PTEN Hamartoma Tumor Syndrome Research Articles

EP062: Clinically significant goiters as the initial presentation of PTEN hamartoma tumor syndrome

PTEN hamartoma tumor syndrome (PHTS) is a multi-systemic tumor predisposition syndrome driven by PTEN germline pathogenic variant. Syndromes previously categorized based on clinical features, such as Cowden syndrome and Bannayan-Riley-Ruvalcaba syndrome, share overlapping features and are now categorized as part of the PHTS spectrum. Its estimated prevalence is 1:200,000, however we believe it is underrecognized due to its rarity and low recognition rates. Patients may present with progressive hamartomas occurring in multiple tissues or organs: polyposis in GI tract, complex vascular malformation such as cavernous hemangiomas, cerebellar dysplastic gangliocytomas, as well as excessive quantity of various types of cutaneous lesions such as skin tags, trichilemmomas, and papillomatous papules.

Considerations on diagnosis and surveillance measures of PTEN hamartoma tumor syndrome: clinical and genetic study in a series of Spanish patients

BackgroundThe limited knowledge about the PTEN hamartoma tumor syndrome (PHTS) makes its diagnosis a challenging task. We aimed to define the clinical and genetic characteristics of this syndrome in the Spanish population and to identify new genes potentially associated with the disease.ResultsWe reviewed the clinical data collected through a specific questionnaire in a series of 145 Spanish patients with a phenotypic features compatible with PHTS and performed molecular characterization through several approaches including next generation sequencing and whole exome sequencing (WES). Macrocephaly, mucocutaneous lesions, gastrointestinal polyposis and obesity are prevalent phenotypic features in PHTS and help predict the presence of a PTEN germline variant in our population. We also find that PHTS patients are at risk to develop cancer in childhood or adolescence. Furthermore, we observe a high frequency of variants in exon 1 of PTEN, which are associated with renal cancer and overexpression of KLLN and PTEN. Moreover, WES revealed variants in genes like NEDD4 that merit further research.ConclusionsThis study expands previously reported findings in other PHTS population studies and makes new contributions regarding clinical and molecular aspects of PHTS, which are useful for translation to the clinic and for new research lines.

Unusual Cause for Abdominal Pain and Chronic Constipation in a Young Female Patient

Question: A 29-year-old woman of Middle Eastern descent presented to our outpatient clinic with a history of progressive abdominal pain spanning >6 months, located mostly in the lower left quadrant. Furthermore, the patient reported chronic constipation, paradoxical diarrhea, and malnutrition with a weight loss of >12 kg in 1 year. The clinical examination revealed a generally cachectic young woman with a disproportionally distended abdomen with ubiquitous tenderness with the punctum maximum in the lower left quadrant. The patient reported chronic use of analgesics, mostly opioids, and cannabis. A colonoscopy showed left-sided ulcerative colitis with histologic proof crypt abscesses and submucosal lipomatosis. Magnetic resonance imaging demonstrated pronounced left-sided large bowel distension and massively increased visceral soft tissue surrounding the whole colon, most prominently the sigmoid (Figure A). In infancy, the patient had undergone a metatarsal amputation of both feet owing to severe deformities. In her adolescence, she had a tumorous connective tissue growth removed, having caused immobilization of the left hip joint. In addition, large soft tissue tumors were apparent in the clinical and radiological examination in pleural, intercostal, and paravertebral locations, accompanied by severe scoliosis. The patient had normal cognitive development and no intellectual disability was apparent. Psychiatric evaluation revealed an anxiety disorder. According to patient history, 1 seizure had taken place at an early age. There were no other known family members who exhibited similar symptoms. What is the diagnosis? See the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The patient suffers either from Proteus or CLOVES syndrome. Proteus syndrome is an extremely rare condition of progressive asymmetric overgrowth of body parts, epidermal or connective tissue nevi, lipomas, and cranial deformities owing to sporadic somatic mosaicism. Proteus syndrome is associated with mosaic mutation in the AKT1 gene encoding the serine-threonine kinase V-Akt murine thymoma viral oncogene homolog 1.1Cohen M.M. Proteus syndrome review: molecular, clinical, and pathologic features.Clin Genet. 2014; 85: 111-119Crossref PubMed Scopus (89) Google Scholar CLOVES syndrome acronymically stands for congenital lipomatous overgrowth, vascular malformations, epidermal nevi and scoliosis, spinal or skeletal abnormalities. CLOVES syndrome seems to be caused by a mosaic activating mutation in PIK3CA, the gene encoding for the phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha. Similar to Proteus syndrome, CLOVES syndrome causes overgrowth and malformations. However, its manifestations are more proportional, less deforming, and usually present already prenatally.2Martinez-Lopez A. Blasco-Morente G. Perez-Lopez I. Herrera-Garcia J.D. et al.CLOVES syndrome: review of a PIK3CA-related overgrowth spectrum (PROS).Clin Genet. 2017; 91: 14-21Crossref PubMed Scopus (69) Google Scholar Importantly, gastrointestinal manifestation is rather atypical for both conditions. Owing to limited information regarding birth and early childhood, a clinical differentiation between CLOVES and Proteus syndromes could not be established in this patient. A previous genetic consultation and sequence analysis of the coding exons of the PTEN gene from whole blood had been normal, making a diagnosis of the group of PTEN hamartoma tumor syndromes (including Proteus-like syndrome) with germline pathogenic PTEN variants, unlikely.3Pilarski R. PTEN hamartoma tumor syndrome: a clinical overview.Cancers. 2019; 11: E844Crossref PubMed Scopus (73) Google Scholar Sequencing of the genes PIK3CA and AKT1 was not desired by the patient. The mass surrounding the colon caused painful obstruction of the gastrointestinal passage. After careful consideration, we recommended an open resection of the colon and the intra-abdominal mass. We performed a laparotomy. Exploration revealed dilation of the entire colon with a diameter of ≤15 cm and hypertrophy of the colonic wall; the rectum was not affected. During dissection of the colon, multiple venous collaterals in the retroperitoneum were apparent, consistent with a diagnosis of Proteus or CLOVES syndrome (vascular malformations are seen in both syndromes). Owing to the dilation and enormous soft tissue mass surrounding the colon, we performed a subtotal colectomy with complete mesocolic excision, formation of a rectal stump, and end-ileostomy. The resected colon measured >120 cm in length and had a weight of >10 kg (Figure B). Histopathological examination showed diffuse tumorous submucosal and subserosal lipomatosis and singular inflammatory fibroid polyps (Figure C). The findings were basically consistent with Proteus syndrome. After a prolonged hospitalization and parenteral feeding, the patient was discharged from the hospital with a normal passage through the ileostomy and a significant improvement in abdominal and gastrointestinal symptoms.

Characterizing dermatologic findings among patients with PTEN hamartoma tumor syndrome: Results of a multicenter cohort study

BackgroundDermatologic phenotypes in PTEN hamartoma tumor syndrome (PHTS) are heterogeneous and poorly documented. ObjectiveTo characterize dermatologic findings among PHTS and conduct an analysis of genotype-dermatologic phenotype associations. MethodsMucocutaneous findings were reviewed in a multicenter cohort study of PHTS. Genotype-dermatologic phenotype associations were tested using multivariable regression. ResultsA total of 201 patients were included. Children were significantly less likely than adults to have oral papillomas, vascular malformations, benign follicular neoplasms, and acral keratoses. There were no cases of skin cancer among children. Basal cell carcinoma, cutaneous squamous cell carcinoma, and melanoma developed in 5%, 2%, and 1% of White adults, respectively. After adjusting for age, missense mutations were associated with 60% lower odds of developing cutaneous papillomatous papules (odds ratio: 0.4; 95% confidence interval [0.2, 0.7]), oral papillomas (0.4; 95% confidence interval [0.2, 0.9]), and vascular malformations (0.4; 95% confidence interval [0.2, 0.8]). LimitationsPartly retrospective data. ConclusionChildren are less likely than adults to have certain dermatologic findings, likely due to age-related penetrance. The risk of pediatric melanoma and the lifetime risk of nonmelanoma skin cancer in PHTS may not be elevated. Missense variants may be associated with the development of fewer dermatologic findings but future validation is required.

Genotypic and Phenotypic Characteristics of Hereditary Colorectal Cancer.

The genomic causes and clinical manifestations of hereditary colorectal cancer (HCRC) might be stratified into 2 groups, namely, familial (FCRC) and a limited sense of HCRC, respectively. Otherwise, FCRC is canonically classified into 2 major categories; Lynch syndrome (LS) or associated spectra and inherited polyposis syndrome. By contrast, despite an increasing body of genotypic and phenotypic traits, some FCRC cannot be clearly differentiated as definitively single type, and the situation has become more complex as additional causative genes have been discovered. This review provides an overview of HCRC, including 6 LS or associated spectra and 8 inherited polyposis syndromes, according to molecular pathogenesis. Variants and newly-identified FCRC are particularly emphasized, including MUTYH (or MYH)-associated polyposis, Muir-Torre syndrome, constitutional mismatch repair deficiency, EPCAM-associated LS, polymerase proofreading-associated polyposis, RNF43- or NTHL1-associated serrated polyposis syndrome, PTEN hamartoma tumor syndrome, and hereditary mixed polyposis syndrome. We also comment on the clinical utility of multigene panel tests, focusing on comprehensive cancer panels that include HCRC. Finally, HCRC surveillance strategies are recommended, based on revised or notable concepts underpinned by competent validation and clinical implications, and favoring major guidelines. As hereditary syndromes are mainly attributable to genomic constitutions of distinctive ancestral groups, an integrative national HCRC registry and guideline is an urgent priority.

Lateralized and Segmental Overgrowth in Children.

Simple SummaryCongenital lateralized or segmental overgrowth (LO) disorders are conditions characterized by excessive tissue growth of a body region often associated with a predisposition to cancer. LOs are caused by mosaic DNA anomalies, that is, they are present only in a part of the cells making up the body. LOs have an extremely heterogeneous clinical presentation: they widely overlap in presentation, are difficult to frame from a clinical point of view and have a diagnostic complexity representing a challenge for the clinician who approaches them. Here we review the key features of the various LOs, expose their molecular causes, and detail the implications for each of them, such as the need for specific cancer screening or the possibility of treatment. The latter represents a recent scientific achievement in medicine, allowed by the development of precision drugs finely tuning cellular pathways involved in growth and tumorigenesis deranged in LO.Congenital disorders of lateralized or segmental overgrowth (LO) are heterogeneous conditions with increased tissue growth in a body region. LO can affect every region, be localized or extensive, involve one or several embryonic tissues, showing variable severity, from mild forms with minor body asymmetry to severe ones with progressive tissue growth and related relevant complications. Recently, next-generation sequencing approaches have increased the knowledge on the molecular defects in LO, allowing classifying them based on the deranged cellular signaling pathway. LO is caused by either genetic or epigenetic somatic anomalies affecting cell proliferation. Most LOs are classifiable in the Beckwith–Wiedemann spectrum (BWSp), PI3KCA/AKT-related overgrowth spectrum (PROS/AROS), mosaic RASopathies, PTEN Hamartoma Tumor Syndrome, mosaic activating variants in angiogenesis pathways, and isolated LO (ILO). These disorders overlap over common phenotypes, making their appraisal and distinction challenging. The latter is crucial, as specific management strategies are key: some LO is associated with increased cancer risk making imperative tumor screening since childhood. Interestingly, some LO shares molecular mechanisms with cancer: recent advances in tumor biological pathway druggability and growth downregulation offer new avenues for the treatment of the most severe and complicated LO.

M163 ASYMPTOMATIC T LYMPHOPENIA IN A YOUNG ADULT WITH PTEN GENE MUTATION

PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal dominant syndrome caused by loss-of-function mutation in the phosphatase and tensin homolog (PTEN) gene. It is characterized by hamartomas, macrocephaly, malignant tumors, and developmental delay. Variable presence of immunodeficiency is an increasingly recognized feature of PTEN mutation.

Interplay Between Class II HLA Genotypes and the Microbiome and Immune Phenotypes in Individuals With PTEN Hamartoma Tumor Syndrome.

Illumina sequencing of bacterial and fungal microbes was carried out on patient-donated fecal samples in a cohort of 67 patients with pathogenic germline PTEN mutations, including 41 individuals with autoimmunity and/or phenotypes consistent with immune dysregulation (cases) and 26 individuals without (controls). From these data, we measured differences in alpha and beta diversity between cases and controls and identified differentially abundant bacterial and fungal taxa using phyloseq and MicrobiomeSeq packages in R. We analyzed correlations between these taxa and specific HLA genotypes, along with correlations between HLA diversity and microbial diversity, by conducting high-resolution HLA genotyping at four class II loci (DRB1, DRB345, DQA1, and DQB1). We found that alpha diversity distributions for both bacterial and fungal genera were statistically different between cases and controls. We identified differentially abundant bacterial and fungal taxa between cases and controls. Network analysis of differentially abundant bacterial taxa revealed some co-varying bacterial genera. We additionally found significant correlations between certain HLA genotypes and certain taxa and significant correlations between HLA diversity and alpha diversity. PTEN-associated immune phenotypes might be influenced by the gut microbiome, and class II HLA molecules, in part, crosstalk with the gut microbiome. These preliminary observations should lay the groundwork for future studies to ultimately derive clinical measures, which could use gut microbiome and HLA molecule biomarkers to predict, and perhaps prevent, immunity and inflammation in patients predisposed to cancer because of germline PTEN mutations.

Red flags for early recognition of adult patients with PTEN Hamartoma Tumour Syndrome

Patients with PTEN Hamartoma Tumour Syndrome (PHTS) are at increased risk of developing cancer. Many adult PHTS patients are not recognized as such and do not receive the cancer surveillance they need. Our aim was to define phenotypic characteristics that can easily be assessed and manifest by early adulthood, and hence could serve as red flags (i.e. alerting signals) for early recognition of adult patients at high risk of PHTS. Phenotypic characteristics including macrocephaly, multinodular goitre (MNG), and oral features were examined in 81 paediatric and 86 adult PHTS patients by one of two medical experts during yearly surveillance visits at our Dutch PHTS expert centre between 1997 and 2020. MNG was defined as signs of thyroid nodules and/or goitre. Oral features included gingival hypertrophy, high palate (adults only) and oral papillomas. Based on the characteristics’ prevalence in different age groups, combinations of phenotypic characteristics were defined and evaluated on their potential to recognize individuals with PHTS. Macrocephaly was present in 100% of paediatric and 67% of adult patients. The prevalence of MNG was ∼50% in paediatric and gradually increased to >90% in adult patients. Similar percentages were observed for any of the oral features. Scoring two out of three of these characteristics yielded a sensitivity of 100% (95%CI 94–100%) in adults. The presence of the combination macrocephaly, MNG, or multiple oral features could serve as a red flag for general practitioners, medical specialists, and dentists to consider further assessment of the diagnosis PHTS in adults. In this way, recognition of adult PHTS patients might be improved and cancer surveillance can be offered timely.

Proteus Syndrome: Case Report with Anatomopathological Correlation

Background Proteus syndrome is characterized by a progressive segmental or patchy growth of bone, skin, adipose tissue, and central nervous system, associated with a wide range of neoplasms, pulmonary pathology, and thrombotic risk. The main histological findings are diffuse patchy overgrowth of skin and subcutaneous tissue, plantar cerebriform connective tissue nevus, and ossification defects. Case report: We present a patient that met the clinical and histological criteria necessary for the diagnosis of the disease. He required multiple surgical interventions, including amputation of the right foot. Genetic evaluation confirmed an AKT1 mutation. Discussion: CLOVES syndrome, neurofibromatosis 1 or PTEN hamartoma tumor syndrome are partially superimposable entities to Proteus syndrome and may generate diagnostic doubt. Although the clinical criteria and histologic findings are indicative, the diagnostic confirmation of this entity is genetic.

See Spots? Look Deeper!

See Spots? Look Deeper!

PTEN Hamartoma Tumor Syndrome: Skin Manifestations and Insights Into Their Molecular Pathogenesis.

Germline PTEN pathogenic variants cause a spectrum of disorders collectively labeled PTEN Hamartoma Tumor Syndrome (PHTS) and featured by hamartomas, developmental anomalies and increased cancer risk. Studies on experimental models provided evidence that PTEN is a “haploinsufficient” tumor-suppressor gene, however, mechanisms involved in the pathogenesis of clinical manifestations in PHTS patients remain elusive. Beyond analyzing clinical and molecular features of a series of 20 Italian PHTS patients, we performed molecular investigations to explore the mechanisms involved in the pathogenesis of PTEN-associated manifestations, with special focus on mucocutaneous manifestations. Typical mucocutaneous features were present in all patients assessed, confirming that these are the most important clue to the diagnosis. The most frequent were papules located in the trunk or extremities (73.7%), oral mucosa papules (68.4%), acral/palmoplantar keratosis and facial papules (both 57.9%), according with literature data. Molecular analyses on one trichilemmoma suggested that the wild-type PTEN allele was retained and expressed, reinforcing the evidence that PTEN does not require a second somatic hit to initiate pathogenic processes. Unexpectedly, one patient also displayed a cutaneous phenotype consistent with atypical mole/melanoma syndrome; no variants were detected in known melanoma genes, but Whole Exome Sequencing showed the rare truncating variant c.495G>A in the CDH13 gene that might have cooperated with PTEN-haploinsufficiency to generate such phenotype. Our findings confirm the reproducibility of known PHTS manifestations in real-world practice, highlighting the role of mucocutaneous manifestations in facilitating prompt diagnosis of the syndrome, and provide some insights into the pathogenic process induced by PTEN alterations, which may contribute to its understanding.

Prevalence and clinical/molecular characteristics of PTEN mutations in Turkish children with autism spectrum disorders and macrocephaly

BackgroundPhosphatase and tensin homolog (PTEN) germline mutations are associated with cancer syndromes (PTEN hamartoma tumor syndrome; PHTS) and in pediatric patients with autism spectrum disorder (ASD) and macrocephaly. The exact prevalence of PTEN mutations in patients with ASD and macrocephaly is uncertain; with prevalence rates ranging from 1% to 17%. Most studies are retrospective and contain more adult than pediatric patients, there is a need for more prospective pediatric studies.MethodsWe recruited 131 patients (108 males, 23 females) with ASD and macrocephaly between the ages of 3 and 18 from five child and adolescent psychiatry clinics in Turkey from July 2018 to December 2019. We defined macrocephaly as occipito‐frontal HC size at or greater than 2 standard deviations (SD) above the mean for age and sex on standard growth charts. PTEN gene sequence analysis was performed using a MiSeq next generation sequencing (NGS) platform, (Illumina).ConclusionPTEN gene sequence analyses identified three pathogenic/likely pathogenic mutations [NM_000314.6; p.(Pro204Leu), (p.Arg233*) and novel (p.Tyr176Cys*8)] and two variants of uncertain significance (VUS) [NM_000314.6; p.(Ala79Thr) and c.*10del]. We also report that patient with (p.Tyr176Cys*8) mutation has Grade 1 hepatosteatosis, a phenotype not previously described. This is the first PTEN prevalence study of patients with ASD and macrocephaly in Turkey and South Eastern Europe region with a largest homogenous cohort. The prevalence of PTEN mutations was found 3.8% (VUS included) or 2.29% (VUS omitted). We recommend testing for PTEN mutations in all patients with ASD and macrocephaly.

PTEN regulates adipose progenitor cell growth, differentiation, and replicative aging

The tumor suppressor phosphatase and tensin homolog (PTEN) negatively regulates the insulin signaling pathway. Germline PTEN pathogenic variants cause PTEN hamartoma tumor syndrome (PHTS), associated with lipoma development in children. Adipose progenitor cells (APCs) lose their capacity to differentiate into adipocytes during continuous culture, whereas APCs from lipomas of patients with PHTS retain their adipogenic potential over a prolonged period. It remains unclear which mechanisms trigger this aberrant adipose tissue growth. To investigate the role of PTEN in adipose tissue development, we performed functional assays and RNA-Seq of control and PTEN knockdown APCs. Reduction of PTEN levels using siRNA or CRISPR led to enhanced proliferation and differentiation of APCs. Forkhead box protein O1 (FOXO1) transcriptional activity is known to be regulated by insulin signaling, and FOXO1 was downregulated at the mRNA level while its inactivation through phosphorylation increased. FOXO1 phosphorylation initiates the expression of the lipogenesis-activating transcription factor sterol regulatory element-binding protein 1 (SREBP1). SREBP1 levels were higher after PTEN knockdown and may account for the observed enhanced adipogenesis. To validate this, we overexpressed constitutively active FOXO1 in PTEN CRISPR cells and found reduced adipogenesis, accompanied by SREBP1 downregulation. We observed that PTEN CRISPR cells showed less senescence compared with controls and the senescence marker CDKN1A (p21) was downregulated in PTEN knockdown cells. Cellular senescence was the most significantly enriched pathway found in RNA-Seq of PTEN knockdown versus control cells. These results provide evidence that PTEN is involved in the regulation of APC proliferation, differentiation, and senescence, thereby contributing to aberrant adipose tissue growth in patients with PHTS.

Hamartomatous polyposis syndrome associated malignancies: Risk, pathogenesis and endoscopic surveillance.

Hamartomatous polyposis syndromes (HPS) are a heterogeneous spectrum of diseases that are characterized by diffuse hamartomatous polyps lining the gastrointestinal (GI) tract together with extra-GI manifestations. Classical HPS includes juvenile polyposis syndrome, Peutz-Jeghers syndrome, PTEN hamartoma tumor syndrome and hereditary mixed polyposis syndrome. Patients with HPS have a higher risk of GI and extra-GI malignancies than the general population, although the underlying mechanisms remain unclear and are obviously different from the carcinogenesis of classical adenocarcinoma and colitis-associated malignancy. In this review we aimed to clarify the risks, possible mechanism and endoscopic surveillance of HPS-associated GI malignancies.

\u201cThyroid nodular disease and PTEN mutation in a multicentre series of children with PTEN hamartoma tumor syndrome (PHTS)\u201d

PurposeTo report the incidence of 4–12% of differentiated thyroid cancer (DTC) and up to 50% of benign thyroid nodular disease and to describe nodular thyroid disease in a multicentre pediatric population with PTEN mutations. Methods: Retrospective data of pediatric patients with PTEN mutations collected from tertiary Departments of Pediatric Endocrinology of Turin, Milan and Genua, Italy, in the period 2010–2020.ResultsSeventeen children with PTEN mutations were recruited in the study. Thyroid involvement was present in 12/17 (70.6%) subjects, showing a multinodular struma in 6/17 (35.3%), nodules with benign ultrasound features in 5/17 (29.4%) and a follicular adenoma in 1/17 (6%). No correlation was found between thyroid disease and gender, puberty, vascular manifestations, delayed development, or brain MRI abnormalities, while multiple lipomas were associated with thyroid disease (p = 0.03), as was macrocephaly. Standard Deviation (SD) score head circumference was 4.35 ± 1.35 cm in subjects with thyroid disease, 3 ± 0.43 cm (p = 0.02) in the group without thyroid disease. Thyroid involvement was present in all subjects with mutations in exon 6 (4/4) and exon 8 (3/3) of the PTEN gene (p = 0.02).ConclusionIn the presented cohort, benign thyroid disorders were prevalent, with no evidence of DTC. A correlation was found between thyroid lesions and head circumference and the occurrence of multiple lipomas. Future studies in larger cohorts should assess whether risk stratification is needed when recommending surveillance strategies in children or young adolescents with PTEN hamartoma syndrome.

A Challenging Diagnosis: PTEN Hamartoma Tumor Syndrome Presenting as Isolated Soft-tissue Vascular Anomalies

Objective: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) has been known to present with a constellation of congenital anomalies including macrocephaly, vascular malformations, and hamartomas. Identifying a pathogenic germline PTEN mutation early is vital as all patients share a markedly increased risk for malignancy. Diagnosing children, however, is challenging as age-related penetrance makes it difficult to meet established diagnostic criteria. Methods: We present 4 patients with isolated soft-tissue masses of the extremity who lacked the classic constellation of systemic features of PHTS but were found to carry germline PTEN mutations on sequencing performed on involved tissue and subsequently confirmed in peripheral blood specimens. Results: Although none of the patients met published diagnostic criteria to indicate genetic PTEN screening, the growing differential diagnosis of soft-tissue vascular anomalies of the extremity increasingly requires sequencing of involved tissue to accurately characterize a lesion. Diagnosing these patients with a cancer predisposition syndrome radically changed their surveillance regimens which have resulted in the identification of concerning lesions of the thyroid and cervix. Conclusion: PTHS can present as an isolated PTEN hamartomas of soft tissue lesion with minimal systemic findings.

Clinicopathologic Characteristics of Thyroid Nodules Positive for PTEN Mutations on Preoperative Molecular Testing

Somatic and germline mutations of PTEN tumor suppressor gene are associated with follicular-pattern thyroid tumors and PTEN Hamartoma Tumor Syndrome (PHTS). The incidence of cancer in thyroid nodules positive for PTEN mutations on fine-needle aspiration (FNA) is not well defined. The aim of this study was to characterize diagnostic and phenotypic features of thyroid nodules with preoperatively detected PTEN mutations and their impact on management. Thyroid nodules with PTEN mutations on ThyroSeq v3 GC testing of FNA and core needle biopsy specimens from November 2017 to July 2020 were identified from the ThyroSeq Molecular Database. Demographic and clinicopathologic data were obtained through retrospective chart review. We identified 49 PTEN mutation-positive nodules from 48 patients. Patients were 57 years old on average (range 14-88) and 80% female. Cytology was predominantly indeterminate (73% atypia of undermined significance, 18% follicular neoplasm). There were 18 (29%) frameshift, 6 (10%) splice site, and 39 (62%) single nucleotide variant PTEN mutations. Fourteen (29%) nodules had two PTEN mutations, 5 (10%) had copy number alterations, and single cases had concurrent BRAF K601N, EZH1, and NRAS mutations. Surveillance was pursued for 27 (56%) and surgery for 21 (44%) patients (16 lobectomies, 5 total thyroidectomies). There were 14 follicular adenomas (FA), 4 oncocytic FA’s, 1 oncocytic hyperplastic nodule, and 1 encapsulated follicular variant papillary thyroid carcinoma (EFVPTC). The EFVPTC had two low-frequency PTEN mutations, PTEN locus loss, an NRAS mutation, and was a low-risk tumor with capsular but no angiolymphatic invasion. Four (8.3%) patients had confirmed or suspected PHTS, all with multiple nodules. Two had surgery finding no malignancies (2 FA). One PHTS patient had a prior thyroidectomy for a MET mutation-positive nodule that was follicular carcinoma. On US, the mean nodule size of patients who had surgery was larger than the surveillance group (3.2 cm vs. 2.3 cm, p=0.02) but there was no difference in TI-RADS level (p=0.54). There was no difference in mean nodule size (3.5 cm vs. 2.6 cm, p=0.35) or TI-RADS level (p=0.81) between PHTS and non-PHTS patients. Among surveillance patients, follow-up US was done at 1 year in 13/19 (68%) and 2 years in 3/6 (50%) of eligible cases. Only 1/19 (5%) underwent repeat FNA for increased nodule size. No thyroid malignancy was found with a mean of 1.75 years of follow-up (range 1.00-2.78). The EFVPTC patient had no recurrence after 1.05 years of follow-up. In summary, thyroid nodules with isolated somatic PTEN mutations are primarily benign and can be safely followed with serial imaging. Nodules with multiple PTEN mutations were only associated with malignancy when accompanied by an additional NRAS mutation. About 8% of patients with PTEN mutations may be PHTS patients who may be at greater risk for malignancy.

The Clinical Spectrum of PTEN Hamartoma Tumor Syndrome: Exploring the Value of Thyroid Surveillance

Introduction: Phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (PHTS) comprises a collection of clinical features characterized by constitutional variants in PTEN. Several guidelines recommend thyroid screening, beginning at the pediatric age at the time of PHTS diagnosis; however, the benefits of early surveillance has not been well defined. Methods: We conducted a retrospective investigation of patients followed up at the Children’s Hospital of Philadelphia with a diagnosis of PHTS between January 2003 and June 2019. In total, 81 patients younger than 19 years were identified. Results: The most common clinical feature at presentation was macrocephaly (85.1%), followed by impaired development (42.0%), skin/oral lesions (30.9%), and autism spectrum disorder (27.2%). A total of 58 of 81 patients underwent thyroid surveillance, with 30 patients (51.7%) found to have a nodule(s). Ultimately, 16 patients underwent thyroidectomy, with 7.4% (6/81) diagnosed with thyroid cancer. All thyroid cancer patients were older than 10 years at diagnosis, and all displayed low-invasive behavior. Of the patients younger than 10 years at the time of thyroid ultrasound (US) surveillance, 71.4% (15/21) had a normal US. The remaining 6 patients had thyroid nodules, including 4 undergoing thyroid surgery with benign histology. Discussion/Conclusion: Patients with macrocephaly, impaired cognitive development and thyroid nodules, and/or early-onset gastrointestinal polyps should undergo constitutional testing for PHTS. There does not appear to be a clinical advantage to initiating thyroid US surveillance before 10 years of age. In PHTS patients with a normal physical examination, thyroid US surveillance can be delayed until 10 years of age.

P048 - Breast cancer surveillance in women with PTEN Hamartoma Tumour Syndrome (PHTS)

P048 - Breast cancer surveillance in women with PTEN Hamartoma Tumour Syndrome (PHTS)