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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).


Presentation

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].
Falling
  • MyBioSource and its authorized distributors reserve the right to refuse to process any order where we reasonably believe that the intended use will fall outside of our acceptable guidelines.[mybiosource.com]
  • In those where repeat sampling still falls within the 'subclinical' range, a blood sample should be taken for IFAB and a short trial of empirical therapy (oral cyanocobalamin 50 micrograms daily for four weeks) should be given while awaiting results of[patient.info]
  • The serum iron is high but falls within 48 h of a single injection of vitamin B 12. The serum vitamin B 12 level is below the normal reference range in 95–97% of cases.[basicmedicalkey.com]
  • (288.60-288.69) immunity disorders (279.0-279.9) 288.9 Unspecified disease of white blood cells 289 Other diseases of blood and blood-forming organs 289.0 Polycythemia, secondary High-oxygen-affinity hemoglobin Polycythemia: acquired benign due to: fall[theodora.com]
  • The self-reported ESS is a 9-item questionnaire, responses are rated on a 4-point (0–3) Likert scale (0 “no chance of falling asleep” to 3 “high chance of falling asleep”), with scores ranging from 0 to 24.[frontiersin.org]
Fever
  • The patient was admitted to our hospital, complaining of severe anemia, slight fever, and general fatigue, but his first episode of anemia was recognized when he was 6 years old. He was treated with V. B 12 before admission.[ci.nii.ac.jp]
  • 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.[symptoma.com]
  • (see Q Fever, [[Q Fever]]) Starvation Tuberculosis (see Tuberculosis, [[Tuberculosis]]) Increased RBC Destruction Hereditary Familial Atypical Hemolytic-Uremic Syndrome (aHUS) (see Hemolytic-Uremic Syndrome, [[Hemolytic-Uremic Syndrome]]) Hemoglobinopathies[mdnxs.com]
  • […] pseudohemophilia 287.9 Unspecified hemorrhagic conditions Hemorrhagic diathesis (familial) 288 Diseases of white blood cells Excludes: leukemia (204.0-208.9) 288.0 Neutropenia Decreased Absolute Neutrophil Count (ANC) Use additional code for any associated: fever[theodora.com]
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]
  • ., 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]
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]
Hepatosplenomegaly
  • 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]
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]
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]
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]
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]

Workup

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.
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]
  • 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]
  • Neuropsychiatric disorders caused by cobalamin deficiency in the absence of anemia or macrocytosis. N Engl J Med . 1988;318(26):1720-1728.Mayo Clinic Proc. 1994;69(2):144-150. 15. Donaldson MS.[consultant360.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]
  • 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]
  • It is a common cause of macrocytic anemia and pancytopenia, and it may indirectly increase the risk of myocardial infarction and stroke by producing hyperhomocysteinemia, an independent risk factor for atherosclerotic disease. 3,11 Vitamin B 12 deficiency[consultant360.com]
  • Morphology Peripheral smear ( Figure ) RBCs - Macrocytic anemia, ovulocytosis - Poikilocytosis if anemia is severe. - Normo / hyperchromasia - Increased polychromatophilic cells. - Many nucleated RBCs may be seen resulting in leucoerythroblastic reaction[sites.google.com]

Treatment

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.

Prognosis

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.

Etiology

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.

Epidemiology

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

Pathophysiology

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.

Prevention

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

Summary

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 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.

References

Article

  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: 2019-07-11 19:59