P 1081. PTEN-Associated Macrocephaly in a 3-Year-Old Girl

Background: Germ line mutations in PTEN gene, a tumor-suppressor gene (10q23.31), lead to autosomal-dominant hamartomatous disorders. PTEN is a regulatory protein in PI3K/AKT/mTOR signal transduction pathway which plays an important role in cell growth, cell migration, and angiogenesis. Pathogenic variants of PTEN gene lead to inordinate cell growth in all three embryonic germ layers. PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by these mutations of the PTEN tumor suppressor gene associated with broad variability in phenotype as well as in prevalence of germ line mutations. Macrocephaly and autism spectrum disorders represent the main symptoms. We report a 3-year-old girl with delayed cognitive development and macrocephaly with an underlying heterozygous mutation in c.518G>A (p.Arg173His) of PTEN gene.

Case Report: The girl was presented at the age of 14 months with secondary macrocephaly (50.7 cm, 3.15 >100 Pc), muscular hypotonia, convergent mircrostrabism, and delay of sensory functions. There were no signs of facial dysmorphia. Milestones of early childhood development were delayed (crawling at the age of 12 months, sitting without any help at the age of 13 months, rising to standing at the age of 14 months). BSID-II showed cognitive developmental disorder with MDI < 50 at the age of 22 months. By SETK-2, a general speech developmental disorder has been diagnosed. Cranial magnetic resonance imaging and laboratory examinations were without any pathological findings. By multigene panel testing, a heterozygous mutation in c.518G>A (p.Arg173His) of PTEN gene was detected.

Conclusion: Heterozygous mutation in c.518G>A (p.Arg173His) of PTEN gene is previously described as pathogenic for Cowden’s syndrome, Bannayan–Riley–Ruvalcaba, and macrocephaly associated with autism spectrum disorder. Here, we present a case of global developmental disorder and secondary macrocephaly without any symptoms of autism spectrum disorder or PTEN PHTS. The particular relevance of the detection of PTEN mutations is in significantly increased life-time risk for various tumor diseases.