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.

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.

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.

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.

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.

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

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.

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.

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.

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.

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.

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.

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.

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.

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

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.

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.

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.

Haemochromatosis is in its manifestations, "i.e.", often presenting with signs or symptoms suggestive of other diagnoses that affect specific organ systems. Many of the signs and symptoms below are uncommon and most patients with the hereditary form of haemochromatosis do not show any overt signs of disease nor do they suffer premature morbidity.

The classic triad of cirrhosis, bronze skin and diabetes is not as common any more because of earlier diagnosis.

The more common clinical manifestations include:

- Fatigue

- Malaise

- Joint and bone pain

- Liver cirrhosis (with an increased risk of hepatocellular carcinoma) Liver disease is always preceded by evidence of liver dysfunction including elevated serum enzymes specific to the liver, clubbing of the fingers, leuconychia, asterixis, hepatomegaly, palmar erythema and spider naevi. Cirrhosis can also present with jaundice (yellowing of the skin) and ascites.

- Insulin resistance (often patients have already been diagnosed with diabetes mellitus type 2) due to pancreatic damage from iron deposition

- Erectile dysfunction and hypogonadism, resulting in decreased libido

- Congestive heart failure, abnormal heart rhythms or pericarditis

- Arthritis of the hands (especially the second and third MCP joints), but also the knee and shoulder joints

- Damage to the adrenal gland, leading to adrenal insufficiency

Less common findings including:

- Deafness

- Dyskinesias, including Parkinsonian symptoms

- Dysfunction of certain endocrine organs:

- Parathyroid gland (leading to hypocalcaemia)

- Pituitary gland

- More commonly a slate-grey or less commonly darkish colour to the skin (see pigmentation, hence its name "diabetes bronze" when it was first described by Armand Trousseau in 1865)

- An increased susceptibility to certain infectious diseases caused by siderophilic microorganisms:

- "Vibrio vulnificus" infections from eating seafood or wound infection

- "Listeria monocytogenes"

- "Yersinia enterocolica"

- "Salmonella enterica" (serotype Typhymurium)

- "Klebsiella pneumoniae"

- "Escherichia coli"

- "Rhizopus arrhizus"

- "Mucor" species

Males are usually diagnosed after their forties and fifties, and women several decades later, owing to regular iron loss through menstruation (which ceases in menopause). The severity of clinical disease in the hereditary form varies considerably. There is evidence suggesting that hereditary haemochromatosis patients affected with other liver ailments such as hepatitis or alcoholic liver disease suffer worse liver disease than those with either condition alone. There are also juvenile forms of hereditary haemochromatosis that present in childhood with the same consequences of iron overload.

Iron is stored in the liver, the pancreas and the heart. Long-term effects of haemochromatosis on these organs can be very serious, even fatal when untreated. For example, similar to alcoholism, haemochromatosis can cause cirrhosis of the liver. The liver is a primary storage area for iron and will naturally accumulate excess iron. Over time the liver is likely to be damaged by iron overload. Cirrhosis itself may lead to additional and more serious complications, including bleeding from dilated veins in the esophagus (esophageal varices) and stomach (gastric varices) and severe fluid retention in the abdomen (ascites). Toxins may accumulate in the blood and eventually affect mental functioning. This can lead to confusion or even coma (hepatic encephalopathy).

Liver cancer: Cirrhosis and haemochromatosis together will increase the risk of liver cancer. (Nearly one-third of people with haemochromatosis and cirrhosis eventually develop liver cancer.)

Diabetes: The pancreas which also stores iron is very important in the body’s mechanisms for sugar metabolism. Diabetes affects the way the body uses blood sugar (glucose). Diabetes is in turn the leading cause of new blindness in adults and may be involved in kidney failure and cardiovascular disease.

Congestive heart failure: If excess iron in the heart interferes with the its ability to circulate enough blood, a number of problems can occur, even death. The condition may be reversible when haemochromatosis is treated and excess iron stores reduced.

Heart arrhythmias: Arrhythmia or abnormal heart rhythms can cause heart palpitations, chest pain and light-headedness and are occasionally life-threatening. This condition can often be reversed with treatment for haemochromatosis.

Pigment changes: Bronze or grey coloration of the skin is caused primarily by increased melanin deposition, with iron deposition playing a lesser role.

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.

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

Splenic diseases include splenomegaly, where the spleen is enlarged for various reasons. On the other hand, a lack of normal spleen function is called asplenia.

Blue nails, or more formally azure lunula, are characterized by a blue discoloration of the lunulae, seen in argyria and cases of hepatolenticular degeneration (Wilson's disease), also having been reported in hemoglobin M disease and hereditary acrolabial telangiectases.

In Wilson's disease the blue color involves the lunula (most intense pigmentation) and fades proximally. In argyria, the nail is permanently pigmented a slate-blue color and is most evident in the lunula. Minocycline and Zidovudine can also turn the nail plate blue-gray. There are also reports of hydroxyurea as a rare cause.

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.