Intrinsic Factor Deficiency

A number sign (#) is used with this entry because hereditary intrinsic factor deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding gastric intrinsic factor (GIF; 609342) on chromosome 11q12.

Description

Congenital pernicious anemia (PA), or intrinsic factor deficiency, is a rare disorder characterized by the lack of gastric intrinsic factor in the presence of normal acid secretion and mucosal cytology and the absence of GIF antibodies that are found in the acquired form of pernicious anemia (170900).

See also pernicious anemia due to defect in the receptor for vitamin B12/intrinsic factor (261100).

Clinical Features

Cases of childhood pernicious anemia have been reported in which, although the gastric mucosa was histologically normal, intrinsic factor was lacking from the acid gastric juice. No antibodies to intrinsic factor or to gastric parietal cells were detected in the patients' serum. Studies in sibs, parents, and grandparents showed no abnormality in the secretion of gastric acid or intrinsic factor and normal vitamin B12 absorption (McIntyre et al., 1965). In 1 such family (Herbert et al., 1964), 2 sibs were affected.

Juvenile 'congenital' pernicious anemia was the designation suggested by Miller et al. (1966) for vitamin B12 deficiency due to congenital lack of gastric intrinsic factor without other apparent abnormality of the stomach or its secretions. Furthermore, serum antibodies to intrinsic factor and gastric parietal cells are conspicuously absent.

McNicholl and Egan (1968) described a brother and sister with congenital PA and stated that 28 cases had been described. They noted that the defect seems to be one of failure of intrinsic factor secretion despite normal gastric acidity and mucosal morphology. The disorder is distinct from juvenile pernicious anemia due to selective intestinal malabsorption of vitamin B12 with proteinuria (261100) and pernicious anemia associated with the polyglandular autoimmune syndrome (240300). It is also distinct from classic adult-onset pernicious anemia (170900). The congenital form is manifest by megaloblastic anemia presenting at about 1 year of age and mental retardation.

Katz et al. (1972) described a 13-year-old male from a consanguineous marriage with normal gastric intrinsic factor by immunoassay but none by biologic test. By means of a new second-antibody radioimmunoassay, Carmel (1983) could detect no immunoreactive intrinsic factor in any of 6 patients studied. One patient, a female Mexican physician, was first diagnosed at age 23 years. The delay in diagnosis was attributable to the fact that after a severe illness, said to be amebiasis, at age 1, the mother had given her monthly liver injections; these had been continued until age 16. At age 23, she was investigated for pancytopenia and found to have florid megaloblastic changes in the circulating blood and bone marrow. Although the author works in Los Angeles, it may be significant that all of his cases were Mexicans distributed in 3 kindreds.

Juvenile PA due apparently to production of intrinsic factor unusually susceptible to degradation in the lumen of the GI tract was described by Levine et al. (1981). See Yang et al. (1985).

Katz et al. (1974) described a type of congenital intrinsic factor defect in which intrinsic factor had normal cobalamin-binding ability and immunoreactivity but showed very poor affinity for the intestinal receptor for intrinsic factor.

In a 26-year-old man, the offspring of first-cousin parents, Remacha et al. (1992) found a defect in vitamin B12 absorption by Schilling test, which was corrected by adding intrinsic factor. The parents and sibs had normal serum vitamin B12 levels, but the father and a sister in whom gastric examination was performed showed decreased IF secretion compatible with heterozygosity. The proband came to medical attention because of an episode of jaundice and anemia. He had recovered from similar crises at ages 2, 4, 8, 16, 22, and 24 years of age with administration of parenteral vitamins complex including vitamin B12. He was found to have macrocytic anemia, moderate leukopenia, and bilirubinemia.

Molecular Genetics

Hewitt et al. (1991) found that Southern analysis of genomic GIF DNA from patients with congenital pernicious anemia due to lack of intrinsic factor showed normal restriction fragment patterns, suggesting that a sizable gene deletion is not responsible for the deficiency.

Gordon et al. (2004) sequenced all the exons of the GIF gene in 5 patients with intrinsic factor deficiency and in the parents of 4 of the patients. A single-nucleotide substitution at position 2 of codon 5 (68A-G) in 1 or both copies of the GIF gene was identified in all of the subjects, with additional changes observed in 2 patients. When COS-7 cells were transfected with plasmids containing either the normal or the mutant cDNA, the secreted GIF proteins had a similar rate of secretion and sensitivity to pepsin degradation. Three subjects were homozygous for the missense mutation, changing codon 5 from CAG (glutamine) to CGG (arginine). Three subjects were homozygous for the mutation and 2 subjects were heterozygous, 1 of whom was apparently a compound heterozygote at positions 1 and 2 of the fifth codon. The other patient heterozygous for position 2 had 1 heterozygous unaffected parent. Most parents were heterozygous for this base exchange, confirming the pattern of autosomal recessive inheritance for congenital IF deficiency. cDNA encoding GIF was mutated at basepair g.68A-G. The apparent size, secretion rate, and sensitivity to pepsin hydrolysis of the expressed IF were similar to native intrinsic factor. The allelic frequency of 68A-G was 0.067 and 0.038 in 2 control populations from Germany and Spain, respectively. Gordon et al. (2004) concluded that the Q5R variant (609342.0001) was not the cause of the phenotype but was associated with congenital IF deficiency in such a way as to serve as a marker for inheritance of this disorder.

In an 11-year-old girl with severe anemia and cobalamin (Cbl) deficiency, Yassin et al. (2004) identified a 4-base deletion in the coding region of the GIF gene (609342.0002). The bone marrow showed frank megaloblastic morphology, and the Schilling test indicated a failure to absorb Cbl that was corrected by coadministration of intrinsic factor. Pentagastrin administration induced acid secretion, but the gastric juice lacked intrinsic factor as determined by Cbl binding and other tests.

In 7 families previously diagnosed with Imerslund-Grasbeck syndrome (261100) due to inconclusive results on radiocobalamin absorption tests, but who were negative for mutations in the cubilin (CUBN; 602997) or the AMN (605799) gene, Tanner et al. (2005) identified homozygosity for 6 different mutations in the GIF gene (609342.0002-609342.0007). Tanner et al. (2005) proposed that rather than radiocobalamin absorption tests, mutation analysis of the CUBN, AMN, and GIF genes may be the diagnostic method of choice for cobalamin absorption disorders.