OBJECTIVE: PTEN hamartoma tumor syndrome (PHTS) is a well-recognized hereditary tumor syndrome and is now also recognized as a common cause of monogenic autism spectrum disorder. There is a vast spectrum of phenotypic variability across individuals with PHTS, and in addition to neurodevelopmental challenges, patients with PHTS may experience a wide variety of neurologic challenges, many of which have only recently been described. Thus, this systematic review aimed to summarize the breadth of the current knowledge of neurologic conditions in individuals with PHTS.
METHODS: We conducted a systematic review using the MEDLINE and EMBASE databases until January 2023. We included studies that reported neurologic signs, symptoms, and diagnoses in patients with a diagnosis of PHTS. Two independent reviewers extracted data (neurologic diagnoses and patient details) from each study. Case reports, case series, prospective studies, and therapeutic trials were included. We assessed the quality of evidence using the appropriate tool from the JBI, depending on study design.
RESULTS: One thousand nine hundred ninety-six articles were screened, and 90 articles met the inclusion criteria. The majority of the included studies were case reports (49/90, 54%) or small case series (31/90, 34%). Epilepsy secondary to cerebral malformations, neurologic deficits from spinal or cranial arteriovenous malformations, and rare tumors such as dysplastic cerebellar gangliocytoma are among the more severe neurologic features reported across patients with PHTS. One interventional randomized control trial examining neurocognitive endpoints was identified and did not meet its efficacy endpoint.
CONCLUSIONS: Our systematic review defines a broad scope of neurologic comorbidities occurring in individuals with PHTS. Neurologic findings can be categorized by age at onset in individuals with PTHS. Our study highlights the need for additional clinical trial endpoints, informed by the neurologic challenges faced by individuals with PHTS.

BACKGROUND: Acute acquired comitant esotropia caused by prolonged near work, such as the use of digital devices, has been frequently reported in recent years. However, intracranial examination is necessary even for patients with nonparalytic comitant esotropia. Lhermitte-Duclos disease is a rare tumor that grows in layers in the cerebellum. Among those with this disease, cases of esotropia have been reported due to abduction limitation of the eye, but there have been no reports of comitant esotropia. Here, we report the case of a young woman with acute acquired comitant esotropia who was found to have Lhermitte-Duclos disease.
METHODS: A 16-year-old Japanese female patient, whose ethnicity was Asian, was referred to our hospital for acute acquired comitant esotropia. Fundus examination revealed papilledema in both eyes, and magnetic resonance imaging of the head revealed a cerebellar tumor in the right cerebellum with obstructive hydrocephalus. She underwent partial tumor resection, and a histopathological diagnosis of Lhermitte-Duclos disease was obtained. However, comitant esotropia status remained unchanged, and she underwent strabismus surgery. Finally, diplopia disappeared completely.
CONCLUSIONS: Neurological and intracranial imaging examinations are essential when acute acquired comitant esotropia is observed. Acute acquired comitant esotropia by Lhermitte-Duclos disease did not improve with partial tumor resection and required strabismus surgery, but good surgical results were obtained.

There are indications for immune dysregulation in PTEN Hamartoma Tumour Syndrome (PHTS), however information on the clinical immune phenotype is lacking. We aimed to assess the frequency of infections and autoimmune disease in PHTS patients. A retrospective cohort study including 81 paediatric and 109 adult PHTS patients and 73 female adult controls and self-reported data from yearly surveillance visits. Differences between adult patients and controls were assessed with odds ratios (OR). Of paediatric patients, 1% reported fungal infections, 23% tonsillectomy/adenoidectomy, 36% bacterial infections requiring antibiotics, and 2% autoimmune disease. Of adult patients, up to 67% repeatedly reported fungal infections, and 73% was ever affected which was similar to controls. Compared to controls, adult patients more often reported (signs of) viral infections: tonsillectomy/adenoidectomy (78%; OR = 7.4 (95%CI: 3.7-15.8)), frequent infections during childhood (43%; OR = 2.5 (95%CI: 1.3-5.2)), and flu or cold infections more often than others (49%; OR = 3.9 (95%CI: 2.0-8.0)). Autoimmune disease was also more frequent (24%, OR = 2.7 (95%CI: 1.1-7.3)) in adult patients, and antibiotics use (38%, OR = 4.7 (95%CI: 1.3-23.0)) in female adult patients. PHTS patients experience a broad clinical phenotype of immune dysregulation. At adult age, this consists of more often viral and bacterial infections and autoimmune disease, and repetitive fungal infections.

BACKGROUND: Cowden syndrome is an autosomal-dominant disorder caused by a germline phosphatase and tensin homolog mutation, giving rise to several tumors with an aggressive clinical course. In the thyroid, there are certain histologic criteria that could be related to this syndrome that could be useful for its early detection. We sought to analyze the loss of phosphatase and tensin homolog in thyroid histologic pieces with certain histologic criteria and to determine the percentage of patients diagnosed with Cowden syndrome with this methodology.
METHODS: Five hundred thirty-five thyroid specimens collected were retrospectively analyzed (2017-2020). Those samples that presented certain histologic criteria were studied for loss of phosphatase and tensin homolog expression. Patients with loss of expression underwent a clinical study to rule out dermatologic or other lesions compatible with Cowden syndrome. Patients with positive clinical study were referred for genetic study.
RESULTS: The phosphatase and tensin homolog study was performed in 6.7% (n = 36) of the thyroidectomy samples, showing loss of expression in 22% (n = 8); the most frequent histologic finding was the presence of multiple monomorphous adenomatous nodules. The samples with loss of expression showed more diffuse oncocytic changes. Of the 8 patients with loss of expression, 5 showed dermatologic lesions that could be associated with Cowden syndrome and 1 had a history of macrocephaly. These patients were referred for genetic study, being positive for Cowden syndromein in one quarter of the cases (n = 2).
CONCLUSIONS: The immunohistochemical study of phosphatase and tensin homolog in pieces of thyroidectomies with histologic criteria suggestive of Cowden syndrome can help in its early diagnosis.

OBJECTIVE: To explore the clinical features and genetic etiology of a Chinese pedigree affected with Cowden syndrome (CS).
METHODS: A CS pedigree diagnosed in November 2022 at the Ningde Municipal Hospital Affiliated to Ningde Normal University was selected as the study subject. Clinical data were collected, and genetic testing was carried out for available members. Pathogenicity analysis was carried out for the candidate variant.
RESULTS: The proband, a 7-year-old male, was found to have autism and intellectual disability. Whole exome sequencing revealed that he has harbored a c.462_463del (p.F154Lfs25) variant of the PTEN gene. The proband\'s 35-year-old mother, who was diagnosed with pulmonary hamartomas at our hospital, has manifested with lipomas, nodular goiter, and adenomas. Sanger sequencing confirmed that she was also heterozygous for the c.462_463del (p.F154Lfs25) variant of the PTEN gene. No other family members has carried the same variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the variant was classified as pathogenic (PVS1+PM2_Supporting+PM6).
CONCLUSIONS: The newly discovered c.462_463del (p.F154Lfs*25) variant of the PTEN gene probably underlay the CS in this pedigree. CS patients have higher risk for developing malignant tumors. Clinicians should be aware of this condition and emphasize follow-up of the patients.

A 66-year-old male patient with a thyroid and nasopharyngeal cancer history visited our hospital because of a positive fecal occult blood test. Total colonoscopy detected sessile or subpedunculated polyps in the ascending colon, sigmoid colon, and rectum. These polyps were endoscopically resected, and the rectal polyp was pathologically diagnosed as adenocarcinoma in adenoma and the others as adenomas. Additionally, multiple sessile lesions were revealed in the sigmoid colon and rectum. A complete gastrointestinal tract examination revealed multiple foci of glycogenic acanthosis in the esophagus, multiple sessile lesions in the stomach, multiple sessile lesions, clubbings (rod-shaped lesions), and venous malformations in the small bowel. Mucocutaneous examination indicated hemangiomas on the body trunk, patchy pigmentation on the glans penis, and keratotic papules in the inguinal region. The National Comprehensive Cancer Network diagnostic criteria for Cowden syndrome were used in this case. The patient met four major and two minor criteria;thus, Cowden syndrome was diagnosed. Moreover, the patient was had phosphatase and tensin homolog deleted on chromosome 10 gene mutation. This is the first reported case of metachronal triple cancers in a male patient with Cowden syndrome, and our results indicate the importance of cancer surveillance.

Basal cell carcinoma (BCC) is a common skin cancer type and affected individuals are known to be at risk of developing multiple consecutive tumours. Research into BCC multiplicity has, thus far, been challenging, due to a lack of national registration. This registry-based cohort study aimed to analyse the occurrence of multiple BCCs in Sweden, and risk factors for subsequent primary BCCs. Data regarding all histopathologically verified, primary BCC tumours in Sweden from 2004 to 2017 was extracted from the Swedish BCC Registry. Risk of developing a subsequent BCC in relation to person-related factors was estimated with Cox regression analysis. Cumulative risk of BCC development after 1 or 3 earlier BCCs was estimated. In total, 39.9% of individuals with a registered BCC had at least 2 registered tumours. The risk of developing a subsequent BCC increased significantly in males, older age, and with residence in southern Sweden. The cumulative 5-year risk of developing an additional BCC after first diagnosis was approximately 30% in males and 27% in females and increased after multiple previous BCCs. This study showed the cumulative risk of a subsequent BCC to increase with a history of multiple BCCs, indicating the need for clinical surveillance in these individuals.

PTEN Hamartoma Tumour Syndrome (PHTS) encompasses diverse clinical phenotypes, including Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like syndrome. This autosomal dominant genetic predisposition with high penetrance arises from heterozygous germline variants in the PTEN tumour suppressor gene, leading to dysregulation of the PI3K/AKT/mTOR signalling pathway, which promotes the overgrowth of multiple and heterogenous tissue types. Clinical presentations of CS range from benign and malignant disorders, affecting nearly every system within the human body. CS is the most diagnosed syndrome among the PHTS group, notwithstanding its weak incidence (1:200,000), for which it is considered rare, and its precise incidence remains unknown among other important factors. The literature is notably inconsistent in reporting the frequencies and occurrences of these disorders, adding an element of bias and uncertainty when looking back at the available research. In this review, we aimed to highlight the significant disparities found in various studies concerning CS and to review the clinical manifestations encountered in CS patients. Furthermore, we intended to emphasize the great significance of early diagnosis as patients will benefit from a longer lifespan while being unceasingly advised and supported by a multidisciplinary team.

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PTEN hamartoma tumor syndrome (PHTS) might be associated with a distinct cognitive and psychological profile. However, previous studies are limited, predominantly based on small and pediatric cohorts, likely affected by selection bias, and show a broad range of findings. We aimed to characterize the neuropsychological functioning of adults with PHTS. A total of 40 participants, with intellectual disability as exclusion criterium, completed an extensive clinical neuropsychological assessment including cognitive tasks, questionnaires, and a clinical diagnostic interview. The cognitive tasks and questionnaire data were categorized as below and above average based on 1.5 SD. About 80% of participants showed an average level of intelligence. In addition, 30% and 24% of participants scored below average on immediate memory recall and speed of information processing, respectively. Furthermore, about 25% reported above average scores on the majority of the questionnaires, indicating psychological distress, signs of alexithymia, and cognitive complaints. Personality of participants was characterized by inflexibility, social withdrawal, and difficulties in recognizing and describing their own emotions. Adults with PHTS demonstrate a heterogeneous yet distinct neuropsychological profile that is characterized by slower information processing, psychological problems, and specific personality traits. These findings provide directions on how to optimize the care and daily lives of adults with PHTS.