MedGen

Primary pulmonary arterial hypertension is a rare, often fatal, progressive vascular lung disease characterized by increased pulmonary vascular resistance and sustained elevation of mean pulmonary arterial pressure, leading to right ventricular hypertrophy and right heart failure. Pathologic features include a narrowing and thickening of small pulmonary vessels and plexiform lesions. There is pulmonary vascular remodeling of all layers of pulmonary arterial vessels: intimal thickening, smooth muscle cell hypertrophy or hyperplasia, adventitial fibrosis, and occluded vessels by in situ thrombosis (summary by Machado et al., 2009 and Han et al., 2013). Heterozygous mutations in the BMPR2 gene are found in nearly 70% of families with heritable PPH and in 25% of patients with sporadic disease. The disease is more common in women (female:male ratio of 1.7:1). However, the penetrance of PPH1 is incomplete: only about 10 to 20% of individuals with BMPR2 mutations develop the disease during their lifetime, suggesting that development of the disorder is triggered by other genetic or environmental factors. Patients with PPH1 are less likely to respond to acute vasodilater testing and are unlikely to benefit from treatment with calcium channel blockade (summary by Machado et al., 2009 and Han et al., 2013). Genetic Heterogeneity of Primary Pulmonary Hypertension See also PPH2 (615342), caused by mutation in the SMAD9 gene (603295) on chromosome 13q13; PPH3 (615343), caused by mutation in the CAV1 gene (601047) on chromosome 7q31; PPH4 (615344), caused by mutation in the KCNK3 gene (603220) on chromosome 2p23; PPH5 (265400), caused by mutation in the ATP13A3 gene (610232) on chromosome 3q29; and PPH6 (620777), caused by mutation in the CAPNS1 gene (114170) on chromosome 19q13. Primary pulmonary hypertension may also be found in association with hereditary hemorrhagic telangiectasia type 1 (HHT1; 187300), caused by mutation in the ENG gene (131195), and HHT2 (600376), caused by mutation in the ACVRL1 (ALK1) gene (601284). Pediatric-onset pulmonary hypertension may be seen in association with ischiocoxopodopatellar syndrome (ICPPS; 147891). The skeletal manifestations of ICPPS are highly variable and may not be detected in children. Parents are not likely to have PAH (Levy et al., 2016). [from OMIM]

Pulmonary arterial hypertension is a progressive disorder characterized by abnormally high blood pressure (hypertension) in the pulmonary artery, the blood vessel that carries blood from the heart to the lungs. Pulmonary arterial hypertension is one form of a broader condition known as pulmonary hypertension. Pulmonary hypertension occurs when most of the very small arteries throughout the lungs narrow in diameter, which increases the resistance to blood flow through the lungs. To overcome the increased resistance, blood pressure increases in the pulmonary artery and in the right ventricle of the heart, which is the chamber that pumps blood into the pulmonary artery. Ultimately, the increased blood pressure can damage the right ventricle of the heart.

Signs and symptoms of pulmonary arterial hypertension occur when increased blood pressure cannot fully overcome the elevated resistance. As a result, the flow of oxygenated blood from the lungs to the rest of the body is insufficient. Shortness of breath (dyspnea) during exertion and fainting spells are the most common symptoms of pulmonary arterial hypertension. People with this disorder may experience additional symptoms, particularly as the condition worsens. Other symptoms include dizziness, swelling (edema) of the ankles or legs, chest pain, and a rapid heart rate. [from MedlinePlus Genetics]

Pulmonary venoocclusive disease primarily affects the postcapillary venous pulmonary vessels and may involve significant pulmonary capillary dilation and/or proliferation. PVOD is an uncommon cause of pulmonary artery hypertension (PPH; see 178600), a severe condition characterized by elevated pulmonary artery pressure leading to right heart failure and death. PVOD accounts for 5 to 10% of 'idiopathic' PPH and has an estimated incidence of 0.1 to 0.2 cases per million. The pathologic hallmark of PVOD is the extensive and diffuse occlusion of pulmonary veins by fibrous tissue, with intimal thickening present in venules and small veins in lobular septa and, rarely, larger veins. Definitive diagnosis of PVOD requires histologic analysis of a lung sample, although surgical lung biopsy is often too invasive for these frail patients. Patients with PVOD respond poorly to available therapy, therefore it is crucial to distinguish PVOD from other forms of PPH. Radiologic characteristics suggestive of PVOD on high-resolution CT of the chest include nodular ground-glass opacities, septal lines, and lymph node enlargement. In addition, because PVOD mainly affects postcapillary vasculature, it causes chronic elevation of pulmonary capillary pressure and thus promotes occult alveolar hemorrhage, which may be a characteristic feature of PVOD (summary by Montani et al., 2008). Genetic Heterogeneity of Pulmonary Venoocclusive Disease See also PVOD2 (234810), caused by mutation in the EIF2AK4 gene (609280) on chromosome 15q15. [from OMIM]

The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (summary by Knebelmann et al., 1991). [from OMIM]

Hereditary hemorrhagic telangiectasia (HHT) is characterized by the presence of multiple arteriovenous malformations (AVMs) that lack intervening capillaries and result in direct connections between arteries and veins. The most common clinical manifestation is spontaneous and recurrent nosebleeds (epistaxis) beginning on average at age 12 years. Telangiectases (small AVMs) are characteristically found on the lips, tongue, buccal and gastrointestinal (GI) mucosa, face, and fingers. The appearance of telangiectases is generally later than epistaxis but may be during childhood. Large AVMs occur most often in the lungs, liver, or brain; complications from bleeding or shunting may be sudden and catastrophic. A minority of individuals with HHT have GI bleeding, which is rarely seen before age 50 years. [from GeneReviews]

Myhre syndrome is a connective tissue disorder with multisystem involvement, progressive and proliferative fibrosis that may occur spontaneously or following trauma or surgery, mild-to-moderate intellectual disability, and in some instances, autistic-like behaviors. Organ systems primarily involved include: cardiovascular (congenital heart defects, long- and short-segment stenosis of the aorta and peripheral arteries, pericardial effusion, constrictive pericarditis, restrictive cardiomyopathy, and hypertension); respiratory (choanal stenosis, laryngotracheal narrowing, obstructive airway disease, or restrictive pulmonary disease), gastrointestinal (pyloric stenosis, duodenal strictures, severe constipation); and skin (thickened particularly on the hands and extensor surfaces). Additional findings include distinctive craniofacial features and skeletal involvement (intrauterine growth restriction, short stature, limited joint range of motion). To date, 55 individuals with molecularly confirmed Myhre syndrome have been reported. [from GeneReviews]

Juvenile polyposis syndrome (JPS) is characterized by predisposition to hamartomatous polyps in the gastrointestinal (GI) tract, specifically in the stomach, small intestine, colon, and rectum. The term "juvenile" refers to the type of polyp rather than to the age of onset of polyps. Most individuals with JPS have some polyps by age 20 years; some may have only four or five polyps over their lifetime, whereas others in the same family may have more than 100. If the polyps are left untreated, they may cause bleeding and anemia. Most juvenile polyps are benign; however, malignant transformation can occur. Risk for GI cancers ranges from 11% to 86%. Most of this increased risk is attributed to colon cancer, but cancers of the stomach, upper GI tract, and pancreas have also been reported. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) is present in most individuals with an SMAD4 pathogenic variant. [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]

Fibrodysplasia ossificans progressiva (FOP) is characterized by congenital bilateral hallux valgus malformations and early-onset heterotopic ossification, which may be spontaneous or precipitated by trauma including intramuscular vaccinations. Painful, recurrent soft-tissue swellings (flare-ups) may precede localized heterotopic ossification. Heterotopic ossification can occur at any location, but typically affects regions in close proximity to the axial skeleton in the early/mild stages, before progressing to the appendicular skeleton. This can lead to restriction of movement as a result of ossification impacting joint mobility. Problems with swallowing and speaking can occur with ossification affecting the jaw, head, and neck, and restriction of the airway and breathing may lead to thoracic insufficiency syndrome. [from GeneReviews]