MedGen

Medulloblastoma is the most common brain tumor in children. It accounts for 16% of all pediatric brain tumors, and 40% of all cerebellar tumors in childhood are medulloblastoma. Medulloblastoma occurs bimodally, with peak incidences between 3 and 4 years and 8 and 9 years of age. Approximately 10 to 15% of medulloblastomas are diagnosed in infancy. Medulloblastoma accounts for less than 1% of central nervous system (CNS) tumors in adults, with highest incidence in adults 20 to 34 years of age. In 1 to 2% of patients, medulloblastoma is associated with Gorlin syndrome (109400), a nevoid basal carcinoma syndrome. Medulloblastoma also occurs in up to 40% of patients with Turcot syndrome (see 276300). Medulloblastoma is thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. Standard treatment includes surgery, chemotherapy, and, depending on the age of the patient, radiation therapy (Crawford et al., 2007). Millard and De Braganca (2016) reviewed the histopathologic variants and molecular subgroups of medulloblastoma. Pretreatment prognosis of medulloblastoma has been refined by histopathologic subclassification into the following variants: large-cell medulloblastoma, anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity (MBEN). The latter 2 groups have been shown to have a significantly superior prognosis as compared to the large cell and anaplastic groups in young children. At the molecular level, medulloblastomas have been categorized into the following subgroups: wingless (WNT), sonic hedgehog (SHH), group 3, and group 4. Each subgroup is characterized by a unique set of genetics and gene expression as well as demographic and clinical features. [from OMIM]

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD. [from GeneReviews]

Pancreatic cancer shows among the highest mortality rates of any cancer, with a 5-year relative survival rate of less than 5%. By the time of initial diagnosis, metastatic disease is commonly present. Established risk factors include a family history of pancreatic cancer, a medical history of diabetes type 2, and cigarette smoking (summary by Amundadottir et al., 2009). Genetic Heterogeneity of Pancreatic Cancer Somatic mutations in pancreatic cancer occur in the KRAS (190070), CDKN2A (600160), MADH4 (600993), TP53 (191170), ARMET (601916), STK11 (602216), ACVR1B (601300), and RBBP8 (604124) genes. Susceptibility loci for pancreatic cancer include PNCA1 (606856), related to mutation in the PALLD gene on chromosome 4q32 (608092); PNCA2 (613347), related to mutation in the BRCA2 gene on chromosome 13q12 (600185); PNCA3 (613348), related to mutation in the PALB2 gene on chromosome 16p12 (610355); PNCA4 (614320), related to mutation in the BRCA1 gene on chromosome 17q21 (113705); and PNCA5 (618680), related to mutation in the RABL3 gene on chromosome 3q13 (618542). Occurrence of Pancreatic Cancer in Other Disorders Several familial cancer syndromes increase the risk of pancreatic cancer. The best characterized include hereditary nonpolyposis colon cancer syndrome (HNPCC; see 120435); hereditary breast-ovarian cancer syndrome due to mutations in BRCA2; Peutz-Jeghers syndrome (175200); the melanoma-pancreatic cancer syndrome (606719), caused by mutations in CDKN2A (600160); von Hippel-Lindau syndrome (193300), ataxia-telangiectasia (208900) (Swift et al., 1976), and juvenile polyposis syndrome (174900). Patients with hereditary pancreatitis (167800) resulting from gain-of-function mutations in the protease serine-1 gene (PRSS1; 276000) have a lifetime pancreatic cancer risk ratio of 57 and a cumulative incidence, to age 70 years, of 40% (Lowenfels et al., 1997). [from OMIM]

Gastrointestinal stromal tumors are mesenchymal tumors found in the gastrointestinal tract that originate from the interstitial cells of Cajal, the pacemaker cells that regulate peristalsis in the digestive tract. Approximately 70% of GISTs develop in the stomach, 20% in the small intestine, and less than 10% in the esophagus, colon, and rectum. GISTs are typically more cellular than other gastrointestinal sarcomas. They occur predominantly in patients who are 40 to 70 years old but in rare cases may occur in younger persons (Miettinen et al., 1999, 1999). GISTs are also seen as a feature in several syndromes, e.g., neurofibromatosis-1 (NF1; 162200) and GIST-plus syndrome (175510). [from OMIM]

Prothrombin deficiency is an extremely rare autosomal recessive bleeding disorder characterized by low levels of circulating prothrombin; it affects about 1 in 2,000,000 individuals. There are 2 main types: type I deficiency, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. Type II deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein. Bleeding symptoms are more variable, depending on the amount of residual functional activity. Variant prothrombin gene alleles can result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals who are compound heterozygous for these 2 types of alleles have variable manifestations. Heterozygous mutation carriers, who have plasma levels between 40 and 60% of normal, are usually asymptomatic, but can show bleeding after tooth extraction or surgical procedures (review by Lancellotti and De Cristofaro, 2009). [from OMIM]

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns). [from GeneReviews]

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns). [from GeneReviews]

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD. [from GeneReviews]

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns). [from GeneReviews]

NR0B1-related adrenal hypoplasia congenita includes both X-linked adrenal hypoplasia congenita (X-linked AHC) and Xp21 deletion (previously called complex glycerol kinase deficiency). X-linked AHC is characterized by primary adrenal insufficiency and/or hypogonadotropic hypogonadism (HH). Adrenal insufficiency is acute infantile onset (average age 3 weeks) in approximately 60% of affected males and childhood onset (ages 1-9 years) in approximately 40%. HH typically manifests in a male with adrenal insufficiency as delayed puberty (i.e., onset age >14 years) and less commonly as arrested puberty at about Tanner Stage 3. Rarely, X-linked AHC manifests initially in early adulthood as delayed-onset adrenal insufficiency, partial HH, and/or infertility. Heterozygous females very occasionally have manifestations of adrenal insufficiency or hypogonadotropic hypogonadism. Xp21 deletion includes deletion of NR0B1 (causing X-linked AHC) and GK (causing glycerol kinase deficiency), and in some cases deletion of DMD (causing Duchenne muscular dystrophy). Developmental delay has been reported in males with Xp21 deletion when the deletion extends proximally to include DMD or when larger deletions extend distally to include IL1RAPL1 and DMD. [from GeneReviews]

DICER1 tumor predisposition (DICER1) is characterized by an increased risk for pleuropulmonary blastoma (PPB), pulmonary cysts, thyroid gland neoplasia (multinodular goiter, adenomas, and/or thyroid cancer), ovarian tumors (Sertoli-Leydig cell tumor, gynandroblastoma, and sarcoma), and cystic nephroma. Less commonly observed tumors include ciliary body medulloepithelioma, nasal chondromesenchymal hamartoma, embryonal rhabdomyosarcoma, pituitary blastoma, pineoblastoma, central nervous system (CNS) sarcoma, other CNS tumors, and presacral malignant teratoid tumor. The majority of tumors occur in individuals younger than age 40 years. PPB typically presents in infants and children younger than age six years. Ovarian sex cord-stromal tumors are most often diagnosed before age 40 years. Cystic nephroma generally presents in young children but has also been reported in adolescents. Additional clinical features that may be seen include macrocephaly, ocular abnormalities, structural anomalies of the kidney and collecting system, and dental anomalies (bulbous crowns). [from GeneReviews]

Monosomy 7 myelodysplasia and leukemia syndrome-1 (M7MLS1) is an autosomal dominant hematologic disorder with highly variable manifestations. Most patients present in early childhood with pancytopenia and dyspoietic or dysplastic changes in the bone marrow. These abnormalities are almost always associated with monosomy 7 in the bone marrow. In severely affected individuals, the phenotype progresses to frank myelodysplastic syndrome (MDS) or acute myelogenous leukemia (AML). Less severely affected individuals may have transient thrombocytopenia or anemia, or have normal peripheral blood counts with transient bone marrow abnormalities or transient monosomy 7. Germline mutations in the SAMD9L gene, located on chromosome 7q, have a gain-of-function suppressive effect on the cell cycle, resulting in decreased cellular proliferation. It is hypothesized that this germline defect leads to selective pressure favoring somatic loss of the chromosome 7 harboring the mutant allele (adaptation by aneuploidy) (summary by Wong et al., 2018). Monosomy 7 or partial deletion of the long arm of chromosome 7 (7q-) is a frequent cytogenetic finding in the bone marrow of patients with myelodysplasia and acute myelogenous leukemia. Furthermore, monosomy 7 or 7q- is the most frequent abnormality of karyotype in cases of AML that occur after cytotoxic cancer therapy or occupational exposure to mutagens. The age distribution of de novo cases shows peaks in the first and fifth decades. Monosomy 7 is found in about 5% of de novo and 40% of secondary cases of AML. These findings suggest that loss of certain genes at this region is an important event in the development of myelodysplasia (summary by Shannon et al., 1989). Genetic Heterogeneity of Monosomy 7 Myelodysplastic and Leukemia Syndrome See also M7MLS2 (619041), caused by germline mutation in the SAMD9 gene (610457) on chromosome 7q21. [from OMIM]

Atrial fibrillation (AF) is the most common sustained cardiac rhythm disturbance, affecting more than 2 million Americans, with an overall prevalence of 0.89%. The prevalence increases rapidly with age, to 2.3% between the ages of 40 and 60 years, and to 5.9% over the age of 65. The most dreaded complication is thromboembolic stroke (Brugada et al., 1997). Genetic Heterogeneity of Familial Atrial Fibrillation ATFB1 shows linkage to chromosome 10q22-q24. ATFB2 (608988) maps to chromosome 6q. ATFB3 (607554) is caused by mutation in the KCNQ1 gene (607542) on chromosome 11. ATFB4 (611493) is caused by mutation in the KCNE2 gene (603796) on chromosome 21. Variants in a region of chromosome 4q25 are associated with ATFB5 (611494). ATFB6 (612201) is caused by mutation in the NPPA gene (108780) on chromosome 1p36. ATFB7 (612240) is caused by mutation in the KCNA5 gene (176267) on chromosome 12p13. ATFB8 (613055) maps to chromosome 16q22. ATFB9 (613980) is caused by mutation in the KCNJ2 gene (600681) on chromosome 17q24.3. ATFB10 (614022) is caused by mutation in the SCN5A gene (600163) on chromosome 3p21. ATFB11 (614049) is caused by mutation in the GJA5 (121013) gene on chromosome 1q21.1. ATFB12 (614050) is caused by mutation in the ABCC9 gene (601439) on chromosome 12p12.1. ATFB13 (615377) is caused by mutation in the SCN1B gene (600235) on chromosome 19q13. ATFB14 (615378) is caused by mutation in the SCN2B gene (601327) on chromosome 11q23. ATFB15 (615770) is caused by mutation in the NUP155 gene (606694) on chromosome 5p13. ATFB16 (see 613120) is caused by mutation in the SCN3B gene (608214) on chromosome 11q24. ATFB17 (see 611819) is caused by mutation in the SCN4B gene (608256) on chromosome 11q23. ATFB18 (617280) is caused by mutation in the MYL4 gene (160770) on chromosome 17q21. Olesen et al. (2014) analyzed 192 Danish Caucasian patients with onset of lone atrial fibrillation before the age of 40 years for the presence of rare variants in 14 AF-associated genes and found that 29 (7.6%) alleles harbored a very rare variant (minor allele frequency less than 1%), a significantly higher percentage than that found in 6,503 individuals in the NHLBI Exome Variant Server database (4.1%; p = 0.0012). Twenty-four of the 29 rare variants found in the lone AF patient cohort had previously been studied, with 23 (96%) showing abnormal ion channel function by patch-clamp analysis. Olesen et al. (2014) suggested that rare variants in AF susceptibility genes may play a role in the pathophysiology of AF. [from OMIM]

No fall in mean pulmonary arterial pressure (mPAP) falls by at least 10 mmHg to an absolute value less than 40 mmHg without a degradation in cardiac output (CO) in response to a short-acting vasoactive agent such as adenosine, epoprostenol, or inhaled nitric oxide. [from HPO]

The dyssegmental dysplasias are lethal forms of neonatal short-limbed dwarfism. Handmaker et al. (1977) coined the term 'dyssegmental dysplasia' because of the marked differences in size and shape of the vertebral bodies (anisospondyly), which he attributed to errors in segmentation. Fasanelli et al. (1985) proposed that there are different forms of dyssegmental dwarfism, a lethal Silverman-Handmaker type (224410) and a less severe Rolland-Desbuquois type. The Rolland-Desbuquois form is lethal in about 40% of patients. Although many patients survive beyond the newborn period, all exhibit neonatal distress (summary by Hennekam et al., 2010). [from OMIM]

Omodysplasia is a rare skeletal dysplasia characterised by severe limb shortening and facial dysmorphism. Two types of omodysplasia have been described: an autosomal recessive or generalised form (also referred to as micromelic dysplasia with dislocation of radius) marked by severe micromelic dwarfism with predominantly rhizomelic shortening of both the upper and lower limbs, and an autosomal dominant form in which stature is normal and shortening is limited to the upper limbs. In total, less than 40 cases of omodysplasia have been described in the literature so far, with the majority of reported cases concerning the autosomal recessive form of the disease. The aetiology remains unknown but a paternally inherited paracentric inversion of 15q13 to q21.3 has been detected in one family. [from SNOMEDCT_US]

A type of angiokeratoma that most commonly occurs on the scrotum of patients who are 40 years old or older. The typical single lesion is a dark red to blue dome-shaped papule 2-4 mm in diameter with a very discrete keratotic surface. Typically, they are multiple and arranged in a line parallel to the raphe mediana of the scrotum. They also occur on the vulva and less commnly on the penis. [from HPO]

Abnormality of left ventricular contraction, often defined operationally as an ejection fraction of less than 40 percent. [from HPO]