The high prevalence of hypospadias is only the peak of the iceberg because there are stigma and isolation, which make not all patients seek a doctor to check up and do counseling. However, failure of psychical, anatomical, and metabolomic development should be faced from childhood age, adolescence, through the puberty years. One hundred years of congenital adrenal hyperplasia (CAH) in Sweden, open the failure of this labium minor fusion is associated with hypermethylation which has many names. Familial cases, in females, bring this case a gender reversal and reconstructive urology repair, were successful, while the cause, CYP21 mutation/blockade/deficiency also known as cytochrome P450 deficiency is neglected. In prevention, lose with reconstruction, psychologic and environmental which reported due to pesticide are favorite. Digging the cause of labium minus fusion failure, which given the real cause, is need to be chased for prevention in the population. Method: Systematic review (SR) using Science Direct search engine cross by PubMed, preferable SR and meta-analysis (MA) design than the other. Keywords: hypospadia-fragile (10),-CYP21 mutation (2). CYP21 deficiency-CAH is the core of this study. Result: Twenty-one references flowchart and table with 4 references in SR and MA which supported Hypospadia-CYP21 deficiency-CAH. More than 3126 cases were studied. Discussion: The association of CAH hormone and behavior (family-genetic), hypospadia-Parkinson (12),-pesticides, gen chromosome 6p,-autism (59),-bipolarism (22) bring to epigenetic hypermethylation cases. The CGG repeat-hypermethylation-gene silencing which produce protein enzyme is the cause of hypospadia. Geographical of Brazil, Latin American, incl. Argentine, SEA such as Thailand, Indonesia, and also Sweden, which all are in wet and warm climate area, has high hypermethylation prevalence due to RNAi in GMO green activity.