Glycogen storage disease VII is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder.

Red cell pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. PK deficiency is also the most frequent enzyme abnormality of the glycolytic pathway (Zanella et al., 2005).

Harderoporphyria (HARPO) is a rare erythropoietic variant form of hereditary coproporphyria (HCP; 121300) characterized by neonatal hemolytic anemia, sometimes accompanied by skin lesions, and massive excretion of harderoporphyrin in feces. During childhood and adulthood, a mild residual anemia is chronically observed (review by Schmitt et al., 2005).

Hereditary thrombotic thrombocytopenic purpura (TTP), also known as Upshaw-Schulman syndrome (USS), is a rare autosomal recessive thrombotic microangiopathy (TMA). Clinically, acute phases of TTP are defined by microangiopathic mechanical hemolytic anemia, severe thrombocytopenia, and visceral ischemia. Hereditary TTP makes up 5% of TTP cases and is caused mostly by biallelic mutation in the ADAMTS13 gene, or in very rare cases, by monoallelic ADAMTS13 mutation associated with a cluster of single-nucleotide polymorphisms (SNPs); most cases of all TTP (95%) are acquired via an autoimmune mechanism (see 188030). Hereditary TTP is more frequent among child-onset TTP compared with adult-onset TTP, and its clinical presentation is significantly different as a function of its age of onset. Child-onset TTP usually starts in the neonatal period with hematological features and severe jaundice. In contrast, almost all cases of adult-onset hereditary TTP are unmasked during the first pregnancy of a woman whose disease was silent during childhood (summary by Joly et al., 2018).

Congenital dyserythropoietic anemia type II (CDA II) is the most common form of CDA (see this term) characterized by anemia, jaundice and splenomegaly and often leading to liver iron overload and gallstones.

GATA1-related cytopenia is characterized by thrombocytopenia and/or anemia ranging from mild to severe. One or more of the following may also be present: platelet dysfunction, mild ß-thalassemia, neutropenia, and congenital erythropoietic porphyria (CEP) in males. Thrombocytopenia typically presents in infancy as a bleeding disorder with easy bruising and mucosal bleeding (e.g., epistaxis). Anemia ranges from minimal (mild dyserythropoiesis) to severe (hydrops fetalis requiring in utero transfusion). At the extreme end of the clinical spectrum, severe hemorrhage and/or erythrocyte transfusion dependence are life long; at the milder end, anemia and the risk for bleeding may decrease spontaneously with age. Heterozygous females may have mild-to-moderate symptoms such as menorrhagia.

The phenotypic spectrum of glucose transporter type 1 deficiency syndrome (Glut1 DS) is now known to be a continuum that includes the classic phenotype as well as paroxysmal exercise-induced dyskinesia and epilepsy (previously known as dystonia 18 [DYT18]) and paroxysmal choreoathetosis with spasticity (previously known as dystonia 9 [DYT9]), atypical childhood absence epilepsy, myoclonic astatic epilepsy, and paroxysmal non-epileptic findings including intermittent ataxia, choreoathetosis, dystonia, and alternating hemiplegia. The classic phenotype is characterized by infantile-onset seizures, delayed neurologic development, acquired microcephaly, and complex movement disorders. Seizures in classic early-onset Glut1 DS begin before age six months. Several seizure types occur: generalized tonic or clonic, focal, myoclonic, atypical absence, atonic, and unclassified. In some infants, apneic episodes and abnormal episodic eye-head movements similar to opsoclonus may precede the onset of seizures. The frequency, severity, and type of seizures vary among affected individuals and are not related to disease severity. Cognitive impairment, ranging from learning disabilities to severe intellectual disability, is typical. The complex movement disorder, characterized by ataxia, dystonia, and chorea, may occur in any combination and may be continuous, paroxysmal, or continual with fluctuations in severity influenced by environmental factors such as fasting or with infectious stress. Symptoms often improve substantially when a ketogenic diet is started.

Deficiency of pyrimidine 5-prime nucleotidase, also called uridine 5-prime monophosphate hydrolase, causes an autosomal recessive hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The enzyme is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Hirono et al. (1988) suggested that this deficiency is the third most common RBC enzymopathy--after G6PD (300908) and pyruvate kinase (see 266200) deficiencies--causing hemolysis (summary by Marinaki et al., 2001).

Any hereditary elliptocytosis in which the cause of the disease is a mutation in the SPTA1 gene.

Gamma-glutamylcysteine synthetase deficiency is 1 of 4 diseases involving enzymes in the gamma-glutamyl cycle (Meister, 1974). The other 3 disorders are glutathione synthetase deficiency (231900), 5-oxoprolinuria, which is a severe or generalized form of glutathione synthetase deficiency (266130), and gamma-glutamyl transpeptidase deficiency (231950). All except gamma-glutamyl transpeptidase deficiency are accompanied by hemolytic anemia (Larsson and Anderson, 2001).

Cryohydrocytosis (CHC) is an exceedingly rare condition characterized by a mild stomatocytic hemolytic state with hyperbilirubinemia. A hallmark of this condition is that red blood cells (RBCs) lyse on storage at 4 degrees centigrade. RBC cation permeability is increased at 37 degrees centigrade, and the cells also accumulate sodium in the cold (summary by Coles et al., 1999). Patients present with fatigue, mild anemia, and pseudohyperkalemia due to a potassium leak from the RBCs (summary by Bogdanova et al., 2010). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.

Overhydrated hereditary stomatocytosis is a variably compensated macrocytic hemolytic anemia of fluctuating severity, characterized by circulating erythrocytes with slit-like lucencies (stomata) evident on peripheral blood smears. OHST red cells exhibit cation leak, resulting in elevated cell Na+ content with reduced K+ content, with increased ouabain-resistant cation leak fluxes in the presence of presumably compensatory increases in ouabain-sensitive Na(+)-K(+) ATPase activity, and red cell age-dependent loss of stomatin/EBP7.2 (EBP72; 133090) from the erythroid membrane. Clinically, patients with OHST exhibit overhydrated erythrocytes and a temperature-dependent red cell cation leak. The temperature dependence of the leak is 'monotonic' and has a steep slope, reflecting the very large leak at 37 degrees centigrade (summary by Bruce, 2009 and Stewart et al., 2011). For a discussion of clinical and genetic heterogeneity of the hereditary stomatocytoses, see 194380.

Hemolytic anemia due to elevated adenosine deaminase (HAEADA) is an X-linked hematologic disorder characterized by onset of mild to moderate red cell anemia soon after birth or in childhood. The anemia is associated with significantly increased activity of ADA (608958) specifically in erythrocyte precursors. ATP levels may be secondarily decreased. Additional features may include low birth weight, thrombocytopenia, hypospadias, and splenomegaly. Males are preferentially affected, although carrier females may show elevated erythrocyte ADA or mild features (Ludwig et al., 2022).

The spectrum of CLCN7-related osteopetrosis includes infantile malignant CLCN7-related autosomal recessive osteopetrosis (ARO), intermediate autosomal osteopetrosis (IAO), and autosomal dominant osteopetrosis type II (ADOII; Albers-Schönberg disease). ARO. Onset is at birth. Findings may include: fractures; reduced growth; sclerosis of the skull base (with or without choanal stenosis or hydrocephalus) resulting in optic nerve compression, facial palsy, and hearing loss; absence of the bone marrow cavity resulting in severe anemia and thrombocytopenia; dental abnormalities, odontomas, and risk for mandibular osteomyelitis; and hypocalcemia with tetanic seizures and secondary hyperparathyroidism. Without treatment maximal life span in ARO is ten years. IAO. Onset is in childhood. Findings may include: fractures after minor trauma, characteristic skeletal radiographic changes found incidentally, mild anemia, and occasional visual impairment secondary to optic nerve compression. Life expectancy in IAO is usually normal. ADOII. Onset is usually late childhood or adolescence. Findings may include: fractures (in any long bone and/or the posterior arch of a vertebra), scoliosis, hip osteoarthritis, and osteomyelitis of the mandible or septic osteitis or osteoarthritis elsewhere. Cranial nerve compression is rare.

Phosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).

Any hereditary spherocytosis in which the cause of the disease is a mutation in the ANK1 gene.

People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities.\n\nThere are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.\n\nHereditary spherocytosis is a condition that affects red blood cells. People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood.

EPB42-related hereditary spherocytosis (EPB42-HS) is a chronic nonimmune hemolytic anemia that is usually of mild-to-moderate severity. EPB42-HS can present with jaundice as early as the first 24 hours of life or can present later in childhood with anemia resulting from a hemolytic crisis or aplastic crisis (usually associated with a viral infection). In addition to the hematologic manifestations, serious complications include splenomegaly, which can become evident in early childhood, and cholelithiasis, which usually becomes evident in the second or third decade of life. Typical laboratory findings in EPB42-HS include anemia (decreased hemoglobin [Hgb] level) and reticulocytosis (increased percentage of reticulocytes), with high mean corpuscular Hgb concentration, presence of spherocytes in the peripheral blood smear, significantly decreased or absent haptoglobin, mildly increased osmotic fragility in osmotic fragility assay, increased Omin (osmolality at which 50% of red blood cells hemolyze), and decreased maximal elongation index (EImax) in osmotic gradient ektacytometry.

People with the mild form may have very mild anemia or sometimes have no symptoms. People with the moderate form typically have anemia, jaundice, and splenomegaly. Many also develop gallstones. The signs and symptoms of moderate hereditary spherocytosis usually appear in childhood. Individuals with the moderate/severe form have all the features of the moderate form but also have severe anemia. Those with the severe form have life-threatening anemia that requires frequent blood transfusions to replenish their red blood cell supply. They also have severe splenomegaly, jaundice, and a high risk for developing gallstones. Some individuals with the severe form have short stature, delayed sexual development, and skeletal abnormalities.\n\nThere are four forms of hereditary spherocytosis, which are distinguished by the severity of signs and symptoms. They are known as the mild form, the moderate form, the moderate/severe form, and the severe form. It is estimated that 20 to 30 percent of people with hereditary spherocytosis have the mild form, 60 to 70 percent have the moderate form, 10 percent have the moderate/severe form, and 3 to 5 percent have the severe form.\n\nHereditary spherocytosis is a condition that affects red blood cells. People with this condition typically experience a shortage of red blood cells (anemia), yellowing of the eyes and skin (jaundice), and an enlarged spleen (splenomegaly). Most newborns with hereditary spherocytosis have severe anemia, although it improves after the first year of life. Splenomegaly can occur anytime from early childhood to adulthood. About half of affected individuals develop hard deposits in the gallbladder called gallstones, which typically occur from late childhood to mid-adulthood.

G6PD deficiency is the most common genetic cause of chronic and drug-, food-, or infection-induced hemolytic anemia. G6PD catalyzes the first reaction in the pentose phosphate pathway, which is the only NADPH-generation process in mature red cells; therefore, defense against oxidative damage is dependent on G6PD. Most G6PD-deficient patients are asymptomatic throughout their life, but G6PD deficiency can be life-threatening. The most common clinical manifestations of G6PD deficiency are neonatal jaundice and acute hemolytic anemia, which in most patients is triggered by an exogenous agent, e.g., primaquine or fava beans. Acute hemolysis is characterized by fatigue, back pain, anemia, and jaundice. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. The striking similarity between the areas where G6PD deficiency is common and Plasmodium falciparum malaria (see 611162) is endemic provided evidence that G6PD deficiency confers resistance against malaria (summary by Cappellini and Fiorelli, 2008).

Hemolytic-uremic syndrome (HUS) is characterized by hemolytic anemia, thrombocytopenia, and renal failure caused by platelet thrombi in the microcirculation of the kidney and other organs. The onset of atypical HUS (aHUS) ranges from the neonatal period to adulthood. Genetic aHUS accounts for an estimated 60% of all aHUS. Individuals with genetic aHUS frequently experience relapse even after complete recovery following the presenting episode; 60% of genetic aHUS progresses to end-stage renal disease (ESRD).

Sitosterolemia is characterized by: Hypercholesterolemia (especially in children) which (1) shows an unexpected significant lowering of plasma cholesterol level in response to low-fat diet modification or to bile acid sequestrant therapy; or (2) does not respond to statin therapy; Tendon xanthomas or tuberous (i.e., planar) xanthomas that can occur in childhood and in unusual locations (heels, knees, elbows, and buttocks); Premature atherosclerosis, which can lead to angina, aortic valve involvement, myocardial infarction, and sudden death; Hemolytic anemia, abnormally shaped erythrocytes (stomatocytes), and large platelets (macrothrombocytopenia). On occasion, the abnormal hematologic findings may be the initial presentation or the only clinical feature of this disorder. Arthritis, arthralgias, and splenomegaly may sometimes be seen and one study has concluded that "idiopathic" liver disease could be undiagnosed sitosterolemia. The clinical spectrum of sitosterolemia is probably not fully appreciated due to underdiagnosis and the fact that the phenotype in infants is likely to be highly dependent on diet.

Hexokinase deficiency is an autosomal recessive disorder characterized by early-onset severe hemolytic anemia (summary by van Wijk et al., 2003).

Congenital dyserythropoietic anemia type IV (CDAN4) is an autosomal dominant red blood cell disorder characterized by ineffective erythropoiesis and hemolysis resulting in anemia. Circulating erythroblasts and erythroblasts in the bone marrow show various morphologic abnormalities. Affected individuals with CDAN4 also have increased levels of fetal hemoglobin (summary by Arnaud et al., 2010). For a discussion of genetic heterogeneity of congenital dyserythropoietic anemia, see CDAN1 (224120).

Neonatal cyanosis is characterized by symptoms in the fetus and neonate that gradually abate by 5 to 6 months of age. The disorder is caused by a defect in the fetal hemoglobin chain, which causes reduced affinity for oxygen due to steric inhibition of oxygen binding and/or due to increased oxidation of the fetal hemoglobin molecule to methemoglobin (Hb FM), which has decreased oxygen-binding capacity. Some patients develop anemia resulting from increased destruction of red cells containing abnormal or unstable hemoglobin. The cyanosis resolves spontaneously by 5 to 6 months of age or earlier, as the adult beta-globin chain (HBB; 141900) is produced and replaces the fetal gamma-globin chain (summary by Crowley et al., 2011).

Primary shunt hyperbilirubinemia (PSHB) is a rare form of clinical jaundice characterized by increased serum levels of unconjugated bilirubin associated with ineffective erythropoiesis and a hyperplastic bone marrow. Peripheral red blood cell survival is normal (summary by Wang et al., 2006). Although primary shunt hyperbilirubinemia is clinically similar to Gilbert syndrome (143500), affected individuals do not have impaired activity of UDP-glucuronosyltransferase (UGT1A1; 191740). The term 'shunt' refers to a 'shortcut' in bilirubin production, from the bone marrow or from very young red blood cells as opposed to being derived from the hemoglobin of mature circulating erythrocytes (Israels et al., 1959).

Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals.

In dehydrated hereditary stomatocytosis (DHS), also known as hereditary xerocytosis, red blood cells exhibit altered intracellular cation content and cellular dehydration, resulting in increased erythrocyte mean corpuscular hemoglobin concentration (MCHC) and decreased erythrocyte osmotic fragility. Blood films show various cell shape abnormalities, the most characteristic being the stomatocyte, with a straight or crescent-shaped central pallor (summary by Rapetti-Mauss et al., 2015). For discussion of clinical and genetic heterogeneity of the stomatocytoses, see DHS1 (194380).

The RH-null phenotype designates rare individuals whose red blood cells lack all Rh antigens. Two RH-null types, the regulator type (RHNR; 268150) and the amorph type (RHNA), arising from independent genetic mechanisms have been distinguished. The regulator type is caused by mutation in the RHAG gene (180297). The amorph type arises from mutations at the RH locus itself that silence Rh expression. The RH locus contains the RHD (111680) and RHCE genes tandemly arranged at chromosome 1p36-p34. Four genes must therefore be silenced to produce the RH-null phenotype. The absence of the D antigen, produced by the RHD gene, is common in the human population; the D-negative phenotype may result from deletion or genetic alteration of the RHD gene. The RH-null amorph phenotype thus arises from inactivating mutations in RHCE on a D-negative background (summary by Huang et al., 1998 and Huang et al., 2000). Clinically, Rh-null patients present mild to moderate hemolytic anemia; cells exhibit characteristic morphologic and functional abnormalities including spherocytosis, stomatocytosis, and diminished lifespan. Rh-null patients rarely develop antibodies without stimulation, and most cases occur in response to pregnancy or transfusion (Silvy et al., 2015).

Fibrosis, neurodegeneration, and cerebral angiomatosis (FINCA) is characterized by severe progressive cerebropulmonary symptoms, resulting in death in infancy from respiratory failure. Features include malabsorption, progressive growth failure, recurrent infections, chronic hemolytic anemia, and transient liver dysfunction. Neuropathology shows increased angiomatosis-like leptomeningeal, cortical, and superficial white matter vascularization and congestion, vacuolar degeneration and myelin loss in white matter, as well as neuronal degeneration. Interstitial fibrosis and granuloma-like lesions are seen in the lungs, and there is hepatomegaly with steatosis and collagen accumulation (Uusimaa et al., 2018).

Individuals with hereditary distal renal tubular acidosis (dRTA) typically present in infancy with failure to thrive, although later presentations can occur, especially in individuals with autosomal dominant SLC4A1-dRTA. Initial clinical manifestations can also include emesis, polyuria, polydipsia, constipation, diarrhea, decreased appetite, and episodes of dehydration. Electrolyte manifestations include hyperchloremic non-anion gap metabolic acidosis and hypokalemia. Renal complications of dRTA include nephrocalcinosis, nephrolithiasis, medullary cysts, and impaired renal function. Additional manifestations include bone demineralization (rickets, osteomalacia), growth deficiency, sensorineural hearing loss (in ATP6V0A4-, ATP6V1B1-, and FOXI1-dRTA), and hereditary hemolytic anemia (in some individuals with SLC4A1-dRTA).

Congenital dyserythropoietic anemia type I (CDA I) is characterized by moderate-to-severe macrocytic anemia presenting occasionally in utero as severe anemia associated with hydrops fetalis but more commonly in neonates as hepatomegaly, early jaundice, and intrauterine growth restriction. Some individuals present in childhood or adulthood. After the neonatal period, most affected individuals have lifelong moderate anemia, usually accompanied by jaundice and splenomegaly. Secondary hemochromatosis develops with age as a result of increased iron absorption even in those who are not transfused. Distal limb anomalies occur in 4%-14% of affected individuals.