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Congenital intrinsic factor deficiency

Synonym(s) Congenital pernicious anemia
Gastric intrinsic factor deficiency
Hereditary juvenile megaloblastic anemia due to intrinsic factor deficiency
Intrinsic factor deficiency
Prevalence <1 / 1 000 000
Inheritance Autosomal recessive
or Not applicable
Age of onset Childhood
  • D51.0
  • C0340957
MeSH -
  • 10070440


Disease definition

Congenital intrinsic factor deficiency (IFD) is a rare disorder of vitamin B12 (cobalamin) absorption that is characterized by megaloblastic anemia and neurological abnormalities.


The incidence and prevalence of IFD are unknown. Fewer than 100 cases have been reported in the literature and fewer than 50 cases have been confirmed molecularly.

Clinical description

The disease usually manifests before the age of 5 but patients in their 10th and 30th decade of life have also been reported. It manifests with failure to thrive and symptoms of anemia (e.g. asthenia, weakness, headache, infections). If untreated, neurological damage may occur such as peripheral neuropathy, subacute combined degeneration of the spinal cord and/or ataxia. Neurological symptoms may include muscular weakness and abnormal gait.


Patients have bi-allelic mutations in the GIF gene on chromosome 11 encoding the gastric Intrinsic Factor (IF), a protein necessary for the absorption of vitamin B12. GIF mutations lead to impaired IF synthesis and thus vitamin B12 (cobalamin) malabsorption and deficiency.

Diagnostic methods

Diagnosis depends on blood tests that show low serum levels of cobalamin and megaloblastic anemia (decreased red blood cell count and increased mean corpuscular volume). Nowadays, measurement of transcobalamin-bound cobalamin (holo-transcobalamin) in serum is preferred to measurement of total serum cobalamin. As cobalamin deficiency affects enterocyte function, thereby enhancing cobalamin malabsorption, it is recommended to treat first with cobalamin in order to reestablish proper enterocyte function before performing any diagnostic malabsorption testing. Acid secretion is usually present but patients may show low or absent IF amounts in the gastric juice. Urine tests show increased amounts of methylmalonic acid (MMA) and total homocysteine (tHcy). There are no auto-antibodies directed against the gastric parietal cells antigen H+/K+ ATPase (anti-GPC) and intrinsic factor (anti-IFA). Commercial genetic testing is not yet available.

Differential diagnosis

Differential diagnosis includes Imerslund-Gräsbeck syndrome, transcobalamin II deficiency, cblF defect, and acquired pernicious anemia (see these terms), which is caused by autoimmunity or Helicobacter infection.

Antenatal diagnosis

Antenatal diagnosis is not available.

Genetic counseling

Both sporadic cases and familial cases with autosomal recessive transmission have been reported.

Management and treatment

The standardized treatment consists of weekly to monthly intramuscular injections of vitamin B12. Hydroxocobalamin injections are preferred over cyanocobalamin as the latter may cause muscular pain and have ophthalmo-neurological side effects. Oral vitamin B12 supplementation may be ineffective and not recommended.


Prognosis is good. Without treatment, neurological and hematopoietic complications can occur that can also be fatal.

Expert reviewer(s)

  • Pr Ralph GRÄSBECK
  • Dr Stephan TANNER

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