Phenotypic Description of Individuals with PTEN Mutations, ASD and Macrocephaly

Background: Autism spectrum disorder (ASD) is a challenging neurodevelopmental disorder, with a multifactorial origin and a complex inheritance. Studying proven susceptibility genes and working on clinical endophenotypes is needed to define more valid genotype-phenotype relationships. PTEN is a tumor suppressor gene whose inactivation results in upregulation of the PI3K/AKT signaling pathway, affecting multiple cellular processes, namely cell growth and proliferation. PTEN germline mutations are associated with tumor susceptibility and neurodevelopmental disorders such as autism. They have been reported in up to 20% of children diagnosed with ASD and major macrocephaly. Studies have emphasized macrocephaly as a consistently encountered clinical finding amongst ASD, estimated in about 15%. Hence, a PTEN mutation testing is a major consideration in cases of ASD and macrocephaly.

Objectives: To report a subset of individuals with a PTEN germline mutation and both ASD and macrocephaly.

Methods: We describe three Caucasian-portuguese patients, two male, with current ages 5, 7 and 13 years old, with a diagnosis of ASD (positive score for both ADI-R and ADOS, and fulfilment of DSM-5 criteria) and macrocephaly (ranging from +3SD to +4SD). Moreover, these ASD children underwent intellectual and functional adaptive evaluations with Griffiths Mental Development Scale and Vineland Adaptive Behaviour Scale (VABS), respectively. Besides PTEN molecular analysis, genetic testing was performed to rule out other medical conditions.

Results: Our findings revealed significant phenotypical heterogeneity. Three PTEN mutations were found: a missense variant c.737C>T (p.Pro246Leu) heterozygous in exon 7 (Patient 1), a de novo duplication in exon 6 [c.493-?_634+?(2)] (Patient 2), and a missense mutation c.359C>A (p.Ala120Glu) heterozygous in exon 5 (Patient 3). Brain Magnetic Resonance Imaging showed enlarged perivascular spaces and white matter abnormalities of both cerebral hemispheres (Patient 1) and had no brain alterations in the other two subjects. All the three ASD subjects had moderate to severe intellectual disability and VABS functional adaptive profiles were lower than the expected for their age (ranging from -2SD (Patient 2) to -3SD (Patients 1 and 3). Noteworthy, all patients have already initiated cancer risk surveillance.

Conclusions: We report concordant data with contemporaneous investigation on the field and add a novel mutation, not yet described, with clinical evidence strongly pointing to the pathogenicity of this variant. We also intend to present functional studies that are being done. A multidisciplinary cancer surveillance regimen extended to adulthood is mandatory in all cases of PTEN mutation. Additional research in ASD patients with known PTEN mutation etiology is necessary to enhance knowledge and disclose the full potential of target therapeutics in this neurobehavioral syndrome.