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].

• Developmental Delay

  delay often with myelopathy or peripheral neuropathy. [treatable-id.org]

  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]

  At 4 months of age, the infant presented with pancytopenia and developmental delay. Our evaluation revealed physical and neurological developmental delay, pancytopenia with macrocytosis, with head imaging showing cortical and subcortical atrophy. [nature.com]

  These defects produce developmental delay and a megaloblastic anemia, which can be alleviated with pharmacologic doses of cobalamin. [emedicine.medscape.com]

  concussion, stroke) severe developmental delay precluding active study participation and self-reporting (e.g., cerebral palsy, severe hypoxic-injury, or genetic syndrome associated with cognitive delays). [frontiersin.org]

• Difficulty Walking

  Symptoms may include: Abnormal paleness or lack of color of the skin Decreased appetite Irritability Lack of energy or tiring easily (fatigue) Diarrhea Difficulty walking Numbness or tingling in hands and feet Smooth and tender tongue Weak muscles The [stanfordchildrens.org]

  The person may lose their balance, feel unsteady, or experience difficulty walking. Neurological issues, such as depression, confusion, memory loss or dementia may appear. [disabled-world.com]

• Sighing

  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]

• Failure to Thrive

  Due to pernicious anemia and megaloblastic anemia, there is failure to thrive and poor nutrition. [symptoma.com]

  […] to thrive, vomiting, diarrhea and developmental delay often with myelopathy or peripheral neuropathy. [treatable-id.org]

  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. [orpha.net]

• Cyanosis

  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]

• Muscle Weakness

  weakness; problems with balance and co-ordination; problems with your eyesight; depression; confusion; and memory loss. [mydr.com.au]

  The most frequent of these are paresthesiae in the extremities, difficulty in walking and muscle weakness. Others include poor vision, stiffness of the limbs, impotence and in advanced cases, impairment of bladder and rectal control. [basicmedicalkey.com]

  This can cause tingling and numbness in your hands and feet, muscle weakness, and loss of reflexes. You also may feel unsteady, lose your balance, and have trouble walking. [theoncologyinstitute.com]

  - Paresthetia, muscle weakness difficultly in walking. · Demyelination of posterior & pyramidal tracts of spinal cord. [sites.google.com]

• Muscle Cramp

  Muscle cramps and tetany may reflect hypomagnesmia in patients with malabsorption. Zinc is absorbed also by a transport system in the small bowel. A zinc-binding ligand transports zinc across the enterocytes to the serosal surface. [saudijgastro.com]

• Abnormal Gait

  Neurological symptoms may include muscular weakness and abnormal gait. Etiology 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. [orpha.net]

  gait PNS Manifestations Neuropathy motor-sensory polyneuropathy (parasthesias, numbness and weakness) mononeuropathy (optic or olfactory) autonomic neuropathy (impotence, urinary or fecal incontinence Myeloneuropathy (combined myelopathy and neuropathy [ispub.com]

• Asthenia

  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. [orpha.net]

  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. [symptoma.com]

• Myelopathy

  […] development/IQ, neurological & systemic manifestations The absence or afunctional status of Intrinsic Factor causes symptoms usually between 1-5 years of age: megaloblastic anemia, failure to thrive, vomiting, diarrhea and developmental delay often with myelopathy [treatable-id.org]

  The myelopathy of vitamin B-12 deficiency is virtually indistinguishable from the vacuolar myelopathy of AIDS. [ispub.com]

  (spinal cord) G95.9 ICD-10-CM Diagnosis Code G95.9 Disease of spinal cord, unspecified 2016 2017 2018 2019 Billable/Specific Code Applicable To Myelopathy NOS in (due to) pernicious anemia D51.0 Neuropathy, neuropathic G62.9 ICD-10-CM Diagnosis Code [icd10data.com]

  The clinical picture in such patients is further complicated by multiple nutrient deficiencies including that of copper, which can produce a myeloneuropathy resembling that seen in vitamin B 12 deficient myelopathy as well as anemia, which may be macrocytic [basicmedicalkey.com]

• Mononeuropathy

  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]

  […] 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]

• 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.

• Enlargement of the Spleen

  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. [symptoma.com]

  There may be slight jaundice, a low-grade pyrexia and slight enlargement of the spleen. Neurologic symptoms, which affect only some patients, usually begin in the lower limbs and are symmetrical. [basicmedicalkey.com]

• Enlargement of the Liver

  Other symptoms of untreated vitamin B12 deficiency may include: Weight loss An enlarged spleen and liver (hepatosplenomegaly) Exaggerated reflexes Mild depression and confusion Hallucinations, personality and mood changes Irritability Damage to the optic [southerncross.co.nz]

  The person may experience and enlargement of their liver, or throat issues and a smooth, red tongue. Infants who are vitamin B12 deficient and do not receive treatment may experience permanent growth issues. [disabled-world.com]

• Macrocytosis

  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]

  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]

  LFTs, TFTs and protein electrophoresis may help in the differential diagnosis of macrocytosis. Vitamin B12: Serum vitamin B12 is currently the standard initial routine diagnostic test. [patient.info]

• 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]

  Showing 1-10 of 147 references Effect of vitamin The New England Journal of Medicine Downloaded from nejm.org at CHILDRENS MERCY Evaluation of macrocytic anemias [pdfs.semanticscholar.org]

  In pernicious anemia, a CBC, or complete blood count, will reveal macrocytic anemia. [study.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]

  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.

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.

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 anemia – megaloblastic 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.