MedGen

The pathogenesis of HIV infection and the progression from infection to AIDS vary significantly between exposed individuals. Infection occurs after the virus, which has macrophage (M)- and T lymphocyte (T)-tropic strains and more than 12 subtypes, survives an array of nonspecific, nongenetic environmental and host factors. [from OMIM]

Three M syndrome is characterized by severe pre- and postnatal growth deficiency (final height 5-6 SD below the mean; i.e., 120-130 cm), characteristic facies, and normal intelligence. Additional features of three M syndrome include short broad neck, prominent trapezii, deformed sternum, short thorax, square shoulders, winged scapulae, hyperlordosis, short fifth fingers, prominent heels, and loose joints. Males with three M syndrome have hypogonadism and occasionally hypospadias. [from GeneReviews]

Waldenstrom macroglobulinemia (WM) is a malignant B-cell neoplasm characterized by lymphoplasmacytic infiltration of the bone marrow and hypersecretion of monoclonal immunoglobulin M (IgM) protein (review by Vijay and Gertz, 2007). The importance of genetic factors is suggested by the observation of familial clustering of WM (McMaster, 2003). Whereas WM is rare, an asymptomatic elevation of monoclonal IgM protein, termed 'IgM monoclonal gammopathy of undetermined significance' (IgM MGUS) is more common. Patients with IgM MGUS can progress to develop WM, at the rate of 1.5% to 2% per year (Kyle et al., 2003). Genetic Heterogeneity of Waldenstrom Macroglobulinemia A locus for susceptibility to Waldenstrom macroglobulinemia (WM2; 610430) has been mapped to chromosome 4q. [from OMIM]

Leprosy is a disease of peripheral sensory nerves that results from infection with Mycobacterium leprae, which was first detected in Bergen, Norway, in 1873 by Dr. Armauer Hansen. It can be effectively treated with long-term multidrug therapy. In 2006, more than 250,000 new cases of leprosy were reported to the World Health Organization. Many infected individuals have self-healing indeterminate lesions. Others with initially indeterminate lesions proceed to develop leprosy that can be classified along a clinical and immunologic spectrum from paucibacillary or tuberculoid leprosy to multibacillary or lepromatous leprosy. Most patients fall somewhere between these 2 polar forms of the disease and are classified, using pathology-based criteria developed by Ridley and Jopling (1966), as borderline tuberculoid, midborderline, and borderline lepromatous. The paucibacillary form is associated with strong M. leprae-specific cell-mediated immunity (CMI), whereas the multibacillary form is notable for the lack of antigen-specific CMI. The prevalence of paucibacillary versus multibacillary leprosy varies in different populations. M. leprae cannot be cultured in vitro and grows slowly in the footpads of mice, the liver and spleen of armadillos, and in some nonhuman primates. A genetic component to leprosy susceptibility has long been suspected. While contact with a multibacillary patient increases the relative risk of acquiring disease, most new patients have no known contact with other patients. For further information, see reviews by Fitness et al. (2002), Mira (2006), Moraes et al. (2006), Scollard et al. (2006), and Alter et al. (2008). [from OMIM]

X-linked hyper IgM syndrome (HIGM1), a disorder of abnormal T- and B-cell function, is characterized by low serum concentrations of IgG, IgA, and IgE with normal or elevated serum concentrations of IgM. Mitogen proliferation may be normal, but NK- and T-cell cytotoxicity can be impaired. Antigen-specific responses are usually decreased or absent. Total numbers of B cells are normal but there is a marked reduction of class-switched memory B cells. Defective oxidative burst of both neutrophils and macrophages has been reported. The range of clinical findings varies, even within the same family. More than 50% of males with HIGM1 develop symptoms by age one year, and more than 90% are symptomatic by age four years. HIGM1 usually presents in infancy with recurrent upper- and lower-respiratory tract bacterial infections, opportunistic infections including Pneumocystis jirovecii pneumonia, and recurrent or protracted diarrhea that can be infectious or noninfectious and is associated with failure to thrive. Neutropenia is common; thrombocytopenia and anemia are less commonly seen. Autoimmune and/or inflammatory disorders (such as sclerosing cholangitis) as well as increased risk for neoplasms have been reported as medical complications of this disorder. Significant neurologic complications, often the result of a CNS infection, are seen in 5%-15% of affected males. Liver disease, a serious complication of HIGM1 once observed in more than 80% of affected males by age 20 years, may be decreasing with adequate screening and treatment of Cryptosporidium infection. [from GeneReviews]

MN antigens reside on GYPA, one of the most abundant red-cell glycoproteins. The M and N antigens are 2 autosomal codominant antigens encoded by the first 5 amino acids of GYPA and include 3 O-linked glycans as part of the epitope. M and N differ at amino acids 1 and 5, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. M is the ancestral GYPA allele and is common in all human populations and Old World apes. GYPA, glycophorin B (GYPB; 617923), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Antigens of the Ss blood group (111740) reside on GYPB, and recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs or MNS blood group system. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015). [from OMIM]

Glycosylphosphatidylinositol is a glycolipid that anchors more than 150 proteins to the cell surface, and these proteins, termed GPI-anchored proteins (GPI-APs), perform a variety of functions as enzymes, adhesion molecules, complement regulators, and coreceptors in signal transduction pathways. Reduced surface levels of GPI-APs or abnormal GPI-AP structure can therefore result in variable manifestations. Glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1) is characterized predominantly by portal hypertension due to portal vein thrombosis. Most patients have absence seizures, cerebral thrombosis, and macrocephaly. Some patients have mildly to moderately impaired intellectual development (summary by Makrythanasis et al., 2016; Pode-Shakked et al., 2019). Genetic Heterogeneity of Glycosylphosphatidylinositol Biosynthesis Defects Also see GPIBD2 (239300), caused by mutation in the PIGV gene (610274); GPIBD3 (614080), caused by mutation in the PIGN gene (606097); GPIBD4 (300868), caused by mutation in the PIGA gene (311770); GPIBD5 (280000), caused by mutation in the PIGL gene (605947); GPIBD6 (614749), caused by mutation in the PIGO gene (614730); GPIBD7 (615398), caused by mutation in the PIGT gene (610272); GPIBD8 (614207), caused by mutation in the PGAP2 gene (615187); GPIBD9 (615802), caused by mutation in the PGAP1 gene (611655); GPIBD10 (615716), caused by mutation in the PGAP3 gene (611801); GPIBD11 (616025), caused by mutation in the PIGW gene (610275); GPIBD12 (616809), caused by mutation in the PIGY gene (610662); GPIBD13 (616917), caused by mutation in the PIGG gene (616918); GPIBD14 (617599), caused by mutation in the PIGP gene (605938); GPIBD15 (617810), caused by mutation in the GPAA1 gene (603048); GPIBD16 (617816), caused by mutation in the PIGC gene (601730); GPIBD17 (618010), caused by mutation in the PIGH gene (600154); GPIBD18 (618143), caused by mutation in the PIGS gene (610271); GPIBD19 (618548), caused by mutation in the PIGQ gene (605754); GPIBD20 (618580), caused by mutation in the PIGB gene (604122); GPIBD21 (618590), caused by mutation in the PIGU gene (608528); GPIBD22 (618879), caused by mutation in the PIGK gene (605087); GPIBD23 (617020), caused by mutation in the ARV1 gene (611647); GPIBD24 (619356), caused by mutation in the PIGF gene (600153); and GPIBD25 (619985), caused by mutation in the C18ORF32 gene (619979). [from OMIM]

IMD28 is caused by autosomal recessive (AR) IFNGR2 deficiency, a rare molecular cause of susceptibility to mycobacterial disease. The clinical presentation of complete AR IFNGR2 deficiency resembles that of complete IFNGR1 deficiency (IMD27A; 209950). The disease manifests early in life, with severe, often fatal, infection. The most commonly encountered pathogens include M. bovis bacillus Calmette-Guerin (BCG), M. avium, and M. fortuitum. Complete AR IFNGR2 deficiency is characterized by an undetectable cellular response to interferon-gamma (IFNG; 147570). There is also a rare partial form of AR IFNGR2 deficiency, reported in 1 child, who retained a residual cellular response to IFNG and presented with a relatively mild infection by M. bovis BCG and M. abscessus (review by Al-Muhsen and Casanova, 2008). [from OMIM]

3-hydroxyacyl-CoA dehydrogenase deficiency is an inherited condition that prevents the body from converting certain fats to energy, particularly during prolonged periods without food (fasting).

Initial signs and symptoms of this disorder typically occur during infancy or early childhood and can include poor appetite, vomiting, diarrhea, and lack of energy (lethargy). Affected individuals can also have muscle weakness (hypotonia), liver problems, low blood glucose (hypoglycemia), and abnormally high levels of insulin (hyperinsulinism). Insulin controls the amount of glucose that moves from the blood into cells for conversion to energy. Individuals with 3-hydroxyacyl-CoA dehydrogenase deficiency are also at risk for complications such as seizures, life-threatening heart and breathing problems, coma, and sudden death. This condition may explain some cases of sudden infant death syndrome (SIDS), which is defined as unexplained death in babies younger than 1 year.

Problems related to 3-hydroxyacyl-CoA dehydrogenase deficiency can be triggered by periods of fasting or by illnesses such as viral infections. This disorder is sometimes mistaken for Reye syndrome, a severe disorder that may develop in children while they appear to be recovering from viral infections such as chicken pox or flu. Most cases of Reye syndrome are associated with the use of aspirin during these viral infections. [from MedlinePlus Genetics]

Ss blood group antigens reside on the red-cell glycoprotein GYPB. The S and s antigens result from a polymorphism at amino acid 29 of GYPB, where S has met29 and s has thr29. The U antigen refers to a short extracellular sequence in GYPB located near the membrane. GYPB, glycophorin A (GYPA; 617922), and glycophorin E (GYPE; 138590) are closely linked on chromosome 4q31. Antigens of the MN blood group (111300) reside on GYPA. The M and N antigens differ at amino acids 1 and 5 of GYPA, where M is ser-ser-thr-thr-gly, and N is leu-ser-thr-thr-glu. The N terminus of GYPB is essentially identical to that of GYPA except that it always expresses the N antigen, denoted 'N' or N-prime. Recombination and gene conversion between GYPA, GYPB, and GYPE lead to hybrid glycophorin molecules and generation of low-incidence antigens. Thus, the MN and Ss blood groups are together referred to as the MNSs blood group system (see 111300). Recombination results in 3 glycophorin-null phenotypes: En(a-) cells lack GYPA due to recombination between GYPA and GYPB; GYPB-negative (S-s-U-) cells lack GYPB due to recombination in GYPB; and M(k) cells (M-N-S-s-U-) lack both GYPA and GYPB due to recombination between GYPA and GYPE. Individuals with glycophorin-null phenotypes have decreased sialic acid content and increased resistance to malarial infection (see 611162). GYPA and GYPB are not essential for red-cell development or survival, and GYPA- and GYPB-null phenotypes are not associated with anemia or altered red-cell function (review by Cooling, 2015). [from OMIM]

Methemoglobinemia is a clinical condition in which more than 1% of hemoglobin is oxidized to methemoglobin, a type of hemoglobin that contains the ferric (Fe3+) form of iron. Patients with hemoglobin M are cyanotic but otherwise asymptomatic. If the mutation occurs in the hemoglobin alpha subunit (141800), cyanosis is apparent at birth, whereas if the beta chain is affected, cyanosis appears later or intensifies when beta subunit production increases. If a newborn carries a fetal M hemoglobin (gamma subunit; 142250), cyanosis disappears when the complete gamma-beta-switch occurs (summary by Mansouri and Lurie, 1993). [from OMIM]

Methemoglobinemia is a clinical condition in which more than 1% of hemoglobin is oxidized to methemoglobin, a type of hemoglobin that contains the ferric (Fe3+) form of iron. Patients with hemoglobin M are cyanotic but otherwise asymptomatic. If the mutation occurs in the hemoglobin alpha subunit, cyanosis is apparent at birth, whereas if the beta chain (141900) is affected, cyanosis appears later or intensifies when beta subunit production increases. If a newborn carries a fetal M hemoglobin (gamma subunit; 142250), cyanosis disappears when the complete gamma-beta-switch occurs (summary by Mansouri and Lurie, 1993). [from OMIM]

Immunodeficiency-27B (IMD27B) results from autosomal dominant (AD) IFNGR1 deficiency. Patients with AD IFNGR1 deficiency commonly present with recurrent, moderately severe infections with environmental mycobacteria or bacillus Calmette-Guerin (BCG). In contrast with patients with complete autosomal recessive (AR) IFNGR1 deficiency (IMD27A), cells from patients with AD IFNGR1 deficiency display residual responses to IFNG in vitro, indicating that the deficiency in IFNGR1 is partial. The clinical features of AD IFNGR1 deficiency are usually less severe than those in children with complete AR IFNGR1 deficiency, and mycobacterial infection often occurs later (mean age of 13.4 years vs 1.3 years), with patients having longer mean disease-free survival. In patients with AD IFNGR1 deficiency, M. avium tends to cause unifocal or multifocal osteomyelitis. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (review by Al-Muhsen and Casanova, 2008). [from OMIM]

X-linked Opitz G/BBB syndrome (X-OS) is a multiple-congenital-anomaly disorder characterized by facial anomalies (hypertelorism, prominent forehead, widow's peak, broad nasal bridge, anteverted nares), genitourinary abnormalities (hypospadias, cryptorchidism, and hypoplastic/bifid scrotum), and laryngotracheoesophageal defects. Developmental delay and intellectual disability are observed in about 50% of affected males. Cleft lip and/or palate are present in approximately 50% of affected individuals. Other malformations (present in <50% of individuals) include congenital heart defects, imperforate or ectopic anus, and midline brain defects (Dandy-Walker malformation and agenesis or hypoplasia of the corpus callosum and/or cerebellar vermis). Wide clinical variability occurs even among members of the same family. Female heterozygotes usually manifest hypertelorism only. [from GeneReviews]

The 8p11 myeloproliferative syndrome is a rare aggressive condition characterized in its typical form by the occurrence, either simultaneously or sequentially, of a BCR/ABL-negative myeloproliferative disorder and a lymphoma, usually a precursor T-lymphoblastic lymphoma. The disease most often terminates in acute myeloid leukemia (Goradia et al., 2008). [from OMIM]

Hematologic neoplasms characterized by the presence of t(8;9)(p22;p24.1) that results in PCM1-JAK2 fusion gene expression. It is associated with eosinophilia, bone marrow findings of left-shifted erythroid predominance, lymphoid aggregates, and often myelofibrosis. Rare cases present as T- or B-acute lymphoblastic leukemia. [from NCI]

A group of rare myeloid and lymphoid neoplasms characterized by rearrangement of the PDGFRA, PDGFRB, FGFR1, or JAK2 genes, resulting in the formation of tyrosine kinase fusion transcripts. Eosinophilia is a characteristic finding but it is not always present. [from NCI]