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).

Celiac disease is a systemic autoimmune disease that can be associated with gastrointestinal findings (diarrhea, malabsorption, abdominal pain and distension, bloating, vomiting, and weight loss) and/or highly variable non-gastrointestinal findings (dermatitis herpetiformis, chronic fatigue, joint pain/inflammation, iron deficiency anemia, migraines, depression, attention-deficit disorder, epilepsy, osteoporosis/osteopenia, infertility and/or recurrent fetal loss, vitamin deficiencies, short stature, failure to thrive, delayed puberty, dental enamel defects, and autoimmune disorders). Classic celiac disease, characterized by mild to severe gastrointestinal symptoms, is less common than non-classic celiac disease, characterized by absence of gastrointestinal symptoms.

Folate-responsive megaloblastic anemia (MEGAF) is an autosomal recessive metabolic disorder characterized by megaloblastic anemia resulting from decreased folate transport into erythrocytes. Although serum levels of folate are normal, there is folate deficiency in tissues, including erythrocytes and possibly nerve cells. Serum homocysteine levels are increased and vitamin B12 levels may be decreased. Treatment with oral folate corrects the anemia and normalizes homocysteine (summary by Svaton et al., 2020)

Diarrhea-6 is a relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis (Fiskerstrand et al., 2012). For a discussion of genetic heterogeneity of diarrhea, see DIAR1 (214700).

Imerslund-Grasbeck syndrome-1 (IGS1) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but sometimes occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Some patients may present later in childhood with neurologic abnormalities related to B12 deficiency, such as sensorimotor neuropathy and/or cognitive disturbances. Treatment with vitamin B12 results in sustained clinical improvement of the anemia and resolution of the neurologic symptoms, if present. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN (605799)/CUBN complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; 609342). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; 600073), which is important for the reabsorption of plasma proteins (summary by Grasbeck, 2006, Storm et al., 2011, Storm et al., 2013). Genetic Heterogeneity of Imerslund-Grasbeck Syndrome See also IGS2 (618882), caused by mutation in the AMN gene (605799) on chromosome 14q32. Congenital pernicious anemia (261000), a distinct disorder with overlapping features, is caused by mutation in the GIF (CBLIF) gene (609342). Adult pernicious anemia (170900) is another distinct autoimmune disorder associated with plasma autoantibodies to gastric parietal cells or gastric intrinsic factor.

Imerslund-Grasbeck syndrome-2 (IGS2) is an autosomal recessive disorder characterized by onset of megaloblastic anemia associated with decreased serum vitamin B12 (cobalamin, Cbl) in infancy or early childhood. Low molecular weight (LMW) proteinuria is frequently present, but usually occurs later and is usually mild or subclinical. Patients often present with vague symptoms, including failure to thrive, loss of appetite, fatigue, lethargy, and/or recurrent infections. Treatment with vitamin B12 results in sustained clinical improvement of the anemia. The proteinuria is nonprogressive, and affected individuals do not have deterioration of kidney function; correct diagnosis is important to prevent unnecessary treatment. The disorder results from a combination of vitamin B12 deficiency due to selective malabsorption of the vitamin, and impaired reabsorption of LMW proteins in the proximal renal tubule. These defects are caused by disruption of the AMN/CUBN (602997) complex that forms the 'cubam' receptor responsible for intestinal uptake of B12/GIF (CBLIF; 609342). In the kidney, AMN/CUBN interacts with the endocytic receptor megalin (LRP2; 600073), which is important for the reabsorption of plasma proteins (summary by Grasbeck, 2006, De Filippo et al., 2013, and Storm et al., 2013). For a discussion of genetic heterogeneity of Imerslund-Grasbeck syndrome, see 261100.

Neurodevelopmental disorder with seizures, hypotonia, and brain imaging abnormalities (NEDSHBA) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay, severe to profound intellectual impairment, early-onset refractory seizures, hypotonia, failure to thrive, and progressive microcephaly. Brain imaging shows cerebral atrophy, thin corpus callosum, and myelination defects. Death in childhood may occur (summary by Marafi et al., 2020).