Natural History With Focus on Oncological Risk Evaluation in Pediatric Patients 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.

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.

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

All children will undergo a brain MRI to evaluate the presence or absence of cerebral anomalies

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.

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).

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.