Hereditary spherocytosis (also known as Minkowski–Chauffard syndrome) abnormality of erythrocytes. The disorder is caused by mutations in genes relating to membrane proteins that allow for the erythrocytes to change shape. The abnormal erythrocytes are sphere-shaped (spherocytosis) rather than the normal biconcave disk shaped. Dysfunctional membrane proteins interfere with the cell's ability to be flexible to travel from the arteries to the smaller capillaries. This difference in shape also makes the red blood cells more prone to rupture. Cells with these dysfunctional proteins are taken for degradation at the spleen. This shortage of erythrocytes results in hemolytic anemia.

It was first described in 1871 and is the most common cause of inherited hemolysis in Europe and North America within the Caucasian population, with an incidence of 1 in 5000 births. The clinical severity of HS varies from symptom-free

carrier to severe haemolysis because the disorder exhibits incomplete penetrance in its expression.

Symptoms include anemia, jaundice, splenomegaly, and fatigue. On a blood smear, Howell-Jolly bodies may be seen within red blood cells. Primary treatment for patients with symptomatic HS has been total splenectomy, which eliminates the hemolytic process, allowing normal hemoglobin, reticulocyte and bilirubin levels.

As in non-hereditary spherocytosis, the spleen destroys the spherocytes. This process of red blood cells rupturing directly results in varying degrees of anemia (causing a pale appearance and fatigue), high levels of bilirubin in the blood (causing jaundice), and splenomegaly.

Acute cases can threaten to cause hypoxia through anemia and acute kernicterus through high blood levels of bilirubin, particularly in newborns. Most cases can be detected soon after birth. An adult with this disease should have their children tested, although the presence of the disease in children is usually noticed soon after birth. Occasionally, the disease will go unnoticed until the child is about 4 or 5 years of age. A person may also be a carrier of the disease and show no signs or symptoms of the disease. Other symptoms may include abdominal pain that could lead to the removal of the spleen and/or gallbladder.

Chronic symptoms include anemia, increased blood viscosity, and splenomegaly, and some symptoms are still unknown at this stage. Furthermore, the detritus of the broken-down blood cells – unconjugated or indirect bilirubin – accumulates in the gallbladder, and can cause pigmented gallstones to develop. In chronic patients, an infection or other illness can cause an increase in the destruction of red blood cells, resulting in the appearance of acute symptoms, a "hemolytic crisis". Spherocytosis patients who are heterozygous for a hemochromatosis gene may suffer from iron overload despite the hemochromatosis genes being recessive.

The vast majority of those with hereditary elliptocytosis require no treatment whatsoever. They have a mildly increased risk of developing gallstones, which is treated surgically with a cholecystectomy if pain becomes problematic. This risk is relative to the severity of the disease.

Folate helps to reduce the extent of haemolysis in those with significant haemolysis due to hereditary elliptocytosis.

Because the spleen breaks down old and worn-out blood cells, those individuals with more severe forms of hereditary elliptocytosis can have splenomegaly. Symptoms of splenomegaly can include:

- Vague, poorly localised abdominal pain

- Fatigue and dyspnoea

- Growth failure

- Leg ulcers

- Gallstones.

Removal of the spleen (splenectomy) is effective in reducing the severity of these complications, but is associated with an increased risk of overwhelming bacterial septicaemia, and is only performed on those with significant complications. Because many neonates with severe elliptocytosis progress to have only a mild disease, and because this age group is particularly susceptible to pneumococcal infections, a splenectomy is only performed on those under 5 years old when it is absolutely necessary.

Hereditary elliptocytosis, also known as ovalocytosis, is an inherited blood disorder in which an abnormally large number of the patient's erythrocytes (i.e. red blood cells) are elliptical rather than the typical disc shape. Such morphologically distinctive erythrocytes are sometimes referred to as elliptocytes or ovalocytes. It is one of many red-cell membrane defects. In its severe forms, this disorder predisposes to haemolytic anaemia. Although pathological in humans, elliptocytosis is normal in camelids.

Hereditary pyropoikilocytosis (HPP) is an autosomal recessive form of hemolytic anemia characterized by an abnormal sensitivity of red blood cells to heat and erythrocyte morphology similar to that seen in thermal burns. Patients with HPP tend to experience severe haemolysis and anaemia in infancy that gradually improves, evolving toward typical elliptocytosis later in life. However, the hemolysis can lead to rapid sequestration and destruction of red cells. Splenectomy is curative when this occurs.

HPP has been associated with a defect of the erythrocyte membrane protein spectrin and with spectrin deficiency.It was characterized in 1975.It is considered a severe form of hereditary elliptocytosis.

Hereditary stomatocytosis describes a number of inherited autosomal dominant human conditions which affect the red blood cell, in which the membrane or outer coating of the cell 'leaks' sodium and potassium ions.

In a peripheral blood smear, the red blood cells will "appear" abnormally small and lack the central pale area that is present in normal red blood cells. These changes are also seen in non-hereditary spherocytosis, but they are typically more pronounced in hereditary spherocytosis. The number of immature red blood cells (reticulocyte count) will be elevated. An increase in the mean corpuscular hemoglobin concentration is also consistent with hereditary spherocytosis.

Other protein deficiencies cause hereditary elliptocytosis, pyropoikilocytosis or stomatocytosis.

In longstanding cases and in patients who have taken iron supplementation or received numerous blood transfusions, iron overload may be a significant problem. This is a potential cause of heart muscle damage and liver disease. Measuring iron stores is therefore considered part of the diagnostic approach to hereditary spherocytosis.

An osmotic fragility test can aid in the diagnosis. In this test, the spherocytes will rupture in liquid solutions less concentrated than the inside of the red blood cell. This is due to increased permeability of the spherocyte membrane to salt and water, which enters the concentrated inner environment of the RBC and leads to its rupture. Although the osmotic fragility test is widely considered the gold standard for diagnosing hereditary spherocytosis, it misses as many as 25% of cases. Flow cytometric analysis of eosin-5′-maleimide-labeled intact red blood cells and the acidified glycerol lysis test are two additional options to aid diagnosis.

Congenital hemolytic anemia (or hereditary hemolytic anemia) refers to hemolytic anemia which is primarily due to congenital disorders.

The condition is usually asymptomatic, and is only noticed when screening for other hemoglobin disorders.

Genetic testing for the presence of mutations in protein molecules is considered to be a confirmatory testing technique. It is important to know the risks regarding the transmission and dangers of HPP.

The anemia associated with CDA type II can range from mild to severe, and most affected individuals have jaundice, hepatosplenomegaly, and the formation of hard deposits in the gallbladder called bilirubin gallstones. This form of the disorder is usually diagnosed in adolescence or early adulthood. An abnormal buildup of iron typically occurs after age 20, leading to complications including heart disease, diabetes, and cirrhosis.

Basically classified by causative mechanism, types of congenital hemolytic anemia include:

- Genetic conditions of RBC Membrane

- Hereditary spherocytosis

- Hereditary elliptocytosis

- Genetic conditions of RBC metabolism (enzyme defects). This group is sometimes called "congenital nonspherocytic (hemolytic) anemia", which is a term for a congenital hemolytic anemia without spherocytosis, and usually excluding hemoglobin abnormalities as well, but rather encompassing defects of glycolysis in the erythrocyte.

- Glucose-6-phosphate dehydrogenase deficiency (G6PD or favism)

- Pyruvate kinase deficiency

- Aldolase A deficiency

- Hemoglobinopathies/genetic conditions of hemoglobin

- Sickle cell anemia

- Congenital dyserythropoietic anemia

- Thalassemia

Hereditary persistence of fetal hemoglobin (HPFH, BrE: "Hereditary persistence of foetal haemoglobin") is a benign condition in which significant fetal hemoglobin (hemoglobin F) production continues well into adulthood, disregarding the normal shutoff point after which only adult-type hemoglobin should be produced.

Congenital dyserythropoietic anemia type II (CDA II), or hereditary erythroblastic multinuclearity with positive acidified serum lysis test (HEMPAS) is a rare genetic anemia in humans characterized by hereditary erythroblastic multinuclearity with positive acidified serum lysis test.

Haematologists have identified a number of variants. These can be classified as below.

- Overhydrated hereditary stomatocytosis

- Dehydrated HSt (hereditary xerocytosis; hereditary hyperphosphatidylcholine haemolytic anaemia)

- Dehydrated with perinatal ascites

- Cryohydrocytosis

- 'Blackburn' variant.

- Familial pseudohyperkalaemia

There are other families that do not fall neatly into any of these classifications.

Stomatocytosis is also found as a hereditary disease in Alaskan malamute and miniature schnauzer dogs.

Spherocytosis is an auto-hemolytic anemia (a disease of the blood) characterized by the production of spherocytes (red blood cells (RBCs)) or erythrocytes that are sphere-shaped rather than bi-concave disk shaped. Spherocytes are found in all hemolytic anemias to some degree. Hereditary spherocytosis and autoimmune hemolytic anemia are characterized by having "only" spherocytes.

Spherocytosis most often refers to hereditary spherocytosis. This is caused by a molecular defect in one or more of the proteins of the red blood cell cytoskeleton, including spectrin, ankyrin, Band 3, or Protein 4.2. Because the cell skeleton has a defect, the blood cell contracts to a sphere, which is its most surface tension efficient and least flexible configuration. Though the spherocytes have a smaller surface area through which oxygen and carbon dioxide can be exchanged, they in themselves perform adequately to maintain healthy oxygen supplies. However, they have a high osmotic fragility—when placed into water, they are more likely to burst than normal red blood cells. These cells are more prone to physical degradation.

Spherocytes are most commonly found in immunologically-mediated hemolytic anemias and in hereditary spherocytosis, but the former would have a positive direct Coombs test and the latter would not. The misshapen but otherwise healthy red blood cells are mistaken by the spleen for old or damaged red blood cells and it thus constantly breaks them down, causing a cycle whereby the body destroys its own blood supply (auto-hemolysis). A complete blood count (CBC) may show increased reticulocytes, a sign of increased red blood cell production, and decreased hemoglobin and hematocrit.

The term "non-hereditary spherocytosis" is occasionally used, albeit rarely.

The issue is thought of as representing any of the following:

- a decreased production of normal-sized red blood cells (e.g., anemia of chronic disease, aplastic anemia);

- an increased production of HbS as seen in sickle cell disease (not sickle cell trait);

- an increased destruction or loss of red blood cells (e.g., hemolysis, posthemorrhagic anemia);

- an uncompensated increase in plasma volume (e.g., pregnancy, fluid overload);

- a B2 (riboflavin) deficiency

- a B6 (pyridoxine) deficiency

- or a mixture of conditions producing microcytic and macrocytic anemia.

Blood loss, suppressed production of RBCs or hemolysis represent most cases of normocytic anemia. In blood loss, morphologic findings are generally unremarkable except after 12 to 24 hrs where polychromasia appears. For reduced production of RBCs, like with low erythropoietin, the RBC morphology is unremarkable. Patients with disordered RBC production, e.g. myelodysplastic syndrome, may have a dual population of elliptocytes, teardrop cells, or other poikilocytes as well as a nucleated RBCs. Hemolysis will often demonstrate poikilocytes specific to a cause or mechanism. E.g. Bite cells and/or blistor cells for oxidative hemolysis, Acanthocytes for pyruvate kinase deficiency or McLeod phenotype, Sickle cells for sickle cell anemia, Spherocytes for immune-mediated hemolysis or hereditary spherocytosis, Elliptocytosis for iron deficiency or hereditary elliptocytosis and schistocytes for intravascular hemolysis. Many hemolytic anemias show multiple poikilocytes such as G6PD deficiency which may show blister and bites cells as well as shistocytes. Neonatal hemolysis may not follow the classic patterns as in adults

A normocytic anemia is defined as an anemia with a mean corpuscular volume (MCV) of 80–100 which is the normal range. However, the hematocrit and hemoglobin is decreased.

Harderoporphyria is a rare disorder of heme biosynthesis, inherited in an autosomal recessive manner caused by specific mutations in the "CPOX" gene. Mutations in "CPOX" usually cause hereditary coproporphyria, an acute hepatic porphyria, however the K404E mutation in a homozygous or compound heterozygous state with a null allele cause the more severe harderoporphyria. Harderoporphyria is the first known metabolic disorder where the disease phenotype depended on the type and location of the mutations in a gene associated with multiple disorders.

In contrast with other porphyrias, which typically present with either cutaneous lesions after exposure to sunlight or acute neurovisceral attack at any age (most commonly in adulthood), harderoporphyria is characterized by jaundice, anemia enlarged liver and spleen, often presenting in the neonatal period. Later in life, these individuals may present with photosensitivity similar to that found in cutaneous porphyrias.

Biochemically, harderoporphyria presents with a distinct pattern of increased harderoporphyrin (2-vinyl-4,6,7-tripropionic acid porphyrin) in urine and particularly in feces, a metabolite that is not seen in significant quantities in any other porphyria. Enzyme tests show markedly reduced activity of coproporphyrinogen oxidase, compared to both unaffected individuals and those affected with hereditary coproporphyria, consistent with recessive inheritance.

Harderoporphyria is a rare condition, with less than 10 cases reported worldwide. It may be underdiagnosed, as it does not have the typical presentation associated with a porphyria. It was identified as a variant type of coproporphyria in 1983, in a family with three children identified at birth with jaundice and hemolytic anemia. There is no standard treatment for harderoporphyria; care is mainly focused on the management of symptoms.

Organs commonly affected by haemochromatosis are the liver, heart, and endocrine glands.

Haemochromatosis may present with the following clinical syndromes:

- Cirrhosis of the liver: Varies from zonal iron deposition to fibrosis (cirrhosis).

- Diabetes due to selective iron deposition in pancreatic islet beta cells leading to functional failure and cell death.

- Cardiomyopathy

- Arthritis, from calcium pyrophosphate deposition in joints. The most commonly affected joints are those of the hands, particularly the knuckles of the second and third fingers.

- Testicular failure

- Bronzing of the skin. This deep tan color, in concert with insulin insufficiency due to pancreatic damage, is the source of a nickname for this condition: "bronze diabetes".

- Joint pain and bone pain

Hepatic porphyrias is a form of porphyria in which the enzyme deficiency occurs in the liver.

Examples include (in order of synthesis pathway):

- Acute intermittent porphyria

- Porphyria cutanea tarda and Hepatoerythropoietic porphyria

- Hereditary coproporphyria

- Variegate porphyria

Iron overload, also known as haemochromatosis, indicates accumulation of iron in the body from any cause. The most important causes are hereditary haemochromatosis (HHC), a genetic disorder, and transfusional iron overload, which can result from repeated blood transfusions.

Neonatal Hemochromatosis is a rare and severe liver disease of unknown origin, though research suggests that it may be alloimmune condition. Its characteristics are similar to hereditary hemochromatosis, where iron deposition causes damage to the liver and other organs and tissues.

Southeast Asian ovalocytosis is a blood disorder that is similar to, but distinct from hereditary elliptocytosis. It is common in some communities in Malaysia and Papua New Guinea, as it confers some resistance to cerebral Falciparum Malaria.

The low incidence of this syndrome is often related to aldolase A's essential glycolytic role along with its exclusive expression in blood and skeletal muscle. Early developmental reliance and constitutive function prevents severe mutation in successful embryos. Infrequent documentation thus prevents clear generalisation of symptoms and causes. However five cases have been well described. ALDOA deficiency is diagnosed through reduced aldoA enzymatic activity, however, both physiological response and fundamental causes vary.

The causes of neonatal hemochromatosis are still unknown, but recent research has led to the hypothesis that it is an alloimmune disease. Evidence supporting this hypothesis includes the high rate among siblings (>80%). This evidence along with other research indicates that neonatal hemochromatosis could be classified as a congenital alloimmune hepatitis.