Alpha-Fetoprotein, Hereditary Persistence Of

A number sign (#) is used with this entry because hereditary persistence of alpha-fetoprotein (HPAFP) is caused by heterozygous mutation in the AFP gene (104150) on chromosome 4q13.

Description

Hereditary persistence of alpha-fetoprotein (HPAFP) is a clinically benign autosomal dominant condition characterized by continued expression of alpha-fetoprotein in adult life (summary by McVey et al., 1993).

Clinical Features

Ferguson-Smith et al. (1984) reported an autosomal dominant hereditary persistence of alpha-fetoprotein. The proband was a 38-year-old woman found to have elevated AFP during pregnancy, as part of screening for neural tube defects. The level of AFP in the amniotic fluid was normal; the mother's elevation persisted after delivery. The infant and 2 of 3 other children also had elevated serum AFP. Subsequently, 21 members of her family, including 9 males, were found to have elevated values.

Rose et al. (1989) reported a family ascertained through a 42-year-old male who had 2 sibs and a daughter with elevated serum alpha-fetoprotein levels. Such elevated alpha-fetoprotein levels complicate the interpretation of findings in patients being screened for malignancy (e.g., hepatocellular carcinoma or teratoma) or in pregnant women being screened for neural tube defects or Down syndrome in the fetus.

Greenberg et al. (1990) reported a family in which a 33-year-old man, 2 of his sibs, and a daughter showed elevated serum AFP levels.

Alj et al. (2004) reported 2 unrelated families with HPAFP, 1 of Indian descent and the other of Italian descent. In both cases, elevated serum AFP was found incidentally in the proband, and neither individual had physical abnormalities associated with the trait; liver studies in both individuals were normal.

Inheritance

The transmission pattern of HPAFP in the families reported by Alj et al. (2004) was consistent with autosomal dominant inheritance.

Mapping

Although close linkage of HPAFP with group-specific component (GC; 139200) was originally excluded (Ferguson-Smith et al., 1984), repeat GC typing with an improved technique of isoelectric focusing showed several misclassifications in the earlier study, and the new calculations were consistent with linkage (lod, 1.7; theta, 0.0) (Ferguson-Smith et al., 1985). Ferguson-Smith et al. (1985) used a cDNA albumin probe which recognizes RFLPs at the ALB locus. No recombination was found between an ALB polymorphism and HPAFP (lod = 6.02; theta = 0).

Molecular Genetics

In members of a large Scottish kindred with hereditary persistence of alpha-fetoprotein, McVey et al. (1993) identified a heterozygous mutation in the AFP gene (104150.0001).

In affected individuals from 2 unrelated families with HPAFP, Alj et al. (2004) identified 2 different heterozygous mutations in the distal (104150.0001) and proximal (104150.0004) HNF1 (142410) binding regions in the promoter of the AFP gene. Both mutations resulted in increased affinity of the promoters for HNF1, resulting in increased levels of gene transcription. The findings highlighted the importance of HNF1 in AFP gene expression. Alj et al. (2004) suggested that unexplained increased AFP should led to AFP promoter gene sequencing to avoid inappropriate explorations or treatment decisions, as HFAPF is a benign trait.