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Congenital Intrinsic Factor Deficiency

Congenital Absence of Intrinsic Factor

Congenital intrinsic factor deficiency is a rare disorder caused by a mutation in the gene encoding gastric intrinsic factor (GIF).


Symptoms of congenital intrinsic factor deficiency are similar to those of vitamin B12 deficiency causing megaloblastic anemia as that is its chief identifiable manifestation. Often the patient is brought and misdiagnosed as being in a poor nutritional state.

  • Irritability: Childen who are generally cranky or peevish. Parents may also complain of capricious behaviour. Sometimes these cases might be detected after 10 years; then these symptoms are easier to note.
  • Diarrhea, chronic and often with undigested food particles. Ill-formed stools, not always accompanied by pain or fever are common.
  • Pale skin: Something easily noted during routine clinical examination and shared with iron deficiency anemia as well. 
  • Reduced appetite: The child does not refuse food but portions consumed are decreasing over time. Child prefers liquids instead or craves sweets, and even pica might be noticed.
  • Weakness: Asthenia in general, mental as well as physical; marked more so by the absence of any underlying infection.
  • Developmental delay: Milestones would be delayed by about 20% of their time zone. It’s not a gross delay but more than one developmental milestone is connected to nutritional insufficiency.
  • Fatigue and shortness of breath with a desire to take long breaths and deep gasps intermittently as if sighing are common to anemia.
  • Tingling sensation, paresthesias , numbness, cramps, ant-like sensation, cob-web sensation are some of the neuropathies associated with the deficiency leading to anemia [5].
  • Fatigue and shortness of breath with a desire to take long breaths and deep gasps intermittently as if sighing are common to anemia.[symptoma.com]
  • CASE DESCRIPTION A 2 year old male (Figure 1) presented with daily persistent emesis, pallor and perioral cyanosis. Past medical history was significant for 2 prior episodes of pneumonia and wheezing.[epostersonline.com]
  • Gender, number of surgeries, pacemaker, cyanosis at birth, first surgery 5 .[frontiersin.org]
  • Reviewing the full spectrum of clinically significant neuropathies, the book contains chapterson common and rare forms including mononeuropathy in the upper and lower extremities, mononeuritismultiplex, diffuse and symmetric polyneuropathies, brachial[books.google.de]
  • Nerve conduction studies and electromyogram are helpful in confirming neuropathy and characterizing the neuropathy; that is, demyelinating, axonal, polyneuropathy, mononeuropathy multiplex, radiculopathy, or plexopathy.[online.epocrates.com]
  • […] independent risk factor for stroke) Spinal Cord Manifestations Myelopathy (Sub acute combined degeneration of spinal cord), ataxia, spasticity and abnormal gait PNS Manifestations Neuropathy motor-sensory polyneuropathy (parasthesias, numbness and weakness) mononeuropathy[ispub.com]
  • Gene GIF (AR) Diagnostic Test Plasma Vitamin B12, Folate Neurological Ataxia, dystonia Non-Neurological Megaloblastic anemia, pancytopenia Treatment HydroxyCobalamin Level of Evidence 4 Clinical Practice Standard of Care Treatment Effect Improves psychomotor[treatable-id.org]
Delayed Milestone
  • Developmental delay: Milestones would be delayed by about 20% of their time zone. It’s not a gross delay but more than one developmental milestone is connected to nutritional insufficiency.[symptoma.com]


All the signs noted for pernicious anemia and megaloblastic anemia can be noted here:

  • Hemogram would show decreased hemoglobin content but normal RBC count. May show raised eosinophils.
  • Mean corpuscular volume will be raised as will be packed cell volume while mean corpuscular hemoglobin will be on the lower side.
  • As a side effect of vitamin B12 deficiency, triglycerides and bilirubin may be raised and PAP smear may be false positive.
  • Serum vitamin B12 levels would be abysmally low.
  • Serum iron studies would be normal.
  • Anaemia and macrocytosis (enlarged red blood cells) are known symptoms of Pernicious Anaemia. A large number of patients however has no anaemia or macrocytosis so this should not stand in the way of a correct diagnosis.[stichtingb12tekort.nl]
  • The diagnosis may be missed or delayed in these ethnic groups because of masking of the hematological features of macrocytosis by coexistent thalassemia or iron deficiency.[basicmedicalkey.com]
  • Drug-induced macrocytosis Macrocytosis due to certain medications, including hydroxyurea, methotrexate, zidovudine, azathioprine, capecitabine, and cladribine. Usually a clinical diagnosis. Serum drug levels may confirm the association.[online.epocrates.com]
  • Laboratory evaluations were notable for pancytopenia with macrocytosis, a bone marrow with marked megaloblastic changes and repeatedly negative blood cultures ( Table 1 ).[nature.com]
  • Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med. 1998 Jun30;318(26):1720-8[ispub.com]
Macrocytic Anemia
  • In children presenting with macrocytic anemia, the differential diagnosis does include myelodysplastic syndrome and bone marrow failure, yet cobalamin and folate deficiency should be considered even in the absence of an obvious explanation.[epostersonline.com]
  • Myelodysplastic syndrome (MDS) Presents with macrocytic anemia and is difficult to differentiate from vitamin B12 deficiency initially.[online.epocrates.com]
  • Definition: Macrocytic Anemia  MCV 100fL  Impaired DNA formation due to lack of vitamin B12 or folate in ultimately active form.  Therefore, maturation of nucleus is delayed relative to that of cytoplasm. 3.[slideshare.net]
  • Cobalamin deficiency, macrocytic anemia and other neurological complications are some of the disorders that are associated with insufficient absorption and metabolism of vitamin B 12, which is the main cause of pernicious anemia.[health-forever.com]
  • Other disorders that interfere with the absorption and metabolism of vitamin B12 can produce cobalamin deficiency, with the development of a macrocytic anemia and neurologic complications.[emedicine.medscape.com]


The mutated gene cannot be repaired so the primary course of treatment is supplementation. Oral supplementation of vitamin B12 is completely ineffective as it is not absorbed from the intestines, as explained above.

Injectable form of vitamin B12 – to the tune of 1,500 mcg per day over a period of time is advisable to bring up the vitamin B12 levels and maintenance of these levels by way of regular injectable supplements is the best known treatment [6].

Along with that folic acid, niacin and thiamine have also shown to help the nutritional deficiencies caused. In cases where the bone marrow is affected, bone marrow transplant and chemotherapy are called for.


Since this disorder is congenital and related to a mutation in the gene, there is nothing that can be done to reverse the mutated gene [4]. Due to pernicious anemia and megaloblastic anemia, there is failure to thrive and poor nutrition. This can be corrected with heavy supplementation of vitamin B12 and in mild to moderate cases the patient can survive for quite a long time based on these supplements.


As the name suggests, it is congenital or hereditary. There is a bi-allelic mutation found in the patients. This mutation occurs on the encoding of chromosome 11 codon sequence number 5 [1]. It causes absence of the enzyme that helps the glycoprotein GIF (Gastric intrinsic factor) break down the cobalamin and get absorbed through the small intestine. Studies have not yet been conducted on the parents or siblings of the patients to know about their involvement at the genetic level or the factors causing the mutation.


Very few cases of actual congenital intrinsic factor deficiency are known. World over there may be about 100 odd such cases of which only 50 have been documented with proper studies and research. The problem is that the manifestation is usually up to 4 years of age, but sometimes it can manifest as late as after the 1st decade or after the 3rd decades of life as well [2].

Another problem is that cases that are detected early in their life, come as failure to thrive and often the diagnosis does not lead to IFD as early as it should.

Sex distribution
Age distribution


The gastric intrinsic factor (GIF) is present along with the hydrochloric acid in the stomach, as well as peptin. Though their amounts may vary, most often than not, HCl has some amount of GIF with it in the stomach. When vitamin B12 enters the stomach, first it gets bound to a glycoprotein called haptocorrin. Then in the duodenum, enzymes digest that haptocorrin and finally in the small intestine the intrinsic factor binds to the vitamin B12. In the absence of GIF, the B12 is not absorbed or bound well and since it is water soluble, it gets wasted [3]. The deficiency of vitamin B12 then causes pernicious anemia or megaloblastic anemia.


Being a congenital disorder of possible genetic mutation, there is no available method of prevention.


Intrinsic factor deficiency or (IFD) is quite a well known and prevalent disorder, but congenital intrinsic factor deficiency or hereditary intrinsic factor deficiency is quite rare and only a few cases are known worldwide.

Essentially, intrinsic factor is a protein found in the acid secreted by the stomach which allows breakdown and absorption of vitamin B12 (cobalamin) through the small intestine. Deficiency of this enzyme causes malabsorption of cobalamin and thus, leads to pernicious anemia or megaloblastic anemia in spite of adequate B12 consumption.

Patient Information

Congenital intrinsic factor deficiency occurs when the stomach fails to produce any intrinsic factor (IF) or produces defective IF. This happens due to a genetic mutation and is therefore hereditary though there are no studies done on the parents of cases of congenital intrinsic factor deficiency, yet.

Often symptoms are noted in the first 5 years of life, if not, they can reveal themselves well after 10 years or during teenage. They reveal themselves disguised as symptoms of anemiamegaloblastic anemia commonly. This is because the absence of the intrinsic factor causes vitamin B12 deficiency (cobalamin) which leads to pernicious anemia or megaloblastic anemia in which red blood cells are larger than normal and therefore get destroyed easily. This leads to poor nutrition for the child and child does not put on weight or grow or gain as he should. This can also be associated with frequent episodes of diarrhea, enlarged liver and spleen and on the mental plane – one may note weakness, lack of concentration and irritability. Most milestones will also be delayed, if not significantly.

The best known treatment for this is vitamin B12 supplementation – by synthetically prepared vitamin B12. Unfortunately this cannot be administered orally and must be taken as an injectable for best results.



  1. Hewitt JE, Gordon MM, Taggart RT, Mohandas TK, et al. Human gastric intrinsic factor: characterization of cDNA and genomic clones and localization to human chromosome 11. Genomics 10 1991(2): 432–40
  2. Berlin H, Berlin R, Brante G. Oral Treatment of Pernicious Anemia with High Doses of Vitamin B12 without Intrinsic Factor. Acta Medica Scandinavica 184 1968 (1–6): 247–258.
  3. Herbert V, Streiff RR, Sullivan, et al. Notes on vitamin B12 absorption, autoimmunity and childhood pernicious anemia, relation of intrinsic factor to blood group substance. Medicine 43: 679-687, 1964.
  4. Katz M, Mehlman CS, Allen RH. Isolation and characterization of an abnormal human intrinsic factor. J. Clin. Invest. 53: 1274-1283, 1974.
  5. Levine JS, Yang Y, Ducos R, Rosenberg AJ, et al. Juvenile pernicious anemia (JPA) due to an abnormal intrinsic factor (IF) that is markedly susceptible to acid and proteolysis. (Abstract) Gastroenterology 80: 1210 only, 1981.
  6. McNicholl B, Egan B. Congenital pernicious anemia: effects on growth, brain, and absorption of B12. Pediatrics 42: 149-156, 1968.

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Last updated: 2018-06-21 17:18