Hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are characterized by paragangliomas (tumors that arise from neuroendocrine tissues distributed along the paravertebral axis from the base of the skull to the pelvis) and pheochromocytomas (paragangliomas that are confined to the adrenal medulla). Sympathetic paragangliomas cause catecholamine excess; parasympathetic paragangliomas are most often nonsecretory. Extra-adrenal parasympathetic paragangliomas are located predominantly in the skull base and neck (referred to as head and neck PGL [HNPGL]) and sometimes in the upper mediastinum; approximately 95% of such tumors are nonsecretory. In contrast, sympathetic extra-adrenal paragangliomas are generally confined to the lower mediastinum, abdomen, and pelvis, and are typically secretory. Pheochromocytomas, which arise from the adrenal medulla, typically lead to catecholamine excess. Symptoms of PGL/PCC result from either mass effects or catecholamine hypersecretion (e.g., sustained or paroxysmal elevations in blood pressure, headache, episodic profuse sweating, forceful palpitations, pallor, and apprehension or anxiety). The risk for developing metastatic disease is greater for extra-adrenal sympathetic paragangliomas than for pheochromocytomas.

Polycythemia vera (PV), the most common form of primary polycythemia, is caused by somatic mutation in a single hematopoietic stem cell leading to clonal hematopoiesis. PV is a myeloproliferative disorder characterized predominantly by erythroid hyperplasia, but also by myeloid leukocytosis, thrombocytosis, and splenomegaly. Familial cases of PV are very rare and usually manifest in elderly patients (Cario, 2005). PV is distinct from the familial erythrocytoses (see, e.g., ECYT1, 133100), which are caused by inherited mutations resulting in hypersensitivity of erythroid progenitors to hormonal influences or increased levels of circulating hormones, namely erythropoietin (EPO; 133170) (Prchal, 2005).

Sneddon syndrome is a noninflammatory arteriopathy characterized by onset of livedo reticularis in the second decade and onset of cerebrovascular disease in early adulthood (summary by Bras et al., 2014). Livedo reticularis occurs also with polyarteritis nodosa, systemic lupus erythematosus, and central thrombocythemia, any one of which may be accompanied by cerebrovascular accidents (Bruyn et al., 1987).

Cerebral amyloid angiopathy (CAA), defined by the deposition of congophilic material in the vessels of the cortex and leptomeninges, is a major cause of intracerebral hemorrhage in the elderly (Vinters, 1987, Greenberg, 1998). Palsdottir et al. (1988) referred to the disorder in Icelandic patients as hereditary cystatin C amyloid angiopathy (HCCAA).

Familial erythrocytosis-2 (ECYT2) is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; 133170), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (Cario, 2005). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors may be hypersensitive to EPO, consistent with a primary, intrinsic process (Prchal, 2005). For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100).

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.

FLNA deficiency is associated with a phenotypic spectrum that includes FLNA-related periventricular nodular heterotopia (Huttenlocher syndrome), congenital heart disease (patent ductus arteriosus, atrial and ventricular septal defects), valvular dystrophy, dilation and rupture of the thoracic aortic, pulmonary disease (pulmonary hypertension, alveolar hypoplasia, emphysema, asthma, chronic bronchitis), gastrointestinal dysmotility and obstruction, joint hypermobility, and macrothrombocytopenia.

Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX. Genetic Heterogeneity of Combined Deficiency of Vitamin K-Dependent Clotting Factors Combined deficiency of vitamin K-dependent clotting factors-2 (VKFCD2; 607473) is caused by mutation in the gene encoding vitamin K epoxide reductase (VKORC1; 608547) on chromosome 16p11.

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.

Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.

Cerebral cavernous malformations (CCMs) are vascular malformations in the brain and spinal cord comprising closely clustered, enlarged capillary channels (caverns) with a single layer of endothelium without mature vessel wall elements or normal intervening brain parenchyma. The diameter of CCMs ranges from a few millimeters to several centimeters. CCMs increase or decrease in size and increase in number over time. Hundreds of lesions may be identified, depending on the person's age and the quality and type of brain imaging used. Although CCMs have been reported in infants and children, the majority become evident between the second and fifth decades with findings such as seizures, focal neurologic deficits, nonspecific headaches, and cerebral hemorrhage. Up to 50% of individuals with FCCM remain symptom free throughout their lives. Cutaneous vascular lesions are found in 9% of those with familial cerebral cavernous malformations (FCCM; see Diagnosis/testing) and retinal vascular lesions in almost 5%.

Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span.

This multisystem disorder is characterized by moyamoya disease, short stature, hypergonadotropic hypogonadism, and facial dysmorphism. Other variable features include dilated cardiomyopathy, premature graying of the hair, and early-onset cataracts. Moyamoya disease is a progressive cerebrovascular disorder characterized by stenosis or occlusion of the internal carotid arteries and the main branches, leading to the development of small collateral vessels (moyamoya vessels) at the base of the brain. Affected individuals can develop acute neurologic events due to stroke-like episodes (summary by Miskinyte et al., 2011). For a general phenotypic description and a discussion of genetic heterogeneity of moyamoya disease, see MYMY1 (252350).

Autosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), whereas others have recurrent thromboses later in childhood (Comp et al., 1984). See also autosomal dominant thrombophilia due to protein S deficiency (THPH5; 612336), a less severe disorder caused by heterozygous mutation in the PROS1 gene.

Seizures, scoliosis, and macrocephaly/microcephaly syndrome (SSMS) is an autosomal recessive neurodevelopmental disorder characterized by global developmental delay apparent from early infancy, impaired intellectual development, behavioral problems, poor or absent speech, seizures, dysmorphic facial features with macro- or microcephaly, and skeletal abnormalities, including scoliosis and delayed bone age. Other features may include hypotonia, gastrointestinal problems, and exostoses (summary by Gentile et al., 2019).

Pseudo-TORCH syndrome-2 (PTORCH2) is an autosomal recessive multisystem disorder characterized by antenatal onset of intracranial hemorrhage, calcification, brain malformations, liver dysfunction, and often thrombocytopenia. Affected individuals tend to have respiratory insufficiency and seizures, and die in infancy. The phenotype resembles the sequelae of intrauterine infection, but there is no evidence of an infectious agent. The disorder results from inappropriate activation of the interferon (IFN) immunologic pathway (summary by Meuwissen et al., 2016). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).

Primary familial and congenital polycythemia (PFCP) is characterized by isolated erythrocytosis in an individual with a normal-sized spleen and absence of disorders causing secondary erythrocytosis. Clinical manifestations relate to the erythrocytosis and can include plethora, the hyperviscosity syndrome (headache, dizziness, fatigue, lassitude, visual and auditory disturbances, paresthesia, myalgia), altered mental status caused by hypoperfusion and local hypoxia, and arterial and/or venous thromboembolic events. Although the majority of individuals with PFCP have only mild manifestations of hyperviscosity such as dizziness or headache, some affected individuals have had severe and even fatal complications including arterial hypertension, intracerebral hemorrhage, deep vein thrombosis, coronary disease, and myocardial infarction. To date 116 affected individuals from 24 families have been reported.

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.

The spectrum of COL4A1-related disorders includes: small-vessel brain disease of varying severity including porencephaly, variably associated with eye defects (retinal arterial tortuosity, Axenfeld-Rieger anomaly, cataract) and systemic findings (kidney involvement, muscle cramps, cerebral aneurysms, Raynaud phenomenon, cardiac arrhythmia, and hemolytic anemia). On imaging studies, small-vessel brain disease is manifest as diffuse periventricular leukoencephalopathy, lacunar infarcts, microhemorrhage, dilated perivascular spaces, and deep intracerebral hemorrhages. Clinically, small-vessel brain disease manifests as infantile hemiparesis, seizures, single or recurrent hemorrhagic stroke, ischemic stroke, and isolated migraine with aura. Porencephaly (fluid-filled cavities in the brain detected by CT or MRI) is typically manifest as infantile hemiparesis, seizures, and intellectual disability; however, on occasion it can be an incidental finding. HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome usually associates asymptomatic small-vessel brain disease, cerebral large vessel involvement (i.e., aneurysms), and systemic findings involving the kidney, muscle, and small vessels of the eye. Two additional phenotypes include isolated retinal artery tortuosity and nonsyndromic autosomal dominant congenital cataract.

Pseudo-TORCH syndrome-3 (PTORCH3) is an autosomal recessive disorder of immune dysregulation and neuroinflammation apparent from early infancy. Affected individuals have developmental delay with acute episodes of fever and multisystemic organ involvement, including coagulopathy, elevated liver enzymes, and proteinuria, often associated with thrombotic microangiopathy. Brain imaging shows progressive intracranial calcifications, white matter abnormalities, and sometimes cerebral or cerebellar atrophy. Laboratory studies show abnormal elevation of interferon (IFN)-stimulated gene (ISG) transcripts consistent with a type I interferonopathy. The phenotype resembles the sequelae of intrauterine infection, but there is usually no evidence of an infectious agent. The disorder results from defects in negative regulation of the interferon immunologic pathway. Death in early childhood is common (summary by Duncan et al., 2019 and Gruber et al., 2020). For a discussion of genetic heterogeneity of PTORCH, see PTORCH1 (251290).

X-linked systemic autoinflammatory disease (SAIDX) is characterized by the onset of systemic autoinflammation in the first months of life. Features include lymphadenopathy, hepatosplenomegaly, fever, panniculitis, and nodular skin rash. Additional manifestations may include inflammation of the optic nerve, intracranial hemorrhage, and lipodystrophy. Laboratory studies show hypogammaglobulinemia, increased or decreased white blood cell count, autoimmune cytopenias, elevated serum inflammatory markers, and a type I interferon signature (de Jesus et al., 2020 and Lee et al., 2022).

Dilated cardiomyopathy-2G (CMD2G) is characterized by early-onset severe dilated cardiomyopathy that progresses rapidly to heart failure in the neonatal period without evidence of intervening hypertrophy. Cardiac tissue exhibits markedly shortened thin filaments, disorganized myofibrils, and reduced contractile force generation, resulting in the severe ventricular dysfunction observed. There is no evidence of skeletal muscle hypertrophy (Ahrens-Nicklas et al., 2019). For a general phenotypic description and a discussion of genetic heterogeneity of dilated cardiomyopathy, see 115200.

Congenital myopathy-2C (CMYO2C) is an autosomal dominant disorder of the skeletal muscle characterized by severe congenital weakness usually resulting in death from respiratory failure in the first year or so of life. Patients present at birth with hypotonia, lack of antigravity movements, poor head control, and difficulties feeding or breathing, often requiring tube-feeding and mechanical ventilation. Decreased fetal movements may be observed in some cases. Of the patients with congenital myopathy caused by mutation in the ACTA1 gene, about 90% carry heterozygous mutations that are usually de novo and cause the severe infantile phenotype. Some patients with heterozygous mutations have a more typical and milder disease course with delayed motor development and proximal muscle weakness, but are able to achieve independent ambulation (CMYO2A; 161800). The severity of the disease most likely depends on the detrimental effect of the mutation, although there are probably additional modifying factors (Ryan et al., 2001; Laing et al., 2009; Sanoudou and Beggs, 2001; Agrawal et al., 2004; Nowak et al., 2013; Sewry et al., 2019; Laitila and Wallgren-Pettersson, 2021). For a discussion of genetic heterogeneity of congenital myopathy, see CMYO1A (117000).

The mitochondrial trifunctional protein, composed of 4 alpha and 4 beta subunits, catalyzes 3 steps in mitochondrial beta-oxidation of fatty acids: long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase activities. Trifunctional protein deficiency is characterized by decreased activity of all 3 enzymes. Clinically, classic trifunctional protein deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden unexplained infant death (SIDS; 272120), infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy (summary by Spiekerkoetter et al., 2003). Some patients with MTP deficiency show a protracted progressive course associated with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy. These patients tend to survive into adolescence and adulthood (den Boer et al., 2003). See mitochondrial trifunctional protein deficiency-1 (609015), caused by mutation in the HADHA gene (600890), the alpha subunit of mitochondrial trifunctional protein.

Neurodevelopmental disorder with intracranial hemorrhage, seizures, and spasticity (NEDIHSS) is an autosomal recessive disorder characterized by prenatal or neonatal onset of intracranial hemorrhage, usually with ventriculomegaly and calcifications, resulting in parenchymal brain damage. Some affected individuals have symptoms incompatible with life and die in utero. Those that survive show profound global developmental delay with almost no motor or cognitive skills, hypotonia, spasticity, and seizures. Other features may include facial dysmorphism, retinal vascular abnormalities, and poor overall growth. The pathogenesis of the disease likely results from dysfunction of vascular endothelial cells in the brain (Lecca et al., 2023).