Alpha thalassemia spectrum is described in the packet as an inherited hemoglobinopathy characterized by impaired synthesis of alpha-globin chains, leading to a variable clinical picture depending on the number of affected alleles. The packet lists two subtypes, monogenic alpha thalassemia spectrum and digenic alpha thalassemia spectrum.

GeneReviews (chapter "Alpha-Thalassemia") identifies hemoglobin Bart hydrops fetalis (Hb Bart) syndrome and hemoglobin H (HbH) disease as the clinically significant phenotypes, with severity depending on the extent of the alpha-globin chain defect relative to beta-globin production.

The packet does not certify a prevalence estimate (category UNKNOWN). GeneReviews notes that population prevalence has been determined using the percentage of Hb Bart in cord blood, which may underestimate prevalence because silent carriers do not always have increased Hb Bart, and that molecular testing has given more precise data. It reports regional variation in allele frequencies across Africa, the Mediterranean, and the Arabian Peninsula.

The packet lists only a small number of phenotype terms (2 in total), so the symptom description draws on the GeneReviews clinical description.

Hb Bart syndrome is described as the most severe condition related to alpha thalassemia. Affected fetuses are either delivered stillborn at 30-40 weeks' gestation or die soon after birth. Main features include generalized edema and pleural and pericardial effusions resulting from congestive heart failure induced by severe anemia. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Retardation in brain growth, hydrocephalus, cardiovascular deformities, and urogenital defects have been reported.

HbH disease is described as variable, with clinical features usually diagnosed during routine hematologic analysis in an asymptomatic individual. The majority have enlargement of the spleen and, less commonly, the liver, mild jaundice, and sometimes mild-to-moderate thalassemia-like skeletal changes affecting facial features. Leg ulcers are rare. Gallstones may develop, acute hemolysis may occur in response to oxidant drugs and infections, and parvovirus B19 infection can rarely cause an aplastic crisis. Most individuals have minor disability, while some are severely affected and require regular blood transfusions. Significant iron overload is uncommon but has been reported in older individuals, usually from repeated transfusions or increased iron absorption.

The packet lists HBA1 and HBA2 as known genes, both on chromosome 16; ClinGen validity classifications are not provided in the packet. The packet's inheritance field is empty. GeneReviews states that alpha thalassemia is usually inherited in an autosomal recessive manner.

GeneReviews describes the genotype-phenotype relationship as dependent on the degree of alpha-globin chain deficiency relative to beta-globin production. Hb Bart syndrome is most often caused by large deletions on both chromosomes affecting all four alpha-globin alleles, and rarely by a non-deletion variant. HbH disease is most often caused by a large deletion on one chromosome together with a single alpha-globin allele deletion or other non-deletion inactivating variant on the opposite chromosome. Individuals homozygous for HBA2 pathogenic variants may also have HbH disease.

GeneReviews reports that the parents of a fetus with Hb Bart syndrome have alpha thalassemia trait caused by deletion or inactivation of two alpha-globin genes on the same chromosome, while the parents of a child with HbH disease usually have different genotypes.

GeneReviews describes Hb Bart syndrome as suspected on fetal ultrasonography showing increased nuchal thickness, thickened placenta, increased cerebral media artery velocity, and increased cardiothoracic ratio at 13-14 weeks' gestation, or generalized edema, ascites, and pleural and pericardial effusions at 22-28 weeks. Its diagnosis in a fetus is described as based on hematologic findings (severe macrocytic hypochromic anemia without blood group incompatibility), hemoglobin analysis showing decreased or absent hemoglobin A with increased Hb Bart, and molecular genetic testing identifying biallelic pathogenic variants in both HBA1 and HBA2 that delete or inactivate all four alpha-globin alleles.

HbH disease is described as suspected in an infant or child with mild jaundice, hepatosplenomegaly, mild thalassemia-like bone changes, or newborn screening findings. GeneReviews notes that newborn screening for sickle cell disease offered by several states or countries may detect Hb Bart in a newborn with alpha thalassemia. The diagnosis in a proband is described as based on mild-to-moderate, rarely severe, microcytic hypochromic hemolytic anemia, HbH inclusions on supravital staining, hemoglobin analysis showing HbH, and molecular genetic testing identifying biallelic pathogenic variants in HBA1 and HBA2 that delete or inactivate three alpha-globin alleles, which GeneReviews states confirms the diagnosis and allows for family studies.

No FDA-approved drug with ACTIVE market status for this condition is present in the packet. The packet lists luspatercept (sponsor Celgene Corporation) with an orphan designation for treatment of alpha-thalassemia; its status is DESIGNATED, which is not an approval.

GeneReviews cites the 2017 Thalassemia International Federation guidelines for non-transfusion-dependent thalassemia, including HbH disease. For Hb Bart syndrome, it states that the condition was previously considered universally fatal and that management now includes prenatal testing, intrauterine blood transfusions, improved transfusion strategies, and, rarely, curative hematopoietic stem cell transplantation; most affected individuals in the cited registry required lifelong transfusion.

For HbH disease, GeneReviews states that most individuals are clinically well and survive without treatment. Those with non-deletional HbH disease and biallelic HBA2 pathogenic variants may be more severely affected and transfusion dependent. Individuals with deletional HbH disease may need occasional red blood cell transfusions during hemolytic or aplastic crises, and iron chelation therapy may be needed for iron loading. Splenectomy is described as reserved for massive splenomegaly or hypersplenism, with the associated risks of sepsis and venous thrombosis noted.

For surveillance in HbH disease, GeneReviews lists hematologic evaluation every six to 12 months, growth and development assessment every six to 12 months in children, and annual serum ferritin determination in transfused or older individuals and those given inappropriate iron supplementation, with periodic liver iron concentration measurement by MRI. Under agents and circumstances of concern, it lists inappropriate iron therapy and oxidant drugs.

The packet certifies no separate prognosis field; this section draws on the GeneReviews clinical description and management text. Hb Bart syndrome is described as historically universally fatal, with affected fetuses stillborn or dying soon after birth, and a very small number of newborns surviving following intrauterine transfusions and repeated transfusions after birth. GeneReviews states that its prognosis is shifting and cites an international registry in which 39 of 69 infants were alive, 40%-50% of survivors had growth restriction, and 20% had neurodevelopmental delay, with congenital anomalies common.

For HbH disease, GeneReviews describes the course as variable: most individuals have minor disability and are clinically well, while some are severely affected. In very rare cases hydrops fetalis is present. These descriptions summarize published reports and do not predict the course in any individual.

The packet certifies active ClinicalTrials.gov records for this condition. Packet titles and sponsors include Phase 3 studies of mitapivat sponsored by Agios Pharmaceuticals, Inc., covering alpha- or beta-thalassemia in transfusion-dependent and non-transfusion-dependent participants, including pediatric participants. Other records have titles referring to an international registry of patients with alpha thalassemia, screening for alpha thalassemia in healthy volunteers, and a European epidemiological platform for rare anemia disorders.

The packet's publication digest is dominated by case reports and case series and notes the presence of gene therapy and biomarker publications. The GeneReviews section on therapies under investigation does not describe specific investigational therapies. The packet lists no patient organizations.