Symptoms and General Pathology

All Conditions

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Neoplasms

Musculoskeletal Diseases

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Syndrome

Autistic Disorder

Hamartoma

Megalencephaly

Hamartoma Syndrome, Multiple

Autism Spectrum Disorder

Child Development Disorders, Pervasive

Developmental Disabilities

Neurodevelopmental Disorders

Mental Disorders

Psychotic Disorders

Neoplasms, Multiple Primary

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

Congenital Abnormalities

Craniofacial Abnormalities

Musculoskeletal Abnormalities

Malformations of Cortical Development

Nervous System Malformations

PTEN Hamartoma Tumor Syndrome

PTEN participants with Autism Spectrum Disorder group

PTEN participants without Autism Spectrum Disorder group

Rajna Filip-Dhima, MS

Jeff Anderson

Julian Martinez, MD, PhD

Robin Libove

Antonio Hardan, MD

Emine Arcasoy

Mustafa Sahin, MD, PhD

Adrienne Victory

David Ritter, MD

Beth Crouser

Charis Eng, MD, PhD

The purpose of this study is to determine cross-sectional and longitudinal medical, behavioral, and cognitive differences between PTEN ASD and other groups, as well as to identify cognitive, neural systems, and molecular biomarkers specific to PTEN ASD. In addition, this study will be creating and maintaining a biorepository and linked phenotypic database for PTEN ASD.

Autism spectrum disorders (ASD) are a set of neurodevelopmental disorders characterized by social communication/interaction impairments and restricted/repetitive behaviors. ASD associated with germline heterozygous PTEN mutations (PTEN ASD) is a genetically defined sub-group that, may be one of the more prevalent genetic disorders contributing to ASD (0.5-2%). The purpose of this research study is to carefully track the phenotypic and molecular characteristics of PTEN ASD and identify biomarkers for intervention studies.

Individuals with PTEN ASD, with macrocephalic ASD without a PTEN mutation (macro-ASD), healthy controls, and individuals with PTEN mutations without ASD (PTEN no-ASD) will be asked to participate in this study if they are 18 months and older. Both males and females will be asked to participate. Additionally, to be eligible for study participation, individuals' primary communicative language must be English.

The study involves 3 on site visits over the course of two years. Study visits will vary in length from about 4 hours to 6 hours. Study visits involve a physical exam, medical history questions, neuropsychological assessments, and a blood draw done for laboratory studies. A subset of participants between the ages of 2 and 11 years old will take part in the EEG portion of the study. Individuals who have a clinically indicated MRI will have an option to provide routine clinical scans for analysis.

Blood draw for future correlative studies in the PTEN Biorepository of the Developmental Synaptopathies Consortium.

170 subjects; 100 existing subjects, 70 newly enrolled participants; 50 controls

Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations

Verbal and non-verbal ability will be evaluated using Stanford Binet -5 or Mullen Scales of Early Learning (MSEL) at 12 months

Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4).

Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 12 months.

Verbal and non-verbal ability will be evaluated using Stanford Binet 5 or Mullen Scales of Early Learning (MSEL) at 24 months

Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 12 months

Working memory will be evaluated using the Stanford Binet 5 at 12 months

Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 12 months

Working memory will be evaluated using the Stanford Binet 5 at 24 months

Processing Speed will be measured using the Processing Speed Index from the Weschler Intelligence Scales at 24 months

Visual perception will be measured using the Beery Developmental Test of Visuomotor Integration (VMI) at 24 months

Communication ability will be evaluated using composite score of the Peabody Picture Vocabulary Test (PPVT-4) at 24 months

Communication ability will be evaluated using composite score of the Expressive Vocabulary Test (EVT-2) at 24 months.

National Institutes of Health (NIH)

National Institute of Neurological Disorders and Stroke (NINDS)

Office of Rare Diseases (ORD)

National Center for Advancing Translational Sciences (NCATS)

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Boston Children's Hospital

Assistant in NeurologyAssociate Professor of Neurology, Harvard Medical School

Patients diagnosed with PTEN Hamartoma Tumor Syndrome and a neurodevelopmental disorder including but not limited to autism spectrum disorder, attention-deficit disorder / attention-deficit hyperactivity disorder, speech language disorder(s), intellectual disability, global developmental delay, oppositional defiant disorder, and / or motor or developmental disorders.

Patients diagnosed with PTEN Hamartoma Tumor Syndrome

Siblings related to patients with diagnosis of PTEN Hamartoma Tumor Syndrome

Unrelated participants with no known genetic or neurodevelopmental disorder

Online survey measuring a variety of developmental domains including anxiety, motor, daily living skills, challenging behaviors, social communication, restrictive and repetitive behaviors, ADHD, executive functioning, mood, quality of life, and sleep

The purpose of this study is to develop a survey completed by parents, caregivers, or other informants that evaluates several important domains of functioning relevant to individuals with neurodevelopmental disorders, including autism spectrum disorder and people with genetic syndromes. Participation in this research will include assisting the research team in the development of the survey measures.

With greater understanding of the biology of PTEN Hamartoma Tumor Syndrome (PHTS), including patients with and without neurodevelopmental disorder (NDD) phenotypes, there is potential to develop novel personalized therapeutics. Given the recent observation that many PHTS patients with and without NDD have significant neurobehavioral manifestations, it will be crucial to broadly track a range of neurobehavioral domains as part of future trials. Unfortunately, there are few well-validated measures that would be appropriate for the full range of presentations in the PHTS population. Further, as a rare genetic syndrome, PHTS patients are geographically distributed making frequent data collection during research very difficult. Thus, the overarching aim of this proposal is to develop and validate an online neurobehavioral evaluation tool (NET) with caregiver-report survey scales and patient-completed webcam-collected performance measures that captures key neurobehavioral information. In partnership with patients, caregivers, and scientist-clinician experts, the study will develop, pilot test, and validate NET survey and performance measures. Specifically, at least 240 caregiver-patient pairs will be recruited (patient ages 4-24) from PHTS without NDD, PHTS with NDD, and controls (sibling and unrelated healthy controls). NET data will be collected at baseline, 1-month, and 4-month follow-up. Aim 1 will focus on the development and validation of brief, psychometrically-sound NET survey scales. Aim 2 will conduct group comparisons on NET measures. Aim 3 will use longitudinal data to evaluate short-term stability of NET survey scales and describe neurobehavioral change within and across study groups. The project will also explore the feasibility of performance measure collection, provide initial psychometric evaluation, and conduct a group comparison of performance measures. If the project aims are achieved, and future validation supports research and clinical use, the NET will be an efficient, reliable, valid, co-normed, multi-modal instrument, that, by virtue of online (at-home) administration, will decrease patient and family burden and increase the temporal resolution and power of future longitudinal studies and clinical trials.

Development and Validation of an Online Neurobehavioral Evaluation Tool for PTEN Patients

Development and Validation of an Online Neurobehavioral Evaluation Tool for PTEN Hamartoma Tumor Syndrome (PHTS)

Plan to upload deidentified data to Open Science Framework

Develop survey questions and scales related content areas for Social Communication Interactions. Social communication refers to the emergence of verbal and nonverbal skills, social interaction, and social cognition

Develop questions and survey scales related to content areas of activities of daily living. Activities of daily living are activities related to personal care. They include bathing or showering, dressing, getting in and out of bed or a chair, walking, using the toilet, and eating.

Develop survey and rating scales related to content areas for restrictive and repetitive behaviors. Restricted and repetitive behaviors and interests are among the three core symptoms of autism. They include repetitive movements with objects, repeated body movements such as rocking and hand-flapping, ritualistic behavior, sensory sensitivities and circumscribed interests

Develop survey questions and scales related to content areas for anxiety. Anxiety is what we feel when we are worried, tense or afraid - particularly about things that are about to happen, or which we think could happen in the future

Develop survey questions and scales related to content areas for motor skills.A motor skill is a function that involves specific movements of the body's muscles to perform a certain task. These tasks could include walking, running, or riding a bike. In order to perform this skill, the body's nervous system, muscles, and brain have

Develop survey questions and rating scales related to content areas for challenging behaviors.A person's behaviour can be defined as "challenging" if it puts them or those around them (such as their carer) at risk, or leads to a poorer quality of life. It can also impact their ability to join in everyday activities. Challenging behaviour can include: aggression. self-harm.

Develop survey questions and rating scales related to content areas for ADHD. Refers to the ongoing pattern of inattention and/or hyperactivity-impulsivity that interferes with functioning or development.

Develop survey questions and rating scales related to content areas for executive functioning. Executive functioning and self-regulation skills are the mental processes that enable us to plan, focus attention, remember instructions, and juggle multiple tasks successfully.

Develop survey questions and rating scales related to content areas for mood. Focusing on particular feelings or a state of mind.

Develop survey questions and rating scales related to content areas for quality of life including family, financial, etc.

Develop survey questions and rating scales related to content areas for sleep patterns and behaviors.

University Hospital Southampton NHS Foundation Trust

John Carroll University

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Influenza, Human

Arm contains all subjects; vaccination with Influvac Tetra will be administered at start of study, response will be measured in 7 and 21 days.

Tetravalent seasonal flu vaccination 2018/2019

Influvac Tetra

this study evaluates the cellular and humoral immune response to seasonal influenze vaccination in PTEN Hamartoma Tumor Syndrome. All subjects will be administered flu vaccination, half of the subjects will be control subjects.

Response of Immune System to Flu Vaccination in PHTS

Registering the Immune Response to a Flu Vaccination Challenge in PTEN Hamartoma Tumour Syndrome

Radboud University Medical Center

Cowden Syndrome

Bannayan-Riley-Ruvalcaba Syndrome

Anti-Infective Agents

Antineoplastic Agents

All Drugs and Chemicals

Sirolimus

Temsirolimus

MTOR Inhibitors

Anti-Bacterial Agents

Antibiotics, Antitubercular

Clotrimazole

Miconazole

Antifungal Agents

Immunosuppressive Agents

Immunologic Factors

Participants that are 5 to 12.99 years old will start at 1 mg/m2/dose. Participants that are 13 to 45.99 years old and \< 39.99 kg in weight will also start on 1 mg/day. Participants that are 13 to 45.99 years old and \> 40 kg in weight will start on 2 mg/day. The target blood level will be 5-15 ng/ml with dose adjustment based on sirolimus levels obtained every 2 to 3 weeks after every dose change.

Experimental: Sirolimus Participants that are 5 to 12.99 years old will start at 1 mg/m2/dose. Participants that are 13 to 45.99 years old and \< 39.99 kg in weight will also start on 1 mg/day. Participants that are 13 to 45.99 years old and \> 40 kg in weight will start on 2 mg/day. The target blood level will be 5-15 ng/ml with dose adjustment based on clinical labs of sirolimus levels. The target blood level will be 5-15 ng/ml with dose adjustment based on sirolimus levels obtained every 2 to 3 weeks after every dose change.

Placebo

John Hegarty, PhD

Mustafa Sahin, MD

Xiangling Wang, MD

The goal of this study is to examine the safety and treatment effects of sirolimus for targeting social communication deficits in people with genetic disorders associated with PTEN germline mutations, which are often referred to as PTEN Harmartoma Tumor Syndrome (PHTS). The mechanism of sirolimus in the body has shown promise for helping to improve social communication skills in case reports of people with PHTS. Everolimus, a closely related compound, also showed benefits in social communication skills in a previous pilot trial in people with PHTS. This is a 6 month double-blind trial followed by at 6 month open label extension trial.

Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

A Randomized Controlled Double-Blind Trial of Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations

Data will be on the National Institute of Mental Health Data Archive (NDA).

Stanford University

Professor

Intellectual Disability

Everolimus

Protein Kinase Inhibitors

Enzyme Inhibitors

RAD001 is formulated as tablets of 5.0 mg or 2.5mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis.

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10.

RAD001 is formulated as tablets of 5.0 mg strength, blister-packed under aluminum foil in units of 10 tablets and dosed on a regular basis. RAD001 tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.

Patients will be instructed to take 4.5 mg/m2 of RAD001 orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

RAD001

Matching placebo will be provided as a matching tablet and will also be blister packed under aluminum foil in units of 10. Matching placebo tablets should be opened only at the time of administration as drug is both hygroscopic and light-sensitive.

Patients will be instructed to take 4.5 mg/m2 of the matching placebo orally with a glass of water at regular intervals at the same time (delete: each day) in the morning after a light, nonfat breakfast.

Phosphatase and TENsin homolog (PTEN) gene germline mutations are associated with a spectrum of clinical manifestations characterized by neurocognitive deficits, intellectual disability, autism symptomatology, skin lesions, macrocephaly, hamartomatous overgrowth of tissues, and an increased risk of cancers. Investigators are conducting research to evaluate the potential safety and efficacy of RAD001 (everolimus) in this patient population, and the potential neurocognitive benefits from treatment with RAD001 or placebo for a six month period. The investigators hope this trial will lead to a better understanding of PTEN and to new forms of treatment that may benefit children and adults with PTEN in the future.

This is a signal seeking Phase I/II 6-month, randomized, double-blind placebo-controlled trial of everolimus in individuals, ages 5 to 45 years with a PTEN mutation, with safety and neurocognition as the primary endpoints.

Participant's or a legal guardian will need to sign an informed consent prior to enrollment in the study. To determine eligibility participants will undergo a series of screening tests and safety measures. If determined to be eligible for the blinded phase of the study, participants will be randomly assigned to take either the study drug or a placebo (pill with no medicine).

The blinded phase of the study involves about eight visits, five of which will occur at the study site, and three of which will be conducted over the phone. These visits will take place over a six month period. Study visits will vary in length. Baseline, three month and six month visits may last up to 8 hours, if optional measures are done, while all other visits will be less than 2 hours. The study visits include blood draws, general health exams, and neuropsychological assessments. The study will also include optional eye-tracking, EEG and auditory evoked potential (AEP) measures, and the collection of microbiome/mycobiome and biomarker blood sample. There is no fee to participate in this study. The study drug will be provided at no charge during the study.

After the 6 month treatment phase, individuals who were randomly assigned to take placebo will be offered inclusion in a 6 month open label phase where the study drug will be provided at no charge. The open label phase assessments will be similar to those done in the blinded phase, but patients/families will only need to return to the study site three times during this phase.

Participants will receive a developmental assessments report after completing the study. After all study data has been analyzed, patients and families will also be informed of the overall results. Treatment on this study may or may not improve an individual's learning skills (neurocognition) or behavior. We hope that future patients and families will benefit from what is learned by this study.

Specific Aims /Objectives Primary objective

-To evaluate the safety of everolimus compared with placebo in patients with PTEN mutations focusing on NCI CTCAE Grade 3 and 4 adverse events, serious adverse events, and Grade 3 and 4 laboratory toxicities.

Secondary objectives

-To evaluate the efficacy of everolimus on neurocognition and behavior in inividuals with PTEN mutations compared to placebo as measured by standardized, direct and indirect neurocognitive tools and behavioral measures.

RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome

A Randomized Double-Blind Controlled Trial of Everolimus in Individuals With PTEN Mutations (RAD001XUS257T)

Data will be shared with the National Database of Autism Research (NDAR)

The primary endpoint will be safety as measured by study drop-out rate due to side effects, comparing everolimus vs. placebo. We will also determine the frequency of adverse events by type and severity.

Working memory will be evaluated using the Stanford Binet 5 or Mullen Scales of Early Learning at 6 months

Processing speed will be evaluated using mean reaction time on the Conner's Continuous Performance Test (CPT)-3.

Fine motor skills will be evaluated using the Purdue Pegboard sub-tests average of both hands

Attention will be measured by Conners' Continuous Performance Test - 3 - Discriminability index (d') and Omissions

Impulsivity will be measured by Conners' Continuous Performance Test-3- Commissions and Bias (B').

Change in global cognitive ability will be measured by Stanford-Binet 5 or Mullen; Full scale, verbal and nonverbal ability (IQ)

Motor functioning will be measured by the Purdue Pegboard (Pegs): Dominant and non-dominant hand combined standard scores and Developmental Coordination Disorder Questionnaire (DCDQ): Total score.

Communication ability will be measured by using standard scores of the Peabody Picture Vocabulary Test (PPVT-4), Expressive Vocabulary Test (EVT-2)

Novartis Pharmaceuticals

PTEN Research

Director, Translational Neuroscience Center/ Professor of Neurology, Harvard Medical School

Digestive System Diseases

Mouth and Tooth Diseases

Ear, Nose, and Throat Diseases

Colorectal Neoplasms

Nasopharyngeal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Pharyngeal Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Nasopharyngeal Diseases

Pharyngeal Diseases

Stomatognathic Diseases

Otorhinolaryngologic Diseases

Herbal and Botanical

Cola

There will be a clinic visit and colonoscopy at study entrance with standard of care sampling and assessment of polyps, including resection of concerning polyps. The investigators will also collect data on well-being via the SF-36 health survey (a validated questionnaire to help monitor this aspect given anecdotal patient-level reports of improvement while on therapy).

Study subjects will then begin sirolimus 2 mg by mouth daily for 1 year.

Laboratories will be checked at 4 days after initiation, at 2 weeks after initiation, then every 4 weeks for 3 months, then every 3 months to complete the year of therapy

Participants will have a clinic visit at 3, 6 and 9 months and include well-being assessment with the SF-36 health survey.

Participants will have a clinic visit with well-being assessment and perform colonoscopy at study closure at 12 months. The investigators will perform standard of care sampling and assessment of polyps, including resection of concerning polyps.

Use of sirolimus 2 mg by mouth daily for 1 year

Peter P Stanich, MD

Colon polyposis (the presence of multiple colon polyps) is very common with Cowden syndrome, as over 60% of patients have 50 or more polyps. In a previous clinical trial, some participants had reduction in the number of colon polyps with the use of the medication sirolimus for a very short time period. This study is investigating sirolimus and its effect on the number of colon polyps in patients with Cowden syndrome and polyposis over a 1 year period.

PTEN is a tumor suppressor gene that regulates the cell cycle through the phosphoinositide 3-kinase (PI3K)/Akt/mTOR pathway. When germline mutations in PTEN occur, the result is Cowden syndrome (or less commonly one of several related disorders collectively called the PTEN hamartoma tumor syndrome). This is characterized by the growth of hamartomas and a high risk of cancer in multiple organ systems. This includes colon polyps in 92.5% of Cowden syndrome patients and 64% with an estimated 50 or more polyps. Although outcomes of this are under reported, series suggest 20-38% of patients will receive colectomy.

Current clinical practice for Cowden syndrome is based on close surveillance for the development of cancers. Sirolimus (also known as rapamycin) is a specific inhibitor of mTOR that is FDA-approved for immunosuppression and use in several types of cancers as chemotherapy. It has also been used successfully in other hamartomatous syndromes including lymphangioleiomyomatosis. There is also a completed pilot clinical trial for adults with Cowden syndrome in which some had reduction in the number of colon polyps with the use of the medication sirolimus for a very short time period.

This will be an open-label pilot trial to determine whether sirolimus reduces colon polyp burden in Cowden syndrome. Sirolimus will be administered for one year. Colonoscopy with polyp estimation will be performed at trial entrance and at study completion.

Sirolimus for Cowden Syndrome With Colon Polyposis

Assessment of change in number of colon polyps. This will be assessed for each segment of colon (ascending, transverse, descending, sigmoid, rectum) and then aggregated into a total number of colon polyps. The entrance result will be compared to the final result for each participant.

Assessment of change in staging of colon polyps by using the International Society for Gastrointestinal Hereditary Tumors (InSIGHT) polyposis staging system. The InSight staging system divides colorectal polyposis into 5 progressive stages based on polyp number and size (Stage 0: \<20 polyps, all \<5 mm; Stage 1: 20-200 polyps, most \<5 mm, none, \>1 cm; Stage 2: 200-500 polyps, \<10 that are \>1 cm; Stage 3: 500-1000 polyps or any number if there are 10-50 that are \>1 cm and amenable to complete polypectomy; Stage 4: \>1000 polyps and/or any polyps grown to confluence and not amenable to simple polypectomy; any high-grade dysplasia or invasive cancer). The entrance result will be compared to the final result for each participant.

Assessment in change in overall health and quality of life as quantified by the SF-36 (Short Form) Health Survey. The SF-36 is a widely-used and standardized survey of participant responses to 36 questions that measures health-related quality of life. Each question has answers that are given a correlating score from 0 to 100, with a high score representing a more favorable health state. Through the combination of specific questions and averaging the scores, there are 8 scales (physical functioning, role limitations due to physical health, role limitations due to emotional problems, vitality, mental health, social functioning, bodily pain, and general health) that are reported with scores from 0 to 100, with a high score representing a more favorable health state. These can also be averaged into a physical component summary score and mental component summary score that is again from 0 to 100, with a high score representing a more favorable health state.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Natural History Study of Individuals With Autism and Germline Heterozygous PTEN Mutations	NCT02461446	PTEN ASD Autism Macrocephaly PTEN Hamartoma ...		18 Months -	Boston Children's Hospital
Development and Validation of an Online Neurobehavioral Evaluation Tool for PTEN Patients	NCT05671107	PTEN Hamartoma ...	NET	3 Years - 45 Years	John Carroll University
Response of Immune System to Flu Vaccination in PHTS	NCT03630523	PTEN Hamartoma ...	Influvac Tetra	18 Years -	Radboud University Medical Center
Sirolimus for Improving Social Abilities in People With PTEN Germline Mutations	NCT06080165	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ...	Sirolimus Placebo	5 Years - 45 Years	Stanford University
RAD001 and Neurocognition in PTEN Hamartoma Tumor Syndrome	NCT02991807	PTEN Gene Mutat... PTEN Hamartoma ...	RAD001 Placebo	5 Years - 45 Years	Boston Children's Hospital
Sirolimus for Cowden Syndrome With Colon Polyposis	NCT04094675	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ... Cowden Syndrome Bannayan Syndro... Bannayan Zonana... Polyposis	Sirolimus	18 Years - 80 Years	Ohio State University
Sirolimus for Cowden Syndrome With Colon Polyposis	NCT04094675	PTEN Gene Mutat... PTEN Hamartoma ... PTEN Hamartoma ... Cowden Syndrome Bannayan Syndro... Bannayan Zonana... Polyposis	Sirolimus	18 Years - 80 Years	Ohio State University

Spots Global Cancer Trial Database for pten hamartoma tumor syndrome