Here, we show evidence that the germline c.4031C>T (p.S1344L) mutation in DICER1 causes a severe subtype of DICER1 syndrome with intellectual disability (ID), macrocephaly, extensive bilateral lung cysts, early onset of Wilms tumour and well-differentiated fetal lung adenocarcinoma—a clinical spectrum similar to, but distinct from, the phenotype reported in two patients with GLOW syndrome with postzygotic hotspot mutations in exons encoding the RNase IIIb domain. The gene discussed is DICER1; the disease is DICER1-related tumor predisposition.