MedGen

Hemoglobin H (HbH) contains four beta-globin chains. It is normally not present at all in blood, but may make up about 1-40 percent of all hemoglobin in HbH disease, a subform of alpha thalassemia. [from HPO]

Hemoglobin H disease is a subtype of alpha-thalassemia (see 604131) in which patients have compound heterozygosity for alpha(+)-thalassemia, caused by deletion of one alpha-globin gene, and for alpha(0)-thalassemia, caused by deletion in cis of 2 alpha-globin genes (summary by Lal et al., 2011). When 3 alpha-globin genes become inactive because of deletions with or without concomitant nondeletional mutations, the affected individual has only 1 functional alpha-globin gene. These people usually have moderate anemia and marked microcytosis and hypochromia. In affected adults, there is an excess of beta-globin chains within erythrocytes that will form beta-4 tetramers, also known as hemoglobin H (summary by Chui et al., 2003). Hb H disease is usually caused by the combination of alpha(0)-thalassemia with deletional alpha(+)-thalassemia, a combination referred to as 'deletional' Hb H disease. In a smaller proportion of patients, Hb H disease is caused by an alpha(0)-thalassemia plus an alpha(+)-thalassemia point mutation or small insertion/deletion. Such a situation is labeled 'nondeletional' Hb H disease. Patients with nondeletional Hb H disease are usually more anemic, more symptomatic, more prone to have significant hepatosplenomegaly, and more likely to require transfusions (summary by Lal et al., 2011). [from OMIM]

The histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC was described as an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (summary by Morgan et al., 2010). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (summary by Kismet et al., 2005). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (Cliffe et al., 2009). Bolze et al. (2012) noted that mutations in the SLC29A3 gene (612373) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (Avitan-Hersh et al., 2011; Colmenero et al., 2012). [from OMIM]

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome. [from GeneReviews]

An acquired form of alpha-thalassemia characterized by a myelodysplastic syndrome (MDS) or more rarely a myeloproliferative disease (MPD) associated with hemoglobin H disease (HbH). [from ORDO]

Adams-Oliver syndrome (AOS) is characterized by aplasia cutis congenita (ACC) of the scalp and terminal transverse limb defects (TTLD). ACC lesions usually occur in the midline of the parietal or occipital regions, but can also occur on the abdomen or limbs. At birth, an ACC lesion may already have the appearance of a healed scar. ACC lesions less than 5 cm often involve only the skin and almost always heal over a period of months; larger lesions are more likely to involve the skull and possibly the dura, and are at greater risk for complications, which can include infection, hemorrhage, or thrombosis, and can result in death. The limb defects range from mild (unilateral or bilateral short distal phalanges) to severe (complete absence of all toes or fingers, feet or hands, or more, often resembling an amputation). The lower extremities are almost always more severely affected than the upper extremities. Additional major features frequently include cardiovascular malformations/dysfunction (23%), brain anomalies, and less frequently renal, liver, and eye anomalies. [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]

C3 glomerulopathy (C3G) is a complex ultra-rare complement-mediated renal disease caused by uncontrolled activation of the complement alternative pathway (AP) in the fluid phase (as opposed to cell surface) that is rarely inherited in a simple mendelian fashion. C3G affects individuals of all ages, with a median age at diagnosis of 23 years. Individuals with C3G typically present with hematuria, proteinuria, hematuria and proteinuria, acute nephritic syndrome or nephrotic syndrome, and low levels of the complement component C3. Spontaneous remission of C3G is uncommon, and about half of affected individuals develop end-stage renal disease (ESRD) within ten years of diagnosis, occasionally developing the late comorbidity of impaired visual acuity. [from GeneReviews]

Long QT syndrome (LQTS) is a cardiac electrophysiologic disorder, characterized by QT prolongation and T-wave abnormalities on the EKG that are associated with tachyarrhythmias, typically the ventricular tachycardia torsade de pointes (TdP). TdP is usually self-terminating, thus causing a syncopal event, the most common symptom in individuals with LQTS. Such cardiac events typically occur during exercise and emotional stress, less frequently during sleep, and usually without warning. In some instances, TdP degenerates to ventricular fibrillation and causes aborted cardiac arrest (if the individual is defibrillated) or sudden death. Approximately 50% of untreated individuals with a pathogenic variant in one of the genes associated with LQTS have symptoms, usually one to a few syncopal events. While cardiac events may occur from infancy through middle age, they are most common from the preteen years through the 20s. Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia. In addition to the prolonged QT interval, associations include muscle weakness and facial dysmorphism in Andersen-Tawil syndrome (LQTS type 7); hand/foot, facial, and neurodevelopmental features in Timothy syndrome (LQTS type 8); and profound sensorineural hearing loss in Jervell and Lange-Nielson syndrome. [from GeneReviews]

Alpha-thalassemia (a-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome (caused by deletion/inactivation of all four a-globin genes; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three a-globin genes; --/-a). Hb Bart syndrome, the more severe form, is characterized by prenatal onset of generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Death usually occurs in the neonatal period. HbH disease has a broad phenotypic spectrum: although clinical features usually develop in the first years of life, HbH disease may not present until adulthood or may be diagnosed only during routine hematologic analysis in an asymptomatic individual. The majority of individuals have enlargement of the spleen (and less commonly of the liver), mild jaundice, and sometimes thalassemia-like bone changes. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs. [from GeneReviews]

Short QT syndrome (SQT) is a cardiac channelopathy associated with a predisposition to atrial fibrillation and sudden cardiac death. Patients have a structurally normal heart, but electrocardiography (ECG) exhibits abbreviated QTc (Bazett's corrected QT) intervals of less than 360 ms (summary by Moreno et al., 2015). Genetic Heterogeneity of Short QT Syndrome Short QT syndrome-2 (SQT2; 609621) is caused by mutation in the KCNQ1 gene (607542). SQT3 (609622) is caused by mutation in the KCNJ2 gene (600681). SQT7 (620231) is caused by mutation in the SLC4A3 gene (106195). [from OMIM]

X-linked agammaglobulinemia (XLA) is characterized by recurrent bacterial infections in affected males in the first two years of life. Recurrent otitis is the most common infection prior to diagnosis. Conjunctivitis, sinopulmonary infections, diarrhea, and skin infections are also frequently seen. Approximately 60% of individuals with XLA are recognized as having immunodeficiency when they develop a severe, life-threatening infection such as pneumonia, empyema, meningitis, sepsis, cellulitis, or septic arthritis. S pneumoniae and H influenzae are the most common organisms found prior to diagnosis and may continue to cause sinusitis and otitis after diagnosis and the initiation of gammaglobulin substitution therapy. Severe, difficult-to-treat enteroviral infections (often manifest as dermatomyositis or chronic meningoencephalitis) can be prevented by this treatment. The prognosis for individuals with XLA has improved markedly in the last 25 years as a result of earlier diagnosis, the development of preparations of gammaglobulin that allow normal concentrations of serum IgG to be achieved, and more liberal use of antibiotics. [from GeneReviews]

Alpha-thalassemia X-linked intellectual disability (ATR-X) syndrome is characterized by distinctive craniofacial features, genital anomalies, hypotonia, and mild-to-profound developmental delay / intellectual disability (DD/ID). Craniofacial abnormalities include small head circumference, telecanthus or widely spaced eyes, short triangular nose, tented upper lip, and thick or everted lower lip with coarsening of the facial features over time. While all affected individuals have a normal 46,XY karyotype, genital anomalies comprise a range from hypospadias and undescended testicles, to severe hypospadias and ambiguous genitalia, to normal-appearing female external genitalia. Alpha-thalassemia, observed in about 75% of affected individuals, is mild and typically does not require treatment. Osteosarcoma has been reported in a few males with germline pathogenic variants. [from GeneReviews]

A partial reduction in level of the complement component Factor H in circulation. [from HPO]

Concentration of the complement component factor H in the blood circulation below the lower limit of normal. [from HPO]

Alpha-thalassemia (a-thalassemia) has two clinically significant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome (caused by deletion/inactivation of all four a-globin genes; --/--), and hemoglobin H (HbH) disease (most frequently caused by deletion/inactivation of three a-globin genes; --/-a). Hb Bart syndrome, the more severe form, is characterized by prenatal onset of generalized edema and pleural and pericardial effusions as a result of congestive heart failure induced by severe anemia. Extramedullary erythropoiesis, marked hepatosplenomegaly, and a massive placenta are common. Death usually occurs in the neonatal period. HbH disease has a broad phenotypic spectrum: although clinical features usually develop in the first years of life, HbH disease may not present until adulthood or may be diagnosed only during routine hematologic analysis in an asymptomatic individual. The majority of individuals have enlargement of the spleen (and less commonly of the liver), mild jaundice, and sometimes thalassemia-like bone changes. Individuals with HbH disease may develop gallstones and experience acute episodes of hemolysis in response to infections or exposure to oxidant drugs. [from GeneReviews]

HDR syndrome (HDRS), also known as Barakat syndrome, is a heterogeneous disorder characterized by the triad of Hypoparathyroidism (H), nerve Deafness (D) and/or Renal disease (R). Variable clinical features include hypogonadotrophic hypogonadism, polycystic ovaries, congenital heart disease, retinitis pigmentosa, and cognitive disability (Barakat et al., 2018). [from OMIM]

VACTERL describes a constellation of congenital anomalies, including vertebral anomalies, anal atresia, congenital cardiac disease, tracheoesophageal fistula, renal anomalies, radial dysplasia, and other limb defects; see 192350. Cases of familial VACTERL with hydrocephalus (H) have been reported with suggestion of autosomal recessive or X-linked inheritance (see 314390). Other patients thought to have VACTERL-H, including 2 unrelated infants reported by Porteous et al. (1992), had been found to have Fanconi anemia (see 227650). Porteous et al. (1992) suggested that chromosomal breakage studies should be performed in all cases of VACTERL/VACTERL-H to rule out Fanconi anemia. Alter et al. (2007) noted that a VATER phenotype had been reported in Fanconi anemia of complementation groups A (227650), C (227645), D1 (605724), E (600901), F (603467), and G (614082). X-linked VACTERL-H is also associated with mutations in the FANCB gene (300515). [from OMIM]

Open angle glaucoma-1H (GLC1H) is characterized by elevated intraocular pressures (IOPs) associated with visual field and optic nerve abnormalities. In some families, affected members present mostly in the 'juvenile-onset' (JOAG) age range (between 3 and 35 to 40 years of age), whereas in other families, affected individuals present mostly in the 'adult-onset' (POAG) age range (after age 35 or 40 years). Patients with early-onset disease generally have a more severe presentation, with higher IOPs and higher likelihood of being blind in at least 1 eye (summary by Mackay et al., 2015; Collantes et al., 2022). For a general phenotypic description and a discussion of genetic heterogeneity of primary open angle glaucoma (POAG), see 137760. [from OMIM]