MedGen

Fanconi anemia (FA) is characterized by physical abnormalities, bone marrow failure, and increased risk for malignancy. Physical abnormalities, present in approximately 75% of affected individuals, include one or more of the following: short stature, abnormal skin pigmentation, skeletal malformations of the upper and/or lower limbs, microcephaly, and ophthalmic and genitourinary tract anomalies. Progressive bone marrow failure with pancytopenia typically presents in the first decade, often initially with thrombocytopenia or leukopenia. The incidence of acute myeloid leukemia is 13% by age 50 years. Solid tumors – particularly of the head and neck, skin, and genitourinary tract – are more common in individuals with FA. [from GeneReviews]

Xeroderma pigmentosum (XP) is characterized by: Acute sun sensitivity (severe sunburn with blistering, persistent erythema on minimal sun exposure) with marked freckle-like pigmentation of the face before age two years; Sunlight-induced ocular involvement (photophobia, severe keratitis, atrophy of the skin of the lids, ocular surface neoplasms); Greatly increased risk of sunlight-induced cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma) within the first decade of life. Approximately 25% of affected individuals have neurologic manifestations (acquired microcephaly, diminished or absent deep tendon stretch reflexes, progressive sensorineural hearing loss, progressive cognitive impairment, and ataxia). The most common causes of death are skin cancer, neurologic degeneration, and internal cancer. The median age at death in persons with XP with neurodegeneration (29 years) was found to be younger than that in persons with XP without neurodegeneration (37 years). [from GeneReviews]

Classic hereditary persistence of fetal hemoglobin (HPFH) is characterized by a substantial elevation of fetal hemoglobin (HbF) in adult red blood cells. There are no other phenotypic or hematologic manifestations. Expression of the HBG1 and HBG2 genes, which encode the gamma isoforms of HbF, is normally suppressed shortly before birth and replaced by expression of the beta- (HBB; 141900) or delta- (HBD; 142000) chains, which form adult hemoglobin. Adults normally have less than 1% HbF, whereas heterozygotes for HPFH have 5 to 30% HbF. HPFH heterozygotes have essentially normal red cell indices and a rather homogeneous distribution of HbF among red cells, termed 'pancellular.' Homozygotes for HPFH can express HbF in up to 100% of red blood cells (Thein and Craig, 1998). Delta-beta thalassemia is a hemoglobin disorder characterized by decreased or absent synthesis of the delta- and beta-globin chains with a compensatory increase in expression of fetal gamma-chain synthesis from the affected chromosome. Individuals with delta-beta thalassemia have hypochromic, microcytic anemia and increased HbF, which may mitigate the anemia depending on the level of HbF. Delta-beta thalassemia and some forms of HPFH result from deletions within the beta-globin gene cluster on chromosome 11p15; this has been referred to as 'deletional' HPFH. HPFH can also result from point mutations in the promoter regions of the gamma globulin genes HBG1 and HBG2; this has been referred to as 'non-deletional' HPFH (Ottolenghi et al., 1982; Forget, 1998). Forget (1998) noted that HPFH and delta-beta thalassemia are not clearly distinct disorders, but rather show partially overlapping features that may defy classification. Higher expression of HbF is often termed 'pancellular,' whereas lower expression of HbF is often termed 'heterocellular,' although these represent a spectrum. Approximately 10% of the population has HPFH manifest as modest elevations of HbF (1 to 4%) present in a subset of red cells (about 4.5%) termed F cells. This is also sometimes referred to as 'heterocellular' HPFH, and is considered to be a multifactorial trait influenced by multiple genetic loci (Thein and Craig, 1998). [from OMIM]

Fetal hemoglobin (HbF) levels vary considerably in healthy normal adults. The distribution of HbF and F cells, erythrocytes that contain measurable HbF, in healthy adults is continuous, although most adults have HbF of less than 0.6% of total Hb. Approximately 10 to 15% of individuals have increases of HbF ranging from 0.8% to 5%, a trait often referred to as hereditary persistence of fetal hemoglobin (HPFH), usually distributed unevenly among red cells. When coinherited with beta-thalassemia (see 613985) or sickle cell anemia (603903), HPFH can increase HbF output to levels that are clinically beneficial (Thein et al., 2007). For a general phenotypic description and a discussion of loci that may affect fetal hemoglobin levels, see HBFQTL1 (141749). [from OMIM]