 thyroid carcinomas, 18 adenomatous thyroid nodules, 6 breast carcinomas, and 3 endometrial carcinomas) and 31 non-CS cases (9 trichilemmomas, 5 sclerotic fibromas, 8 adenomatous thyroid nodules, and 3 thyroid, 3 breast, and 3 endometrial carcinomas) were available for PTEN immunohistochemical staining. PTEN expression was lost in 43 (96%) of 45 CS-associated lesions and retained in 30 (97%) of 31 sporadic tumors. The overall sensitivity and specificity of PTEN loss of expression as a screening test for CS were 96% and 97%, respectively. CONCLUSIONS: PTEN immunohistochemistry on CS-associated tumors, especially trichilemmomas, can serve as a readily accessible and cost-effective screening test for CS.

Lhermitte-Duclos disease with excessive calcification in a septuagenarian: A case report.

RATIONALE: Lhermitte-Duclos disease (LDD), or dysplastic cerebellar gangliocytoma (DCG), is a rare tumor originating from the cerebellar cortex. LDD is a benign neuroglial tumor with uncertain prognosis. Over 200 cases have been reported in the literature mostly in the form of case reports. Thus, we present a spectacular case of LDD with excessive calcification in a female septuagenarian. PATIENT CONCERNS: A 72-year-old female presented with progressive dizziness for 8 months and suffered a head and sacrococcygeal region injury 20 days prior to her admission in our neurosurgery department. DIAGNOSIS: Computed tomography scan showed a right nonspecific cerebellar mass with striated calcification. Magnetic resonance imaging revealed a right "tiger-striped" alteration of the cerebellar cortex. H&E staining revealed a low grade glial neural tumor which was consistent with the diagnosis of LDD or DCG. INTERVENTION: The lesion was total resected. OUTCOMES: The patient recovered well and the cerebellar dysfunctional symptoms subsided 3 months after the operation and 2 years follow-up revealed no recurrence of the lesion and no neurological deficits. LESION: We postulate that the calcification of LDD is age-related and the pathogenesis of disease often observed in young adulthood.

Arteriovenous malformations as a presenting sign of PTEN hamartoma tumor syndrome: A case series.

High-flow vascular malformations have been associated with multiple syndromes including capillary malformation-arteriovenous malformation (CM-AVM) syndrome, hereditary hemorrhagic telangiectasia syndrome, and less commonly, phosphatase and tensin homolog hamartoma tumor syndrome (PHTS). We present a series of three patients with clinically challenging complex AVMs who were found to have underlying PHTS. In all patients, diagnosis was delayed, and the presence of the AVM prompted sampling and genetic testing for PHTS in the absence of other clinical features of the condition. This series highlights the importance of screening for PHTS in the setting of high-flow vascular malformations.

A rare case of oral squamous cell carcinoma in a patient with Cowden syndrome: Association or coincidence?

Cowden Syndrome (CS) is a rare genetic disease caused by mutations in the PTEN tumor suppressor gene, often presenting a challenging diagnosis due to its diverse clinical manifestations. Although extensively linked to several types of cancer, the precise association between CS and oral malignancies, particularly squamous cell carcinoma (SCC), remains poorly understood. This report describes a unique case of late diagnosis of CS in a 53-year-old female patient who later developed SCC in the inferior alveolar ridge, even without exposure to classic risk factors. The need to increase awareness in the medical and dental communities about CS and its manifestations in the oral cavity is highlighted. Early recognition and management of conditions associated with CS have a significant impact on patients' quality of life. Encouraging the publication of similar cases is recommended to encourage detailed analyzes and investigations in order to better understand the possible association between the syndrome and the development of malignancies in the oral cavity.

Giant cell collagenoma in a patient with Cowden syndrome: A rare case report and literature review with a focus on the spectrum of sclerotic fibroma and giant cell collagenoma.

Sclerotic fibroma (SF) is a rare subset of dermal fibromas that occurs sporadically or in association with Cowden syndrome (CS). We report a case of a patient with known CS and a solitary lesion on the scalp. Histologic examination demonstrated a well-circumscribed lesion with sclerotic dermis and a whorled collagen pattern, multinucleated giant cells, and dendritic spindle cells. Nuclear atypia or mitotic figures were not noted. The giant cells were negative for Melan-A, SOX-10, EMA, SOX-10, and factor XIIIa. These findings are consistent with a giant cell collagenoma (GCC). Despite possible overlap with SF, GCC has not been associated with CS. This makes our case unique and suggests that GCC should be included in the spectrum of CS-associated cutaneous lesions. The diagnosis of SF may lead to the identification of previously undiagnosed CS; accordingly, GCC, even when present as a solitary lesion, may indicate the need for further work-up and screening for CS.

A New Frameshift Mutation of PTEN Gene Associated with Cowden Syndrome-Case Report and Brief Review of the Literature.

Cowden syndrome (CS) is a rare disease that was first described in 1963 and later included in the large group of genodermatoses. It is the most common syndrome among the PTEN-associated hamartomatous tumor syndromes (PHTS). CS has an autosomal dominant inheritance pattern, with increased penetrance and variable expressivity, making early diagnosis difficult. Mutations in the PTEN gene (phosphatase and TENsin homolog) are involved in its pathogenesis, involving many organs and systems originating in the three embryonic layers (ectodermum, endodermum, and mesodermum). The consequence is the development of hamartomatous lesions in various organs (brain, intestines, thyroid, oropharyngeal cavity, colon, rectum, etc.). Multiple intestinal polyps are common in patients with CS, being identified in over 95% of patients undergoing colonoscopy. The authors describe the case of a patient who presented the first signs of the disease at 3 ½ years (tonsil polyp) but was diagnosed only at the age of 20 following a colonoscopy that revealed hundreds of intestinal polyps, suggesting further molecular testing. A heterozygous frameshift mutation was identified in the PTEN gene, classified as a potentially pathogenic variant (c.762del.p(Val255*)). The authors present this case to highlight the path taken by the patient from the first symptoms to the diagnosis and to emphasize the clinical aspects of this mutational variant that have still not been identified in other patients with this syndrome.

Diagnosis of PTEN mosaicism: the relevance of additional tumor DNA sequencing. A case report and review of the literature.

BACKGROUND: PTEN hamartoma syndrome (PHTS) is an autosomal dominant disorder characterized by pathogenic variants in the tumor suppressor gene phosphatase and tensin homolog (PTEN). It is associated with an increased risk of muco-cutaneous features, hamartomatous tumors, and cancers. Mosaicism has been found in a few cases of patients with de novo PHTS, identified from blood samples. We report a PHTS patient with no variant identified from blood sample. Constitutional PTEN mosaicism was detected through sequencing of DNA from different tumoral and non-tumoral samples. CASE PRESENTATION: Our patient presented clinical Cowden syndrome at 56 years of age, with three major criteria (macrocephaly, Lhermitte Duclos disease, oral papillomatosis), and two minor criteria (structural thyroid lesions, esophageal glycogenic acanthosis). Deep sequencing of PTEN of blood leukocytes did not reveal any pathogenic variants. Exploration of tumoral (colonic ganglioneuroma, esophageal papilloma, diapneusia fibroids) and non-tumoral stomach tissues found the same PTEN pathogenic variant (NM_000314.4 c.389G > A; p.(Arg130Gln)), with an allelic frequency of 12 to 59%, confirming genomic mosaicism for Cowden syndrome. CONCLUSIONS: This case report, and review of the literature, suggests that systematic tumor analysis is essential for patients presenting PTEN hamartoma syndrome in the absence of any causal variant identified in blood leukocytes, despite deep sequencing. In 65 to 70% of cases of clinical Cowden syndrome, no pathogenic variant in the PTEN is observed in blood samples: mosaicism may explain a significant number of these patients. Tumor analysis would improve our knowledge of the frequency of de novo variations in this syndrome. Finally, patients with mosaicism for PTEN may not have a mild phenotype; medical care identical to that of heterozygous carriers should be offered.

Detection and yield of thyroid cancer surveillance in adults with PTEN hamartoma tumour syndrome.

Thyroid cancer surveillance (TCS) with ultrasound (US) is advised for PTEN hamartoma tumour syndrome (PHTS) patients due to increased thyroid cancer (TC) risk. However, data supporting TCS guidelines are scarce. We aimed to assess the detection and yield of annual TCS with US in adult PHTS patients without a TC history and to evaluate the impact of a reduced US interval on the TCS yield. A retrospective cohort study was conducted, including adult PHTS patients and medical record data between 2005 and 2021. The yield from annual TCS was compared with hypothetical biennial and triennial TCS after two initial US with annual interval by counting delayed detection of nodular growth, thyroid adenoma, and TC. During 279 follow-up years, 84 patients (median age 40 years) underwent 349 US. Thyroidectomy was performed in 6/84 (7%) patients, revealing a minimally invasive follicular TC in one patient aged 22 and a thyroid adenoma in two patients aged 21 and 53. Multiple thyroid nodules were diagnosed in 73/84 (87%) patients (median age 36 years). Nodular growth was detected in 9/56 (16%) patients, and its detection would have been delayed in 4-7% US rounds with biennial TCS, and in 2-6% US rounds with triennial TCS. US-based thyroiditis and indeterminate non-malignant lymph nodes were found in 8/74 (11%) and 7/72 (10%) patients, respectively. Following our findings combined with the literature, we propose starting TCS before age 18 and reducing the follow-up frequency after the initial two US from annual to biennial if no suspicious findings are detected.

Novel dermatological and skeletal features associated with PTEN variant in PTEN hamartoma tumor syndrome.

PTEN hamartoma tumor syndromes (PHTS) comprise hamartomatous overgrowth syndromes associated with PTEN germline mutations. In this case report, we describe a variant identified by next generation sequencing causing peculiar dermatological and skeletal features not yet described in the literature. Being cognizant of such unique disease presentations in PHTS, that manifest at a very young age, could help facilitate a timely diagnosis by clinicians and thus the early education of families on active cancer surveillance. This specific case also strengthens the concept of variable presentation of PHTS and the need for genetic testing early on, even if not all criteria for PHTS are met for a formal clinical diagnosis.

Identification of a novel pathogenic deep intronic variant in PTEN resulting in pseudoexon inclusion in a patient with juvenile polyps.

Colorectal, hamartomatous juvenile polyps occur as part of different hereditary syndromes, including Juvenile polyposis syndrome and PTEN-hamartoma tumour syndrome. However, based on clinical manifestations alone, it is difficult to differentiate between the syndromes, and genetic analysis with an NGS-panel is often used to aid diagnostics. We report a 59-year-old male with colorectal juvenile polyps, who had been referred to genetic testing but had normal genetic analysis. He did not fulfil the clinical criteria of PTEN- hamartoma tumour syndrome, but the clinical criteria of Juvenile polyposis syndrome. With Whole Genome Sequencing we detected a novel intronic variant of unknown significance in PTEN (NC_000010.11:g.89687361 A > G(chr10, hg19), NM_000314.8:c.209 + 2047 A > G). RNA analysis classified the variant as likely pathogenic as it results in a pseudoexon inclusion introducing a frameshift and a premature stop codon. The patient was then diagnosed with PTEN-hamartoma Tumour syndrome. To our knowledge this is the first report of a variant resulting in pseudoexon inclusion in PTEN.

Yield of annual endometrial cancer surveillance in women with PTEN Hamartoma Tumor Syndrome.

OBJECTIVE: Expert-opinion based guidelines state that endometrial cancer surveillance (ECS) might be considered for patients with PTEN Hamartoma Tumor Syndrome (PHTS) based on an elevated lifetime risk of endometrial cancer. We aimed to evaluate the yield of ECS by annual transvaginal ultrasound (TVUS) and endometrial biopsy (EMB) in PHTS patients. METHODS: PHTS patients who visited our PHTS expert center between August 2012 and September 2020 and opted for annual ECS were included. Data on surveillance visits, diagnostics, reports of abnormal uterine bleeding and pathology results were retrospectively gathered and analyzed. RESULTS: Surveillance was initiated in 25 women with a total of 93 gynecological surveillance visits during 76 surveillance years. The median age at first visit was 39 years (range 31-60) with a median follow-up duration of 38 months (range 6-96). Hyperplasia with and without atypia was detected six and three times, respectively, in seven (28%) women. The median age at hyperplasia detection was 40 years (range 31-50). In six asymptomatic women hyperplasia was detected during annual surveillance visits, while in one patient hyperplasia with atypia was detected during an additional visit due to abnormal uterine bleeding. In seven out of nine hyperplasias detected with EMB, TVUS beforehand showed no abnormalities. No (interval) carcinomas occurred. CONCLUSIONS: ECS in women with PHTS enables detection of a substantial number of asymptomatic premalignancies, such as hyperplasia with and without atypia, suggesting that ECS may be beneficial with regard to cancer prevention. The addition of EMB to TVUS likely improves the detection of premalignancies.

Development of informant-report neurobehavioral survey scales for PTEN hamartoma tumor syndrome and related neurodevelopmental genetic syndromes.

There are few well-validated measures that are appropriate for assessing the full range of neurobehavioral presentations in PTEN hamartoma tumor syndrome (PHTS) and other neurodevelopmental genetic syndromes (NDGS). As potential therapeutics are developed, having reliable, valid, free, and easily accessible measures to track a range of neurobehavioral domains will be crucial for future clinical trials. This study focused on the development and initial psychometric evaluation of a set of freely available informant-report survey scales for PHTS-the Neurobehavioral Evaluation Tool (NET). Concept elicitation, quantitative ratings, and cognitive interviewing processes were conducted with stakeholders and clinician-scientist experts, used to identify the most important neurobehavioral domains for this population, and to ensure items were appropriate for the full range of individuals with PHTS. Results of this process identified a PHTS neurobehavioral impact model with 11 domains. The final NET scales assessing these domains were administered to a sample of 384 participants (median completion time = 20.6 min), including 32 people with PHTS, 141 with other NDGS, 47 with idiopathic neurodevelopmental disorder (NDD), and 164 neurotypical controls. Initial psychometric results for the total scores of each scale indicated very good model (ω = 0.83-0.99) and internal consistency reliability (α = 0.82-0.98) as well as excellent test-retest reproducibility at 1-month follow-up (r = 0.78-0.98) and stability at 4-month follow-up (r = 0.76-0.96). Conditional reliability estimates indicated very strong measurement precision in key score ranges for assessing PHTS and other people with NDGS and/or idiopathic NDD. Comparisons across domains between PHTS and the other groups revealed specific patterns of symptoms and functioning, including lower levels of challenging behavior and more developed daily living and executive functioning skills relative to other NDGS. The NET appears to be a reliable and potentially useful tool for clinical characterization and monitoring of neurobehavioral symptoms in PHTS and may also have utility in the assessment of other NDGS and idiopathic NDD. Additional validation work, including convergent and discriminant validity analyses, are needed to replicate and extend these observations.

PTEN hamartoma tumour syndrome: case report based on data from the Iranian hereditary colorectal cancer registry and literature review.

BACKGROUND: PTEN hamartoma tumour syndrome (PHTS) is a rare hereditary disorder caused by germline pathogenic mutations in the PTEN gene. This study presents a case of PHTS referred for genetic evaluation due to multiple polyps in the rectosigmoid area, and provides a literature review of PHTS case reports published between March 2010 and March 2022. CASE PRESENTATION: A 39-year-old Iranian female with a family history of gastric cancer in a first-degree relative presented with minimal bright red blood per rectum and resistant dyspepsia. Colonoscopy revealed the presence of over 20 polyps in the rectosigmoid area, while the rest of the colon appeared normal. Further upper endoscopy showed multiple small polyps in the stomach and duodenum, leading to a referral for genetic evaluation of hereditary colorectal polyposis. Whole-exome sequencing led to a PHTS diagnosis, even though the patient displayed no clinical or skin symptoms of the condition. Further screenings identified early-stage breast cancer and benign thyroid nodules through mammography and thyroid ultrasound. METHOD AND RESULTS OF LITERATURE REVIEW: A search of PubMed using the search terms "Hamartoma syndrome, Multiple" [Mesh] AND "case report" OR "case series" yielded 43 case reports, predominantly in women with a median age of 39 years. The literature suggests that patients with PHTS often have a family history of breast, thyroid and endometrial neoplasms along with pathogenic variants in the PTEN/MMAC1 gene. Gastrointestinal polyps are one of the most common signs reported in the literature, and the presence of acral keratosis, trichilemmomas and mucocutaneous papillomas are pathognomonic characteristics of PHTS. CONCLUSION: When a patient presents with more than 20 rectosigmoid polyps, PHTS should be considered. In such cases, it is recommended to conduct further investigations to identify other potential manifestations and the phenotype of PHTS. Women with PHTS should undergo annual mammography and magnetic resonance testing for breast cancer screening from the age of 30, in addition to annual transvaginal ultrasounds and blind suction endometrial biopsies.

Hamartomatous polyps: Diagnosis, surveillance, and management.

Hereditary polyposis syndrome can be divided into three categories: Ade-nomatous, serrated, and hamartomatous polyps. Hamartomatous polyps, malformations of normal tissue presenting in a disorganized manner, are characterized by an autosomal dominant inheritance pattern. These syndromes exhibit hamartomatous gastrointestinal polyps in conjunction to extra-intestinal manifestations, which require conscientious and diligent monitoring. Peutz-Jeghers syndrome, Cowden syndrome, and juvenile polyposis syndrome are the most common displays of hamartomatous polyposis syndrome (HPS). Diagnosis can be pursued with molecular testing and endoscopic sampling. Early identification of these autosomal dominant pathologies allows to optimize malignancy sur-veillance, which helps reduce morbidity and mortality in both the affected patient population as well as at-risk family members. Endoscopic surveillance is an important pillar of prognosis and monitoring, with many patients eventually requiring surgical intervention. In this review, we discuss the diagnosis, surveillance, and management of HPS.

Clinical and genetic diagnosis of Cowden syndrome: A case report of a rare PTEN germline variant and diverse clinical presentation.

INTRODUCTION: Cowden syndrome is a rare autosomal dominant disease characterized by the development of hamartomas and increased risks of other tumors, including breast, thyroid, and uterine cancers. Most patients with Cowden syndrome show mutations of the phosphatase and tensin homolog (PTEN) gene on chromosome 10; however, some patients with mutations do not show clinical symptoms, while patients with clinical symptoms may not have detectable PTEN mutations. CASE PRESENTATION: A 39-year-old woman with macrocephaly had previously been diagnosed with Cowden syndrome at another hospital, when she presented with the onset of breast cancer. A wide variety of complications were detected, including cerebellar tumors treated by resection, hydrocephalus, and multiple polyps in the stomach and large intestine. She was further diagnosed with adult-onset Lhermitte-Duclos disease as a complication of Cowden syndrome. She subsequently developed a dural arteriovenous fistula treated by transvenous embolization. After transfer to our hospital, she developed adenomatous goiter treated by resection, recurrent breast cancer treated with hormonal therapy, and multifocal oral mucosal papillomatosis. Her older sister had previously been diagnosed with Cowden syndrome and her father was undiagnosed but had macrocephaly, hydrocephalus, and multifocal oral mucosal papillomatosis, suggestive of Cowden syndrome. After consultation with a genetic specialist, analysis of the PTEN gene showed a rare but likely pathogenic germline c.801 + 2T>A variant located at the splice donor site of intron 7. The patient's clinical diagnosis of Cowden syndrome was accordingly confirmed by the genetic findings. Appropriate surveillance procedures were put in place to detect any further tumors. CONCLUSIONS: The clinical symptoms of Cowden syndrome do not always correlate with the genetic results. However, recent improvements in genetic testing suggest the importance of diagnosing this disease using both clinical and genetic approaches, in collaboration with genetic experts, to ensure an accurate diagnosis and appropriate surveillance for malignant tumors.

Longitudinal neurobehavioral profiles in children and young adults with PTEN hamartoma tumor syndrome and reliable methods for assessing neurobehavioral change.

BACKGROUND: Individuals with PTEN hamartoma tumor syndrome (PHTS) demonstrate a distinct neurobehavioral profile suggesting primary disruption of frontal lobe symptoms, with more severe cognitive deficits in those with associated autism spectrum disorder (ASD) that extend to other areas of neurobehavioral function as well (e.g., adaptive behavior, sensory deficits). The current study sought to characterize longitudinal neurobehavioral profiles in individuals with PHTS who completed serial assessments (2-3 evaluations) over a 2-year time period. METHODS: Comprehensive neurobehavioral evaluations were conducted on 92 participants (age range 6-21) with PHTS and/or ASD. Spaghetti plots and linear mixed effects models were used to visualize the individual patient profiles and group trends and examine the group differences in cognitive/behavioral test scores over time. Practice-adjusted reliable change indices (RCIs) and standardized regression-based change scores (SRBs) were calculated for those measures in the battery with adequate sample sizes and test-retest reliabilities for future use in assessing neurobehavioral change in children and young adults with PHTS. RESULTS: Wide individual differences were observed at baseline across all measures. Encouragingly, baseline differences between patient groups persisted at the same magnitude over a 2-year time period with no differences in longitudinal neurobehavioral profiles within any one group. Test-retest reliabilities were generally high, ranging from 0.62 to 0.97, and group mean change from baseline to 12 months was small (range - 3.8 to 3.7). A Microsoft Excel calculator was created that clinicians and researchers can use to automatically calculate RCI and SRB thresholds at both 80% and 90% confidence intervals using test scores from a given child or young adult with PHTS. CONCLUSIONS: Our results suggest that the neurobehavioral phenotypes observed in individuals with PHTS remain relatively stable over time, even in those with ASD. The RCIs and SRBs provided can be used in future research to examine patient outcomes at the individual level as well as to detect negative deviations from the expected trajectory that can be used to inform intervention strategies.

Cancer Risk Associated With PTEN Pathogenic Variants Identified Using Multigene Hereditary Cancer Panel Testing.

PURPOSE: PTEN-associated clinical syndromes such as Cowden syndrome (CS) increase cancer risk and have historically been diagnosed based upon phenotypic criteria. Because not all patients clinically diagnosed with CS have PTEN pathogenic variants (PVs), and not all patients with PTEN PVs have been clinically diagnosed with CS, the cancer risk conferred by PTEN PVs calculated from cohorts of patients with clinical diagnoses of CS/CS-like phenotypes may be inaccurate. METHODS: We assessed a consecutive cohort of 727,091 individuals tested clinically for hereditary cancer risk, with a multigene panel between September 2013 and February 2022. Multivariable logistic regression models accounting for personal and family cancer history, age, sex, and ancestry were used to quantify disease risks associated with PTEN PVs. RESULTS: PTEN PVs were detected in 0.027% (193/727,091) of the study population, and were associated with a high risk of female breast cancer (odds ratio [OR], 7.88; 95% CI, 5.57 to 11.16; P = 2.3 × 10-31), endometrial cancer (OR, 13.51; 95% CI, 8.77 to 20.83; P = 4.2 × 10-32), thyroid cancer (OR, 4.88; 95% CI, 2.64 to 9.01; P = 4.0 × 10-7), and colon polyposis (OR, 31.60; CI, 15.60 to 64.02; P = 9.0 × 10-22). We observed modest evidence suggesting that PTEN PVs may be associated with ovarian cancer risk (OR, 3.77; 95% CI, 1.71 to 8.32; P = 9.9 × 10-4). Among patients with similar personal/family history and ancestry, every 5-year increase in age of diagnosis decreased the likelihood of detecting a PTEN PV by roughly 60%. CONCLUSION: We demonstrate that PTEN PVs are associated with significantly increased risk for a range of cancers. Together with the observation that PTEN PV carriers had earlier disease onset relative to otherwise comparable noncarriers, our results may guide screening protocols, inform risk-management strategies, and warrant enhanced surveillance approaches that improve clinical outcomes for PTEN PV carriers, regardless of their clinical presentation.

Clinical Spectrum and Science Behind the Hamartomatous Polyposis Syndromes.

The hamartomatous polyposis syndromes are a set of clinically distinct disorders characterized by the occurrence of hamartomatous polyps in the gastrointestinal tract. These syndromes include juvenile polyposis syndrome, Peutz-Jeghers syndrome, and PTEN hamartoma tumor syndrome. Although each of the syndromes has distinct phenotypes, the hamartomatous polyps can be challenging to differentiate histologically. Additionally, each of these syndromes is associated with increased lifetime risks of gene-specific and organ-specific cancers, including those outside of the gastrointestinal tract. Germline pathogenic variants can be identified in a subset of individuals with these syndromes, which facilitates molecular diagnosis and subsequent gene-enabled management in the setting of genetic counseling. Although the malignant potential of hamartomatous polyps remains elusive, timely recognition of these syndromes is important and enables presymptomatic cancer surveillance and management before symptom exacerbation. Presently, there are no standard agents to prevent the development of polyps and cancers in the hamartomatous polyposis syndromes.

Benign goiters requiring thyroidectomy as the signal for PTEN hamartoma tumor syndrome diagnosis.

PTEN hamartoma tumor syndrome (PHTS) is a rare genetic cancer and tumor predisposition syndrome. Due to the wide spectrum of clinical manifestations and variable age at onset, the pathways leading to a PHTS diagnosis are difficult and highly variable. Many patients were found to have PHTS after a cancer diagnosis, missing the opportunity of prevention or enhanced cancer screening. This retrospective study evaluated a PHTS cohort followed in a high-risk surveillance clinic in a comprehensive cancer institution. A significant portion of the patients (60.9%, 14/23) had at least one cancer diagnosis (average age 34.6 years at diagnosis). A significant portion (78.3%, 18/23) were affected with clinically significant goiters (age 27.9 years), and many (60.9%, 14/23) had partial or total thyroidectomy (age 27.1 years). The average age at goiter diagnosis or thyroidectomy is younger than a cancer diagnosis. In 12 individuals who were affected with clinically significant goiter and cancer, all cancers were diagnosed after the thyroid disease (6.3 years). As clinically significant thyroid nodules in childhood or early young adulthood are common in PHTS, but uncommon for general population, these early onset thyroid nodules may alert the clinician to initiate PHTS-targeted evaluation and genetic testing.