This is an observational study in pediatric patientis carryng PTEN pathogenic variants aimed to define oncological risk in children and provide a deeper insight of the clinical course, establishing an updated follow-up protocol.
PTEN is a tumor suppressor gene that was first linked to cancer predisposition syndromes but, in the following years, its phenotypic spectrum has been in continuous evolution and expansion, and nowadays we know that pathogenic variants n this gene may also be found in children presenting with Autism Spectrum Disorder (ASD), and/or DD and macrocephaly, or also with macrocephaly alone. Thus, the term PTEN Hamartoma Tumor Syndrome (PTHS) is now used when referring to PTEN-related conditions. Nowadays, there is no recognized standard protocol for pediatric follow-up. The screening in mostly single-Centre-based and generally not performed in infancy, with large variability in protocols and timing. The penetrance, which was previously believed to follow an age-related pattern, nowadays seems rather to be age-specific, as children mainly present macrocephaly and neuropsychiatric problems (DD/ASD), while adults are diagnosed mostly because of gastrointestinal malignancies, breast cancer, thyroid carcinoma or other tumors. However, it is not always true that adult symptoms never occur in PTHS children and, conversely, pediatric signs may also persist through adulthood. The present study aims to collect PTEN mutated patients and their relatives diagnosed in Italy and followed in different Centers, offering a large pediatric cohort with a full clinical description and trying to provide a deeper insight of the clinical course and oncological manifestations of PTEN-related syndrome; we would like to establish an updated follow-up protocol in order to address all the possible clinical needs of these children.
Study Type
OBSERVATIONAL
Enrollment
50
Fondazione IRCCS Istituto Neurologico Carlo Besta
Milan, Italy
RECRUITINGRate of tumor onset in the pediatric subjects with PTEN pathogenic variants
In the 5 years follow-up the subjects must complete annually the provided follow-up. Most of the exams are performed in order to exclude the onset of PTEN-related tumors, in particular: * blood tests: thyroid function, renal function, hepatic function, blood count cell exam: screening for thyroid, kidney, liver and intestinal tumors * fecal occult blood (FOB): screening for colorectal cancer and polyps * dermatological evaluation (at the diagnosis, further evaluations if clinically needed) * thyroid US: screening for thyroid tumors * abdominal US: screening for kidney, liver and intestinal tumors * clinical follow-up (performed either by a geneticist, a pediatrician or a pediatric neurologist): exams evaluation and global monitoring. The oncological risk of the patients would be estimated basing on the number of patients who will develop a tumor, benign or malignant, in the 5-years follow-up.
Time frame: 5 years
Rate of tumor onset in the adult relatives of the pediatric subjects also carrying the PTEN pathogenic variant
The oncological risk of tumor onset in the pediatric cohort will be compared with that of relatives carrying pathogenic variants. Pediatric patients will undergo annual follow-up for the 5 years of the study. Within the same time frame, adult relatives of the index case carrying the same PTEN variant will also be monitored in order to compare oncological risk in adult and pediatric populations and to evaluate phenotypic differences across different stages of life.
Time frame: 5 years
Rate of major malformations
Children will be evaluated in order to exclude the presence of major malformations, including: * heart malformations: a heart US would be also performed at diagnosis * skin anomalies and global examination: a subcutaneous US will be performed if signs of possible peripheral vascular anomalies are present * kidney and liver anomalies: those would be also assessed in the abdominal US already planned yearly * limbs anomalies: in particular number of fingers/toes and limbs asymmetry
Time frame: 5 years
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Rate of incidence of brain MRI anomalies
All children will undergo a brain MRI to evaluate the presence or absence of cerebral anomalies
Time frame: 5 years
Rate of incidence of neurological comorbidities
The presence or absence of possible neurological comorbidities will be investigated at diagnosis and at every clinical follow-up and data will be recorded in order to estimate the prevalence of the problem in the PTEN cohort. Specifically, data about the following issues will be collected: * epilepsy * clinical neurological signs * sleep disorder * other neurological comorbidities.
Time frame: 5 years
Rate of incidence of neurodevelopmental disorders
The presence or absence of neurodevelopmental diagnosis will be investigated at diagnosis, if not already assessed, and at every clinical follow-up and data will be recorded in order to estimate the prevalence of the problem in the PTEN cohort. Global development and/or Intelligence Quotient level will be evaluated with standardized assessment tools, optimized for age and development. Griffiths Mental Development Scale - GMDS, Wechsler Preschool and Primary Scale of Intelligence - WPPSI, Wechsler Intelligence Scale for Children - WISC, and Leiter scales. The presence of signs and symptoms of Autism Spectrum Disorder and other possible behavioral problems would also be assessed with standardized tools, both scales (Autism Diagnostic Observation Schedule - ADOS) and questionnaires (Child Behavior Checklist - CBCL, Social Responsiveness Scale - SRS, Adaptive Behavior Assessment System - ABAS).
Time frame: 5 years
To analyze Head Circumferences and development of growth HC curves in PTEN patients (data of affected parents will be also recorded)
The HC measures will be monitored at diagnosis at at every follow-up visit in order to follow the head growth of the patients; data about the affected parents will also be recorded. To record data, WHO growth charts will be used as standardized charts. Data will be used to develop a PTEN-specific head circumference growth chart.
Time frame: 5 years