Congenital Deficiency versus Hereditary Persistence of Human Alpha-fetoprotein: A Meta-analysis and Overview of Potential Biomedical Consequences

Abstract

Human alpha-fetoprotein (AFP) is a 70 kD tumor-associated fetal protein (oncofetal protein) which has been utilized clinically as a biomarker for both multiple cancers and for fetal defects including neural tube defects and chromosomal abnormalities. Extreme low and high levels of serum AFP in conjunction with gene mutations have now been established in disorders such as congenital deficiency (CD) and hereditary persistence (HP) of AFP. The objectives of the present review are to compare the clinical manifestations and analyze the mutational basis of these two AFP genetic disorders in accordance with presently accepted models of AFP gene regulation. The regulatory elements of AFP gene expression i.e., enhancers, promoters, and silencers are described in light of the genetic alterations expressed by the CD- and HP-AFP patients. By use of structure/function peptide mapping of the full-length AFP amino acid sequence, the potential biomedical consequences exhibited by CD-AFP and HP-AFP patients are presented and discussed. A new prospective on placental dysfunction in these AFP genetic disorders has also been introduced. Using AFP reference levels in maternal serum, cord blood, newborn blood, pediatric and adult serum, AFP serum concentrations are presented that could alert the obstetrician of potential CD-AFP during pregnancy. Knowledge of such serum values could provide tools to allow clinicians to distinguish between adult HP-AFP and malignant/non-malignant diseases such as liver and germ cell tumors, cirrhosis, hepatitis, and various liver disorders. Knowledge of AFP reference levels might serve to guide the clinician in avoiding: a) misguided diagnoses; b) unnecessary treatments and therapies; and c) undue anxieties and stress during pregnant and non-pregnant states.

Keywords

• alpha-fetoprotein, genetic disorder, autosomal recessive, autosomal dominant, gene mutation, pedigree, deficiency, persistence

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