There is an ongoing debate regarding the impact of phenylketonuria (PKU) and its treatment on growth. To date, evidence from studies is inconsistent, and data on the whole developmental period is limited. The primary aim of this systematic review was to investigate the effects of a phenylalanine (Phe)-restricted diet on long-term growth in patients with PKU. Four electronic databases were searched for articles published until September 2018. A total of 887 results were found, but only 13 articles met eligibility criteria. Only three studies had an adequate methodology for meta-analysis. Although the results indicate normal growth at birth and during infancy, children with PKU were significantly shorter and had lower weight for age than reference populations during the first four years of life. Impaired linear growth was observed until the end of adolescence in PKU. In contrast, growth impairment was not reported in patients with mild hyperphenylalaninemia, not requiring dietary restriction. Current evidence indicates that even with advances in dietary treatments, “optimal” growth outcomes are not attained in PKU. The majority of studies include children born before 1990s, so further research is needed to show the effects of recent dietary practices on growth in PKU.

The traditional treatment for phenylketonuria (PKU) is a phenylalanine (Phe)-restricted diet, supplemented with a Phe-free/low-Phe protein substitute. Pharmaceutical treatment with synthetic tetrahydrobiopterin (BH4), an enzyme cofactor, allows a patient subgroup to relax their diet. However, dietary protocols guiding the adjustments of protein equivalent intake from protein substitute with BH4 treatment are lacking. We systematically reviewed protein substitute usage with long-term BH4 therapy. Electronic databases were searched for articles published between January 2000 and March 2020. Eighteen studies (306 PKU patients) were eligible. Meta-analyses demonstrated a significant increase in Phe and natural protein intakes and a significant decrease in protein equivalent intake from protein substitute with cofactor therapy. Protein substitute could be discontinued in 51% of responsive patients, but was still required in 49%, despite improvement in Phe tolerance. Normal growth was maintained, but micronutrient deficiency was observed with BH4 treatment. A systematic protocol to increase natural protein intake while reducing protein substitute dose should be followed to ensure protein and micronutrient requirements are met and sustained. We propose recommendations to guide healthcare professionals when adjusting dietary prescriptions of PKU patients on BH4. Studies investigating new therapeutic options in PKU should systematically collect data on protein substitute and natural protein intakes, as well as other nutritional factors.

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