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Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. [from GeneReviews]

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. [from GeneReviews]

MUTYH polyposis (also referred to as MUTYH-associated polyposis, or MAP) is characterized by a greatly increased lifetime risk of colorectal cancer (CRC). Although typically associated with ten to a few hundred colonic adenomatous polyps, CRC develops in some individuals in the absence of polyposis. Serrated adenomas, hyperplastic/sessile serrated polyps, and mixed (hyperplastic and adenomatous) polyps can also occur. Duodenal adenomas are common, with an increased risk of duodenal cancer. The risk for malignancies of the ovary and bladder is also increased, and there is some evidence of an increased risk for breast and endometrial cancer. Additional reported features include thyroid nodules, benign adrenal lesions, jawbone cysts, and congenital hypertrophy of the retinal pigment epithelium. [from GeneReviews]

Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997). Patients with antenatal forms of Bartter syndrome typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome (see BARTS3, 607364) present later in life and may be sporadically asymptomatic or mildly symptomatic (summary by Simon et al., 1996 and Fremont and Chan, 2012). For a discussion of genetic heterogeneity of Bartter syndrome, see 607364. [from OMIM]

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. [from GeneReviews]

In a review article on the genetic predisposition to gastric cancer, Bevan and Houlston (1999) concluded that several genes may be associated with an increased risk of gastric cancer. Gastric cancer is a manifestation of a number of inherited cancer predisposition syndromes, including hereditary nonpolyposis colon cancer (HNPCC1; see 120435), familial adenomatous polyposis (FAP; 175100), Peutz-Jeghers syndrome (PJS; 175200), Cowden disease (CD; 158350), the Li-Fraumeni syndrome (151623), and diffuse gastric and lobular breast cancer syndrome (DGLBC; 137215). Canedo et al. (2007) provided a review of genetic susceptibility to gastric cancer in patients infected with Helicobacter pylori (see 600263). [from OMIM]

Lynch syndrome is characterized by an increased risk for colorectal cancer (CRC) and cancers of the endometrium, ovary, stomach, small bowel, urinary tract, biliary tract, brain (usually glioblastoma), skin (sebaceous adenomas, sebaceous carcinomas, and keratoacanthomas), pancreas, and prostate. Cancer risks and age of onset vary depending on the associated gene. Several other cancer types have been reported to occur in individuals with Lynch syndrome (e.g., breast, sarcomas, adrenocortical carcinoma). However, the data are not sufficient to demonstrate that the risk of developing these cancers is increased in individuals with Lynch syndrome. [from GeneReviews]

A carcinoma of the endometrium, the mucous lining of the uterus. [from HPO]

Lynch syndrome-5 (LYNCH5), or hereditary nonpolyposis colorectal cancer type 5 (HNPCC5), is a cancer predisposition syndrome characterized by onset of colorectal cancer and/or extracolonic cancers, particularly endometrial cancer, usually in mid-adulthood. The disorder shows autosomal dominant inheritance with incomplete penetrance (summary by Castellsague et al., 2015). For a general phenotypic description and a discussion of genetic heterogeneity of Lynch syndrome, see 120435. [from OMIM]

Mismatch repair cancer syndrome-2 (MMRCS2) is an autosomal recessive childhood cancer predisposition syndrome characterized by hematologic malignancy, brain tumors, and gastrointestinal tumors. Multiple cafe-au-lait spots reminiscent of neurofibromatosis type I (NF1; 162200) may be present. Microsatellite instability may be detected in tumor samples (Muller et al., 2006). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome (MMRCS), see MMRCS1 (276300). [from OMIM]

Multiple mitochondrial dysfunctions syndrome-2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014). For a general description and a discussion of genetic heterogeneity of multiple mitochondrial dysfunctions syndrome, see MMDS1 (605711). [from OMIM]

Congenital bile acid synthesis defect type 2 is a disorder characterized by cholestasis, a condition that impairs the production and release of a digestive fluid called bile from liver cells. Bile is used during digestion to absorb fats and fat-soluble vitamins, such as vitamins A, D, E, and K. People with congenital bile acid synthesis defect type 2 cannot produce (synthesize) bile acids, which are a component of bile that stimulate bile flow and help it absorb fats and fat-soluble vitamins. As a result, an abnormal form of bile is produced.

The signs and symptoms of congenital bile acid synthesis defect type 2 often develop in infancy. Affected infants usually have a failure to gain weight and grow at the expected rate (failure to thrive) and yellowing of the skin and eyes (jaundice) due to impaired bile flow and a buildup of partially formed bile. Excess fat in the feces (steatorrhea) is another feature of congenital bile acid synthesis defect type 2. As the condition progresses, affected individuals can develop liver abnormalities including inflammation or chronic liver disease (cirrhosis). Some individuals with congenital bile acid synthesis defect type 2 cannot absorb certain fat-soluble vitamins, which can result in softening and weakening of the bones (rickets) or problems with blood clotting that lead to prolonged bleeding.

If left untreated, congenital bile acid synthesis defect type 2 typically leads to cirrhosis and death in childhood. [from MedlinePlus Genetics]

Hyper-IgE syndrome-2 with recurrent infections (HIES2) is an autosomal recessive immunologic disorder characterized by recurrent staphylococcal infections of the skin and respiratory tract, eczema, elevated serum immunoglobulin E, and hypereosinophilia. It is distinguished from autosomal dominant HIES1 (147060) by the lack of connective tissue and skeletal involvement (Renner et al., 2004). For a discussion of genetic heterogeneity of hyper-IgE syndrome, see 147060. See also TYK2 deficiency (611521), a clinically distinct disease entity that includes characteristic features of both autosomal recessive HIES2 and mendelian susceptibility to mycobacterial disease (MSMD; 209950) (Minegishi et al., 2006). [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]

Mismatch repair cancer syndrome-3 (MMRCS3) is an autosomal recessive childhood cancer predisposition syndrome characterized by brain tumors, hematologic malignancy, and gastrointestinal tumors. Multiple cafe-au-lait spots, axillary freckling, and, rarely, Lisch nodules reminiscent of neurofibromatosis type I (NF1; 162200) may be present (Hegde et al., 2005, Ostergaard et al., 2005). Microsatellite instability may be detected in tumor samples (Hegde et al., 2005). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome, see MMRCS1 (276300). [from OMIM]

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]

Patients with chromosome 2q37 deletion syndrome show highly variable clinical manifestations likely resulting from different deletion sizes and deletions of different genes. Variable clinical features included brachydactyly type E (BDE), affecting the metacarpals and metatarsals (in about 50% of patients), short stature, mild to moderate intellectual disability, behavioral abnormalities, and dysmorphic facial features. However, many individuals with deletions do not show cognitive deficits (summary by Villavicencio-Lorini et al., 2013, Wheeler et al., 2014, Jean-Marcais et al., 2015). [from OMIM]

MHC class II deficiency-5 (MHC2D5) is an autosomal recessive disorder characterized by defective cell surface expression of class II HLA molecules on the surface of peripheral blood B cells, monocytes, and activated T cells. Affected individuals may present in infancy with recurrent infections and hypogammaglobulinemia, but patients do not develop severe infections, as observed in other forms of MHC class II deficiency. Some individuals may be asymptomatic (Wolf et al., 1995). For a discussion of genetic heterogeneity of MHC class II deficiency, see MHC2D1 (209920). [from OMIM]

MHC class II deficiency (MHC2D), also known as bare lymphocyte syndrome type II (BLS type II), is a rare autosomal recessive primary immunodeficiency showing genetic heterogeneity. The disorder is characterized by the loss of expression of MHC class II antigens (HLA-DR, HLA-DQ, and HLA-DP) on antigen-presenting cells (APCs) resulting from mutations in regulatory genes required for proper transcription of the MHC class II genes. Affected individuals present in early infancy with severe recurrent infections (bacteria, viruses, fungi, and protozoa), usually affecting the gastrointestinal and respiratory tracts. Protracted diarrhea and failure to thrive is often present. About 20% of patients develop autoimmune features, mainly cytopenias. Laboratory studies show reduced CD4+ T cell counts with an inverted CD4:CD8 ratio, hypogammaglobulinemia, and abnormal lymphocyte proliferation to foreign antigens. Death in infancy or early childhood often occurs, although some patients may have longer survival. MHC type II deficiency may not detected by newborn screening for T-cell receptor excision circles (TRECs). Bone marrow transplantation may be curative, although complications are common (summary by Hanna and Etzioni, 2014; El Hawary et al., 2019). In HLA class II deficiency, the abnormal expression of HLA molecules has been shown to be secondary to defective synthesis (Lisowska-Grospierre et al., 1985), due in turn to an abnormal transacting regulatory gene located outside the major histocompatibility complex (MHC) (Marcadet et al., 1985; de Preval et al., 1985). The transacting regulatory factor, known as RFX, binds to class II promoters and is defective in hereditary HLA deficiency type II, otherwise known as the 'bare lymphocyte syndrome.' The failure of HLA expression leads to immunodeficiency affecting both cellular and humoral responses to antigens. DeSandro et al. (1999) reviewed the molecular bases of the several forms of MHC deficiency. Genetic Heterogeneity of MHC Class II Deficiency MHC2D2 (620815) is caused by mutation in the RFXANK gene (603200); MHC2D3 (620816) and MHC2D5 (620818) are caused by mutation in the RFX5 gene (601863); and MHC2D4 (620817) is caused by mutation in the RFXAP gene (601861). See also MHC class I deficiency (MHC1D1; 604571). [from OMIM]

Chloroquine is used for the treatment of uncomplicated malaria and extra-intestinal amebiasis. Malaria is caused by infection of Plasmodium parasites. Chloroquine is active against the erythrocytic forms of susceptible strains of Plasmodium falciparum (P. falciparum), Plasmodium malariae (P. malariae), Plasmodium ovale (P. ovale), and Plasmodium Vivax (P. vivax). Chloroquine is not active against the gametocytes and the exoerythrocytic forms including the hypnozoite stage (P. vivax and P. ovale) of the Plasmodium parasites. Additionally, resistance to chloroquine and hydroxychloroquine has been reported in Plasmodium species, thus chloroquine therapy is not indicated if the infection arose in a region with known resistance. Chloroquine is used in first-line treatment of P. vivax malaria with primaquine. Studies have indicated chloroquine is effective against the trophozoites of Entamoeba histolytica (E. histolytica), which causes amebic dysentery, or amebiasis. Chloroquine also has off-label uses for treatment of rheumatic diseases and has been investigated as a potential antiviral therapy as well as an adjuvant chemotherapy for several types of cancer. Chloroquine accumulates in cellular acidic compartments such as the parasitic food vacuole and mammalian lysosomes, leading to alkalinization of these structures. This change in pH can impair the action of enzymes responsible for the formation of hemozoin by the parasite from ingestion of the host’s hemoglobin; this reaction occurs in the parasitic vacuole. Thus, chloroquine targets the blood-stage of the malaria parasites but cannot eliminate dormant hypnozoites and must be administered with a drug that targets the dormant parasitic form. Chloroquine, developed in the 1940s, has been superseded as the first-line recommended antimalarial therapy by both the US Centers for Disease Control (CDC) and World Health Organization (WHO), with the exceptions of during the first trimester of pregnancy or for malarial prophylaxis of a pregnant individual who is also deficient for glucose-6-phosphate dehydrogenase (G6PD). Among antimalarial medications, chloroquine is less likely than other medicines to cause hemolysis in G6PD-deficient individuals; however, the FDA-approved drug label states there is still a risk of hemolysis. In contrast, the Clinical Pharmacogenetics Implementation Consortium (CPIC) performed a systematic review of the available clinical literature and found low-to-no risk of acute hemolytic anemia for individuals with G6PD deficiency who take hydroxychloroquine or chloroquine. It should be noted that G6PD deficiency has a range of severity; CPIC advises caution for all medications when used by an individual with a severe G6PD deficiency with chronic non-spherocytic hemolytic anemia (CNSHA). [from Medical Genetics Summaries]