Based on our findings and assessment of patient phenotypes (Table 1; Tables S1 and S2), our data indicate that individuals carrying PTEN variants such as PTEN-R173C, which retain their PIP3 phosphatase function but are nuclear excluded, tend to follow a characteristic progression of known PHTS disease phenotypes: early signs such as neurological abnormalities – including macrocephaly and global developmental delay – alongside cutaneous features, which together lead to a PHTS diagnosis during childhood. This evidence concerns the gene PTEN and Global developmental delay.