Primary Lymphedema

The main symptom associated with primary lymphedema is edema in different parts of the body due to accumulation of lymph in the soft layers of tissue under the epidermis. Swelling frequently occurs in one or both legs, but may also be present in the trunk, face, genitalia and arms. When lymphedema develops in the arms or legs, swelling is usually most noticeable furthest from the heart (distally) but may involve the whole limb. In some people, swelling may cause sensations of tightness, heaviness, discomfort and unusual tingling (paresthesia) in the affected areas. The affected area heals poorly even after minor trauma (e.g., cut or insect bite). The skin of the affected area may become abnormally dry and scaly (hyperkeratosis) and fibroadipose tissue may form beneath the skin resulting in deep fissures and a woody texture. Other skin problems may develop such as bleeding from fluid-filled sacs (vesicles), leakage of lymph fluid from the skin (lymphorrhea), and warty growth (papillomatosis).

Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient, absent or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Variants in more than 20 genes have been identified as causing primary lymphedema as an isolated clinical feature or as part of a syndrome or complex lymphatic anomaly, and research continues about other possible genetic causes.

Primary lymphedema affects approximately 1.15 in 100,000 individuals < 20 years old. Primary lymphedema affects females more often than males, with a ratio of 3.5/1. Primary lymphedema during adolescence is more common among girls while boys are more commonly affected during infancy. Worsening lymphedema during hormonal changes associated with puberty, menses and pregnancy may explain the gender difference.

Symptoms of the following disorders can be similar to those of primary lymphedema presenting as a clinical feature of a multisystem disorder (syndrome) or presenting as the consequence of a complex lymphatic anomaly involving internal structures and/or organs. Peripheral edema may also be a consequence of a complicated vascular anomaly involving lymphatic vessels. Comparisons may be useful for a differential diagnosis. For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database

Primary lymphedema confined to the limbs can be diagnosed through clinical evaluation ninety percent of the time. For example, inability to pinch the skin on the dorsum of the foot (Stemmer sign) is fairly sensitive (92%) and specific (56%) for the condition. Radionuclide lymphoscintigraphy is the definitive imaging study for diagnosis of primary lymphedema. During lymphoscintigraphy, a radioactively labeled colloid substance (tracer) is injected through the skin (intradermally) into either the hands or feet and monitored as it is transported through the body. The time required for the tracer to be transported from the point of injection to the regional lymph nodes is recorded. Findings suggestive of primary lymphedema include delayed transit time, dermal backflow (accumulation of tracer in the lymphatics of the skin), asymmetrical uptake in the lymph nodes, formation of collateral lymphatic channels, and pathological uptake by lymph nodes deep in the elbow or knee areas. In congenital-onset primary lymphedema, the tracer may not move at all from the site of injection.


Primary myelofibrosis

Most of the symptoms of primary myelofibrosis are related to abnormalities affecting the production of the three main types of blood cells: red and white cells and platelets. Most blood cells are produced in the bone marrow and released into the bloodstream to travel throughout the body performing their specific functions. Red blood cells deliver oxygen to the body, white blood cells help in fighting off infections and platelets allow the body to form clots to stop bleeding.

The underlying cause of primary myelofibrosis is unknown (idiopathic). Approximately, 50 percent of people with PMF have a mutation of the JAK2 gene. This gene is also mutated in essential thrombocythemia and polycythemia vera. Mutations in the CALR gene occur in approximately 20% of the patients. Approximately 10 percent of those affected have mutations of the MPL gene. The exact role that JAK2, CALR or MPL gene mutations play in the development of primary myelofibrosis is not fully understood.

Primary myelofibrosis is a chronic blood disorder that affects males and females in equal numbers. It can occur at any age although it usually affects individuals more than 50 years of age. The median age at diagnosis is approximately 65. The incidence is estimated to be 1.5 cases per 100,000 people in the United States. In studies of Northern European countries, the incidence was estimated to be .5 cases per 100,000 people. The worldwide incidence is unknown. When primary myelofibrosis affects children, it is usually before three years of age. In younger children, girls are affected twice as often as boys.

Symptoms of the following disorders can be similar to those of primary myelofibrosis. Comparisons may be useful for a differential diagnosis.

Diagnosis of primary myelofibrosis may be made based upon a thorough clinical evaluation, detailed patient history, and various specialized tests. In many people, the presenting sign of the disorder is an abnormally enlarged spleen (splenomegaly) that may be detected upon routine examination or low levels of circulating red blood cells. A complete blood count (CBC) may demonstrate low levels of red blood cells or elevated levels of platelets or white blood cells. Since blood cell counts vary at different times in affected individuals, blood counts are not definitive in diagnosing primary myelofibrosis. Surgical removal and microscopic examination of bone marrow tissue (biopsy) is often used to confirm a suspected diagnosis of primary myelofibrosis.


Primary orthostatic tremor

The main symptom of primary orthostatic tremor is the occurrence of a rapid tremor affecting both legs while standing. A tremor is involuntary, rhythmic contractions of various muscles. Orthostatic tremor causes feelings of vibration, unsteadiness or imbalance in the legs. The tremor associated with primary orthostatic tremor has such high frequency that it may not visible to the naked eye but can be palpated by touching the thighs or calves, by listening to these muscles with a stethoscope, or by electromyography. The tremor is position-specific (standing) and disappears partially or completely when an affected individual walks, sits or lies down. In many cases, the tremor becomes progressively more severe and feelings of unsteadiness become more intense. Some affected individuals can stand for several minutes before the tremor begins; others can only stand momentarily. Eventually, affected individuals may experience stiffness, weakness and, in rare cases, pain in the legs. Orthostatic tremor, despite usually becoming progressively more pronounced, does not develop into other conditions or affect other systems of the body.

The exact cause of primary orthostatic tremor is unknown (idiopathic). Some researchers believe that the disorder is a variant or subtype of essential tremor. Other researchers believe the disorder is a separate entity. Some individuals with primary orthostatic tremor have had a family history of tremor suggesting that in these cases genetic factors may play a role in the development of the disorder. However, more research is necessary to determine the exact, underlying cause(s) of primary orthostatic tremor.

Primary orthostatic tremor affects females slightly more frequently than males. Because many affected individuals of primary orthostatic tremor often go unrecognized or misdiagnosed, the disorder is believed by some to be under-diagnosed, making it difficult to determine the true frequency of this disorder in the general population.

Tremors, involuntary quivering, or trembling movements can occur in association with many disorders. They may occur at any age and may be rhythmic or intermittent. Tremors mainly occur in disorders of the central nervous system, and especially in disorders of the cerebellum or basal ganglia. Examples of cerebellar diseases might be tumors of the cerebellum, multiple sclerosis involving the cerebellum, or a degenerative disease such as spinocerebellar degeneration. Examples of disorders of the basal ganglia include Parkinson’s disease (discussed in more detail below), Wilson’s disease, and many other rare and common disorders. Tremor may also occur as a result of anxiety, medication, or be of unknown cause (idiopathic).

A diagnosis of primary orthostatic tremor is based upon a thorough clinical evaluation, a detailed patient history, and supported by specialized tests such as a surface electromyogram (EMG). Misdiagnosis is common. Many individuals may be initially suspected of having a psychogenic disorder (a disorder caused by a psychological cause rather than a physical one).


Primary sclerosing cholangitis

Primary sclerosing cholangitis primarily involves the bile ducts. The formation of bile is one of the functions of the liver. Bile is a fluid that contains water, certain minerals that carry an electric charge (electrolytes), and other materials including bile salts, phospholipids, cholesterol, and an orange-yellow pigment (bilirubin) that is a byproduct of the natural breakdown of the hemoglobin of red blood cells. Bile flow accomplishes two important tasks within the body, it aids in digestion and absorption of dietary fats, vitamins, and other nutrients and helps eliminate excess cholesterol, bilirubin, waste, and toxins from the body. Therefore, a problem with normal bile flow often results in malabsorption of vital nutrients and the accumulation of toxic materials in the body.

Primary sclerosing cholangitis is a multifactorial disorder, which means that several different factors such as genetic, environmental and immunologic ones occurring in combination are necessary for the development of the disorder. The specific factors involved in the development of PSC have not been conclusively identified.

Primary sclerosing cholangitis is a rare disorder that affects males twice as often as females. Although it may affect individuals of any age, the disorder most often occurs in middle-aged adults. The exact incidence and prevalence of the disorder is unknown. One estimate places the incidence at approximately 1 person per each 100,000 in the general population in the United States or Europe. Some studies suggest that the incidence of PSC is increasing. PSC is one of the leading reasons people require a liver transplant in the United States. In Nordic countries, PSC is the number one cause for a liver transplant.

Symptoms of the following disorders can be similar to primary sclerosing cholangitis. Comparisons may be useful for a differential diagnosis:

Primary biliary cholangitis (PBC) is a rare liver disorder that primarily affects females and typically becomes apparent during middle age. It is characterized by yellow discoloration of the skin (jaundice) associated with obstruction and inflammation of the bile ducts (cholestasis). Additional symptoms include fatigue, pain in the upper right portion of the abdomen, diarrhea, itching (pruritus), dry eyes, dry mouth, swelling of the feet and ankles, and the formation of small fatty deposits (xanthomas) on the skin around the eyes or in the skin creases of the palms, soles, elbows or knees. In some cases, serious complications can develop including cirrhosis, portal hypertension, osteoporosis, and vitamin deficiencies. Affected individuals are at risk of developing liver cancer. Although the exact cause of PBC is unknown, various factors including immunologic, genetic, and environmental ones are believed to play a role in the development of the disorder. (For more information on this disorder, choose primary biliary cholangitis as your search term in the Rare Disease Database.)


Primary Visual Agnosia

Primary visual agnosia is a rare neurological disorder characterized by the total or partial loss of the ability to recognize and identify familiar objects and/or people by sight. This occurs without loss of the ability to actually see the object or person. The symptoms of visual agnosia occur as a result of damage to certain areas of the brain (primary) or in association with other disorders (secondary).

People with primary visual agnosia may have one or several impairments in visual recognition without impairment of intelligence, motivation, and/or attention. Vision is almost always intact and the mind is clear. Some affected individuals do not have the ability to recognize familiar objects. They can see objects, but are unable to identify them by sight. However, objects may be identified by touch, sound, and/or smell. For example, affected individuals may not be able to identify a set of keys by sight, but can identify them upon holding them in their hands.

Primary visual agnosia is a rare neurological disorder that occurs as a result of damage to the brain. Symptoms develop due to the inability to retrieve information from those damaged areas that are associated with visual memory. Lesions may occur as a result of traumatic brain injury, stroke, tumor, or overexposure to dangerous environmental toxins (e.g., carbon monoxide poisoning). In some cases, the cause of the brain damage may not be known. Symptoms may vary, according to the area of the brain that is affected.

Primary visual agnosia is an extremely rare neurological disorder that affects males and females in equal numbers. The first detailed account of visual agnosia in the medical literature occurred in 1890.

The following disorders may precede the development of primary visual agnosia. They can be useful in identifying an underlying cause of some forms of this disorder.

A variety of psychophysical tests can be conducted to pinpoint the nature of the visual process that is disrupted in an individual. Brain damage that causes visual agnosia may be identified through imaging techniques, including computed tomography (CT scan) and magnetic resonance imaging (MRI).


Proctitis

Proctitis is a chronic inflammatory disease arising in the rectum and characterized by bloody diarrhea.  There are two types of proctitis, ulcerative and gonorrheal, which are differentiated by the means in which they are contracted. Gonorrheal proctitis is transmitted through sexual contact.

Symptoms of proctitis are most frequently pain in the rectal area and a frequent desire to pass feces.  Bloody diarrhea, painful defecation and bleeding in the rectal area are also common.  Diarrhea may be followed by constipation with spasm and severe straining of the rectal muscles (tenesmus).  In some cases, stools may be well formed but surrounded by blood and mucus.

Proctitis can be caused by the pus-producing bacteria gonococci and by the herpes simplex virus, primary and secondary syphilis, chlamydia trachomatis and the human papilloma viruses.  Gonococcal Proctitis usually results from passive anal intercourse with men who have infection in the canal that empties urine from the bladder (urethra).

Proctitis is increasing in incidence.  Gonococcal Proctitis is most frequently found in women and homosexual men who practice anal-receptive intercourse.

Symptoms of the following disorders can be similar to those of Proctitis. Comparisons may be useful for a differential diagnosis:

Ulcerative Colitis is an acute inflammation of the large intestine (colon) characterized by multiple, irregular, superficial ulcerations.  The inflammation results in thickening of the wall of the colon with scar tissue and polyp-like growths.  The primary symptom of Ulcerative Colitis is bloody diarrhea.  The disease may involve only one side of the colon or it may eventually spread throughout the entire large intestine.  (For more information on this disorder, choose Ulcerative Colitis as your search term in the Rare Disease Database.)


Progressive multifocal leukoencephalopathy (PML) (1) is a neurological disorder characterized by destruction of cells that produce myelin, an oily substance that helps protect nerve cells in the brain and spinal cord, also known as central nervous system (CNS) white matter. It is caused by a virus called JC virus (JCV), named after the initials of the patient in whom it was first discovered. The virus is widespread, found in up to 85% of the general adult population. It remains inactive in healthy individuals and causes disease only when the immune system has been severely weakened, such as in people with HIV/AIDS, hematological malignancies and those receiving certain immunosuppressant medications. Altogether, PML occurs in approximately one in 200,000 people. Each year, it is estimated that 4,000 people develop PML in the United States and Europe combined. The term progressive in PML means that the disease continues to get worse and often leads to serious brain damage. The term multifocal means that JCV causes disease in multiple parts of the brain. However, it is possible for an individual with PML to have only one brain lesion instead of several lesions. The term leukoencephalopathy means that the disease affects mainly the white matter of the brain or myelin, although in some patients the gray matter neurons are also involved.

Symptoms of PML vary from person to person because lesions may occur anywhere in the central nervous system. Most patients present with subacute neurological damage, which may include some degree of mental impairment and a variety of other symptoms such as vision loss, speech disturbances, facial drooping, weakness, problems with coordination, gait and sensory loss. In addition, approximately one third of PML patients can present with seizures during the course of their disease.

The JC virus usually enters the bloodstream during childhood. It can be found via blood tests in healthy children with no symptoms of PML. Because the virus is also frequently found in the urine of healthy individuals, it is possible that the initial infection may occur through urine-oral contamination.

In the advent of the human immunodeficiency virus (HIV) epidemic, PML was soon recognized as a major opportunistic infection of acquired immunodeficiency syndrome (AIDS) occurring in up to 5% of patients.(8) Based on a study of 91 cases of PML from 1994 to 2019, 49% of PML patients have HIV infection, 31% have hematological malignancies, 30% have exposure to chemotherapeutic medications and 19% have exposure to monoclonal antibody therapies.(9)

Inflammatory Progressive Multifocal Leukoencephalopathy

The brain MRI is the first step in diagnosing PML. Cerebrospinal fluid, collected via a spinal tap, is also a dependable way to diagnose PML. Based on the 2013 consensus criteria, the diagnosis of PML can be made by the presence of positive CSF JC virus PCR in conjunction with typical clinical and imaging findings. Alternatively, brain biopsy may be necessary in some patients to confirm the diagnosis.(33) Due to the expanded population of individuals at risk for PML, early diagnosis has become of critical importance.


Progressive myoclonic epilepsy

Epilepsy, Myoclonic Progressive Familial

Progressive myoclonus epilepsy (PME) is a group of conditions involving the central nervous system and representing more than a dozen different diseases. These diseases share certain features, including a worsening of symptoms over time and the presence of both muscle contractions (myoclonus) and seizures (epilepsy). Patients may have more than one type of seizure, such as petit mal or grand mal. PME is progressive, but the rate of progression may be quick or slow, depending on the underlying disease.

Myoclonus is usually a greater problem than seizures for patients with PME because it is not helped much by the anticonvulsants that do help to control the seizures.  The twitching occurs more frequently in the early part of the day or when the patient is under stress of various sorts.  Positive myoclonus alludes to jerking of the hands and arms.  Negative myoclonus refers to the sudden onset of loss of control of the muscles of the legs that leads to falls and injuries.  As the frequency of myoclonic jerks increases, it may build to a crescendo myoclonus or a convulsion, after which the condition improves for a few days.

There are many different types of PME, each with a different underlying cause.

EPM1 occurs throughout the world but the prevalence is highest in the North African countries of Tunisia, Algeria and Morocco and also in Finland.  The prevalence in Finland is approximately 1/20,000 births.

Symptoms of the following disorders can be similar to those of Progressive Myoclonus Epilepsy.  Comparisons may be useful for a differential diagnosis:

In general, myoclonus is a group of movement disorders characterized by sudden, involuntary contractions of a skeletal muscle or group of muscles. It may be divided into two groups, rhythmical and arrhythmic myoclonus. Myoclonus may accompany a number of neurological diseases including seizure disorders, brain injuries, hereditary brain disorders, viral infections, and brain tumors.  Hereditary, and idiopathic forms also exist.  In Postanoxic Myoclonus the disorder begins after the brain is deprived of oxygen.  (For more information about other types of myoclonus, choose myoclonus as your search term in the Rare Disease Database.)


Progressive osseous heteroplasia

The symptoms of POH are usually present at birth (congenital) or within the first few weeks of life, and they tend to progress slowly and asymmetrically as an affected individual grows older. Infants with POH typically have a maculopapular rash (with patchy areas of bone within the dermis). Initially, affected skin may feel abnormally rough.

Some cases of POH may be caused by disruption or changes (mutations) of the GNAS gene.  About three-fourths of examined POH patients have inactivating GNAS gene mutations.

More than 50 affected individuals with POH have been identified around the world. Although the majority of the cases initially reported occurred in females, the disorder appears to affect males and females in similar numbers. Because POH often goes unrecognized or misdiagnosed, determining the true frequency of the disorder in the general population is difficult. In the most severe cases, symptoms are usually apparent at birth or within the first few weeks of life. Symptoms usually progress as affected individual’s age.

Symptoms of the following diseases may be similar to those of progressive osseous heteroplasia. Comparisons may be useful for differential diagnosis:

The diagnosis of POH may be confirmed by a thorough clinical evaluation, characteristic physical findings, and tests that demonstrate the presence of heterotopic ossification (e.g., x-ray or roentgenograms and CT scans) with characteristic appearance for POH in the deep connective of the fascia, muscles, tendons, muscles and/or ligaments.


Progressive supranuclear palsy

The signs and symptoms of PSP vary from person to person, but patients generally fall into one of four clinical syndromes (phenotypes): Richardson syndrome, atypical Parkinsonism, corticobasal syndrome, and pure akinesia and gait freezing. Less commonly, patients present with cognitive loss and no motor signs.

The cause of PSP is not known, but it is a form of tauopathy, in which abnormal phosphorylation of the protein tau is associated with destruction of vital protein filaments in nerve cells. This neurofibrillary degeneration is hypothesized to cause the death of nerve cells, and most experimental treatments are aimed at preventing tau pathology. The signs and symptoms of PSP are determined by the distribution of tau pathology in the brain. Recent work suggests that the disease is at least partly genetic. Many researchers now believe that various genetic and environmental factors interact to produce this disorder.

PSP is under-diagnosed, so it is difficult to know how many people are affected. This disorder is believed to affect at least 20,000 people in the United States. According to some reports, PSP is estimated to affect as many as 5-17 in 100,000 people, but recent autopsy studies found PSP pathology in 2-6% of elderly people that had no diagnosis of PSP before death. The onset of this disorder occurs between 45 and 75 years of age, with the average age of onset at about 63 years. Men and women are affected more or less equally.

Symptoms of the following disorders can resemble those of progressive supranuclear palsy. Comparisons may be useful for a differential diagnosis.

The diagnosis of progressive supranuclear palsy may be suspected based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic physical findings.


Prolactinoma

A prolactinoma is a benign tumor of the pituitary gland (adenoma) that produces an excessive amount of the hormone prolactin. In women, hyperprolactinemia is characterized by irregular menstrual periods or even absence of periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). The most common symptom in men is impotence.

Many of the symptoms of prolactinoma are caused by an excessive amount of prolactin in the blood (hyperprolactinemia) which decreases the ovarian and testicular function. In women, prolactinoma is characterized by irregular menstrual periods, infertility and production of breast milk in women who are not pregnant (galactorrhea). Some women experience diminished sexual desire or painful intercourse. The most common symptom in men is impotence, with Infertility and decreased muscle power being of concern. Both genders can develop low bone mass (osteopenia to osteoporosis).

The cause of pituitary tumors is unknown. Most pituitary tumors are sporadic and not associated with genetic factors that are inherited or can be passed on to children.

Pituitary tumors that produce enough prolactin to affect health occur in approximately 14 out of 100,000 people.

Comparisons with the following conditions may be useful for a differential diagnosis:

All patients who are shown to have a pituitary adenoma on MRI or CT imaging should have a serum prolactin level checked and if their prolactin level is >150-200 ng/ml the patient likely harbors a prolactin secreting tumor which should be treated with a dopamine agonist medication rather than surgery. If the level is less, this could be due to a tumor <10 mm or lack of normal inhibition by hypothalamic dopamine which then permits the normal prolactin secreting cells to hypersecrete (stalk effect). The effect of certain medications, recreational drugs, macroprolactin (big prolactin molecule with no effect on the body), other medical conditions (like low thyroid function, hepatic or renal insufficiency) should be evaluated for these lower levels. A specialist consultation should be considered for such patients by an experienced endocrinologist.

Prolactinoma is treated with medications that act like dopamine (dopamine agonists) such as bromocriptine, quinagolide and cabergoline because dopamine inhibits prolactin secretion. These medications reduce the size of the tumor and reduce the amount of prolactin secretion in approximately 80-90% of patients. Surgery may be recommended if medical therapy is not effective or bothersome side effects (dizziness, mental fogginess, nausea, vomiting). For both medical therapy and surgery, cure rates depend on the size and location of the tumor and the prolactinoma can recur in some affected individuals. Radiation therapy is sometimes used to control growth of a prolactinoma if no response to medications and not amenable to surgery.


Propionic acidemia

Symptoms most commonly develop during the first weeks of life and may include vomiting, listlessness (lethargy), low muscle tone (hypotonia), failure to grow and gain weight at the expected rate (failure to thrive), and dehydration. Approximately 30% of affected infants may also develop seizures. The recurrence or worsening of symptoms may be associated with an infection, constipation, or consumption of high amounts of protein. In some affected infants, episodes of symptoms may alternate with periods of apparently normal health and development.

Propionic acidemia is caused by changes (mutations) in the PCCA and PCCB genes resulting in a deficiency of the enzyme propionyl-CoA carboxylase. This enzyme is required for the proper breakdown of the amino acids isoleucine, valine, threonine, and methionine. These amino acids are needed for proper growth and development. Propionyl-CoA carboxylase is also involved in the breakdown of cholesterol, certain fatty acids, and other substances (metabolites) necessary for metabolic actions or processes. Propionyl-CoA carboxylase deficiency leads to accumulation of toxic chemicals (metabolites). Some of these accumulated chemicals harm the mitochondria (power houses inside cells responsible for energy production). [16-20].

Propionic acidemia affects males and females in equal numbers. The prevalence varies among different populations and regions. It affects around 1/100,000 to 1/250,000 individuals in most regions of the world. In the Middle East, where there is a high rate of marriage between blood relatives (consanguineous), around 1/20,000 to 1/45,000 individuals are affected. There are around 1/5,000 to ½,000 individuals with this disease in some Saudi tribes. The highest reported rate of propionic acidemia, with 1/1,000 people, has been reported in Greenlandic Inuits [21-29].

Symptoms of the following disorders may be similar to those of propionic acidemia. Comparisons may be useful for a differential diagnosis: isolated methylmalonic academia; maple syrup urine disease; non-ketotic hyperglycinemia; biotinidase deficiency; urea cycle disorders; pyruvate dehydrogenase complex deficiency; and pyruvate carboxylase deficiency.  (For more information on these disorders, search for them in the Rare Disease Database.)

Propionic acidemia can be identified at birth through expanded newborn screening by measuring levels of certain metabolites such a propionylcarnitine and methionine in a blood sample. [9, 30].


Protein C Deficiency

遗传性蛋白C缺乏所致严重遗传性血栓症

Hereditary thrombophilia due to protein C deficiency

Individuals with the mild form of protein C deficiency are at risk for developing blood clots, particularly in the veins (venous thromboembolisms). They are also at risk for a skin disease following treatment with a blood thinner called warfarin (warfarin-induced skin necrosis). Whether protein C deficiency increases the risk of blood clots in the arteries (arterial thrombosis) is not fully understood.

Protein C deficiency is caused by an alteration (mutation) in the PROC gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Protein C deficiency affects men and women in equal numbers. The prevalence of the milder form is about 1 in 200-500 people in the general population. Prevalence is the number of people in a population that have a disorder at a given time. The prevalence of severe protein C deficiency is about 1 in 500,000-750,000 people in the general population.

Symptoms of the following disorders can be similar to those of protein C deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of protein C deficiency is based upon identification of characteristic symptoms (e.g. repeated blood clot formation), a detailed patient and familial history (e.g. history of blood clots in the family), a thorough clinical evaluation and certain specialized tests.


Protein S Deficiency

hereditary thrombophilia due to protein S deficiency

Protein S deficiency is a rare genetic disorder of blood coagulation that is caused by a variation in the PROS1 gene. This variation is inherited in an autosomal dominant manner. Affected individuals are at an increased risk of developing blood clots in the legs (deep venous thrombosis), which can break off and travel to the lungs, which is termed pulmonary embolism. Affected individuals are deficient in protein S, which is a specialized blood protein. Specifically, protein S is involved in inhibiting coagulation. This means that it helps to prevent the blood from clotting too much. Affected individuals who inherit one abnormal protein S gene are at risk for developing blood clots. Although very rare, there is a severe form that is present at birth (congenital) due to the presence of 2 abnormal protein S genes that can potentially cause widespread small clots in the body and life-threatening complications in infancy. Occasionally protein S deficiency may be acquired as a result of acquired conditions such as kidney disease (i.e., nephrotic syndrome), pregnancy, or the use of oral contraceptives.

Individuals with protein S deficiency are at risk for developing blood clots, specifically blood clots that begin in veins (venous thromboembolisms). Veins are the blood vessels in the body that carry blood to the heart. The exact risk of a blood clot, the age of onset of the disease, the severity of the disease, and the number and frequency and location of blood clots will vary greatly among affected individuals. This is due, in part, to the amount of residual protein S activity there is in the body. Some individuals with protein S deficiency due to inheritance of a single abnormal protein S gene (termed heterozygous) may never develop a blood clot and others may not develop one until adulthood.

Protein S deficiency is caused by a variation in the PROS1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, absent, or overproduced. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Protein S deficiency is a rare disorder that affects both men and women. The exact prevalence the common form of protein S deficiency (the number of people who have the disorder in a given population) and incidence (new cases identified each year) of the disorder overall is unknown. Severe protein S deficiency is an extremely rare disorder and often goes undiagnosed or misdiagnosed making it difficult to determine its frequency in the general population.

Symptoms of the following disorders can be similar to those of protein S deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of protein S deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Some indications of a possible protein S deficiency include blood clots that develop before the age of 50 without an obvious cause, recurrent blood clots, blood clots in a person in a family with history of blood clot formation, and blood clots that occur in sites that are not normally affected by blood clots including veins in the small bowel (mesenteric veins), veins of the liver (portal veins), and veins in the brain (cerebral veins).

There is not a specific therapy for patients with protein S deficiency. The use of anticoagulant therapy however is highly effective in the treatment and prevention of blood clots in patients with the common type of protein S deficiency (due to inheritance of one abnormal protein S gene). Such therapies are generally effective regardless of the underlying risk factor or genetic abnormality predisposing a patient to developing a blood clot.


Proteus syndrome

Proteus syndrome may affect bone and connective tissue, fatty tissues, skin, central nervous system and internal organs (viscera). Bone, connective tissue and fat are the most commonly affected tissues in the body. The specific symptoms and severity vary greatly from person to person. Some individuals may exhibit only a few, mild symptoms of Proteus syndrome, making diagnosis challenging.

Proteus syndrome is caused by a variant in a growth regulatory gene called AKT1 that occurs after fertilization (somatic mutation). Affected persons have some cells with a normal copy of this regulatory gene and some cells with the abnormal gene (mosaic). The variability of symptoms associated with Proteus syndrome is due in part to the ratio of cells with and without the gene variant. When all cells have the AKT1 gene variant, the condition is not compatible with life. Proteus syndrome is not inherited but is caused by a mutation that occurs during development. Researchers believe that this somatic mutation occurs randomly for no apparent reason (sporadically).

Proteus syndrome is an extremely rare disorder. It affects males slightly more than females. Approximately 200 patients have been reported in the medical literature and it seems to affect people of all ethnic and racial groups. However, researchers with extensive experience in Proteus syndrome reviewed these reports and determined that just fewer than 100 met the stringent diagnostic criteria for Proteus syndrome.

Symptoms of the following disorders can be similar to those of Proteus syndrome. Comparisons may be useful for a differential diagnosis.

Diagnosis of Proteus syndrome is made using published clinical diagnostic criteria and molecular testing. Confirming a diagnosis of Proteus syndrome can be difficult and the interpretation of the clinical diagnostic criteria is controversial. The identification of the causative gene variant in AKT1 can allow molecular diagnosis, although this too can be challenging. The gene change is not present in the blood and therefore DNA testing must be performed on biopsies of affected tissue, most often skin. Other diagnostic techniques that may be used in an evaluation include plain x-rays (radiography), computed tomography (CT) scans for skull lesions or lung cysts and magnetic resonance imaging (MRI) of the brain, abdomen, pelvis and limbs. Ultrasound is used to detect scrotal or ovarian masses and can be used to evaluate deep vein thromboses.


Prune belly syndrome

Prune-Belly syndrome, also known as Eagle-Barrett syndrome, is a rare disorder characterized by partial or complete absence of the stomach (abdominal) muscles, failure of both testes to descend into the scrotum (bilateral cryptorchidism), and/or urinary tract malformations. The urinary malformations may include abnormal widening (dilation) of the tubes that bring urine to the bladder (ureters), accumulation of urine in the ureters (hydroureter) and the kidneys (hydronephrosis), and/or backflow of urine from the bladder into the ureters (vesicoureteral reflux). Complications associated with Prune-Belly syndrome may include underdevelopment of the lungs (pulmonary hypoplasia) and/or chronic renal failure. The exact cause of Prune-Belly syndrome is not known.

Prune Belly syndrome is characterized by partial absence of some or most abdominal muscles giving rise to a wrinkled or prune-like appearance.  Often, the attachments of the muscles to the bones are present, but the muscles diminish in size and thickness over the bladder.  The abdomen appears large and lax, the abdominal wall is thin and the intestinal loops can be seen through the thin abdominal wall.  Skin folds may radiate from the navel or occur as transverse folds across the abdomen.  A midline crease from the navel to pubic area may be present in some cases.  The navel may appear as a vertical slit, or as a linear central scar, but it can also appear normal.  Sometimes the navel is connected with the bladder through a canal (urachus) or a cyst.  The chest is often deformed.  Flaring of the rib margins or a horizontal depression under the chest (Harrison groove) can appear in many children born with Prune Belly Syndrome.  Narrowing of the chest in the transverse direction (pigeon breast) may also occur.

The exact cause of Prune Belly syndrome is unknown.  There are several theories.

Prune Belly syndrome is a very rare disorder that is present at birth.  The disorder affects mostly males but a few female cases have been described in the medical literature.

The diagnosis is usually obvious from birth, but care and time are required to determine the location and number of abnormalities. A full understanding of the complications will involve imaging tests such as ultrasound, X-ray, and, in order to determine the extent of involvement of the genitourinary tract, intravenous pyelogram (IVP). An IVP makes use of a dye to map the degree of involvement of the kidneys and their ducts.


Prurigo Nodularis

皮肤异色症伴中性粒细胞减少

The rash associated with prurigo nodularis varies in appearance from patient to patient and is thought to occur from excessive, chronic scratching and picking due to sensations of intense itchiness (pruritus), burning and stinging. Pruritus associated with PN is usually severe; occurs in episodes but can be continuous; and is chronic, lasting longer than 6 weeks. It is typically worsened by sweat, heat, clothing, and stress.

Although the exact cause of prurigo nodularis is not known, symptoms are thought to stem from dysregulation of the nerves and immune system in the skin.

The number of new cases of PN per year (incidence) in the US is estimated to be 72 per 100,000 people, or 87,634 people a year in people aged 18 to 64 years old. PN is more common in the elderly, and in women (54.2%) compared to men (45.5%), with women experiencing more severe pruritus. While PN can occur at any age, it is more likely to occur between ages 40 to 69 years old. Younger patients with PN are more likely to have other skin disorders associated with allergic states, such as eczema. PN is 3.4 times more common in African Americans. It is more prevalent among patients with HIV infection.

PN is typically diagnosed based on clinical symptoms. Due to this and symptom overlap with other conditions that cause severe, chronic pruritus, PN can be mistaken for other skin diseases and can co-occur with some of them as well. These include:

For the best accuracy in diagnosis and to distinguish rashes of PN from similar skin disorders, clinical examination of signs and symptoms by a dermatologist combined with microscopic examination of lesions is recommended. Microscopic examinations include dermoscopy and biopsy, and these two methods combined together provide the best likelihood of an accurate diagnosis. With dermoscopy, dermatologists use a magnifying scope that shines light onto the skin to examine its structure through a portion of the dermis. It is a relatively new exam that was originally used to distinguish between different skin cancers but is now used to diagnose other skin disorders, including inflammatory and infectious ones. It is non-invasive and therefore not painful or likely to cause infection. Biopsy, on the other hand, is simple procedure where portions of the skin are removed with a blade to allow dermatologists to see the skin in greater detail under a microscope.

Standard treatments for PN are both behavioral and medical. No FDA-approved treatment currently exists for PN, but many medications used to treat other skin disorders or immune dysfunction are used to treat PN.


Mucolipidosis type III

Pseudo-Hurler polydystrophy (mucolipidosis type III) is a rare genetic metabolic disorder characterized by a defective enzyme known as UPD-N-acetylglucosamine-1-phosphotransferase. This defective enzyme ultimately results in the accumulation of certain complex carbohydrates (mucopolysaccharides) and fatty substances (mucolipids) in various tissues of the body. The symptoms of this disorder are similar, but less severe than those of I-cell disease (mucolipidosis type II) and may include progressive joint stiffness, curvature of the spine (scoliosis), and/or skeletal deformities of the hands (e.g., claw-hands). Growth delays accompanied by deterioration of the hip joints typically develop in children with pseudo-Hurler polydystrophy. Additional symptoms may include clouding of the corneas of the eyes, mild to moderate coarseness of facial features, mild intellectual disability, easy fatigability, and/or heart disease. Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait.

In most cases, children with pseudo-Hurler polydystrophy do not exhibit symptoms until 2-4 years of age. Specific symptoms and rate of progression may vary from case to case although the disorder is often slowly progressive.

Pseudo-Hurler polydystrophy is inherited as an autosomal recessive trait. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Pseudo-Hurler polydystrophy affects males and females in equal numbers. The prevalence of the disorder is unknown. Pseudo-Hurler polydystrophy is often misdiagnosed making it difficult to determine its true frequency in the general population. One estimate places the frequency at 1 in 1 million births.

Symptoms of the following disorders can be similar to those of pseudo-Hurler polydystrophy. Comparisons may be useful for a differential diagnosis:

A diagnosis of pseudo-Hurler polydystrophy may be suspected based upon a thorough clinical evaluation, a detailed patient history and identification of characteristic findings. A variety of specialized tests may confirm a diagnosis. These tests include detecting elevated lysosomal enzyme activity in serum or decreased enzyme levels in white blood cells or cultured connective tissue cells (fibroblasts).


Pseudoachondroplasia

Pseudoachondroplasia shows variable expression with the severity varying within and between families. Infants with pseudoachondroplasia have normal birth parameters and cannot be distinguished from unaffected newborns. Generally, the first sign is diminished linear growth starting between 9 to 12 months first affecting length and eventually height, falling approximately two years behind the standard growth curve. Disproportionate short stature becomes more apparent with age. Affected children usually begin to walk between 12-18 months but gait is abnormal and described as ‘waddling’ reflecting underlying skeletal abnormalities involving the hips. The face has been described as angular. Disproportionate shortening of the arms and legs becomes apparent between 3-5 years of age. The hands and toes are very short, have redundant skin folds and marked joint laxity. Interestingly in contrast, the elbow may have limited extension. Joint laxity at the knees contributes to the lower extremity deformities that range from bowing (genu varum), knock knee (genu valgum) deformities or bowing in one leg and a knock knee deformity in the other called a windswept deformity. Surgical correction is generally required but should be delayed to get maximum sustainable correction.

Mutations in the COMP gene cause pseudoachondroplasia. Genes provide instructions for creating proteins that play critical roles in many functions of the body. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. COMP mutations specifically affect chondrocytes in the growth centers, which are the cells that specify for linear growth. The articular cartilage at the ends of all the long bones also contains chondrocytes and is easily eroded causing osteoarthritis and painful joints.

The exact birth prevalence of pseudoachondroplasia is unknown, but estimated to be 1 in 50,000-100,000. Males and females are equally affected.

Symptoms of the following skeletal dysplasia disorders can be similar to those of pseudoachondroplasia and are considered in the differential diagnosis.

The diagnosis of pseudoachondroplasia is based upon identification of characteristic clinical and radiographic findings, detailed patient history and mutational testing. The diagnosis is rarely made at birth because short stature is not present. The distinctive features develop over time, and this sets it apart from other short stature conditions.


Pseudocholinesterase Deficiency

Pseudocholinesterase deficiency is an uncommon genetic disorder that makes an affected person very sensitive to any of several anesthetic agents, especially those derived from the drug known as choline. When anesthetic drugs such as succinylcholine or mivacurium are administered to a susceptible person, the muscles that work the lungs may become paralyzed. Mechanical ventilation is essential until the excess anesthetic agent is metabolized and normal breathing is resumed.

Individuals with pseudocholinesterase deficiency have a shortage or absence of the enzyme pseudocholinesterase in their blood serum.  If the drug succinylcholine (or another anesthetic derivative of choline) is given during surgery, the respiratory muscles become paralyzed and the patient stops breathing (apnea).  Artificial respiration (mechanical ventilation) may be necessary until the drug is eliminated from the body and the affected individual is able to resume breathing.  If the person with pseudocholinesterase deficiency is not exposed to a choline-derived anesthetic, he or she may never be aware of having a deficiency of the enzyme pseudocholinesterase.

Pseudocholinesterase deficiency is inherited as an autosomal recessive trait.  The faulty gene is located on chromosome 3 (3q26.1-q26.2).

Pseudocholinesterase deficiency is present at birth and occurs in approximately 1 out of every 1,500 to 2,500 people in the United States.  Among Caucasian Americans, it seems to affect males almost twice as often as females.

Apnea is the temporary cessation of breathing during sleep.  Infantile apnea refers to pauses in breathing during an infant’s sleep.  Apnea is called central apnea or diaphragmatic apnea when there are no chest movements during the pauses in breathing.  When there are chest movements but no passage of air through the mouth or nostrils, the disorder is known as obstructive apnea or upper airway apnea.  Central apnea followed by or intermixed with an obstructive apnea is called mixed apnea.  (For more information choose apnea as your search term in the Rare Disease Database.)


Pseudohypoparathyroidism

Pseudohypoparathyroidism (PHP) is a hereditary disorder characterized by an inadequate response to the parathyroid hormone, although the hormone is present in normal amounts. Parathyroid hormone controls the amounts of calcium, phosphorus and vitamin D in bones and blood. This impacts bone growth and may cause facial and skeletal deformities. Affected individuals may have short stature, a round face and unusually short fourth fingers. They may also experience headaches, unusual sensations, weakness, fatigue, lack of energy, blurred vision, abnormal sensitivity (hypersensitivity) to light, body pains and weakness, muscle twitches and spasms, and intellectual disabilities. There are multiple subtypes of PHP, which are caused by harmful changes (variants) in certain genes, one of which is GNAS1. These subtypes show some variation in symptoms, and other hormones may also be affected (growth hormone, thyroid hormone, etc.). The symptoms of pseudohypoparathyroidism are usually first noticed in childhood. Possible treatments include calcium supplements, vitamin D supplements, low phosphate diets and growth hormone therapy. People with pseudohypoparathyroidism can lead a normal life.

There are two types of PHP, type 1 and type 2. Type 1 is broken into subtypes 1a, 1b, and 1c. Pseudopseudohypoparathyroidism (PPHP) is a limited form of PHP-1a, where an individual has the physical symptoms but not the hormone problems. Type 1a, type 1b, and PPHP are the most common subtypes. Both type 1 and type 2 PHP are characterized by resistance to parathyroid hormone, resulting in elevated phosphate levels and low calcium levels in the blood. The low calcium levels in the blood seen in all types of PHP may lead to childhood seizures in some individuals. Involuntary sudden movements, such as seen with paroxysmal kinesigenic dyskinesia (PKD), have also been reported in affected individuals. Beyond these shared characteristics, type 1 and type 2 differ greatly. Additional symptoms of type 1 are well-characterized while little is known about type 2.

Pseudohypoparathyroidism is inherited as an autosomal dominant condition and caused by changes (variants) in the GNAS gene. GNAS variants have been found in about 76% percent of affected individuals, with 38% of those individuals having an affected parent. In the remaining individuals, the cause is unknown.

PHP is a rare disorder that affects both males and females. The prevalence of PHP and AHO has been estimated to be 0.79 per 100,000 individuals.

Symptoms of the following disorders can be similar to those of PHP. Comparisons may be useful for a differential diagnosis:

Turner syndrome is a rare chromosomal disorder that affects females. The disorder is characterized by partial or complete loss (monosomy) of one of the second sex chromosomes. Turner syndrome is highly variable and can differ dramatically from one person to another. Affected females can potentially develop a wide variety of symptoms, affecting many different organ systems. Common symptoms include short stature and premature ovarian failure, which can result in the failure to attain puberty. (For more information, choose Turner as your search term in the Rare Disease Database.)

Treatment of pseudohypoparathyroidism should aim to bring calcium and phosphorus levels into the normal range. This can be achieved using calcium supplements and vitamin D supplements, which promote reabsorption of calcium in the kidneys. Low-phosphate diets or medications that bind phosphate may be used to reduce the effects of high phosphorus levels. Growth hormone therapy may also be used to improve height.


Pseudoxanthoma elasticum

Pseudoxanthoma elasticum (PXE) is an inherited disorder caused by mutations in the ABCC6 transporter gene that affects connective tissue in some parts of the body. Elastic tissue in the body becomes mineralized; that is, calcium is deposited in the tissue. This can result in changes in the skin, eyes, cardiovascular system, and gastrointestinal system. Clinicians first recognized PXE more than 100 years ago. Researchers have made a number of significant advances in the past few years.

PXE results in a variety of signs and symptoms that vary in their number, type, and severity from person to person. Certain effects of PXE can cause serious medical problems, while others have less impact. Effects may include: skin changes, changes in the retina of the eye that may result in significant loss of central vision, changes in the cardiovascular system that may involve calcification of arteries and decreased blood flow in the arms and legs, and/or changes in the gastrointestinal system that may lead to bleeding in the stomach or intestines. At present, there is no way to predict the exact progression of the disorder for a particular individual. Some people have no skin lesions; others have no vision loss. Many people do not experience gastrointestinal complications or cardiovascular difficulties. A few have no manifestations of PXE except for a positive skin biopsy or irregular streaks resembling a blood vessel (angioid) in the retina of the eye. The effects of PXE and its rate of progression seem to have no discernible pattern.

PXE is an inherited disorder caused by changes (mutations) in the ABCC6 transporter gene. ABCC6 is one of a group of genes that transport certain molecules back and forth across cell membranes. It isn’t known at this time what molecules ABCC6 transports, but it is thought that they may play a role in keeping the elastic fibers found in certain body tissues healthy.

Estimates of the incidence of PXE range from 1 in 100,000 people to 1 in 25,000. However, the true incidence of PXE is not known in any population. It is likely that many individuals with PXE have not been diagnosed, particularly people with mild signs of PXE or those whose signs are not typical.

Symptoms of the following disorders may be similar to those of Pseudoxanthoma Elasticum. Comparisons may be useful for a differential diagnosis:

Ehlers-Danlos syndrome is a rare inherited connective tissue disorder. It is characterized by the ability of affected individuals to flex their bodies beyond the normal range (articular hypermobility), to abnormally stretch their skin (hyperelasticity of the skin), and widespread tissue fragility (i.e., skin, blood vessels, and other tissues can rupture from even minor trauma). Many forms of Ehlers-Danlos Syndrome are inherited as an autosomal dominant genetic trait, but some forms of the disorder are inherited as either an autosomal recessive or an X-linked recessive genetic trait. (For more information on this disorder, choose Ehlers-Danlos as your search term in the Rare Disease Database).


Psittacosis

Psittacosis is an uncommon infectious disease that is most often transmitted to humans through exposure to infected birds, especially parrots, cockatiels, parakeets and similar pet birds. Psittacosis can affect the lungs and may cause inflammatory illness of the lungs (pneumonia). Additional common symptoms include fever, muscle pain (myalgia), headaches, and a dry cough.

The symptoms and severity of psittacosis can vary greatly. Some individuals may not develop any symptoms (asymptomatic) or only have a very mild infection; others can develop serious widespread infection that affects several organ systems of the body. The incubation period, which is the time between exposure to the bacterium to symptom development, is anywhere from five to 15 days. The onset of symptoms may be abrupt or gradual (insidious). The associated symptoms tend to be nonspecific and common to many different conditions.

Psittacosis is caused in humans by exposure to the bacterium, Chlamydia psittaci, which is most often transmitted to humans from infected birds, especially parrots and poultry, especially turkeys.

Psittacosis affects males and females in equal numbers. Anyone who handles an infected bird is at risk of developing psittacosis. Since the disease can become epidemic in animals, discovery of a single case of the disease should be reported to local public health authorities. The number of report cases of psittacosis in the United States has varied, ranging from 50 to 200 per year. Many researchers believe the disorder is under-diagnosed and the true number of cases that occur per year is unknown.

Symptoms of the following disorders can be similar to those of psittacosis. Comparisons may be useful for a differential diagnosis.

The diagnosis of psittacosis is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic findings and a variety of specialized tests such as specialized blood tests that reveal characteristic antibodies, produced by the body in response to psittacosis infection. Antibodies are specialized proteins produced by the body to fight off foreign material such as bacteria.


PTEN hamartoma tumor syndrome

PTEN错构瘤肿瘤综合征

The PTEN hamartoma tumor syndrome (PHTS) is a spectrum of disorders caused by changes (variants or mutations) of the PTEN tumor suppressor gene in egg or sperm cells (germline). These disorders are characterized by multiple hamartomas that can affect various areas of the body. Hamartoma is a general term for a benign tumor-like malformation composed of mature cells and tissue normally found in the affected area that have grown in a disorganized manner. Individuals with a variety of clinical diagnoses who ultimately have been found to carry a germline PTEN variant as the underlying cause are said to have PHTS.

The primary findings in PHTS include increased risk for certain types of cancer, benign tumors and tumor-like malformations (hamartomas) and neurodevelopmental disorders. The symptoms of PHTS vary greatly from person to person and can develop at any age.

PHTS is caused by a germline variant of PTEN, a tumor suppressor gene. PTEN stands for phosphatase and tensin homologue. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Variants in a tumor suppressor gene often lead to uncontrolled cell growth manifesting as cancer. The PTEN gene regulates the production of an enzyme (the ‘phosphatase’ in PTEN’s name) which is believed to be important in stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human malignancies. More recent studies also revealed that PTEN plays an important role in brain and nervous system development and function. These studies help explain why some individuals with PHTS also have neurodevelopmental disorders, such as autism spectrum disorder.

Cowden syndrome was estimated to affect 1 in 200,000 individuals; this study was conducted just as PTEN was discovered. However, because the disorder is difficult to recognize, researchers believe it is under-diagnosed, making it difficult to determine its true frequency in the general population. Males and females are affected equally with PHTS. PHTS is not more commonly found in persons of a particular racial or ethnic group.

Symptoms of the following disorders can be similar to those of PHTS.

A diagnosis of PHTS may be suspected based upon a thorough clinical evaluation, a detailed patient history and the presence of characteristic findings. Recently, a variant risk calculator has been developed which can estimate the risk for adults to have a PTEN variant based on their personal history characteristics; this tool is available online at https://www.lerner.ccf.org/gmi/ccscore/. The diagnosis can only be confirmed when a variant of the PTEN gene is identified.


常染色体隐性遗传多灶性翼状胬肉综合征

Autosomal recessive multiple pterygium syndrome

Multiple pterygium syndrome is a very rare genetic disorder characterized by minor facial anomalies, short stature, vertebral defects, multiple joints in a fixed position (contractures) and webbing (pterygia) of the neck, inside bend of the elbows, back of the knees, armpits and fingers. Multiple pterygium syndrome usually follows autosomal recessive inheritance but can also follow autosomal dominant inheritance.

Multiple pterygium syndrome is a very rare disorder characterized by permanently bent fingers (camptodactyly), short stature, rocker-bottom or club feet, joints that are bent in a fixed position (contractures), union or webbing of the skin between the fingers (syndactyly), and/or webbing of the neck, inside bend of the elbows, back of the knees and armpits.  The webbing of skin and contractures of the joints that are found in this disorder may restrict movement.

Multiple pterygium syndrome is a very rare genetic disorder that affects males and females equally.  There have been approximately fifty cases of this disorder reported in the medical literature.  Multiple pterygium syndrome has been found in Germany, France and England.

Symptoms of the following disorders can be similar to those of multiple pterygium syndrome.  Comparisons may be useful for a differential diagnosis:

Popliteal pterygium syndrome is a disorder characterized by cleft lip and/or cleft palate, lower lip pits, webbed skin (pterygium) on the backs of both legs (popliteal) and between the legs (intercrural), malformation and/or underdevelopment of the genitals, webbing or fusion of the fingers and/or toes (syndactyly), adhesion of upper and lower jaw and adhesion of upper and lower eyelids.  A cone-shaped fold of skin on the nail of the big toe is a very distinctive finding in this condition.  Popliteal pterygium syndrome is at the severe end of the spectrum of disorders caused by abnormalities in the interferon regulatory factor (IRF6) gene.  (For more information about this disorder, choose IRF6-related disorders as your search term in the Rare Disease Database.)

Therapy is supportive and depends on the severity of the webbing and spinal abnormalities. Orthopedic specialists should be consulted once a diagnosis is made because scoliosis develops before age five in most patients. Affected individuals have an increased risk for developing pneumonia due to a small rib cage so respiratory infections should be treated promptly. Patients with multiple pterygium syndrome may benefit from plastic surgery in the areas of webbing. This must be done with extreme caution as there may be major nerves and blood vessels in the area that are too short to allow for full extension of the limbs. Plastic surgery may also be performed to improve fused fingers and correct the cleft palate when present. Physical therapy can be of benefit to help in preventing the joints from becoming fixed.


Pulmonary Alveolar Proteinosis

自身免疫性肺泡蛋白沉积症

The lung is composed of millions of tiny air sacs (alveoli) with very thin walls that allow oxygen in the air we breathe to pass through into the blood. Surfactant is an oily substance comprising phospholipids, lesser amounts of cholesterol and proteins and is made in alveoli. It is present as a thin layer on the surface of alveolar walls and helps them stay open allowing air to come in and out as we breathe. Once used, surfactant is removed (cleared) from alveoli by cells called alveolar macrophages. This helps prevent surfactant from building up too much. Alveolar macrophages require a signaling or ‘messenger’ molecule called granulocyte/macrophage-colony stimulating factor (GM-CSF) to stimulate alveolar macrophages to function properly and maintain a normal surfactant level in alveoli. This process, called surfactant homeostasis, requires GM-CSF to stimulate alveolar macrophages to remove excess surfactant normally.

In autoimmune PAP, a feeling of breathlessness (dyspnea) is the most common symptom. Most patients develop dyspnea very slowly over time typically noticing it only with activity at first and eventually also at rest. As the disease gets worse from the buildup of surfactant, the fingertips can become bluish in color (cyanosis) due to a low level of oxygen in the blood. Cough is the next most common symptom. This can be a dry cough or a productive cough that produces whitish phlegm (sputum). Coughing up phlegm with streaks of blood (hemoptysis), with or without fever, usually indicates that infection is also present. Rounding of the fingernails and swelling of the fingertips (clubbing) is not a sign of autoimmune PAP. Fatigue, weight loss, chest pain or a general feeling of ill health (malaise) can also occur. Less commonly, secondary infections can occur in or outside the lungs. The disease activity over time (natural history) varies among patients with some experiencing life-threatening respiratory failure while others having a ‘smoldering’ or slowly progressing course and others (about 5-7 percent) may undergo spontaneous improvement. At any given time, about thirty percent of patients may not have any symptoms and the disease is discovered accidentally (incidental).

Primary PAP is caused by reduced GM-CSF stimulation of alveolar macrophages, which reduces their ability to remove surfactant from alveoli and results in surfactant build up and breathlessness. Since GM-CSF is also necessary to help alveolar macrophages (and white blood cells) kill and remove bacteria and viruses, loss of GM-CSF stimulation can also result in secondary infections. Primary PAP includes two diseases: autoimmune PAP and hereditary PAP.

While the frequency of diseases causing PAP in the general population (prevalence) is not well studied, it is thought that autoimmune PAP accounts for 85 – 90 % of all cases. Hereditary PAP, secondary PAP and congenital PAP each account for roughly 5%. Autoimmune PAP occurs in 6-7 people per million individuals in the general population. It most commonly presents in adults of 30 – 40 years of age but can occur in children as young as three years old. It is more common in men, presumably because more men smoke. Hereditary PAP usually presents in children less than ten years old but can present in adults as old as 35 years. The presentation of secondary PAP is linked to the development of another disease capable of causing PAP. The presentation of congenital PAP is variable, ranging from respiratory failure at the time of birth (associated with harmful variants in SFTPB, ABCA3 or NKX2.1 genes) or slow development of interstitial lung disease in children, adolescents or adults (associated with harmful variants in SFTPC or ABCA3 genes).

Symptoms of the following disorders can be similar to those of PAP. Comparisons may be useful for a differential diagnosis.

PAP may be suspected based upon the history (breathlessness of very slow onset) and physical examination (occasionally, crackles heard by listening with a stethoscope and rarely, cyanosis). Routine blood tests are usually normal. A diagnosis of PAP is typically supported by results from a chest X-ray or computed tomography (CT scan), which typically reveal extensive white patches within the lungs (ground glass opacity) with superimposed angular lines (reticular densities). This pattern is known as ‘crazy paving’ and is characteristic, but not diagnostic, of PAP.


Heritable pulmonary arterial hypertension

PAH symptoms are those that are usually due to not having enough oxygen in the blood or inability of the heart to pump enough blood to meet the demands of the body. In most cases, the initial symptom is severe shortness of breath following exertion. Additional symptoms include excessive fatigue, weakness, chest pain, dizzy spells, and fainting episodes.

The exact cause of PAH is unknown. Researchers believe that injury to the layer of cells that line the small blood vessels of the lung, perhaps then causing or in concert with changes in the smooth muscle cells in the vessel wall, initiates blood vessel disease. This injury, which occurs for unknown reasons, results in the contraction of smooth muscle and therefore narrows the vessel. Researchers also think that some people who develop PAH have blood vessels that are particularly sensitive to certain internal or external factors and constrict, or narrow, when exposed to these factors.

PAH occurs 3-5 times more frequently in females than in males. It tends to affect females between the ages of 30 and 60. New cases are estimated to occur in one to two individuals per million each year in the U.S. The incidence is estimated to be similar in Europe. Approximately 500-1000 new cases of PAH are diagnosed each year in the U.S. There is no ethnic or racial group that is known to have a higher frequency of patients with PAH. An exception to this is an apparent paucity of cases of HPAH among subjects of African ancestry, although this may relate to reporting bias and has not been rigorously studied.

Pulmonary hypertension is a general term that means high blood pressure that occurs only in the arteries in the lungs may affect the right side of the heart. The term PAH refers to a specific cause of pulmonary hypertension, but there are other causes of pulmonary hypertension as well. There are four other main causes of pulmonary hypertension:

Most advanced stages of cardiac conditions affecting the left heart can cause pulmonary hypertension through back up of fluid into the lung blood vessels. These cardiac diseases include ischemic heart disease, valvular disease, and cardiomyopathy. They can be ruled out as the cause of pulmonary hypertension by careful history, and using electrocardiography, echocardiography, and cardiac catheterization. This kind of pulmonary hypertension is sometimes called pulmonary venous hypertension. Pulmonary venous hypertension can lead to accumulation of blood in the lung which puts the affected individual at a higher risk for developing pleural effusions and pulmonary edema. Like PAH, pulmonary venous hypertension can cause high blood pressure in the pulmonary artery, difficulty breathing, fatigue, and cough.


Pure autonomic failure

The autonomic nervous system controls involuntary actions such as widening or narrowing of our blood vessels. Failure in this system can lead to orthostatic hypotension, which means a sudden drastic drop in blood pressure especially from a lying or sitting down position. The exact cause of pure autonomic failure (PAF) is not known, but is defined as autonomic failure without central nervous system (brain or spinal cord) involvement.

The main symptom of PAF is orthostatic hypotension. Due to the drop in blood pressure, people can have dizziness or faintness including syncope (loss of consciousness) in severe cases.

PAF is caused by abnormal accumulation of a protein called alpha-synuclein in autonomic nerves. This protein helps nerve cells communicate, but its function is not fully understood. Patients with PAF have a loss of nerve cells (neurons) in the intermediolateral column of the spinal cord.

The worldwide prevalence of PAF is not known. The age of onset is during adulthood usually in individuals over 60 years. It is more common in males than in females.

Symptoms of the following disorders can be similar to those of PAF. Comparisons may be useful for a differential diagnosis.

PAF is diagnosed by exclusion of other disorders. Multiple blood pressure measurements that show a fall in blood pressure by more than 20 mm systolic or 10 mm diastolic after at least 1 minute of standing is typical.


Pure Red Cell Aplasia, Acquired

Acquired Pure Red Cell Aplasia is a rare bone marrow disorder characterized by an isolated decline of red blood cells (erythrocytes) produced by the bone marrow. Affected individuals may experience fatigue, lethargy, and/or abnormal paleness of the skin (pallor). Acquired Pure Red Cell Aplasia may occur for unknown reasons (idiopathic) or as a primary autoimmune disorder. It is also believed that Acquired Pure Red Cell Aplasia may occur secondary to a tumor of the thymus gland (thyoma), viral infections, or certain drugs.

Acquired Pure Red Cell Aplasia is characterized by a decrease in the number of red blood cells produced in the bone marrow.  Individuals with this disorder are deficient in the number of precursors of red blood cells (erythroblasts).  Levels of the hormone erythropoietin that stimulates the bone marrow to produce red blood cells are usually elevated.

Acquired Pure Red Cell Aplasia is thought to be an autoimmune disorder possibly caused either by a tumor of the thymus gland, certain drugs or a viral infection. It is one of a group of bone marrow failure syndromes.

Acquired Pure Red Cell Aplasia is a rare disorder affecting males and females in equal numbers.

Symptoms of the following disorders are similar to those of Acquired Pure Red Cell Aplasia.  Comparisons may be useful for a differential diagnosis:

Aplastic Anemia is characterized by failure of the bone marrow to produce red blood cells, white blood cells and platelets.  Certain other anemias are due either to excessive red cell destruction or a limited production of red blood cells.  Aplastic Anemia may occur for unknown reasons, or it may be the result of a toxic reaction to radiation, certain drugs or chemicals.  In rare cases, the disorder may be caused by a tumor in the thymus gland.  (For more information on this disorder, choose Aplastic Anemia as your search term in the Rare Disease Database.)

Acquired Pure Red Cell Aplasia usually goes into remission when certain drugs such as sulfonylureas (used for treating diabetes), gold for treatment of arthritis, penicillin, phenytoin and phenobarbitol used for treating epilepsy, or the anesthetic halothane which can cause this disorder are discontinued. In affected individuals under 30 years of age, the disorder may initially be treated with the immune suppressant drug prednisone and/or antithymocyte globulin. The drugs cyclophosphamide, azathioprine, or 6-mercaptopurine which also suppress the immune system may be used for treating older individuals with Acquired Pure Red Cell Aplasia or those who fail to respond to steroids or antithymocyte globulin. Patients in both age groups may require periodic blood transfusions until the drugs take effect. The drug treatment is slowly decreased when remission of the disorder is acheived.


Pycnodysostosis

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of the potential associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all the symptoms discussed below. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

Pycnodysostosis is caused by a change (mutation) in the cathepsin K (CTSK) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body.

Pycnodysostosis is an extremely rare disorder that affects both males and females. About 200 people have been reported in the medical literature with this disorder. It is estimated to affect about 1 in 1.7 million people in the general discussion. Pycnodysostosis may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population.

Symptoms of the following disorders can be similar to those of pycnodysostosis. Comparisons may be useful for a differential diagnosis.

A diagnosis of pycnodysostosis is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and x-ray studies. X-ray studies can show many of the characteristic bone changes that are associated with this disorder.


Pyoderma Gangrenosum

Pyoderma gangrenosum (PG) is an inflammatory skin disorder that is characterized by small, red bumps (papules or nodules) or pustules that eventually erode to form swollen open sores (ulcerations). The size and depth of the ulcerations vary greatly, and they are often extremely painful. In approximately 50 percent of cases, PG occurs secondary to another disorder such as inflammatory bowel disease. The exact cause of PG is unknown (idiopathic). Some researchers believe it may be an autoimmune disorder.

Pyoderma gangrenosum often begins as small, quick-spreading reddish- or purple-colored bumps or pustules. These small growths eventually develop into swollen, open sores (ulcerations) with a well-defined blue or violet-colored border. The size and depth of ulcerations vary. Ulcerations may spread, widen and deepen and may become extremely painful. In individual cases, ulcerations may continue to spread, remain unchanged, or heal without treatment.

The exact cause of pyoderma gangrenosum is unknown (idiopathic) although it is suspected to be an autoimmune disease. Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against foreign or invading organisms begin to attack healthy tissue for unknown reasons.

Pyoderma gangrenosum affects women slightly more often than men. It occurs most often between the ages of 20 to 50 years. Infants or adolescents account for fewer than 4 percent of cases. One estimate places the incidence of PG at 1 in every 100,000 people in the United States.

Symptoms of the following disorders resemble pyoderma gangrenosum clinically or histologically. Comparisons may be useful for a differential diagnosis:

Sweet syndrome is a rare skin disorder characterized by fever, inflammation of the joints (arthritis) and the sudden onset of a rash. The rash consists of bluish-red, tender papules that usually occur on the arms, legs, face or neck, most often on one side of the body (asymmetric). In many cases, Sweet syndrome occurs by itself for no known reason (idiopathic). In some cases, the disorder is associated with an underlying malignancy, usually a hematologic malignancy such as certain types of leukemia. The exact cause of Sweet syndrome is unknown. (For more information on this disorder, choose Sweet as your search term in the Rare Disease Database).


Pyridoxine-dependent epilepsy

Pyridoxine-dependent epilepsy (PDE) is a rare cause of stubborn, difficult to control, (intractable) seizures appearing in newborns, infants and occasionally older children. More than 200 patients have now been reported in the medical literature. PDE presents in a variety of forms with variable signs and symptoms (phenotypically heterogeneous). The one clinical feature characteristic of all patients with PDE is intractable seizures that are not controlled with anticonvulsant drugs but which do respond both clinically and usually on EEG (electroencephalographically) to large daily supplements of pyridoxine. These patients are not pyridoxine-deficient. They are metabolically dependent on the vitamin. In other words, even though they get the recommended daily allowance (RDA) of pyridoxine from their normal diet, they require substantially more of the vitamin than an otherwise normal individual. Patients with PDE require pyridoxine therapy for life.

Patients with the classic neonatal PDE experience seizures soon after birth. In retrospect, many mothers describe rhythmic movements in the uterus (womb) that may start in the late second trimester and which likely represent fetal seizures. Affected neonates frequently have periods of irritability, unusual eye and facial movements, fluctuating tone, and poor feeding (encephalopathy) that precede the onset of clinical seizures. Abnormal Apgar scores (which measure heart rate, respiration, muscle tone, reflex irritability and color at birth plus one minute and at birth plus five minutes) and cord blood gases may also be seen. Under such conditions, it is not uncommon for these infants to be diagnosed initially as laboring under insufficient oxygen with consequent damage to the nervous system. Similar periods of encephalopathy may be seen in older infants with PDE, particularly prior to the onset of a recurrence of clinical seizures. Pyridoxine-treated patients who have been lax in taking their medicine (non-compliant) or those patients whose daily vitamin requirement may have increased due to growth or an intercurrent infection (particularly fever or gastroenteritis) may also experience recurrent seizures.

Mutations in the antiquitin gene (ALDH7A1) were identified in 2006 as the cause of PDE. Antiquitin is an enzyme that plays a role in the metabolism of lysine, an amino acid. Abnormal function of antiquitin secondarily results in elevations of the chemical alpha-aminoadipic semialdehyde (α-AASA) which leads to reduced activity of several enzymes in the brain that regulate the transmission of signals between neurons as well as brain development.

PDE is considered to be a rare disease, and only a few epidemiologic studies have been published. For example, a study from the United Kingdom and the Republic of Ireland reported a point prevalence of 1:687,000 for definite and probable cases of PDE, while a survey conducted in the Netherlands reported an estimated birth incidence of 1:396,000. PDE is quite likely under-diagnosed and a higher birth incidence is suspected. This notion is supported by a study from a German center where pyridoxine administration is part of a standard treatment protocol for neonatal seizures and a birth incidence of probable cases of 1:20,000 was reported. Recently, an international genetics study of 185 PDE subjects together with the analysis of population-based genomic databases concluded that the birth incidence of PDE is approximately 1:64,000 live births.

While PDE due to antiquitin deficiency should be considered when evaluating possible causes of intractable seizures in young patients, other more common causes must be ruled out, including a variety of brain malformation syndromes, serious acquired disorders of the central nervous system (such as hemorrhagic conditions and infections), and other inborn errors of metabolism. There are two additional neonatal metabolic disorders that have similarities to form of PDE that is due to mutations in ALDH7A1. One of these is a rare form of pyridoxine-dependent neonatal seizures due to abnormalities in the PLPBP gene which encodes the pyridoxal phosphate homeostasis protein. Infants with this disorder have a similar clinical presentation but do not have an abnormality in lysine metabolism with elevations in α-AASA. In this disorder, seizures do respond to pyridoxine. Another closely related neonatal metabolic epilepsy is pyridoxamine-5′-phosphate oxidase deficiency (PNPO deficiency). Babies with this genetic disorder also have intractable seizures, but the seizures in these patients respond to pyridoxal-5’-phosphate (P5P, the biologically active form of pyridoxine) but in most instances do not respond to pyridoxine. Other genetic pyridoxine-dependency states have been described (e.g. pyridoxine-dependent anemia and pyridoxine-dependent forms of homocystinuria, xanthurenic aciduria and cystathioninuria), but these conditions are not genetically related to PDE, and intractable seizures are not a feature of these other disorders.

Until the third year of life, PDE must be considered as a possible cause of intractable seizures in any patient. In particular, this diagnosis needs to be investigated in any newborn (neonate) with encephalopathy and seizures when there is no convincing evidence of oxygen deprivation, brain hemorrhage, other identifiable underlying metabolic disturbance or brain malformation. PDE must also be suspected in all young patients with intractable seizures with a history of a similar disorder in a sibling. Prior to the discovery of the abnormal gene and biochemical markers, the diagnosis could only be made on a clinical basis by observing over the course of days to weeks a patient’s response to pyridoxine therapy. Importantly, there are no definitive EEG or imaging features that will confirm a diagnosis of PDE. A clinical diagnosis may be made on an acute basis in patients experiencing prolonged or very frequent seizures by administering 100 mg of pyridoxine intravenously while monitoring the EEG, oxygen saturation and vital signs. In most patients with PDE, clinical seizures will cease and a corresponding change in the EEG will be noted. If a response is not demonstrated, the dose should be repeated up to a maximum of 500 mg. In some patients with PDE, significant neurologic and cardiorespiratory adverse effects followed this trial; therefore, close systemic monitoring is essential. For patients who are experiencing shorter seizures which occur at least daily, the diagnosis can be made by administering 30 mg/kg/day of pyridoxine orally. Patients with PDE who are treated in this fashion should stop having clinical seizures within a week. In either case, to confirm the diagnosis of PDE, a patient whose seizures stop after the use of pyridoxine should have blood or urine tested for α-AASA, or a test of the ALDH7A1 gene. With the development of multi-gene epilepsy panels and whole exome sequencing, PDE may be an unanticipated diagnosis in patients with intractable epilepsy and its discovery should lead to an immediate change in management.


Pyruvate carboxylase deficiency

Pyruvate carboxylase deficiency (PC deficiency) is a rare genetic disorder present at or shortly after birth and characterized by failure to thrive, developmental delay, recurrent seizures and failure of the body to produce the necessary fuels for energy and neurotransmitters important for brain function. In its most severe form, PC deficiency leads to progressive damage to the tissue and organs, especially in the nervous system. PC deficiency is inherited as an autosomal recessive genetic condition.

Three types of PC deficiency have been described and are called type A, type B and type C.

PC deficiency is caused by changes (variants) in the pyruvate carboxylase (PC) gene resulting in a missing or decreased amount of pyruvate carboxylase enzyme. This enzyme functions in the energy producing centers of cells (mitochondria) to make oxaloacetate. Brain energy is essential for the synthesis of the protective sheath around nerve cells (myelin) and the production of neurotransmitters in the brain.

PC deficiency is a very rare disorder that affects males and females in equal numbers. The frequency of this condition has been estimated to be 1 in 250,000 births. Type A occurs more often in native tribes of North America and type B occurs more often in Europe, especially in France, but also in Germany and England.

Symptoms of the following disorders can be like those of pyruvate carboxylase deficiency. Comparison may be useful for a differential diagnosis.

PC deficiency is suspected in individuals with failure to thrive, developmental delay, recurrent seizures and metabolic acidosis.

Treatment of PC deficiency is aimed at providing alternative sources of energy for the body and alternative means of metabolizing pyruvate (anaplerotic therapy). A diet that is low in fat and high in carbohydrates and protein is recommended. Intravenous fluids, hydration and correction of the metabolic acidosis can aid in individual flare-ups for disease management. Thiamine, lipoic acid, dichloroacetate, aspartic acid and citrate can sometimes help to reduce the levels of pyruvate and lactate. Biotin can sometimes improve the function of the pyruvate carboxylase enzyme. Triheptanoin has reportedly benefited three PC type C patients by presumably providing a source of acetyl-CoA and propionyl-CoA. Triheptanoin also may show promise in reversing neurological affects, but further studies are needed to address this suggestion. One PC type A patient also benefited from triheptanoin with reversal of hepatic failure and biochemical abnormalites, but life expectancy was not prolonged in this single reported patient.


Pyruvate dehydrogenase deficiency

Pyruvate Dehydrogenase Complex Deficiency

intermittent ataxia with pyruvate dehydrogenase deficiency

Pyruvate dehydrogenase complex deficiency (PDCD) is a rare disorder of carbohydrate metabolism caused by a deficiency of one of the three enzymes in the pyruvate dehydrogenase complex (PDC). The age of onset and severity of disease symptoms vary widely. Individuals with PDCD symptom onset in the prenatal period or in infancy usually die in early childhood. Those who develop PDCD later in childhood may have neurological symptoms but usually survive into adulthood. Most individuals with PDCD have an abnormality in the PDHA1 gene located on the X chromosome. A smaller percentage of affected individuals have forms of the disorder that follow autosomal recessive inheritance.

Individuals with PDCD are affected by a broad spectrum of symptoms ranging from fatal lactic acidosis in infancy to chronic neurological dysfunction. Not all individuals with PDCD are affected at birth, but almost all show signs of the disease during their first year of life. The most common presenting features of PDCD, including poor feeding, lethargy and rapid breathing (tachypnea), are due to increased blood levels of lactic acid. Other early symptoms include neurological function impairments, such as motor delays, poor muscle tone (hypotonia) and seizures, as well as brain structural abnormalities on neuroimaging. Many individuals with PDCD also have developmental delays, incoordination (ataxia) and respiratory infections/distress. When symptoms begin during the prenatal period or soon after birth, neurological development can be severely impacted leading to major deficits. However, individuals with symptom onset well after birth may have normal neurologic development with intermittent displays of symptoms such as ataxia.

PDCD is caused by abnormalities in the genes that encode the components of the pyruvate dehydrogenase complex. The pyruvate dehydrogenase complex contains three enzymes, E1, E2, and E3, and multiple coenzymes. The E1 enzyme is comprised of an alpha and a beta subunit. PDCD is most commonly caused by abnormalities in the gene that encodes the E1 alpha subunit, E1-alpha subunit pyruvate dehydrogenase gene or PDHA1. There are many different abnormalities in the PDHA1 gene, also called PDHA1 variants, which are known to cause PDCD. Most PDHA1 variants are sporadic meaning they are new changes to the PDHA1 gene and were not inherited. However, because this gene is located on the X chromosome, when it is inherited, it follows an X-linked recessive pattern of inheritance.

Several hundred children with PDCD have been reported, but the overall frequency is unknown. More males than females are affected by X-linked PDCD. Female carriers of X-linked PDCD may be less severely affected and more difficult to diagnose.

Symptoms of the following disorders can be similar to those of pyruvate carboxylase complex deficiency. Comparison may be useful for a differential diagnosis.

Biochemical abnormalities vary from severe acidosis (abnormally high blood levels of lactic acid) shortly after birth to mildly elevated levels, oftentimes following a meal high in carbohydrates. In some patients, elevation of blood lactate levels is seen only during the acute episodes. Excretion of abnormally large amounts of the amino acid alanine (alaninuria) may occur only during acute episodes. Imaging studies such as magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) may reveal structural brain abnormalities associated with severe disease. A definitive clinical diagnosis can be made by measuring abnormal PDC enzyme levels or function in leukocytes, fibroblasts or from a tissue biopsy.


Pyruvate Kinase Deficiency

红细胞丙酮酸激酶缺乏所致溶血性贫血

Symptoms from pyruvate kinase deficiency can be highly variable. How it affects one person can be significantly different from how it affects another person. In some people, the disorder can be life-threatening at birth. Other individuals may have mild or no symptoms of the disorder and go undiagnosed into adulthood. Others may develop symptoms during childhood or as adults. The main finding, hemolytic anemia, is a chronic, lifelong condition.

Pyruvate kinase deficiency is caused by an alteration in the PKLR gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent.

Pyruvate kinase deficiency is a rare disorder that affects both males and females. The frequency of the disorder is unknown, although one estimate suggests that approximately 1 in 20,000 Caucasian people develop the disorder. In clinical practice, the frequency is closer to 1 in 1,000,000 people. PKD has been identified most in the US and Europe. However, rare disorders like PKD often go misdiagnosed or undiagnosed making it difficult to determine their true frequency in the general population.

Symptoms of the following disorders can be similar to those of pyruvate kinase deficiency. Comparisons may be useful for a differential diagnosis.

A diagnosis of pyruvate kinase deficiency is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation, an initial laboratory evaluation, and a variety of specialized tests.