MedGen

Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. It is unlikely that factor V Leiden thrombophilia (i.e., heterozygosity or homozygosity for the Leiden variant) is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes (preeclampsia, fetal growth restriction, and placental abruption). The clinical expression of factor V Leiden thrombophilia is influenced by the following: The number of Leiden variants (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk). Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk. Acquired thrombophilic disorders: antiphospholipid antibody (APLA) syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and advancing age. [from GeneReviews]

The phenotypic spectrum of GARS1-associated axonal neuropathy ranges from GARS1 infantile-onset SMA (GARS1-iSMA) to GARS1 adolescent- or early adult-onset hereditary motor/sensory neuropathy (GARS1-HMSN). GARS1-iSMA. Age of onset ranges from the neonatal period to the toddler years. Initial manifestations are typically respiratory distress, poor feeding, and muscle weakness (distal greater than proximal). Weakness is slowly progressive, ultimately requiring mechanical ventilation and feeding via gastrostomy tube. GARS1-HMSN. Age of onset is most commonly during the second decade (range eight to 36 years). Initial manifestations are typically muscle weakness in the hands sometimes with sensory deficits. Lower limb involvement (seen in ~50% of individuals) ranges from weakness and atrophy of the extensor digitorum brevis and weakness of toe dorsiflexors to classic peroneal muscular atrophy with foot drop and a high steppage gait. [from GeneReviews]

Factor V Leiden thrombophilia is characterized by a poor anticoagulant response to activated protein C (APC) and an increased risk for venous thromboembolism (VTE). Deep vein thrombosis (DVT) is the most common VTE, with the legs being the most common site. Thrombosis in unusual locations is less common. Evidence suggests that heterozygosity for the Leiden variant has at most a modest effect on risk for recurrent thrombosis after initial treatment of a first VTE. It is unlikely that factor V Leiden thrombophilia (i.e., heterozygosity or homozygosity for the Leiden variant) is a major factor contributing to pregnancy loss and other adverse pregnancy outcomes (preeclampsia, fetal growth restriction, and placental abruption). The clinical expression of factor V Leiden thrombophilia is influenced by the following: The number of Leiden variants (heterozygotes have a slightly increased risk for venous thrombosis; homozygotes have a much greater thrombotic risk). Coexisting genetic thrombophilic disorders, which have a supra-additive effect on overall thrombotic risk. Acquired thrombophilic disorders: antiphospholipid antibody (APLA) syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors. Circumstantial risk factors including but not limited to pregnancy, central venous catheters, travel, combined oral contraceptive (COC) use and other combined contraceptives, oral hormone replacement therapy (HRT), selective estrogen receptor modulators (SERMs), obesity, leg injury, and advancing age. [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]

Congenital melanocytic nevus syndrome is characterized by pigmentary skin defects apparent at birth. Most individuals have 1 or more large or giant lesions greater than 20 cm and up to over 60 cm in diameter, which may cover up to 80% of total body area. These lesions may or may not be hairy. Smaller 'satellite' pigmented lesions numbering in the hundreds may also be present all over the body. Congenital melanocytic nevi (CMN) can be associated with malignant melanoma (see CMM1, 155600), but the risk appears to be low, ranging from 1 to 2% for all individuals, but rising to 10 to 15% in those with very large nevi (greater than 40 cm). A small subset of patients with CMNS have abnormalities of the central nervous system, known as 'neurocutaneous melanosis' or 'neuromelanosis' (249400), which may be symptomatic. Patients with CMNS also tend to have a characteristic facial appearance, including wide or prominent forehead, periorbital fullness, small short nose with narrow nasal bridge, round face, full cheeks, prominent premaxilla, and everted lower lip (summary by Kinsler et al., 2008; Kinsler et al., 2012). Spitz nevi are benign melanocytic melanomas composed of epithelioid or spindle cell melanocytes. They usually present as solitary skin tumors but can occur in multiple patterns, having agminated, dermatomal, and disseminated forms (summary by Sarin et al., 2013). Nevus spilus, also known as speckled lentiginous nevus, is a congenital hyperpigmented patch that progressively evolves, with affected individuals developing dark macules and papules during childhood and adolescence. Over time, nevus spilus may give rise to common lentigines, melanocytic nevi, Spitz nevi, and melanomas (summary by Sarin et al., 2014). [from OMIM]

Von Willebrand disease (VWD), a congenital bleeding disorder caused by deficient or defective plasma von Willebrand factor (VWF), may only become apparent on hemostatic challenge, and bleeding history may become more apparent with increasing age. Recent guidelines on VWD have recommended taking a VWF level of 30 or 40 IU/dL as a cutoff for those diagnosed with the disorder. Individuals with VWF levels greater than 30 IU/dL and lower than 50 IU/dL can be described as having a risk factor for bleeding. This change in guidelines significantly alters the proportion of individuals with each disease type. Type 1 VWD (~30% of VWD) typically manifests as mild mucocutaneous bleeding. Type 2 VWD accounts for approximately 60% of VWD. Type 2 subtypes include: Type 2A, which usually manifests as mild-to-moderate mucocutaneous bleeding; Type 2B, which typically manifests as mild-to-moderate mucocutaneous bleeding that can include thrombocytopenia that worsens in certain circumstances; Type 2M, which typically manifests as mild-moderate mucocutaneous bleeding; Type 2N, which can manifest as excessive bleeding with surgery and mimics mild hemophilia A. Type 3 VWD (<10% of VWD) manifests with severe mucocutaneous and musculoskeletal bleeding. [from GeneReviews]