Prenatal, Perinatal, and Familial Risk Factors in the Differential Diagnosis Between Autism Spectrum Disorder and Phenylketonuria: A Retrospective Case-Control Study in the Absence of Neonatal Screening

Background Autism spectrum disorder (ASD) and phenylketonuria (PKU) share overlapping neurodevelopmental features. In regions lacking systematic neonatal screening, the differential diagnosis remains a major clinical challenge. Objective To identify specific prenatal, perinatal, and familial factors that distinguish children with ASD from those with PKU, and to characterize the clinical profile of ASD compared with typically developing (TD) children. Methods A retrospective case-control study was conducted including 117 children (34 ASD, 12 PKU, and 71 TD). Data were extracted from medical records and standardized parental questionnaires. Multivariate logistic regression was used to identify independent predictors for each condition. Results Familial factors were highly discriminative: consanguinity was significantly more frequent in PKU than in ASD (85.7% vs 23.5%; P = .001). Regarding prenatal/perinatal factors, advanced paternal age at conception was a significant marker for ASD compared with PKU (42.3 ± 8.08 vs 33.0 ± 5.37 years; P = .015). Neonatal complications were present in 20.6% of ASD cases but absent in the PKU group. Multivariate analysis identified consanguinity (odds ratio [OR] = 12.68) and intellectual disability (OR = 11.89) as independent predictors of PKU. Compared with TD children, ASD cases were associated with higher rates of macrosomia, prematurity, and maternal bleeding. The strongest clinical predictors for ASD were sleep disorders (OR = 32.59) and intellectual disability (OR = 20.87). Conclusions Prenatal, perinatal, and familial markers specifically consanguinity and paternal age are vital for differentiating ASD from undiagnosed PKU in the absence of neonatal screening. In consanguineous populations, these factors should guide clinicians toward metabolic screening to avoid diagnostic uncertainty.