Biliary Atresia

Biliary atresia is a rare gastrointestinal disorder characterized by destruction or absence of all or a portion of the bile duct that lies outside the liver (extrahepatic bile duct). The bile duct is a tube that allows the passage of bile from the liver into the gall bladder and, eventually, the small intestine. Bile is a liquid secreted by the liver that plays an essential role in carrying waste products from the liver and promoting absorption of fats and vitamins by the intestines. In biliary atresia, absence or destruction of the bile ducts results in the abnormal accumulation of bile in the liver. Affected infants have yellowing of the skin and whites of the eyes (jaundice) and scarring of the liver (fibrosis). In some cases, additional abnormalities may be present, including heart defects and intestinal, spleen and kidney malformations. The exact cause of biliary atresia is unknown.

The symptoms of biliary atresia usually appear by the age of two to six weeks and include a yellowish coloration of the skin and whites of the eyes (jaundice), abnormally pale stools, and dark urine. Infants may also have swollen (distended) stomach and/or abnormal enlargement of the liver (hepatomegaly). By the age of six to 10 weeks, additional symptoms may also develop including poor weight gain, irritability and/or an increase in blood pressure within the veins that carry blood from the intestine to the liver (portal hypertension). Bile ducts inside the liver (intrahepatic bile ducts) are also involved. If left untreated, biliary atresia may result in permanent scarring of the liver (cirrhosis) and, eventually, liver (hepatic) failure.

The exact cause of biliary atresia is unknown, but several factors contribute to the development of the disorder, including immunologic, infectious/toxic, and genetic factors. Although the bile ducts may be normal at birth, one or more of these factors initiate epithelial damage (independently or with the help of an activated immune system) and trigger rapid production of fibrous tissue (sclerosis) causing an obstruction of bile ducts. Several viruses, including cytomegalovirus, reovirus type 3 and rotavirus infections are being studied as possible causative agents.

Biliary atresia is a rare disorder with a slight increased frequency in females. It occurs in approximately 1 in 10,000 to 15,000 births in the United States. Approximately 400-600 new cases of biliary atresia are encountered in the United States each year. According to one estimate, the prevalence of biliary atresia in Europe is approximately 1 in 12,000 births. Biliary atresia is the most common cause of end-stage liver disease and liver transplantation in children.

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

Neonatal hepatitis (sometimes referred to as neonatal cholestasis) is a term used to describe a group of disorders that present with jaundice due to inflammation of the liver and/or injury of the bile duct structure within the liver (intrahepatic). Despite the name hepatitis, most of these disorders are not caused by infections. Some of the more common disorders are the Alagille syndrome, deficiency of alpha-1-antitrypsin protein, cystic fibrosis, progressive familial intrahepatic cholestasis, and defects in synthesis of bile acids. The cause for neonatal hepatitis in some infants remains unknown. In these infants, some studies suggest an association with an infectious or viral disease. Symptoms of neonatal hepatitis typically appear during the first few weeks of life and may include a yellow discoloration of the skin and whites of the eyes (jaundice), an abnormally enlarged liver (hepatomegaly), poor feeding, slow growth, itchy skin, abdominal discomfort, lightly colored stools, and/or dark urine. (For more information on this disorder, choose Neonatal Hepatitis as your search term in the Rare Disease Database.)


Maxillonasal dysplasia

Although researchers have been able to establish characteristic or core symptoms, much about Binder type nasomaxillary l dysplasia is not fully understood. Several factors including the small number of identified affected individuals, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing an accurate picture of associated symptoms and prognosis.

The exact, underlying cause of Binder type nasomaxillary dysplasia is not fully understood. In many cases, the disorder is believed to occur spontaneously, for no apparent reason (sporadically). However, there have been reports in the medical literature of families in which more than one family member was affected. This suggests that genetic factors play a role in some affected individuals. Some researchers have suggested that Binder type nasomaxillary dysplasia is a genetic disorder inherited in either an autosomal dominant or recessive manner. Other researchers have suggested that the disorder is caused by complex genetic factors, specifically the interaction of many different genes, possibility in combination with environmental factors (multifactorial inheritance).

Binder type nasomaxillary dysplasia is a rare congenital condition that affects males and females in equal numbers. The exact incidence or prevalence is unknown. One estimate suggests that Binder syndrome occurs in less than 1 per 10,000 live births. However, individuals 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 Binder type nasomaxillary dysplasia. Comparisons may be useful for a differential diagnosis.

A diagnosis of Binder syndrome is based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. Certain specialized tests can be used to confirm the diagnosis.


Biotinidase deficiency

Infants with BTD may be born without signs of the condition. Symptoms of BTD usually appear after the first few weeks or months of life. Treating BTD with biotin supplements before symptoms show up can prevent them from happening. Below is a list of symptoms that infants and children with profound untreated BTD may have. It is important to know that not every person with BTD will show all of these symptoms.

Biotinidase deficiency is a genetic disorder caused by changes (mutations) in the BTD gene. The BTD gene instructs the body in creating the enzyme biotinidase that helps the body recycle an important vitamin called biotin (vitamin H). When the body is not able to recycle biotin, health concerns like the symptoms above can happen.

Biotinidase deficiency is a rare disorder. The early-onset form (profound BTD) usually begins during the newborn (neonatal) period. The juvenile form (partial BTD) usually begins at about three months of age. Both males and females are affected in equal numbers.

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

Biotinidase deficiency can be diagnosed in newborns through newborn screening. Newborn screening is a special type of screening test that newborns receive to see if they have certain diseases. Because the newborn screen is a screening test, a positive result does not mean that an infant definitely has the disease. Often, a repeat test must be done to confirm the diagnosis. A clinical diagnosis is possible after birth by testing for biotinidase activity in the blood. Usually, this is performed when signs and symptoms of BTD become clearer. In some infants, a genetic test may be ordered to identify the specific gene changes (mutation) that are causing BTD. Prenatal testing of sample fluid from the womb for biotinidase activity is available as early as 12 weeks of pregnancy (this includes chorionic villi sampling and amniocentesis).


Birt-Hogg-Dubé syndrome

The symptoms of Birt-Hogg-Dubé syndrome vary from person to person. The most common symptoms are multiple, benign skin lesions, lung (pulmonary) cysts, increased risk of repeated collapsed lungs (pneumothorax) and kidney (renal) neoplasia (malignant and benign tumors). Skin papules are the most frequent symptom occurring in up to 85% of individuals with BHD, but some affected individuals may develop lung cysts/pneumothorax and renal neoplasia without skin lesions. Symptoms of BHD may vary in affected members of a single BHD family who inherit the same FLCN gene variant, and patients may develop one, two or all three of the characteristic features in any combination.

BHD syndrome is caused by changes (pathogenic variant or mutations) in the FLCN gene. The FLCN gene carries the instructions to produce (encode) folliculin, a protein whose precise function is not known, but which interacts with proteins that function in cellular pathways involved in cell growth, energy production and metabolism. The FLCN gene is a tumor suppressor gene, a gene that keeps cell growth in check or slows its growth, 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 predispose individuals to develop cancer, but having a gene variant does not absolutely guarantee development of the disease.

Birt-Hogg-Dubé syndrome is a rare disorder that affects males and females in equal numbers. About 600 families (kindreds) affected with BHD have been described to date in the medical literature. Some researchers believe BHD syndrome is under-diagnosed, making it difficult to determine its true frequency in the general population.

Symptoms of the following disorders can be similar to those of Birt-Hogg-Dubé syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Birt-Hogg-Dubé syndrome is made based upon a thorough clinical evaluation, detailed patient history and identification of characteristic symptoms including two or more fibrofolliculomas, history of spontaneous pneumothorax or bilateral, multiple chromophobe or hybrid oncocytic renal tumors.


Björnstad syndrome

Bjornstad syndrome is characterized by the presence of abnormally flat and twisted hair shafts defined as pili torti. BS patients usually present with dry, fragile, lusterless, and/or coarse scalp hair. When studied under an electron microscope, hair shafts from the scalp appear flattened and/or twisted (torti) at regular intervals. Body hair may exhibit the same characteristic twisting (pili torti) as scalp hair. In some patients, patchy areas of hair loss (alopecia) may be present on the scalp as well as on other areas of the body. However, the eyebrows and eyelashes are typically not affected. Light colored eyes and hair could be associated with BS and some individuals may also experience a lack of sweating (anhidrosis). Most BS patients have deafness due to an impaired ability of the auditory nerves to transmit sensory input to the brain (sensorineural hearing loss).

Bjornstad syndrome is caused by changes (mutations) in the BCS1L gene. This gene codes for a chaperone protein that is a member of the AAA family of ATPases. An ATPase is an enzyme that uses ATP (adenosine triphosphate), the main energy source in cells, to drive chemical reactions. This particular ATPase is involved in the assembly of complex III in the mitochondrial electron transport chain. The electron transport chain is responsible for generating the energy that cells require. Complex III also produces reactive oxygen species. When present in high numbers, these reactive compounds will cause damage to tissue. Even though this abnormal protein leads to a decrease in the activity of complex III, the complex will produce more reactive oxygen species.

Bjornstad syndrome is an extremely rare disorder. In theory, it affects males and females in equal numbers. However, in observed cases, more females than males have been identified. Less than 50 cases are reported in the medical literature.

Some genetic disorders present symptoms that can be similar to those of Bjornstad syndrome. Comparisons may be useful for a differential diagnosis:

Menkes disease is an inherited X-linked recessive genetic disorder caused by disruption of copper metabolism and affects many systems in the body. Affected infants are often born prematurely and may have non-specific symptoms such as hypothermia, hypoglycemia, and prolonged jaundice. One obvious and specific physical sign is steely or kinky hair that usually develops by several months of age. Menkes disease is also associated with seizures, stunted growth, failure to thrive, unstable body temperature and intellectual disability. (For more information on this disorder, choose Menkes as your search term in the Rare Disease Database.)

There is no specific therapy for BS patients. Treatment is symptomatic and supportive and directed toward the specific symptoms present in each child. Care may require the skills of a team of specialists. Pediatricians, specialists who assess and treat hearing loss (audiologists) and physicians who specialize in diagnosing and treating disorders involving the skin (dermatologists) may coordinate their efforts to ensure the comprehensive, systematic treatment of affected children.


Bladder Exstrophy-Epispadias-Cloacal Exstrophy Comple

Bladder exstrophy-epispadias-cloacal exstrophy complex is a spectrum of anomalies involving the urinary tract, genital tract, musculoskeletal system and sometimes the intestinal tract. In classic bladder exstrophy, most anomalies are related to defects of the abdominal wall, bladder, genitalia, pelvic bones, rectum and anus.

The bladder-exstrophy-epispadias-cloacal exstrophy complex can take many forms depending on the extent of the developmental abnormality that causes it.  The mildest form is when there is an opening in the urethra (epispadias).  The most severe form is when there is an opening in the urethra, bladder and bowel (cloacal exstrophy).

In normal development, the cloacal membrane temporarily separates the urogenital and anal structures and them breaks when tissue that will form abdominal muscles begins to grow in its place.   The bladder exstrophy-epispadias-cloacal exstrophy complex is caused by a developmental abnormality that occurs 4-5 weeks after conception in which the cloacal membrane is not replaced by tissue that will form the abdominal muscles.  The underlying cause of this error in development is not known.

The birth prevalence of classic bladder exstrophy has been estimated to be between 1 in 10,000 and 1 in 50,000 livebirths.  Males are affected 2-3 times more often than females.  Isolated epispadias occurs in approximately 1 in 112,000 live male births and 1 in 400,000 live female births.  Cloacal exstrophy occurs in approximately 1 in 400,000 live births.

Prenatal ultrasound examination of a fetus with the complex may reveal absence of bladder filling, low-set umbilical cord, separation of pubic bones, small genitals and an abdominal mass that increases in size as the pregnancy progresses.


Blastomycosis

Blastomycosis is a rare infectious multisystem disease that is caused by the fungus Blastomyces dermatitidis. The symptoms vary greatly according the affected organ system. It is characterized by fever, chills, cough, and/or difficulty breathing (dyspnea). In the chronic phase of the disease, the lungs and skin are most frequently affected. The genitourinary tract and bones may also be involved.

Blastomycosis is an infectious disease characterized by fever, chills, headaches, chest pain, weight loss, night sweats, cough, and/or difficulty breathing (dyspnea).  Some affected individuals do not experience these symptoms although they are actively infected (asymptomatic).  Muscle and joint pain may occur during the acute stage which typically lasts less than three weeks.  The disease may resolve on its own or persist into the chronic form of the infection.  Chronic Blastomycosis, which lasts more than three weeks, may affect the lungs, skin, bones, joints, genitourinary tract, and/or central nervous system.

Blastomycosis is a rare infectious disease caused by the fungus Blastomyces dermatitidis.  This fungus grows and is inhaled through mold spores.  In the body the fungus converts to yeasts and invades the lungs.  It travels throughout the body through the blood.  Blastomycosis usually affects people with a compromised immune system.

Blastomycosis affects males and females in equal numbers.  The organism that causes this disease (Blastomyces dermatitidis) is most common (endemic) in the south central and southeastern portions of the United States.  It may also be found around the perimeter of the Great Lakes, and along the St. Lawrence River in Canada.  Blastomycosis has also been reported in Mexico, the Middle East, Africa, India, and South and Central America.

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

Paracoccidioidomycosis (PCM) is a chronic infectious tropical disease caused by the fungus Paracoccidioides brasiliensis.  The initial infection usually occurs in the lungs, but may also spread to the skin, mucous membranes, and other parts of the body.  The symptoms generally develop about five years after the initial exposure to the fungus and vary according to the area of the body that is infected.  In Mucocutaneous Paracoccidioidomycosis, ulcers appear on the mucous membranes, especially those of the mouth and nose.  When the lungs are affected, symptoms may include cough, difficulty breathing (dyspnea), fatigue, and/or chest pain.  (For more information on this disorder, choose Paracoccidioidomycosis as your search term in the Rare Disease Database.)


睑裂狭小-上睑下垂-倒转型内眦赘皮综合征

Blepharophimosis, Ptosis, Epicanthus Inversus Syndrome

Blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) is a rare developmental condition affecting the eyelids and ovary. Typically, four major facial features are present at birth: narrow eyes, droopy eyelids, an upward fold of skin of the inner lower eyelids and widely set eyes. These features cause difficulty in opening the eyes fully and may affect an affected individual’s quality of vision. BPES type I involves premature ovarian insufficiency (POI) in females as well as the characteristic facial features, whereas BPES type II is characterized by these facial features alone. Potential treatments include corrective eyelid surgery, hormone replacement therapy for premature ovarian insufficiency and embryo/egg donation for consequent problems with fertility.

The four major features that are characteristic symptoms of BPES are present at birth: narrowing of the eye opening (blepharophimosis), droopy eyelids (ptosis), formation of an upward fold of the inner lower eyelid (epicanthus inversus) and increased distance between the eyes (telecanthus). There are two types of BPES, BPES type I and type II, which are both characterized by the typical eyelid malformation. However, BPES type I is also associated with loss of ovarian function or premature ovarian insufficiency (POI). Menstrual periods in women with POI become less frequent over time and stop before the age of 40 thus leading to either difficulty (subfertility) or inability to conceive (infertility).  Other minor facial features frequently observed in both types include lazy eye (amblyopia), crossed eyes (strabismus), low-set ears, a short distance between the upper lip and nose, and a broad nasal bridge.

FOXL2 is the only gene known to cause BPES. This gene controls the production of the FOXL2 protein, which is involved in the development of the muscles in the eyelid as well as the growth and development of ovarian cells. Disease-causing changes (mutations) in the FOXL2 gene result in the signs and symptoms described above.

The prevalence of BPES is unknown, but there are no differences in prevalence based on ethnicity, sex, race or age.

As POI is part of the phenotypic spectrum of BPES type I, FOXL2 was assumed to be a possible candidate gene for nonsyndromic POI. However, only a handful of mutations in FOXL2 have been described in patients with nonsyndromic POI.

The diagnosis of BPES is based on four clinical findings which are present at the time of birth. The first of these findings is narrowing of the eyelids (blepharophimosis). The second finding is drooping of the upper eyelid (ptosis). With this condition, affected individuals usually compensate by tilting their heads backward with their chin up and wrinkling their foreheads to pull the eyebrows upward to maintain full vision. These compensatory mechanisms result in a characteristic facial appearance. The third clinical finding is a skin fold that arises from the lower eyelid and runs inwards and upwards (epicanthus inversus). The final clinical finding used for diagnosis is widely set eyes (telecanthus). There are two types of BPES. Type I is diagnosed based on the four major features mentioned as well as premature ovarian insufficiency causing infertility or subfertility in females. Type II is diagnosed based on the presence of the four major features alone.


Bloom syndrome

Bloom syndrome (BSyn) is a rare genetic disorder characterized by short stature; a sun-sensitive, red rash that occurs primarily over the nose and cheeks; mild immune deficiency with increased susceptibility to infections; insulin resistance that resembles type 2 diabetes; and most importantly, a markedly increased susceptibility to many types of cancer, especially leukemia, lymphoma and colorectal tumors. Diagnosis typically involves identification of the characteristic clinical features and/or molecular testing to identify changes (variants) in the BLM gene. BSyn is inherited in an autosomal recessive pattern, meaning that it occurs when a person inherits two disease-causing variants in the BLM gene. Because the most common BLM variant is present at a high frequency in the Eastern European Jewish (Ashkenazi) population, it is often included among the Jewish genetic diseases. The genetic abnormality in Bloom syndrome causes problems with DNA repair, resulting in a high number of chromosome breaks and rearrangements. The abnormal DNA repair is responsible for the increased risk for cancer.

The most consistent clinical feature of BSyn, seen throughout all stages of life, is poor growth that affects height, weight and head circumference. This growth deficiency begins before birth, and the affected fetus is typically smaller than normal for gestational age. Body proportions are normal. The average adult height of affected males and females is below normal and the average head circumference was below normal at all ages in a study of 136 Bsyn patients.

Bloom syndrome is caused by disease-causing variants in the BLM gene. The BLM gene is responsible for making a protein known as BLM. The BLM protein that is abnormal in people with Bloom syndrome is a RecQ helicase. Helicases help in DNA replication and repair by temporarily unzipping or unwinding the double helix of DNA so that it can be replicated. When this helicase is defective, as is the case in BSyn, a cell cannot detect and repair errors as effectively. This means that DNA damage during the course of a cell’s life is not found and repaired, so the cell cannot continue to function. The cell may die, or in some cases the damaged cells may continue to grow in an abnormal fashion and result in cancer.

Bloom syndrome is rare, with about 294 cases reported to the Bloom Syndrome Registry. Although it occurs in many ethnic groups, it is more prevalent in people of Ashkenazi Jewish heritage whose ancestors were from Poland or the Ukraine. Among Ashkenazi Jews living in the U.S, the carrier frequency is about one in 157. Among Ashkenazi Jews living in Israel, the carrier frequency is about one in 111. Bloom syndrome has been diagnosed in people all over the world, and about 75% of cases occur in people who are not of Jewish ancestry.

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

Three recently discovered disorders show increased SCE, a feature originally thought to be unique to BSyn, and are associated with small stature similar to that of BSyn. These disorders involve genes (RMI1, RMI2, and TOP3A) that code for proteins that interact with the BLM protein to repair DNA. However, cancer has not been observed in persons with RMI1 and RMI2 disorders yet. TOP3A disorder has also been associated with cardiomyopathy, which is not commonly found in patients with BSyn.

The treatment of Bloom syndrome is symptomatic and supportive. Health supervision recommendations that address diagnosis, treatment and surveillance for complications in persons with Bloom syndrome have been published [Cunniff et al. 2018].


Blue Diaper Syndrome

Blue diaper syndrome is a rare, genetic metabolic disorder characterized by the incomplete intestinal breakdown of tryptophan, a dietary nutrient. Symptoms typically include digestive disturbances, fever, irritability and visual difficulties. Some children with blue diaper syndrome may also develop kidney disease. Infants with this disorder may have bluish urine-stained diapers. Blue diaper syndrome is inherited as an autosomal or X-linked recessive trait.

Blue diaper syndrome is a rare inborn error metabolism that is usually detected when urine produces unusual blue stains on an infant’s diapers (indoluria). This occurs when intestinal bacteria break down excessive amounts of unabsorbed tryptophan.

Blue diaper syndrome is a rare disorder inherited as an autosomal recessive trait although X-linked recessive inheritance has not been completely ruled out. Genetic diseases are determined by two genes, one received from the father and one from the mother.

Blue diaper syndrome is an extremely rare metabolic disorder that affects males and females in equal numbers. The incidence of the disorder in the general population is unknown.

Symptoms of the following disorder can be similar to those of blue diaper syndrome. Comparison may be useful for a differential diagnosis.

A diagnosis of blue diaper syndrome is made based upon a thorough clinical evaluation, a detailed patient history, identification of characteristic symptoms, and the demonstration of indican in a fresh urine sample (indicanuria).


Blue rubber bleb nevus

Blue rubber bleb nevus syndrome (BRBNS) is a rare blood vessel (vascular) disorder that affects the skin and internal organs of the body. Multiple distinctive skin lesions are usually characteristic of this disorder and are often present at birth or present during early childhood. Lesions in the gastrointestinal tract frequently become apparent during childhood or early adulthood. The lesions are multifocal venous malformations, resulting from abnormal embryonic blood vessel development.

BRBNS is characterized by soft, elevated lesions on the skin or just under the skin that are dark blue, red, purple-red or black in color. The venous malformations may be tender, contain blood and be easily compressed and are usually located on the upper limbs, trunk and soles of the feet but can occur anywhere. The lesions increase in size and become more apparent over time but have not been reported to become cancerous. The organ system most commonly affected by BRBNS is the gastrointestinal (GI) tract, particularly the small intestine. The lesions in the GI tract often bleed and can lead to mild or severe anemia. Iron replacement and/or frequent blood transfusions may be required. The GI lesions can also cause an obstruction or blockage (intussusception) of part of the bowel. Skeletal abnormalities and venous malformations in muscle are sometimes associated with BRBNS.

Blue rubber bleb nevus syndrome is sporadic.  Although families have been described in which the condition follows autosomal dominant inheritance, these families actually have other multifocal venous malformations.

Blue Rubber Bleb Nevus Syndrome affects males and females in equal numbers. Approximately 150 cases have been reported in the medical literature.

Arteriovenous malformation (AVM) is a congenital defect in which arteries and veins are tangled and not connected by capillaries. The lack of capillaries allows blood traveling through the abnormal vessels to flow rapidly and under high pressure and prevents the nutrient rich blood in the arteries from reaching the tissues. AVM can occur in many different parts of the body, but those located in the brain, brainstem and spinal cord (neurological AVM) can affect the entire body. (For more information about arteriovenous malformation, choose arteriovenous malformation as your search term in the Rare Disease Database).

BRBNS is diagnosed by physical examination and a procedure in which the GI tract is illuminated and visualized (endoscopy). Genetic testing for BRBNS is available on a research basis only.


Bohring-Opitz syndrome

BOS presents typically at birth, but not all signs may be evident immediately. Infants with BOS may display poor growth prenatally (intrauterine growth restriction), and may have brain abnormalities evident on prenatal ultrasound, including but not limited to agenesis of the corpus callosum, enlarged ventricles, or Dandy-Walker malformation.

BOS is thought to be caused by changes (mutations) in the ASXL1 gene. This gene is thought to play a role in chromatin remodeling, which is responsible in part for the packaging of genetic material in the body. The ASXL1 gene is also thought to be involved in activating and silencing other genes in the HOX family.

BOS is not thought to affect one population of individuals more than another, and does not show any higher prevalence in males or females. There are no areas of the world where BOS is thought to be more common due to founder mutations or inbreeding (consanguinity). The current prevalence is unknown; there have been approximately 50 individuals reported in the literature but there may be others who have either not had testing or who have not come to medical attention.

Bainbridge-Roper syndrome (BRS) – Bainbridge-Roper syndrome is a congenital and developmental disorder caused by mutations in the ASXL3 gene, similar to the gene that causes BOS. Individuals with BRS may have similarly delayed milestones and developmental differences, poor growth, feeding difficulties, low tone, and microcephaly. Individuals with BRS do not typically have the birthmarks seen in children with BOS or the posturing of the hands and elbows seen in BOS.

The definitive diagnosis of BOS is made after molecular testing for mutations in the ASXL1 gene. Clinical suspicion for BOS may be raised if an individual displays the characteristic BOS posturing of the hands and elbows, is having delayed growth and developmental milestones, and has the characteristic facial features seen in BOS, including the presence of characteristic birthmarks. While the aforementioned characteristics are considered classic, individuals may present more variably, so BOS should not be entirely excluded necessarily on clinical presentation alone, unless obvious signs of another condition are present.


Bosma Arhinia Microphthalmia Syndrome

无鼻畸形-鼻后孔闭锁-小眼畸形综合征

Researchers have been able to delineate a recognizable syndrome with characteristic or core symptoms, but much about this disorder is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies and other factors have prevented physicians from developing a complete picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals may not have all of the symptoms discussed below or may have symptoms that are not discussed. Every patient is unique, and the disorder can be different in one child when compared to another. Parents should talk to their child’s physicians and medical team about their specific case, associated symptoms and overall prognosis.

In 2017, two independent teams of researchers discovered that BAM syndrome is caused by a change (variant) in the SMCHD1 gene. The gene variant is usually a spontaneous (de novo) change in SMCHD1 that occurs in the egg or sperm cell. In such situations, it is not inherited from a parent. Rarely, an SMCHD1 gene variant can be inherited from a parent.

BAM syndrome is an extremely rare disorder that is known to affect patients from many different ethnic groups. As with many rare disorders, the exact incidence or prevalence of this disorder is unknown. The disorder probably goes misdiagnosed or undiagnosed making it difficult to determine the true frequency in the general population. Fewer than 100 people with this disorder have been reported in the medical literature.

Symptoms of the following disorders can be similar to those of BAM syndrome. For more information on each of these disorders, enter the disease name as your search term in the Rare Disease Database.

Arhinia is apparent at birth and can sometimes be suspected prenatally. A medical geneticist, pediatrician, or other pediatric subspecialist should do a complete physical exam and order tests to look for the two other major features of BAM syndrome: eye defects and genital/hormone defects. Molecular genetic testing for variants in the SMCHD1 gene that are associated with BAM syndrome is available at specialized laboratories.


Botulism

Botulism is a rare but serious paralytic illness caused by a toxin usually produced by the bacterium Clostridium botulinum. There are four generally recognized naturally occurring types; foodborne, wound, infant, and, rarely, adult intestinal colonization. Iatrogenic and inhalational botulism may also occur. Foodborne botulism is caused by eating foods that contain botulinum toxin. Wound botulism occurs when C. botulinum spores germinate and produce toxin in a contaminated wound or abscess. The most common form of botulism in the United States, infant botulism, is caused when ingested C. botulinum spores colonize and subsequently produce toxin in the intestines of affected infants. In rare instances, C. botulinum intestinal colonization and toxin production have also occurred among adults with anatomical or functional bowel abnormalities. Additionally, iatrogenic botulism has infrequently occurred after intramuscular injection of botulinum toxin for treatment of certain dystonias and other disorders. Finally, inhalational botulism, though not naturally occurring, was reported among three German laboratory workers who inadvertently inhaled aerosolized toxin and could potentially occur after a deliberate aerosolization of toxin in a bioterrorism event. Any case of foodborne or unexplained botulism is considered to be a public health emergency because of the potential for toxin-containing foods to injure others who eat them and because of the potential misuse of botulinum toxin as a biological weapon. State and local public health officials by law must be informed immediately whenever botulism is suspected in a human patient.

The incubation period for foodborne botulism is usually 12 – 36 hours but may range from a few hours to 10 days. Symptom onset might occur faster in an inhalational botulism scenario. Symptoms can range from mild to severe. The classic medical triad of botulism is a weakness or paralysis and reduced muscle tone in a patient without fever (afebrile) and with a clear sensorium (alert and able to respond to questions). Fever might occur after a secondary infection (e.g., aspiration pneumonia).

Foodborne botulism is the result of ingestion and absorption of toxin that is produced by C. botulinum in contaminated foods. Wound botulism is caused by toxin produced from a wound infected with C. botulinum. Unlike foodborne and wound botulism, infant botulism and adult intestinal colonization botulism result from ingestion of the bacterial spore(s) that grow and produce botulinum toxin within the large intestine. Honey is the one identified and avoidable food reservoir of these spores for infant botulism. After testing over the years of hundreds of foods, beverages and other items placed in infants’ mouths with negative results, it was concluded that the source of spores for most infant botulism patients is unknown but may be from ingestion of microscopic dust particles on which the spores travel.

Infant botulism occurs globally and is the most common form of human botulism in the United States. Patients diagnosed with botulism demonstrated a predominance of toxin type A west of the Rocky Mountains and type B east of the Rocky Mountains, while type E is more prevalent in the Pacific Northwest, Alaska and the Great Lakes area. Type E also occurs in northern latitudes and Japan. National botulism surveillance information is available from Centers for Disease Control and Prevention (CDC) at the following link:

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

The clinical diagnosis of botulism may be made based upon a thorough clinical evaluation and a detailed patient history. The mouse bioassay and mass spectrometry–based testing (Endopep-MS) are the gold standard methods for laboratory confirmation of the clinical diagnosis and may demonstrate the presence of botulinum toxin in serum, gastric fluid, stool (mouse bioassay testing only) or food (foodborne botulism) specimens. Botulism can also be confirmed by culture of C. botulinum organisms from gastric fluid, stool, or a contaminated wound (wound botulism).


Bowen Hutterite Syndrome

Bowen Hutterite syndrome is a rare genetic disorder that is apparent at birth (congenital). The disorder is characterized by growth delays before birth (intrauterine growth retardation); failure to grow and gain weight at the expected rate (failure to thrive) during infancy; malformations of the head and facial (craniofacial) area, resulting in a distinctive appearance; and other physical abnormalities. These may include restricted joint movements, abnormal deviation (clinodactyly) or permanent flexion (camptodactyly) of the fifth fingers, foot deformities, and/or undescended testes (cryptorchidism) in affected males. Some affected infants may also have kidney (renal), brain, and/or other malformations. Bowen Hutterite syndrome is inherited as an autosomal recessive trait.

Bowen Hutterite syndrome is primarily characterized by distinctive malformations of the head and facial (craniofacial) area as well as additional skeletal, genital, kidney (renal), and/or brain abnormalities.

Bowen Hutterite syndrome is transmitted as an autosomal recessive trait.  Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Bowen Hutterite syndrome appears to affect males and females in equal numbers. Since the disorder was originally described in two brothers in 1976 (P. Bowen), over 20 cases have been reported in the medical literature.  Most affected individuals are Hutterites.  The Hutterites are members of a religious sect (Anabaptists) originally from Moravia who live communally in certain regions of the United States (e.g., Montana, North and South Dakota) and Alberta, Canada.

Treatment of Bowen Hutterite Syndrome is symptomatic and supportive. Feeding through a surgical opening into the stomach (gastrostomy) may be needed in some cases.


Branchio-oculo-facial syndrome

Branchio-oculo-facial syndrome (BOFS) is a rare genetic disorder with defects of the head and neck that are apparent at birth (congenital) and usually diagnosed in childhood. As of 2018, fewer than 100 cases have been reported in the medical literature, although additional patients are probably followed world-wide.

Infants with BOFS may have a low birth weight and may continue to experience abnormally slow growth after birth (postnatal growth retardation).

BOFS is caused by mutations in the TFAP2A gene and follows an autosomal dominant pattern of inheritance.

BOFS is a very rare disorder that apparently affects males and females in equal numbers. Fertility does not appear to be affected since there are many affected parents and children. People vary within families and compared to other families.

Cleft lip and cleft palate are among the most common congenital malformations. Clefts of the lip or palate result when the development of the face or mouth in an embryo is incomplete. Children born with this condition have an opening in their upper lip or the roof of the mouth. The defect ranges from a slight notch-like deformity to complete clefts of the lip and palate. Symptoms may include flattened nose and splayed lips, nasal quality voice, speech defects, deformed maxillary arch and an excessive number or absence of teeth.

The diagnostic criteria have been based on the hallmark features that include a branchial skin defect, ocular anomaly, and facial anomalies (B, O, F). If all three of the hallmark abnormalities are present, it would be characterized as branchio-oculo-facial syndrome. If two of the three hallmark defects are present, plus thymus tissue found in an abnormal location (ectopic thymus) or if a parent or child is affected, it would be characterized as branchio-oculo-facial syndrome.


BOR syndrome

Most people with BOR/BOS syndrome have some type of hearing loss. The hearing loss may be due to nerve damage (sensory), blockage of sound waves (conductive), or both. The degree of hearing loss varies from mild to profound, and can differ between the two ears. The deafness can be stable or progressive. Other abnormalities related to the ear that may be present include pits or outgrowths of cartilage (tags) in front of the outer ear; a cupped or small outer ear; and/or a narrow or upward slanted outer ear canal.

BOR/BOS syndrome is caused by mutations in the EYA1(BOR1, BOS2), SIX5 (BOR2), and SIX1 (BOR3, BOS3) genes.

BOR/BOS syndrome affects males and females in equal numbers. It is estimated that 1 in 40,000 people have this disorder. BOR/BOS syndrome is found in approximately 2 to 3 percent of children with profound deafness.

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

Branchio-oculo-facial syndrome is a rare disorder inherited as an autosomal dominant trait. Major symptoms may include abnormal sinuses, growth delay, premature aging and an unusual facial appearance. Other features of this disorder may include low birth weight; graying of the hair; a highly arched palate; abnormalities of the teeth; and/or cysts under the skin of the scalp. (For more information on this disorder, choose branchio as your search term in the Rare Disease Database.)


Bronchopulmonary dysplasia

Bronchopulmonary dysplasia (BPD) is a chronic respiratory disease that most often occurs in low-birthweight or premature infants who have received supplemental oxygen or have spent long periods of time on a breathing machine (mechanical ventilation), such as infants who have acute respiratory distress syndrome. BPD can also occur in older infants who experience abnormal lung development or some infants that have had an infection before birth (antenatal infection) or placental abnormalities (such as preeclampsia). Antenatal steroid treatment prior to preterm birth and early treatment with surfactant have reduced the need for high levels of respiratory support after birth.

Some infants who develop BPD have a condition called respiratory distress syndrome (RSD), which is a breathing disorder that affects some premature infants immediately after birth. It is characterized by rapid, shallow breathing and leads to the need for oxygen and respiratory support in the first days of life. Affected infants may also exhibit fast breathing with signs of shortness of breath, a chronic cough or wheezing, flaring of the nostrils when breathing and bluish discoloration of the skin due to low levels of oxygen in the blood (cyanosis). Some infants may grunt when breathing out (exhaling). Additional symptoms may include abnormally fast breathing (tachypnea), wheezing or a crackling or rattling sound that is heard in the lungs when inhaling.

BPD is caused by damage to the delicate tissue of the lungs, usually related to the degree of prematurity. This damage most often occurs in infants who have required extended treatment with supplemental oxygen or breathing assistance with a machine (mechanical ventilation) such as infants who are born prematurely and have acute respiratory distress syndrome.

Bronchopulmonary dysplasia can affect both males and females. The exact incidence of BPD is unknown but is highest in infants born with extreme prematurity. The National Institutes of Health estimates that 10,000-15,000 babies born in the United States develop BPD each year. The risk of developing BPD increases the earlier a baby is born (gestational age) and the lower the birth weight. Infants born weighing less than 2.2 pounds are at the greatest risk for developing BPD. The number of cases of BPD has been increasing, most likely because of modern advances in medicine, which have enabled doctors to keep more low birth weight, premature babies alive than in the past. BPD was first described in the medical literature in 1967.

A diagnosis of BPD is made based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests including blood tests, chest x-rays and echocardiograms. Blood tests may show low levels of oxygen in the blood that require treatment with higher levels of oxygen or respiratory support. Chest x-rays may show distinctive changes in the lungs including abnormal development of the lungs. An echocardiogram is used to rule out other conditions that can cause breathing difficulties in infants such as congenital heart defects and helps show how the heart is working and the presence of a large PDA. During an echocardiogram, sound waves are directed toward the heart, enabling doctors to study cardiac function and motion.


Brown Syndrome

身材高大-智力障碍-面部畸形综合征

Brown Syndrome is a rare eye disorder characterized by defects in eye movements. This disorder may be present at birth (congenital) or may occur as the result of another underlying disorder (acquired). Muscles control the movements of the eyes. Some of these muscles turn the eyeball up and down, move the eyeball from side to side, or enable the eyeball to rotate slightly in its socket. The superior oblique tendon sheath of the superior oblique muscle surrounds the eyeball. The symptoms of Brown Syndrome are caused by abnormalities of this tendon sheath including shortening, thickening, or inflammation. This results in the inability to move the affected eye upward.

People with Brown Syndrome have limited eye movement in the affected eye. The ability to move the eyeball toward the center (adduction), or outward from the center (abduction), may be restricted or absent.  One eye may appear to be out of alignment with the unaffected eye, especially when looking upward.  The symptoms of Brown Syndrome may also include a droopy eyelid (ptosis), widening of the eye (palpebral fissure) when looking upward, crossing of the eyes (strabismus), and/or a backward head tilt.  A downward appearance (hypotropia) is usually present in the affected eye when the individual is looking straight ahead (primary position) or in an upward direction.  One eye is usually affected, but both eyes (bilateral) may be affected in approximately 10 percent of people with Brown Syndrome.

The exact cause of most cases of Congenital Brown Syndrome is not known.  The symptoms of congenital Brown Syndrome may occur due to shortening of the tendon sheath of the superior oblique muscle or thickening of the sheath that restricts its movement.  However, acquired Brown Syndrome may be the result of trauma, surgery, and/or inflammation due to another underlying disorder such as Lupus or Rheumatoid Arthritis.

Brown Syndrome is a rare eye disorder that affects slightly more females than males.  The symptoms of the congenital form of the disease are usually present at birth.  The acquired form may occur at any age.

Symptoms of the following disorder can be similar to those of Brown Syndrome. Comparisons may be useful for a differential diagnosis:

Duane Syndrome is a rare inherited eye disorder that is present at birth (congenital) and most commonly affects males.  It is characterized by limited horizontal movement of the affected eye.  Generally only one eye is affected. The ability to move the eye away from the center (abduction) is reduced or absent.  Movement of the eye toward the center (adduction) is also limited, and there may be weakness in focusing (convergence).  Attempted eye movements result in retraction of the eyeball.  An abnormally small eye (microphthalmus), an unusually small cornea (microcornea), and an irregularly shaped cornea (keratoconus) may also occur.  (For more information on this disorder, choose Duane as your search term in the Rare Disease Database.)

Some people with congenital Brown Syndrome may not require treatment. Alignment of the eyes may improve with age, especially in those children whose eyes are normally aligned when looking straight ahead. Other individuals with Brown Syndrome may require surgery to correct the alignment of the eyes. During surgery part of the tendon which connects the superior oblique muscle may be removed (sheathectomy with inferior oblique tuck). The results of surgery are usually excellent, but the condition may recur.


Brown Séquard Syndrome

Brown-Séquard syndrome is a rare spinal disorder that results from an injury to one side of the spinal cord in which the spinal cord is damaged but is not severed completely. It is usually caused by an injury to the spine in the region of the neck or back. In many cases, affected individuals have received some type of puncture wound in the neck or in the back that damages the spine and causes symptoms to appear.

Symptoms of Brown-Séquard syndrome usually appear after an affected individual experiences a trauma to the neck or back. First symptoms are usually loss of the sensations of pain and temperature, often below the area of the trauma. There may also be loss of bladder and bowel control. Weakness and degeneration (atrophy) of muscles in the affected area may occur.  Paralysis on the same side as that of the wound often occurs. Paralysis may be permanent if diagnosis is delayed.

This syndrome is often a consequence of a traumatic injury by a knife or gunshot to the spine or neck.  In many cases, however, it is caused by, or is the result of, other spinal disorders such as cervical spondylosis, arachnoid cyst or epidural hematomas.  Brown-Séquard syndrome may also accompany bacterial or viral infections.  Blunt traumas, such as occur in a fall or automobile accident, on rare occasions may be the cause of the Brown-Séquard syndrome.

Brown-Séquard syndrome is a rare disorder that affects males and females in equal numbers. More than 500 cases have been reported to date. The incidence of Brown-Séquard syndrome has been estimated to be 2% of all traumatic spinal cord injuries. The annual incidence of all forms of spinal cord injury is estimated to be 30-40 per 1,000,000 people.

Symptoms of the following disorders can be similar to those of Brown-Séquard Syndrome.  Comparisons may be useful for a differential diagnosis:

Motor Neuron Disease is a degeneration of motor neurons.  Motor neurons control the behavior of muscles.  Motor Neuron Disease may affect the upper motor neurons, which control the signals from the brain to the spinal cord, or the lower motor neurons which lead from the spinal cord to the muscles of the body.  (For more information on this disorder, choose Motor Neuron Disease as your search term in the Rare Disease Database.)

There is no specific treatment for individuals with Brown-Séquard syndrome. In most instances, treatment focuses on the underlying cause of the disorder. Treatment may involve drugs that control muscle symptoms, and there is some dispute as to whether high-dose steroid administration is effective.


Brucellosis

Brucellosis is an infectious disease that affects livestock and may be transmitted to humans. It is rare in the United States, but occurs more frequently in other parts of the world. The disorder is caused by one of four different species of bacteria that belong to the genus Brucella. Initial symptoms of infection may be nonspecific including fevers, muscle pain, headache, loss of appetite, profuse sweating, and physical weakness. In some cases, the symptoms occur suddenly (acute), whereas, in others, symptoms may develop over the course of a few months. If brucellosis is not treated, the disease may take months to resolve once appropriate therapy is begun.

The symptoms of brucellosis vary greatly among affected individuals. Some individuals may have no apparent symptoms (asymptomatic); others can develop serious complications affecting various organ systems. The incubation period may range from 1-3 weeks to several months.

Brucellosis is caused by the infectious bacterium Brucella. Most cases result from exposure to infected animals or contaminated animal products. Humans can contract the disease by eating or drinking food or liquids contaminated by Brucella, breathing in (inhaling) the bacteria, or through direct contact through an open wound. Most cases occur from eating contaminated food products especially improperly pasteurized milk, cheese, or raw meat. Animals may carry the bacteria without any symptoms, which results in the contamination of animal food products such as meat or dairy products. Brucella is most commonly found among cattle, sheep, goats, camels, deer, elk, and pigs.

Brucellosis affects males and females in equal numbers. The disorder is rare in the United States since pasteurization of milk is routine and cattle are vaccinated against this disease. Fewer than 100 new cases are reported each year in the United States. These are thought to be brought into this country from areas where the infection is present (endemic) or they may be related to the consumption of unpasteurized cow and goat milk.

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

A diagnosis of brucellosis is made based upon a thorough clinical evaluation, a detailed patient history and certain tests called cultures that can detect the presence of the bacterium Brucella in the blood, bone marrow, or tissue of affected organs. Cultures of blood, bone marrow, cerebrospinal fluid (when meningitis is present), or the tissue of any affected organ system may be performed to identify whether the bacterium Brucella is present.


Brugada syndrome

An affected individual with Brugada syndrome typically begins to show symptoms around the age of 40. Individuals with Brugada syndrome may experience irregular heartbeats (ventricular arrhythmias) or may have no apparent symptoms (asymptomatic). Irregular heartbeats may cause difficulty breathing, loss of consciousness or fainting (syncope), and sudden death.

Brugada Syndrome is caused mainly by mutations in the SCN5A gene which encodes the α-subunit of the voltage-gated Nav1.5, the cardiac sodium channel responsible for regulating rapid sodium current –INa-. It induces a disturbed functioning of sodium channel subunits or proteins that regulate them. Dysfunction of the sodium channels leads to local conduction blockages in the heart.

Brugada syndrome affects both men and women, but occurs more often in men (5-8 times more). The incidence rate is currently unknown due to its recent identification and discovery. It is estimated to affect 5 out of every 10,000 people. Brugada syndrome occurs worldwide, but is seen more frequently in individuals of Southeast Asia and Japan. According to the medical literature, Brugada syndrome may account for 4 to 12 percent of all sudden deaths and up to 20 percent of all sudden deaths in individuals with structurally normal hearts.

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

Romano-Ward syndrome is an inherited heart (cardiac) disorder characterized by abnormalities affecting the electrical system of the heart. The severity of Romano-Ward syndrome varies greatly from patient to patient. Some individuals may have no apparent symptoms (asymptomatic); others may develop abnormally increased heartbeats (tachyarrhythmias) resulting in episodes of unconsciousness (syncope), cardiac arrest, and potentially sudden death. Romano-Ward syndrome is inherited as an autosomal dominant trait. One type of Romano-Ward syndrome called long QT syndrome type 3 (LQT3) is caused by abnormalities in the SCN5A gene; therefore, LQT3 and Brugada syndrome may be different types of the same disorder. (For more information on this disorder, choose Romano-Ward as your search term in the Rare Disease Database.)


Budd Chiari Syndrome

Budd-Chiari syndrome is a rare disorder characterized by narrowing and obstruction (occlusion) of the veins of the liver (hepatic veins). Symptoms associated with Budd Chiari syndrome include pain in the upper right part of the abdomen, an abnormally large liver (hepatomegaly), and/or accumulation of fluid in the space (peritoneal cavity) between the two layers of the membrane that lines the stomach (ascites). Additional findings that may be associated with the disorder include nausea, vomiting, and/or an abnormally large spleen (splenomegaly). The severity of the disorder varies from case to case, depending upon the site and number of affected veins. In some cases, if the major hepatic veins are involved, high blood pressure in the veins carrying blood from the gastrointestinal (GI) tract back to the heart through the liver (portal hypertension) may be present. In most cases, the exact cause of Budd-Chiari syndrome is unknown.

Budd-Chiari syndrome involves obstruction or narrowing (occlusion) of the outflowing veins from either large regions of the liver or the entire liver. Blood clots or congenital webbing occur at the junction of these vessels with the large vein that carries the blood from the lower part of the body (inferior vena cava) to the right upper chamber (atrium) of the heart. This syndrome may begin gradually or abruptly.

The exact cause of approximately 70% of all cases of Budd-Chiari syndrome is unknown. Approximately 10% of individuals with Budd-Chiari syndrome have polycythemia vera. (For more information on this disorder, see the Related Disorders section of this report.)

Budd-Chiari syndrome affects males and females in equal numbers. Most cases tend to affect individuals between the ages of twenty and forty.

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

Lesions of the Hepatic (liver) Artery. Hepatic artery blockage (occlusion) is usually caused by clotting (thrombosis/embolism) or surgical ligation. The blockage may result in the destruction of tissue in the liver. However, the outcome is unpredictable since each individual reacts to these situations differently. Ballooning of the vessel wall (aneurysm) of the hepatic artery can occur as a result of infection, arteriosclerosis, trauma, or other disorders. Aneurysms are often multiple and tend to rupture into the abdominal cavity (peritoneum), common bile duct, or adjacent hollow organs. The ruptured hepatic artery aneurysm can cause upper abdominal colic, obstructive jaundice, or gastrointestinal (GI) tract bleeding (hemorrhage). Early surgery on the hepatic artery aneurysm is recommended to avoid complications.


Buerger disease

Inflammatory Occlusive Peripheral Vascular Disease

Buerger’s disease, also known as thromboangiitis obliterans, is a rare disorder that, in most cases, affects young or middle-aged male cigarette smokers. It is characterized by narrowing or blockage (occlusion) of the veins and arteries of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). The legs are affected more often than the arms. In most cases, the first symptom is extreme pain of the lower arms and legs while at rest. Affected individuals may also experience cramping in the legs when they walk that, in rare cases, may cause limping (claudication). In addition, affected individuals may have sores (ulcers) on the extremities, numbness and tingling and a lack of normal blood flow to the fingers and/or toes when exposed to cold temperatures (Raynaud’s phenomenon), and/or inflammation and clotting of certain veins (thrombophlebitis). In severe cases, individuals with Buerger’s disease may exhibit tissue death (gangrene) of affected limbs. The exact cause of Buerger’s disease is not known; however, most affected individuals are heavy tobacco users.

Buerger’s disease is characterized by narrowing or blockage (occlusion) of the intermediate and/or small sized arteries and veins of the extremities, resulting in reduced blood flow to these areas (peripheral vascular disease). Buerger’s disease tends to occur in sudden (acute) episodes that may last from one to four weeks. The disorder runs a recurrent course.

The exact cause of Buerger’s disease is unknown.  However, the use of tobacco is associated with the development of the disorder. In fact, most researchers believe that past or present use of tobacco products by an individual is a requirement for the diagnosis of Buerger’s disease.  The exact relationship tobacco products have with Buerger’s disease is not completely understood.

Buerger’s disease is a very rare disorder that, in most cases, affects young or middle-aged male cigarette smokers with onset of symptoms before 40-45 years of age. In recent years, more affected women have been reported in the medical literature. Some scientists have speculated that this is due to an increase in the amount of women who smoke. At one time the ratio of affected men to women was 100:1, recent articles in the medical literature have speculated that ratio may be 10:1 or closer. In extremely rare cases, individuals who do not smoke have developed Buerger’s disease.

Symptoms of the following disorders can be similar to those of Buerger’s disease. Comparisons may be useful for a differential diagnosis:

A diagnosis of Buerger's disease may be made based upon the identification of characteristic physical features and symptoms. Many physicians require a history of recent or current tobacco use in a diagnosis of Buerger's disease. A test such as an angiography or noninvasive techniques may be used to confirm a diagnosis. During an angiography, injection of a specialized dye is used to make the blood vessels visible on x-rays.


Bullous Pemphigoid

Bullous pemphigoid (BP) is a rare, autoimmune, chronic skin disorder characterized by blistering, urticarial lesions (hives) and itching. Less commonly these blisters can involve the mucous membranes including the eyes, oral mucosa, esophagus and genital mucosa.  It typically presents in older adults as a generalized intensely itchy blistering skin condition.

The first symptom of BP is usually redness and itching of the skin. Within weeks to months, thin-walled, tense blisters with clear fluid centers (bullae) appear on the arms and legs (flexor surfaces), in the armpits (axillae), on the abdomen, and/or in the skinfolds of the groin. Mucous membranes may also be involved but are less commonly seen than skin blisters.

Bullous pemphigoid is an autoimmune blistering disease. Autoimmune disorders are generated when the body’s natural defenses against foreign or invading organisms, attack healthy tissue for unknown reasons. In BP, an autoantibody binds to a component of the skin that holds the dermis and epidermis together, causing separation of these two layers, thus forming a blister. The autoantibodies recognize components of the basement membrane zone called BP antigen 1 and 2 (and in some cases other basement membrane zone antigens). These proteins are part of complexes that hold the skin together, called hemidesmosomes, and provide structural support to the skin. When the body attacks these proteins, the skin becomes more fragile and the clinical manifestations of BP become apparent.

BP is a rare disorder that affects males and females in equal numbers. This disorder primarily affects the elderly, with an average age around 80 years old. Rare cases have been reported in infants and adolescents.

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

Pemphigus is a general term for a group of rare autoimmune blistering skin disorders. All forms of pemphigus are characterized by the development of blistering eruptions on the outer layer of the skin (epidermis). The blisters that occur in pemphigus may be referred to as flaccid bullae because they are not firm and break open (rupture) easily. In pemphigus vulgaris, lesions develop on the mucous membranes such as those lining the inside the mouth. Mucous membranes are the thin, moist coverings of many of the body’s internal surfaces. Pemphigus is also an autoimmune blistering condition similar to BP but with different target antigens in the skin (desmoglein 1 and 3) (For more information on this disorder, choose pemphigus as your search term on the Rare Disease Database.)


Borjeson-Forssman-Lehmann syndrome

Börjeson-Forssman-Lehmann syndrome (BFLS) is an extremely rare disorder characterized by intellectual disability, obesity, seizures, failure of the testes in males or the ovaries in females to produce hormones (hypogonadism), and distinctive facial features. Affected infants often experience delays in reaching developmental milestones. The exact symptoms vary from case to case, even among members of the same family. BFLS is caused by disruptions or changes (mutations) of the PHF6 gene on the X chromosome. This mutation is usually transmitted as an X-linked recessive trait, which means the disorder is fully expressed predominantly in males. Females who carry a single copy of the disease gene (heterozygous carriers) may develop some variable features of the disorder, however, in some instances they can have features similar to the affected males (i.e. be considered as affected with the syndrome).

Börjeson-Forssman-Lehmann syndrome has been considered to be fully expressed only in males given the X-chromosome localization of the responsible gene (see below). However, there have been several reports of affected females with the syndrome. Generally, the symptoms of females vary dramatically, from no clinical presentations to fully affected status. The symptoms associated with BFLS are variable even in males and even in individuals of the same family.

Börjeson-Forssman-Lehmann syndrome is caused by a mutation of the plant homeodomain finger protein 6 (PHF6) gene. This mutation is inherited as an X-linked recessive trait. The gene PHF6 contains instructions (encodes) for creating a specific type of protein. One of the functions of this protein is to prevent cancer at least in some blood cells (T-lymphocytes important in immunity), but the other functions are not that well understood. More recent findings suggest that PHF6 protein is important for movement (migration) and function of neurons in the brain.

Börjeson-Forssman-Lehmann syndrome is a rare disorder that can be fully expressed in males as well as in females. The phenotypic expression in females is highly variable and cannot yet be predicted. BFLS was originally described in the medical literature in 1962 in three related males as well as three of their more mildly affected female relatives. The exact incidence of BFLS is unknown, but with the identification of singleton affected females we assume it is underascertained. Approximately 40 unrelated families and various isolated cases (males and a growing number of females) have been reported in the medical literature with mutations in the PHF6 gene. However, it is plausible to speculate that the real number of individuals with PHF6 mutation is higher as many, even diagnosed cases are not reported and thus not captured.

Symptoms of the following disorders can be similar to those of Börjeson-Forssman-Lehmann syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of Börjeson-Forssman-Lehmann syndrome is made based upon a thorough clinical evaluation, a detailed patient history, and identification of characteristic features. X-rays of the skeletal (skeletal radiography) may be used to detect the presence and assess the severity of potential skeletal defects and support a diagnosis of BFLS. Molecular genetic testing for mutations in the PHF6 gene is available to confirm the diagnosis.


C syndrome

One of the major features of OTCS is a condition in which the skull is a triangular shape. This occurs due to premature closure of the bones (trigonocephaly or prominent metopic suture due to its premature fusion). Patients with this disorder also have a distinct face in which the nasal bridge is broad with a short nose, there are vertical folds over the inner corners of the eyes (epicanthus) and paralysis of facial muscles (facial palsy). These children may have abnormalities of the outer ear, crossed eyes (strabismus), thin upper lip, smooth vertical groove between the base of the nose and the border of the upper lip (philtrum),an undersized jaw (micrognathia), a short neck and loose skin. Additional characteristics can include abnormalities of the breastbone (sternum), webbed fingers and/or toes (syndactyly), short limbs, heart, pancreas, kidney and lung abnormalities and failure of one or both testicles to move down into the scrotum (cryptorchidism).

There is no common genetic cause for OTCS. Recent research has found that changes (mutations) in specific genes could be associated with this condition: MAGEL2, FOXP1, IFT140 and ASXL3.

Only about 60 patients with OTCS have been reported in the world’s medical literature. OTCS is a very rare disorder that seems to affect males and females in equal numbers. The prevalence is between 1/800,000 and 1/1,000,000.

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

Bohring-Opitz syndrome (BOS) is a rare, multiple anomaly syndrome that affects growth, development, and variable organ-systems. Individuals with BOS often have severe growth restriction and are therefore quite small; they may have feeding difficulties, characteristic facial features, and the presence of a red or pink birthmark (nevus flammeus) on the forehead or eyelids. Individuals may also have seizures, heart anomalies, and a characteristic ‘BOS posture’ where the elbows are bent and wrists angle outwards. Additional abnormalities may include a smaller than average head size (microcephaly), a visible ridge over the forehead (metopic ridge), a cleft lip and/or palate, eye abnormalities, recurrent infections, and pauses during breathing while asleep (sleep apnea), as well as sleep difficulties. Children with BOS may have varying degrees of learning differences, but these are generally severe, and most children do not learn to talk or walk. BOS is caused by mutations in the ASXL1, ASXL2, and KLHL7 genes. (For more information, search for Bohring-Opitz syndrome in the Rare Disease Database.)


常染色体显性大脑动脉病-皮质下梗死-脑白质病

Cerebral autosomal dominant arteriopathy-subcortical infarcts-leukoencephalopathy

cerebral autosomal dominant arteriopathy w/subcortical infarcts & leukoencephalopathy

CADASIL is a rare genetic disorder affecting the small blood vessels in the brain. The term CADASIL was first coined in 1993. The age of onset, severity, specific symptoms and disease progression varies greatly from one person to another, even among members of the same family. CADASIL is an acronym that stands for:

Hallmark symptoms of CADASIL may include: 1) recurrent strokes, 2) cognitive impairment, 3) migraine with aura, and 4) psychiatric disturbances. These symptoms are caused by damage to small blood vessels, especially those within the brain. The specific symptoms and severity of the disorder can vary greatly among affected individuals, even among members of the same family.

CADASIL is caused by changes (mutations) in the NOTCH3 gene. The NOTCH3 gene contains instructions to create a protein that is predominantly expressed in smooth muscle cells in the walls of small arteries. Mutations in the NOTCH3 gene result in abnormal accumulation of this protein at the surface of smooth muscle cells. Ultimately, NOTCH3 mutations lead to progressive damage to the small blood vessels in the brain, premature destruction of smooth muscle cells, and narrowing of the lumen and thickening the vessel wall of the small blood vessels. Microscopic protein accumulations of debris called granular osmiophilic material (GOM) accumulate in blood vessels of CADASIL patients.  As a consequence of these changes, there is reduction of blood flow to the brain causing small strokes (or lacunes), small bleeds (microbleeds), dilated spaces surrounded the vessels (dilated perivascular spaces) and tissue loss in the surface of the brain (cortex) as well underneath the cortex (subcortical region).

CADASIL affects males and females in equal numbers. The disorder is found worldwide and affects all races. The disease affects approximately 2 to 5 of 100,000 people. Research suggests that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine the true frequency of CADASIL in the general population.

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

CADASIL is suspected based on symptoms, family history, and brain MRI lesions compatible with the disease. Although MRI can identify characteristic changes in the brains of individuals with CADASIL, such changes are not unique to CADASIL and can occur with other disorders. As such, the CADASIL diagnosis can only be confirmed by DNA testing of blood samples for characteristic mutations in the NOTCH3 gene or by identifying granular osmiophilic material (GOM) inclusions on a skin biopsy.


Campomelic Syndrome

Campomelic syndrome is a rare congenital disorder in which multiple anomalies are present. It is characterized by bowing and angular shape of the long bones of the legs, especially the tibia; multiple minor anomalies of the face; cleft palate; other skeletal anomalies such as abnormalities of the shoulder and pelvic area and eleven pairs of ribs instead of the usual twelve; underdevelopment of the trachea; developmental delay in some cases and incomplete development of genitalia in males such that they appear to be females.

Campomelic syndrome is a rare form of skeletal dysplasia characterized by bowing and an angular shape of the long bones of the legs.  Eleven sets of ribs instead of the usual twelve may be present.  The pelvis and shoulder blade may be underdeveloped.   The skull may be large, long and narrow.  The face may appear flat with forward tilting nostrils, high forehead, small chin, and cleft palate.  Babies may regurgitate formula through the nose, are susceptible to middle ear infections and frequently experience respiratory distress.

Campomelic syndrome was once thought to be inherited as an autosomal recessive genetic trait but this is no longer thought to be true.  Molecular genetic research has shown that a change (mutation) in a single copy of the SOX9 gene on chromosome 17 or disturbance in the regulation of this gene causes campomelic syndrome.  The regulation of the SOX9 gene is sometimes disturbed by a rearrangement of genes on chromosome 17 (translocation).  It is now believed that campomelic syndrome is inherited as an autosomal dominant trait.  Some families have been reported in which multiple children are affected but both parents are unaffected.  This may be due to one parent having a mixture of sperm or egg cells with normal and abnormal SOX9 genes (gonadal mosaicism).  As a result, one or more of this parent’s children may inherit the gene mutation and exhibit the disorder even though the parent has no apparent symptoms.

Campomelic syndrome is a rare disorder that is thought to affect females twice as often as males.  These numbers may not be accurate as some patients with this disorder have associated sex reversal and have been mistakenly identified as the opposite sex.  Approximately one hundred cases of this disorder have been reported in the medical literature.

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

Achondroplasia is a rare musculoskeletal disorder belonging to a group of congenital abnormalities known as the chondrodystrophies. The chondrodystrophies are disorders that affect the manner in which cartilage is converted into bone.  Acondroplasia is characterized by short-limbed dwarfism along with curvature of the spine and abnormalities of the skull.  (For more information on this disorder, choose Achondroplasia as your search term in the Rare Disease Database.)


Cranioectodermal dysplasia

The first signs and symptoms of CED are usually limb pain, a waddling gait, muscle weakness, and extreme tiredness. If the bones at the base of the skull are affected, the individual may experience headaches, hearing loss, vision problems, vertigo, tinnitus, and even facial paralysis. Additional musculoskeletal features include scoliosis, joint contractures, knock knees, and flat feet. The individual may also present with abnormally long limbs in proportion to the height of their body, a decrease in muscle mass and body fat, visible prominence of the long bones in the legs, and rarely delayed puberty. While the first signs and symptoms can appear at varying ages, most appear during childhood or adolescence.

CED is caused by mutations in TGFB1 which encodes transforming growth factor beta-1 protein. This protein helps control the growth and proliferation of cells, the process by which the cells mature and begin to specify (differentiate), cell movement, and cell directed self-destruction (apoptosis). The specific protein plays a huge role during prenatal development in the formation of blood vessels, the regulation of muscle tissue and body fat development, wound healing, and immune system function. The protein is most abundant in skeletal tissue and the extracellular matrix that provides structural support and nutrients to the surrounding cells.

The prevalence of CED is unknown; more than 300affected people have been reported worldwide.

Symptoms of the following disorders can be similar to those of CED. For more information on these disorders, enter the disease name as your search term in the Rare Disease Database.

The diagnosis of CED is based on a physical examination after an individual presents with limb pain and weakness. Imaging studies such as X-rays show thickening of the long bones which can initially be asymmetric, but progresses to become bilateral and symmetric. The bones involved are usually the femur, tibia, fibula, humerus, radius, ulna, and the skull base. Molecular genetic testing for mutations in TGFB1 is available to confirm the diagnosis.


Argininosuccinic aciduria

Canavan disease is rare genetic neurological disorder characterized by the spongy degeneration of the white matter in the brain. Affected infants may appear normal at birth, but usually develop symptoms between 3-6 months of age. Symptoms may include an abnormally large head (macrocephaly), lack of head control, severely diminished muscle tone resulting in floppiness, and delays in reaching developmental milestones such as independent sitting and walking. Most affected children develop life-threatening complications by 10 years of age. Canavan disease occurs because of mutations in the aspartoacylase (ASPA) gene that affects the breakdown (metabolism) of the N-acetylaspartic acid (NNA). It is inherited as an autosomal recessive condition.

The symptoms and progression of Canavan disease varies from case to case. The disorder usually becomes apparent between 3 and 6 months of age and the initial symptoms usually include extremely poor head control, an abnormally large head (macrocepahly), and severely diminished muscle tone (hypotonia) resulting in floppiness. Affected infants may be generally unresponsive (apathetic), lethargic or irritable. Some infants may experience difficulty swallowing (dysphagia), which contributes to feeding difficulties.

Canavan disease is caused by disruptions or changes (mutations) to the aspartoacylase (ASPA) gene. This mutation is inherited as an autosomal recessive trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother.

Canavan disease affects males and females in equal numbers. It affects all ethnic groups, but occurs with greater frequency in individuals of Ashkenazi Jewish descent. In this population, the carrier frequency is estimated to be as high as one in 40-58 people. The risk for an affected child born to Ashkenazi Jewish parents is between 1 and 6,400 and 1 in 13,456. The carrier frequency in other populations is not known, but most likely far lower. The overall incidence of Canavan disease in the general population is unknown.

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

A diagnosis of Canavan disease may be suspected in infants with the characteristic findings of the disorder (e.g., poor head control, macrocephaly, etc.). A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history, and a variety of specialized tests. Such tests may include may include gas chromatography-mass spectrometry, a device that can detect elevated levels of NAA in the urine. Elevated levels of NAA can also be detected in the blood and cerebrospinal fluid (CSF). Examination of certain connective tissue cells from the skin (cultured fibroblasts) can reveal deficiency of the enzyme aspartoacylase. Aspartoacylase activity is also absent in white blood cells.


常染色体隐性型脑动脉病，伴皮质下梗死和白质脑病

Cerebral autosomal recessive arteriopathy-subcortical infarcts-leukoencephalopathy

cerebral autosomal recessive arteriopathy w/subcortical infarcts and leukoencephalopathy

Classic CARASIL is a rare genetic disorder that is characterized by damage to the small blood vessels in the brain. Individuals with CARASIL are at risk of developing multiple strokes, even if they do not have cardiovascular risk factors. The symptoms of CARASIL result from damage to various small blood vessels, especially those within the brain. Individuals with CARASIL may develop a variety of symptoms relating to white matter involvement or changes in deep white matter in the brain (leukoaraiosis), which are observed on MRI or CT). Such symptoms include an increasing muscle tone (spasticity), pyramidal signs and pseudobulbar palsy. Pseudobulbar palsy is a group of neurologic symptoms that includes difficulty with chewing, swallowing and speech. Eventually, gait disturbance and dementia may result. About a third of patients have stroke-like episodes. The age of onset is between 20 to 50 years old. CARASIL is an acronym that stands for:

The cerebral symptoms of CARASIL are caused by damage to cerebral small blood vessels. The specific symptoms and severity of the disorder can vary greatly among affected individuals. Onset of the disorder is usually in early adulthood but may range from the early 20s to the mid-40s. CARASIL is often rapidly progressive.

CARASIL is caused by changes (pathogenic variants or mutations) of the HTRA1 gene. CARASIL is inherited as an autosomal recessive pattern. Recessive genetic disorders occur when an individual inherits a mutated gene from each parent. If an individual receives one normal gene and one mutated gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms.

Classic CARASIL is extremely rare and is more common in Asians but has also been reported in Caucasian populations. Equal numbers of males and females are affected.

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

CARASIL should be suspected in individuals with early onset changes in deep white matter in the brain (leukoaraiosis), alopecia in the teens or the twenties and acute lower back pain (lumbago) with spondylosis. However, some patients do not have these symptoms. Diagnosis of CARASIL is based on these characteristic symptoms, a detailed history, thorough clinical evaluation and a variety of tests, including special imaging techniques. Imaging may include magnetic resonance imaging (MRI), which uses magnetic fields and radio waves to produce cross-sectional images of specific organs and body tissues, including the brain MRI can identify characteristic changes in the brain of CARASIL patients with CADASIL, including bilateral lesions in the anterior temporal regions, external capsule, and spinocerebellar tract CARASIL patients may have a characteristic change in the brainstem called the Ark sign.


Carbamoyl-phosphate synthetase 1 deficiency

Carbamoyl Phosphate Synthetase 1 Deficiency

Carbamoyl phosphate synthetase 1 deficiency (CPSID) is a rare inherited disorder characterized by complete or partial lack of the carbamoyl phosphate synthetase (CPS) enzyme. This is one of five enzymes that play a role in the breakdown and removal of nitrogen from the body, a process known as the urea cycle. The lack of the CPSI enzyme results in excessive accumulation of nitrogen, in the form of ammonia (hyperammonemia), in the blood. Affected children may experience vomiting, refusal to eat, progressive lethargy, and coma. CPSID is inherited as an autosomal recessive genetic disorder.

CPSID may be associated with complete or partial absence of the CPS enzyme.  Complete lack of the CPS enzyme results in the severe form of the disorder, in which symptoms occur shortly after birth (neonatal period). Partial lack of the CPS enzyme results in a milder form of the disorder that can occur at any time during the life of the patient.

CPSID is inherited as an autosomal recessive genetic disorder and is caused by mutations in the CPSI gene.  Mutations in the CPSI gene result in production of an abnormal carbamoyl phosphate synthetase enzyme.

The estimated frequency of CPSID is 1 in 150-200,000 births. The estimated frequency of urea cycle disorders collectively is one in 30,000.  However, because urea cycle disorders like CPSID often go unrecognized, these disorders are under-diagnosed, making it difficult to determine the true frequency of urea cycle disorders in the general population.

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

The urea cycle disorders are a group of rare disorders affecting the urea cycle, a series of biochemical processes in which nitrogen is converted into urea and removed from the body through the urine. Nitrogen is a waste product of protein metabolism. The symptoms of all urea cycle disorders vary in severity and result from the excessive accumulation of ammonia in the blood and body tissues (hyperammonemia). Common symptoms include lack of appetite, vomiting, drowsiness, seizures, and/or coma. The liver may be abnormally enlarged (hepatomegaly). In some cases, life-threatening complications may result. In addition to CPS deficiency, the other urea cycle disorders are: argininosuccinic acid synthetase deficiency (citrullinemia type 1); argininosuccinase acid lyase deficiency; ornithine transcarbamylase (OTC) deficiency; arginase deficiency and N-acetylglutamate synthetase (NAGS) deficiency. Disorders in transport in the urea cycle (citrin deficiency or citrullinemia type 2 and ornithine transport) will also present with similar symptoms in severe forms(For more information on these disorders, choose the specific disorder name as your search terms in the Rare Disease Database.)


Carcinoid syndrome

Carcinoid syndrome is a disease consisting of a combination of symptoms, physical manifestations, and abnormal laboratory findings. Carcinoid syndrome is seen in individuals who have an underlying carcinoid tumour with spread to the liver. Carcinoid tumors are well-differentiated neuroendocrine tumours with secretory properties, releasing serotonin, along with a number of other active peptides. These tumors can arise anywhere along the primitive gut and are therefore found in the bronchial tree (airways) and along the gastrointestinal tract. The tumor cells can also migrate (metastasize) to the liver.

Symptoms may be non-hormonal, secondary to tumor bulk and therefore depend on location; or hormonal as a result of carcinoid syndrome. Those caused by the tumour may include abdominal pain, anemia, pneumonia, cough and haemoptysis (cough productive of blood). Carcinoid tumors can also be present without producing any symptoms and may often go undetected for a long period of time.

The underlying cause of carcinoid tumors remains unclear. Some studies have suggested risk factors such as smoking and dietary intake, however, further research is needed to confirm these findings. In the majority of cases tumors are slow-growing and can produce hormonal chemical substances such as serotonin, bradykinins, tachykinins and prostaglandins. If the original carcinoid cells spread (metastasize) to the liver, these substances are no longer broken down to their inactive form and are released into the systemic (main) circulation, causing the signs and symptoms of carcinoid syndrome. When tumors affect organs other than the gastrointestinal tract, such as the ovaries, carcinoid syndrome can occur in the absence of liver metastases.

Carcinoid tumors are rare, with only 27 new cases per million diagnosed in the U.S. per year. Of these, only about 10% will develop carcinoid syndrome. The syndrome affects males and females in equal numbers. All races can be affected though there is a slightly increased prevalence in black African males. All ages can be affected but most gastrointestinal cases occur in middle-age. Bronchial (airway) tumors are most often seen in the fifth decade but can affect people at any age. Carcinoid syndrome may be more prevalent than suspected because diagnosis is difficult and sometimes overlooked; some patients may not exhibit all three of the hallmark symptoms of flushing, wheezing, and diarrhea.

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

Multiple endocrine neoplasia (MEN) type 1 is a rare genetic disorder in which benign (noncancerous) tumors arise from the cells of various glands of the endocrine system. The endocrine system is the network of glands that secrete hormones into the bloodstream where they travel to various areas of the body. These hormones regulate the chemical processes (metabolism) that influence the function of various organs and activities within the body. Hormones are involved in numerous vital processes including regulating heart rate, body temperature and blood pressure as well as cell differentiation and growth and also in modulation of several metabolic processes. In individuals with MEN type 1, benign tumors develop in multiple endocrine glands, most often the parathyroid, pancreas and pituitary glands. These affected glands secrete excessive amounts of hormones into the bloodstream, which can result in a variety of symptoms. Some benign tumors associated with MEN type 1 can become malignant (cancerous). MEN type 1 can run in families or can occur as the result of a spontaneous new gene mutation in the affected person.


CARD9 Deficiency

CARD9缺陷导致侵袭性真菌感染易感

The signs and symptoms (or manifestations) of CARD9 deficiency appear quite varied.

CARD9 deficiency is caused by mutations in the CARD9 gene. This gene is responsible for production of the CARD9 protein which is normally expressed by only two specific types of white blood cells: neutrophils and monocytes (monocytes in the blood become macrophages once they go into tissues). In CARD9 deficiency, the CARD9 protein is abnormal, and both of these types of cells (neutrophils and monocytes/macrophages) have difficulty responding to fungus, which allows one of the above fungal diseases to develop.

CARD9 deficiency affects males and females in apparently equal numbers and has been reported all over the world. However, the exact frequency of this condition in the general population is unknown. It may be relatively more frequently found in some parts of the world because of a local founder effect. A founder effect occurs in history when a new population is established by a very small number of individuals; over generations, carriers may become more common, allowing two carriers to have children, who are then affected.

The invasive fungal disease that is seen in CARD9 deficiency can also occur in other primary immunodeficiencies. For example, in chronic granulomatous disease (CGD), where the ability of white blood cells to produce a respiratory burst does not work properly, those patients can get infections with certain fungi. Also, patients with genetic mutations in the pathway that control the interleukin(IL)-12/Interferon-gamma pathway can also get invasive infections with certain molds.

A diagnosis of CARD9 deficiency is suspected based upon a thorough clinical evaluation, a detailed patient history, particularly one in which there is invasive fungal infection without any of the typical risk factors listed above, and a variety of blood tests.


Cardiofaciocutaneous syndrome

Most individuals are initially referred because of feeding difficulties (poor suck) and failure to thrive. Later, cognitive developmental delay and other clinical manifestations may be observed.

CFC syndrome is a dominant genetic disorder caused by an abnormality (mutation) in one of four genes: BRAF (~75%), MAP2K1 (MEK1), MAP2K2 (MEK2) (~25%) and KRAS (<2%). These genes are part of a pathway called Ras/Mitogen-activated protein kinase (MAPK) that is important in cell growth and cell division. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC.

Currently, there is no study providing an accurate estimate of the population prevalence of CFC syndrome. However one study in Japan, reported the incidence to be approximately 1 in 810,000. It is thought that males and females are affected equally. There are patients are reported from all continents. The number of affected individuals reported in the medical literature is now close to 400 and the total number worldwide is estimated to be more than this. This may be an underestimate, however, because mildly affected adults may go undiagnosed.

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

Noonan syndrome, a common genetic disorder occurring in approximately 1 in 2500 individuals, is another RASopathy. It is characterized by a distinctive facial appearance similar to that seen in children with CFC syndrome, such as webbing of the neck, short stature, characteristic abnormalities of the chest, congenital heart defects, and/or other abnormalities. In individuals with the disorder, malformations of the head and facial (craniofacial) area may include widely set eyes (ocular hypertelorism); downwardly slanting eyelid folds (palpebral fissures); drooping of the upper eyelids (ptosis) or unusually thick, hooded eyelids; a prominent upper lip; and/or low-set, prominent external ears (pinnae) that are abnormally rotated toward the back of the head (posteriorly angulated).


Carney complex

Carney complex is a rare genetic disorder characterized by multiple benign tumors (multiple neoplasia) most often affecting the heart, skin and endocrine system and abnormalities in skin coloring (pigment) resulting in a spotty appearance to the skin of affected areas. Benign tumors of connective tissue (myxomas) are common in individuals with Carney complex and, most often, are found in the heart where they can potentially cause serious, life-threatening complications including stroke, valvular obstruction or heart failure. A wide variety of endocrine abnormalities potentially can occur in Carney complex affecting a variety of glands. Additional tumors include myxomas affecting the skin and nerve sheath tumors (schwannomas). Skin pigment abnormalities include tiny flat (freckle-like) black or brown spots (multiple lentigines) and small, blue or bluish-black spots (blue nevi). The specific symptoms and severity of Carney complex can vary greatly from one person to another. In many cases, Carney complex is due to mutations of the PRKAR1A gene. The mutation can occur randomly for no apparent reason (i.e., new mutation) or be inherited as an autosomal dominant trait.

The symptoms and severity of Carney complex can vary greatly from one person to another, even among members of the same family. The disorder may be evident at birth, but the median age of diagnosis is 20. Many of the signs and symptoms of Carney complex become apparent during the teen-age years or during early adulthood.

Some cases of Carney complex occur due to mutations of the PRKAR1A gene. This mutation may occur randomly for no apparent reason (i.e., new mutation) with no family history or be inherited as an autosomal dominant trait. The majority of cases of Carney complex have occurred in individuals with a family history of the disorder.

Carney complex affects males and females in equal numbers. Approximately 600 affected individuals have been reported since the disorder was first described in the medical literature in 1985. The disorder can present at any age, but the mean age at diagnosis is 20.

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

A diagnosis of Carney complex is made based upon a detailed patient history, a thorough clinical evaluation, a variety of specialized tests and identification of characteristic symptoms. According to the medical literature, identification of two or more of the following symptoms in typical fashion is indicative of Carney complex: cardiac myxoma: skin myxoma; lentiginosis; multiple blue nevi; primary pigmented nodular adrenocortical disease (PPNAD); testicular tumors; acromegaly; thyroid tumors, melanotic schwannoma; or an osteochondromyxoma.