Interatrial communication

Atrial septal defects (ASDs) are a group of rare disorders of the heart that are present at birth (congenital) and involve a hole in the wall (septum) that separates the two upper-chambers (atria) of the heart.

Ostium secundum atrial septal defect is the most common form of this group of heart defects.  The middle portion of the atrial septum in the region of the foramen ovale fails to close during fetal development.  The size of the opening may vary, along with the severity of the symptoms.

Most cases of atrial septal defects occur on their own for no apparent reason (sporadically).  The exact nature of the developmental defect or defects that may occur during embryonic development (embryogenesis) remain unclear.

Atrial septal defects are rare congenital heart defects that affect more females than males (2 or 3:1).   Approximately 1 percent of all infants in the United States are born with a form of congenital heart defect.  About 10 percent of these infants have atrial septal defects.

Symptoms of the following disorders may be similar to those of atrial septal defects.  Comparisons may be useful for a differential diagnosis:

Atrioventricular septal defect is a rare heart defect that is present at birth (congenital) and is characterized by the improper development of the septa and valves of the heart.  Infants with the complete form of the defect usually develop congestive heart failure.  Excessive fluid accumulates in other areas of the body, especially the lungs.  This pulmonary congestion may lead to difficulty breathing (dyspnea).  Other symptoms may include a bluish discoloration of the skin (cyanosis), poor feeding habits, abnormally rapid breathing (tachypnea) and heart rate (tachycardia), and/or excessive sweating (hyperhidrosis).  Adults with atrioventricular septal defect may experience abnormally low blood pressure, irregular heartbeats, and/or a rapid heartbeat.  (For more information on this disorder, choose atrioventricular septal defect as your search term in the Rare Disease Database.)


Atrioventricular septal defect

Atrioventricular septal defect (AVSD) is a general term for a group of rare heart defects that are present at birth (congenital). Infants with AVSDs have improperly developed atrial and ventricular septa and adjoining valves.

Infants with the complete form of atrioventricular septal defect usually develop a limited ability to circulate blood to the lungs and the rest of the body resulting in fluid buildup in the heart, lung and various body tissues (congestive heart failure). Pulmonary congestion may lead to difficulty breathing (dyspnea) and fatigue. Infants with complete atrioventricular septal defect often have a bluish discoloration of the skin and mucous membranes (cyanosis) due to insufficient oxygen supply to these tissues.

The exact cause of atrioventricular septal defect is not known (idiopathic). This birth defect can occur alone with no apparent cause (sporadically), or it can occur in association with other disorders such as Down syndrome.

Atrioventricular septal defect affects males and females in equal numbers. Approximately 50 percent of cases occur in association with other disorders, especially Down syndrome. AVSD may also occur with other congenital heart defects, in 10 percent of cases it occurs in association with patent ductus arteriosus or tetralogy of Fallot. (For more information on these disorders, choose the exact disorder name as your search term in the Rare Disease Database.)

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

Atrial septal defects are common congenital heart defects characterized by the presence of a small opening between the two atria of the heart.  This defect leads to an increase in the workload on the right heart, and excessive blood flow to the lungs.  The symptoms, which may become apparent during infancy, childhood, or adulthood, can vary greatly and depend on the severity of the defect.  The symptoms tend to be mild at first and may include difficulty breathing (dyspnea), increased susceptibility to respiratory infections, abnormal bluish discoloration of the skin and/or mucous membranes (cyanosis).  Some people with atrial septal defects may be at increased risk for the formation of blood clots that can travel to the major arteries (embolism) blocking blood circulation.  (For more information on this disorder, choose atrial septal defect as your search term in the Rare Disease Database.)


Atypical hemolytic uremic syndrome

The onset of atypical hemolytic uremic syndrome ranges from before birth (prenatally) to adulthood. In young children, the disorder often develops suddenly and usually follows an infection, particularly an upper respiratory infection or gastroenteritis. When it follows an episode of gastroenteritis it can more easily be confused with Stx HUS which almost always is preceded by diarrhea. The disease has different causes and can be unpredictable in how it will progress in one individual as opposed to another.

Most cases of aHUS are associated with mutations amongst the multiple genes that produce (encode) proteins involved in the alternate pathway of complement, which is part of the complement system of the innate immune system. The complement system is a complex group of proteins that work together to fight infection in the body. Complement proteins respond to bacteria, viruses or other foreign substances in the body and ultimately produce a large multi-protein complex that directly attacks these foreign invaders. Other complement proteins regulate the formation of this attack complex in order to protect the body’s own cells from being damaged. Most individuals with aHUS have a mutation in one or more of the genes that encode these regulatory proteins.

In childhood, aHUS affects males and females in equal numbers. In adulthood, females are affected more often than males, most likely because pregnancy is a triggering event. The exact overall incidence and prevalence is unknown. One study placed the incidence in the United States at 2 individuals per 1 million in the general population. In Europe, the disorder is estimated to affect approximately .11 per 1 million individuals between the ages of 0-18. aHUS accounts for approximately 5-10% of all cases of hemolytic uremic syndrome.

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

Diagnosing aHUS is complicated by the fact that it is more difficult to establish without a family history of the disorder. The diagnostic criteria associated with aHUS are hemolytic anemia (anemia in the presence of broken red blood cells), low platelet count (thrombocytopenia) and kidney dysfunction. aHUS is considered genetic when two or more members of the same family are affected by the disease at least six months apart and exposure to a common triggering infectious agent has been excluded, or when a disease-causing mutation(s) is identified in one of the genes known to be associated with aHUS, irrespective of familial history.


Auditory Neuropathy Spectrum Disorder

If you are a parent and notice any or all of the following, it’s essential to consult a doctor.

Sound waves usually enter thought the outer ear and travel via the ear canal. When they arrive at the eardrum, it vibrates. Those vibrations are then transmitted via a series of bones to the cochlea, a fluid-filled structure with a membrane that contains two types of cells: outer and inner hair cells. The inner ones are responsible for 95% of the information sent to the brain via the auditory nerve, while the outer cells amplify the sound stimulus. Damage to any of these sites may lead to hearing loss. A defect in the inner hair cells, the auditory nerve, the connection between them or the connection between the nerve and brain can lead to ANSD. If any or all are affected, the brain will receive a disorganized signal (hard to understand) or no signal at all (functionally deaf). Most of the time, ANSD affects both ears, but in some patients it can affect only one ear. A head injury can cause a lesion in the auditory nerve and lead to ANSD. However, this cause is rare and auditory neuropathy is most often due to health problems before or during birth, especially in children.

Auditory neuropathy occurs equally in males and females with a slightly higher frequency in males. Prevalence and incidence remain uncertain as many studies report different figures due to the variability of clinical presentations in ANSD patients. Overall, it is estimated that 1 to 3 children per 10,000 births are affected by this disorder. It can occur at any stage of life. Children, adults and seniors can be affected. However, in most cases, it’s detected in newborns, particularly those admitted to the neonatal intensive care units (NICU). In the NICU, 10 to 15% of the babies are diagnosed with a sensorineural hearing loss (SNHL).

There are other disorders that result in hearing loss due to damage to outer hair cells that are different from ANSD. These include acquired hearing loss related to aging or noise exposure, hearing loss at birth from infections (rubella, herpes simplex) and genetic conditions such as Usher syndrome.

There are several tests that may be performed when someone is suspected of having hearing problems. In most screening programs, only the otoacoustic emission (OAE) is used, which is insufficient to detect ANSD. ANSD is classically characterized by normal OAE with an abnormal auditory brainstem response (ABR) test. Measuring the middle ear muscle reflex (MEMR) test or cochlear microphonic (CM) tests can be helpful in the diagnosis of ANSD. The following tests may be ordered:


Autoimmune hepatitis

Symptoms can vary from person to person with AIH; some may not even have any symptoms. Common initial symptoms can include fatigue, nausea, vomiting, abdominal pain, weight loss, light colored stools, dark colored urine, joint pain, rashes, and loss of menstruation in women. Some may develop an enlarged liver (hepatomegaly) and/or spleen (splenomegaly).

At this time, the exact cause of autoimmune hepatitis is unknown. It is believed to be due to a combination of environmental, genetic, and immunologic factors. A few environmental triggers, such as prescribed medications and infections, have been associated with the development of AIH. Some of the medications thought to play a role in those with drug-induced AIH include nitrofurantoin, minocycline, and hydralazine. Infections such as viral hepatitis (hepatitis A, B, C, and D), herpes simplex virus, and cytomegalovirus have also been linked to disease onset.

Autoimmune hepatitis is a rare disorder that affects females 4 times as often as males. Type 1 is more common and is usually diagnosed in adults. Type 2 is more common in children and often involves a more severe disease process. There are also variant types of AIH; these include individuals with AIH and one of the other autoimmune liver diseases (primary sclerosing cholangitis or primary biliary cholangitis).Those with other autoimmune conditions have a 25-50% chance of developing another one and thus a higher risk for developing AIH. The new cases per year (incidence) are estimated at 1-2 per 100,000 and total cases (prevalence) are approximately 24 per 100,000. Studies suggest that the incidence of AIH is increasing and the reason is unknown.

Other disorders can have similar symptoms to autoimmune hepatitis and need to be considered when making a diagnosis.

Diagnosis of AIH can be complex, and is frequently completed after going through several steps. This includes meeting with your doctor to discuss your past medical problems, your current symptoms, a complete physical exam, blood work, and a liver biopsy.


自身免疫性多内分泌腺病2型

Autoimmune Polyendocrine Syndrome Type II

Diabetes Mellitus, Addison's Disease, Myxedema

Autoimmune polyendocrine syndrome type II, also known as Schmidt syndrome, is a rare autoimmune disorder in which there is a steep drop in production of several essential hormones by the glands that secrete these hormones. When first described, this disorder was thought to involve only adrenal insufficiency (Addison’s disease) and thyroid insufficiency (Hashimoto’s thyroiditis). However, over time, as more patients were studied, the scope of the disorder was expanded to include disorders of other underperforming endocrine glands. These include the gonads, which secrete sex hormones; the pancreas which secretes insulin and is intimately tied up with diabetes mellitus; and sometimes the parathyroid glands. Failure of the endocrine glands to function is usually accompanied by signs of malnutrition because the ability of the intestinal tract to absorb nutrients is reduced dramatically.  Since the combination of affected glands differs from patient to patient, the signs of this disorder are diverse.

Many conditions and symptoms are associated with this disorder.  The symptoms may vary greatly among affected individuals.

The exact cause of AIPS-II is not known, but it is thought to result from one or more abnormal immune responses.  Autoimmune reactions occur when, for reasons not quite clear, the body mistakenly reacts to a normal antibody as if it were a foreign one.

Report suggest that the prevalence of AIPS-II is about 14 to 20 cases per million of population and that it affects females 3 to 4 times as often as it does males.  AIPS-II usually strikes in the third or fourth decade of life.

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

APECED Syndrome (Autoimmune-Polyendocrinopathy-Candidiasis-Ectodermal) is a very rare genetic syndrome involving the autoimmune system.  APECED Syndrome is a Type I polyglandular Autoimmune syndrome.  This disorder is characterized by a combination of at least two of the following diseases: Hypoparathyroidism, Adrenocortical Failure or Candidiasis.  Beginning in childhood, yeast infections of either the mouth or nails is usually one of the first apparent symptoms of this syndrome.  There may be an inability to adequately absorb nutrients with resulting diarrhea.  Anemia, autoimmune thyroid disease, and loss or delay of sexual development may also occur. (For more information on this disorder choose APECED Syndrome as your search term in the Rare Disease Database.)

Each disorder in a case of autoimmune polyendocrine type II is treated separately. For many of the specific disorders, treatment is focused on hormone replacement therapy.


Autoimmune polyendocrinopathy type 1

自身免疫性多内分泌腺病1型

Autoimmune Polyglandular Syndrome Type 1

Autoimmune polyglandular syndrome type 1 (APS-1) is a rare and complex recessively inherited disorder of immune-cell dysfunction with multiple autoimmunities. It presents as a group of symptoms including potentially life-threatening endocrine gland and gastrointestinal dysfunctions. Autoimmune disorders occur when antibodies and immune cells are launched by the body against one or several antigens of its own tissues. APS-1 is caused by changes (mutations) in the autoimmune regulator (AIRE) gene. HLA-DR/DQ genes also play a role in predisposing to which of the component autoimmune disease the patient actually develops.

While the symptoms of APS-1 are variable in each patient, they often will have components of at least two of the three major conditions that result from this syndrome: chronic mucocutaneous candidiasis, hypoparathyroidism, and adrenocortical insufficiency.

APS-1 is caused by mutations in the AIRE gene. To date, more than 60 mutations in the AIRE gene have been identified in people with APS-1.

APS-I is a very rare disorder that tends to cluster in certain homogenous populations, including certain groups of Finns, Iranian Jews, and Sardinians. However, it can be found in numerous populations and among multiple ethnic groups. In the US, APS-1 probably affects as few as 1 in every 2-3 million newborns.

The following disorders, which are components of APS-1, can also occur on their own, separate from the diagnosis of APS-1:

APS-1 is diagnosed definitively through DNA analysis (via blood test) of mutations in the AIRE gene. The diagnosis should be strongly considered in people under 30 years of age who present with at least two of the three typical disease components (CMC, hypoparathyroidism, and/or Addison’s disease). Recently, typical AIRE mutations have been identified in patients who have only one of these three cardinal features, but have other less common APS-1 associated autoimmunities. Since virtually all APS-1 patients have interferon autoantibodies, such antibodies when more freely available will serve as a less expensive diagnostic test.


周期性发热-小儿小肠结肠炎-自体炎症综合征

Autoinflammation with Infantile Enterocolitis

Autoinflammation with infantile enterocolitis (AIFEC) is a newly identified and extremely rare inflammatory disorder that manifests early in infancy and affects patients throughout adulthood. AIFEC is caused by a change (mutation) in the NLRC4 gene, resulting in increased inflammation and damage to healthy tissues (autoinflammation). Patients with NLRC4 mutations present with enterocolitis (inflammation of the digestive tract causing diarrhea) in infancy and flares of severe and sometimes life-threatening autoinflammation throughout life. Macrophage activation syndrome (MAS), the type of autoinflammation seen in AIFEC, causes fevers, enlarged spleen, blood disturbances, and can progress to organ damage and death if not treated.

AIFEC is characterized by a variety of symptoms related to the activation of inflammatory processes. The overactivation of the patient’s immune system is destructive to the patient’s healthy tissues and may be life-threatening. Symptoms often occur in flares alternating with largely symptom-free periods. The exact cause of the flares is not completely understood, but may be linked to emotional stress, physical stress, and/or stresses on the immune system such as viral or bacterial infections.

AIFEC is caused by a mutation in the NLCR4 gene resulting in activation of the NLRC4 protein, an important component of the immune system in healthy individuals. Proteins found on the surface of certain bacteria such as Salmonella and Pseudomonas are normally recognized by a receptor (NAIP) found on the patient’s immune system and intestinal cells – this is a way for the human body to recognize foreign bacteria so that it can begin to fight them off. When the NAIP receptor senses bacteria, it then activates NLRC4. Once activated, NLRC4 quickly works with other proteins to form a complex called the NLRC4 inflammasome. This inflammasome complex works inside cells of the immune system (including macrophages) to generate inflammatory cytokines, like IL-1 and IL-18, and to trigger cells infected with the bacteria to die. The activated immune system can also cause intestinal cells infected with the bacteria to be shed into the gut lumen. This causes diarrhea, but also prevents the bacteria from crossing over from the gut into the rest of the body where they could cause more damage.

Very few patients have been identified with the activating NLRC4 mutations that cause AIFEC. Seven patients have been identified since the first patients were diagnosed in 2014. Due to the low number of patients, it is so far unclear what puts patients at increased risk of acquiring the disease-causing mutation other than having a parent with the disease.

NLRC4 gene mutations (different ones than those implicated in AIFEC) are also associated with familial cold autoinflammatory syndrome (FCAS4). Symptoms of FCAS4, which occur after exposure to cold temperatures, included fevers, joint and muscle pain, skin rashes, conjunctivitis (pink eye), and limb swelling. (For more information on this condition, search for FCAS in the Rare Disease Database.)

The physician will first perform a clinical evaluation based on the patient’s symptoms. Blood tests will likely show a variety of blood abnormalities including: markers of inflammation (high CRP, high ferritin, high IL2R), signs of overactive NLRC4 (high IL18), as well as pancytopenia (decreased cells in the blood). Exam of the patient’s gastrointestinal tract (endoscopy or colonoscopy), including intestinal biopsies, may show intestinal lesions/injuries and inflammation in infants. A bone marrow biopsy may show signs that overactive immune cells are targeting healthy cells. If skin lesions are present, the physician may biopsy them to see if inflammatory cells are present. Eventually genetic tests will show an activating mutation of the NLCR4 gene.


Autosomal Dominant Hereditary Ataxia

常染色体显性遗传小脑型共济失调

Ataxia is most often associated with degeneration of the region of the brain known as the cerebellum where movement, posture, and balance are coordinated. Thus, many of the symptoms and signs are those expected from cerebellar dysfunction. Ataxia may also be associated with damage (lesions) to the spinal cord. Symptoms and signs often include a characteristic wide-based and unsteady way of walking (gait) that may be accompanied by awkward eye-hand coordination and slow, weak, or imprecise speech.

As noted above, some forms of the hereditary ataxias are transmitted in a dominant mode, others are transmitted through a recessive mode, and still others are transmitted in an X-linked fashion. This report deals with the disorders transmitted in an autosomal dominant fashion.

Hereditary ataxias affect males and females in equal numbers. It is estimated that 150,000 people in the United States are affected by, or at risk for, hereditary ataxia. There is variation among the specific forms of hereditary ataxia as to when they typically first appear. Some ataxias are more common in certain ethnic groups.  For example, SCA3 is more common in the Portuguese population, SCA10 is more common in the Mexican population, and DRPLA is more common in Japan.

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

Olivopontocerebellar atrophy (OPCA) refers to a group of ataxias characterized by progressive neurological degeneration affecting the cerebellum, the pons and the inferior olives. OPCA may be classified based on clinical, genetic, or neuropathological findings; thus, there are many classifications of the disorder. Many of these cases now fall into the SCA category and the term OPCA is relatively unused nowadays. Among the different classifications, there is wide variation in severity and age of onset. The symptoms of OPCA differ from person to person. Most patients experience difficulty with balance and coordination of the legs and arms (ataxia) and slurred speech (dysarthria). Other symptoms may include muscle spasms or weakness and stiffness of the muscles; numbness or tingling of the hands or feet; shaking (tremor) of the hand or arm; reduction or slowness of movements; loss of thinking and/or memory skills; difficulty controlling the bladder or bowels; and feeling faint when standing up. Some patients also have fatigue and/or trouble with sleep. Generally, symptoms of OPCA begin in mid-adult life and progress slowly over the course of many years. (For more information on this disorder, choose Olivopontocerebellar Atrophy, Hereditary as your search term in the Rare Disease Database.)


Autosomal Dominant Hyper IgE Syndrome

常染色体显性高IgE综合征

Autosomal dominant hyper IgE syndrome (AD-HIES) is a rare multisystem primary immunodeficiency disorder. Symptoms often become apparent early during infancy or childhood. The disorder is characterized by repeated bacterial infections of the skin and lungs (pneumonia), skeletal abnormalities, and characteristic facial features. The first symptom is often the development of a dry, red flaky skin rash (eczema) at birth or early during infancy. Researchers have discovered that mutations in the STAT3 gene cause AD-HIES in over 60% of the patients. Most cases of AD-HIES occur as the result of a new mutation in this gene. There are two main forms of hyper IgE syndrome – one inherited in an autosomal dominant pattern and one in an autosomal recessive pattern. Both involve defects of the immune system and elevated levels of immunoglobulin E (hyper IgE) in the blood. For years, researchers considered them different expressions of the same disorder, but now researchers consider them similar, yet distinct disorders.

The symptoms of AD-HIES may vary greatly from person to person. AD-HIES affects the immune system as well as the development of the skeleton, connective tissue, and teeth. Symptoms may become apparent at birth, during infancy, or during early childhood. In some cases, symptoms may not become apparent until adulthood, and it is not uncommon that the diagnosis is made late.

Mutations in the STAT3 gene cause AD-HIES. The STAT3 gene is responsible for production of one of the signal transducer and activator of transcription (STAT) proteins that are involved in signaling the immune system to respond to pathogens. The mutations associated with AD-HIES result in a normal amount of STAT3 protein produced but the function of the protein is affected resulting in defective host defense.

AD-HIES affects males and females in equal numbers and occurs in all ethnic groups. More than 200 cases of hyper IgE syndrome (both the dominant and recessive forms) have been described in the medical literature. However, these disorders may often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Although AD-HIES is present during infancy, diagnosis may not be made until adolescence and, in some cases, adulthood.

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

A diagnosis of AD-HIES is made based upon a thorough clinical evaluation, especially a detailed patient history and identification of characteristic findings by a physician with experience with the syndrome. Laboratory studies that may aid in a diagnosis include blood tests that demonstrate elevated levels of IgE in the blood and elevated levels of certain white blood cells known as eosinophils (eosinophilia). IgE levels may drop to normal or near normal levels in adulthood and, therefore, normal IgE levels in an adult do not necessarily rule out a diagnosis of AD-HIES.


Autosomal Dominant Polycystic Kidney Disease

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic disorder characterized by the formation of cysts within the kidneys. Symptoms caused by cyst formation in the kidneys include high blood pressure (hypertension), pain on the sides of the body between the last rib and the hip (flank pain), blood in the urine (hematuria) and progressively poor function of the kidneys (kidney insufficiency).   In most patients, ADPKD eventually progresses to cause end stage renal disease, requiring renal replacement therapy, either dialysis or renal transplantation. ADPKD is not simply a kidney disorder and other organ systems of the body can potentially be affected (multisystem disorder) by the development of cysts. The specific symptoms present in each person depend upon the specific organ systems involved. The liver, pancreas, a membrane covering the spinal cord and brain (arachnoid membrane), the prostate, and the glands of the male reproductive tract that produce fluid that is part of semen (seminal vesicles) may become involved. Abnormalities affecting the heart and blood vessels (cardiovascular system) may also occur in individuals with ADPKD. ADPKD usually does not become apparent until the fourth or fifth decade and was once known as adult polycystic kidney disease. However, it has been reported in children and infants. ADPKD is caused by mutations of one of two genes that create certain proteins essential for the proper health of the kidneys and other parts of the body. Approximately 85 % have ADPKD1, the most aggressive form of the disease; those with ADPKD2 progress to kidney insufficiency about 20 years later.

The specific symptoms and their severity can vary greatly from one person to another, even among members of the same family. Most affected individuals develop symptoms between the third and fifth decades of life. However, symptoms may occur during childhood or even in infancy. Some affected individuals never develop obvious symptoms (asymptomatic) and may be diagnosed with ADPKD incidentally in the eighth or ninth decade of life. ADPKD is a highly variable, multisystem disorder; it is important to note that affected individuals will not have all of the symptoms discussed below.

ADPKD is caused by mutations of one of two genes, the ADPKD1 gene or the ADPKD2 gene. Mutations of the ADPKD1 gene account for approximately 85 percent of cases; the ADPKD2 gene accounts for approximately 15 percent of cases. These mutations are inherited as an autosomal dominant trait. In approximately 10 percent of cases, the mutation occurs randomly for no apparent reason (sporadically). Mutations of the ADPKD1 gene are generally associated with more severe disease, earlier age of onset and early age of onset of end stage renal disease.

ADPKD affects males and females in equal numbers. Although a head-count has never been done, autopsy records show that between 1 in 400-1,000 people in the general population had ADPKD. There are approximately 6,000 new cases diagnosed each year in the United States. Approximately 6-10 percent of individuals receiving dialysis and renal transplant treatments in the United States have ADPKD. ADPKD is estimated to affect approximately 200,000 to 600,000 in the United States and another 12,000,000 people million worldwide, but only about one-fourth may know they have the disease.

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

ADPKD is diagnosed by a thorough clinical evaluation, a complete patient and family history, and imaging techniques, such as ultrasonography, computed tomography and magnetic resonance imaging. Such imaging studies are typically conducted for individuals with symptoms suggestive of ADPKD; in addition, they may be recommended as screening procedures for relatives of those diagnosed with ADPKD. Ultrasonography is a diagnostic study in which reflected echoes of high-frequency sound waves create an image of certain internal organs such as the kidneys. In some affected individuals, additional imaging studies, such as computerized tomography (CT) and magnetic resonance (MR) imaging, may also be recommended to help detect small cysts and determine the full extent of the disorder. During CT scanning, a computer and x-rays are used to create cross-sectional images of certain tissue structures.


Autosomal Dominant Porencephaly Type I

COL4-A1相关家族性血管性白质脑病

Autosomal dominant porencephaly type I is a rare genetic disorder in which fluid-filled cysts and cavities develop on the surface of the brain. Autosomal dominant porencephaly type I is caused by changes (mutations or pathogenic variants) in the COL4A1 gene. Affected individuals are predisposed to damage to small blood vessels, including the small vessels within the brain. The signs and symptoms of this disorder vary greatly from one individual to another but may include weakness or paralysis of one side of the body (hemiparesis or hemiplegia), seizures, varying degrees of cognitive impairment and migraines.

The age of onset, specific symptoms, disease progression and severity of autosomal dominant porencephaly type I vary greatly from one individual to another, even among members of the same family. The term porencephaly refers to the formation of fluid-filled cysts or cavities on the surface of the brain. The size and exact locations of such cysts and cavities contribute to the clinical variability of this disorder. In some children, serious, life-threatening complications may occur in infancy; in others, only minor complications may occur and intelligence is unaffected. Still other individuals may not develop any symptoms (asymptomatic) until well into adulthood. Affected individuals should talk to their physicians and medical team about their specific medical history and associated symptoms.

This genetic form of porencephaly is caused by variants in the COL4A1 gene and is inherited in an autosomal dominant pattern. Most individuals with autosomal dominant porencephaly type I have a parent with a pathogenic variant in the COL4A1 gene. In an unknown number of cases, the COL4A1 variant occurs randomly for no apparent reason (de novo).

Autosomal dominant porencephaly type I affects males and females in equal numbers. The incidence of the disorder in the general population is unknown. Autosomal dominant porencephaly type I may go undiagnosed or misdiagnosed, making it difficult to determine the true frequency of this disorder.

Symptoms of the following disorders can be similar to those of autosomal dominant porencephaly type I. Comparisons may be useful for a differential diagnosis.

A diagnosis of autosomal dominant porencephaly type I is suspected based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests such as advanced imaging techniques. Such imaging techniques may include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of certain tissue structures. A MRI uses a magnetic field and radio waves to produce cross-sectional images of particular organs and bodily tissues.

The treatment of autosomal dominant porencephaly type I is geared toward the specific symptoms that are present in each individual. For example, treatment may include physical therapy, speech therapy, anti-convulsant medications for seizures and a shunt to treat hydrocephalus by draining excess fluid from the skull. Individuals with high blood pressure (hypertension) must receive appropriate therapy because of the increased risk of stroke. Smoking, which also increases the risk of stroke, physical activities that can cause head trauma and the use of anti-clotting (anticoagulant) medications should also be avoided.


常染色体显性遗传性肾小管间质性肾病

Autosomal Dominant Tubulo-Interstitial Kidney Disease

Autosomal dominant tubulointerstitial kidney disease (ADTKD) describes a group of diseases that affect the tubules of the kidney. These conditions have the following characteristics:  They are inherited in an autosomal dominant manner; this means that a parent has a 50% chance of passing the disease on to their children. Often many family members are affected. (2) Chronic kidney disease develops. This initially is noticed as an elevated blood creatinine level. There are no symptoms from an elevated creatinine until it is very high, so often the elevated creatinine is found out on blood testing at a doctor’s office or in the hospital. Often, doctors are uncertain why the creatinine is elevated. As chronic kidney disease progresses, and the creatinine rises more, patients develop symptoms of fatigue, anemia, and feel cold all the time. Decreased appetite and fluid retention develop as the patient nears the need for dialysis. (3) Dialysis or kidney transplant is required sometime between the 4th and 7th decade of life. (4) Several types of the disease are associated with elevated uric acid concentrations in blood and gout, which sometimes starts in the teenage years. In ADTKD-UMOD and ADTKD- REN, some – but not all – family members are affected by gout.

All individuals with ADTKD show slow loss of kidney function that may be present as early as childhood. Patients may first be diagnosed with this disease when they are found to have an elevated blood creatinine level (measure of kidney function) on a routine blood test at their doctor’s office. For many individuals, there may be no other symptoms. Doctors will check the urine, and will find that it does not contain blood and little or no protein. A kidney ultrasound is usually normal, and even a kidney biopsy may not point to a cause for this condition. Doctors are often confused because the patient has an elevated creatinine but the urine tests and the kidney ultrasound look normal. Thus, ADTKD is frequently not properly diagnosed. The kidney disease progresses slowly, and patients eventually develop symptoms of kidney failure (nausea, fluid retention) and require dialysis or kidney transplant. The age that kidney transplant or dialysis is required is highly variable, with some individuals requiring it as early as age 17, while other family members may not even require it at age 70. The reason for this variation is unclear.

All types of autosomal dominant tubulointerstitial kidney disease follow autosomal dominant inheritance. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. We all have two copies of each gene. Individuals with ADTKD have one normal copy and one abnormal copy. The parent has a 50/50 chance of passing the abnormal gene on to their child. Thus, children of an affected individual have a 50/50 chance of having the disease. The risk is the same for males and females. There are usually a number of family members affected, with at least a parent and child almost always affected.

All types of autosomal dominant tubulointerstitial kidney disease are very uncommon.

Symptoms of the following disorders can be similar to those of autosomal dominant tubulointerstitial kidney disease. Comparisons may be useful for a differential diagnosis.

Several lab tests are very helpful in pointing to this diagnosis. First, a blood test is done to measure the blood creatinine. In this condition, the blood creatinine is usually elevated, beginning in the second decade of life. A blood uric acid level is also tested and is almost always elevated in ADTKD-UMOD and ADTKD-REN (though not elevated early on in ADTKD-MUC1). A urine test (urinalysis) is done. The absence of blood or protein in the urine rules out other possible causes of kidney damage. Thus, most individuals with this condition have high blood creatinine levels, and a normal urinalysis. A kidney ultrasound is also frequently done and usually shows normal kidneys, though some individuals may be found to have cysts in the middle of the kidney. The real key to the diagnosis is that a parent and a child are usually both affected with kidney disease. Kidney biopsy may be performed, but the kidney biopsy cannot specifically diagnose ADTKD: genetic testing is required.


Autosomal Recessive Hyper IgE Syndrome

The symptoms of AR-HIES vary from case to case. AR-HIES affects the immune system as well as the central nervous system. Symptoms may be apparent at birth or during infancy or early childhood.

AR-HIES 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.

AR-HIES affects males and females in equal numbers. These disorders may often go unrecognized or misdiagnosed, making it difficult to determine their true frequency in the general population. Although AR-HIES is present during infancy, diagnosis may not be made until adolescence and, in some cases, adulthood.

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

Due to the great variety of clinical features of AR-HIES early diagnosis can be challenging and genetic testing for DOCK8 deficiency may be essential.


Autosomal Recessive Polycystic Kidney Disease

Autosomal recessive polycystic kidney disease (ARPKD) is a rare genetic disorder characterized by the formation of fluid-filled sacs (cysts) in the kidneys. Most affected infants have enlarged kidneys during the newborn (neonatal) period and some cases may be fatal at this time. ARPKD is not simply a kidney disease and additional organ systems of the body may also be affected, especially the liver. High blood pressure (hypertension), excessive thirst, frequent urination and feeding difficulties may also occur. Some affected children may also have distinctive facial features and incomplete development of the lungs (pulmonary hypoplasia) causing breathing (respiratory) difficulties. The severity of the disorder and the specific symptoms that occur can vary greatly from one person to another. Some affected children eventually develop end-stage renal disease sometime during the first decade of life. In some patients, symptoms do not develop until adolescence or even adulthood. ARPKD is caused by changes (mutations) in the PKHD1 gene.

The severity and progression of ARPKD can vary greatly from one person to another, even among members of the same family. In severe cases, ARPKD can cause life-threatening complications during infancy. In other cases, affected individuals may not develop symptoms until later during childhood or adolescence. Some children may need a kidney (renal) transplant early in childhood; others may not need a transplant until early adulthood, or not at all. In rare cases, individuals may not develop symptoms until young adulthood. Generally, individuals who develop ARPKD later in life have milder kidney disease, but more severe liver disease.

ARPKD is caused by mutations of the PKHD1 gene and is inherited in an autosomal recessive pattern.

ARPKD affects males and females in equal numbers. The incidence of ARPKD is estimated to occur in approximately 1 in 20,000 individuals in the general population. Approximately ~1/70 people carry a single mutation in the PKHD1 gene. Because some people may go undiagnosed, it is difficult to determine the true frequency of ARPKD in the general population. Although most patients are diagnosed in utero or at birth, mild cases may not become apparent until adolescence or adulthood. ARPKD can affect individuals of any ethnic group.

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

ARPKD may be suspected before birth based upon clinical findings (e.g., palpable flank mass, underdeveloped lungs, oligohydramnios, and hypertension). Radiologic imaging including sonograms, ultrasound and magnetic resonance imaging (MRI) can be used to aid in obtaining a diagnosis of ARPKD. In addition to detecting kidney abnormalities, various radiologic imaging techniques can also be used to identify non-obstructive widening (dilatation) of the intraheptic ducts within the liver.


Axenfeld-Rieger syndrome

ARS is caused by changes (mutations) in several different genes and follows an autosomal dominant pattern of inheritance.

ARS is estimated to occur in about 1 in 1/50,000 newborns worldwide. It has been observed in patients from different ethnic origins including the Middle East as well as European, African, Asian, and South and North American populations. ARS seems to affect males and females in about equal numbers and is usually diagnosed in infants and children. Glaucoma, on the other hand, usually develops later in childhood or in adulthood.

The following disorders may share genetic or structural similarities with ARS.

ARS is commonly recognized by the presence of characteristic ocular features that may include non-ocular abnormalities. Depending on the clinical situation, genetic testing can help confirm a suspected diagnosis of ARS.


Babesiosis

Babesiosis is a rare infectious disease caused by single-celled microorganisms (protozoa) belonging to the Babesia family. It is believed that the Babesia protozoa are usually carried and transmitted by ticks (vectors). Babesiosis occurs primarily in animals; however, in rare cases, babesiosis infection may occur in humans. Certain Babesia species are known to cause babesiosis infection in humans (e.g., Babesia microti), and the deer tick is a known vector. Human babesiosis infection may cause fever, chills, headache, nausea, vomiting, and/or muscle aches (myalgia). Symptoms may be mild in otherwise healthy people; in addition, some infected individuals may exhibit no symptoms (asymptomatic). However, a severe form of babesiosis, which may be life-threatening if untreated, may occur in individuals who have had their spleens removed (splenectomized) or who have an impaired immune system. A different form of babesiosis has been reported in Europe that is associated with a more severe expression of symptoms.

Most people with babesiosis do not experience any symptoms (asymptomatic) or experience only mild symptoms. However, in some cases, babesiosis can cause severe complications. These severe cases usually only occur in individuals greater than 50 years of age, individuals who have impaired immune systems (immunocompromised), or individuals who have had their spleen removed (splenectomized).

Babesiosis is caused by single-celled microorganisms (protozoa) from the genus Babesia. These microorganisms are parasites that invade red blood cells (erythrocytes).

Babesiosis is a rare infectious disease that affects males and females in equal numbers. It can affect individuals of any age although it is more likely to occur in people over 50 years of age, people who have weakened immune systems, and people who have had their spleens removed.

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

Malaria is an infectious disease that is caused by single-celled microorganisms (protozoa) of the Plasmodium genus and spread by the bite of an infected mosquito (Anopheles). Major symptoms may include fever, chills, listlessness, loss of appetite, headaches, muscle aches, and other flu-like symptoms. Additional symptoms may include muscle spasms and rigidity, profuse sweating, cold sores, abnormally fast heartbeat, and difficulty breathing. The severity of the symptoms varies greatly from case to case. Low levels of circulating red blood cells (anemia), weight loss, and a mild yellowish discoloration of the skin, mucous membranes, and whites of the eyes (jaundice) may also occur. Four different species of the Plasmodium genus may cause malaria. (For more information on this disorder, choose Malaria as your search term in the Rare Disease Database.)


全身发育迟缓-脱发-大头畸形-面部畸形-结构性脑异常综合症

Global developmental delay-alopecia-macrocephaly-facial dysmorphism-structural brain anomalies syndrome

ODC1 gain-of-function-related neurodevelopmental disorder

Bachmann-Bupp syndrome (BABS) is a rare genetic disorder caused by gain-of-function changes (pathogenic variants or mutations) in the ODC1 gene. Affected individuals have a distinctive type of hair loss (alopecia), global developmental delay, low muscle tone (hypotonia), nonspecific abnormal physical characteristics (dysmorphic features) and behavioral abnormalities. There is no cure for the disorder, but research is underway to better understand and treat this disease. Current treatment is aimed at the specific symptoms present in each individual.

There are 9 patients reported in the medical literature with BABS. From their histories, pathogenic variants in the ODC1 gene are thought to be responsible for the following:

BABS is caused by changes (pathogenic variants or mutations) in the ornithine decarboxylase (ODC1) gene that are located at one end of the gene, the C terminus. Genes provide instructions for creating proteins which play a critical role in many bodily functions. Pathogenic variants in the ODC1 gene that cause BABS result in an elevated level of ODC protein followed by an increased conversion of ornithine to putrescine and increased accumulation of putrescine in the cells. These are called gain-of-function pathogenic variants.

BABS is a rare disorder that was first reported in the medical literature in 2018. As of November 2022, fewer than 30 affected individuals have been identified with the disorder worldwide. Rare diseases often 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 BABS. Comparisons may be useful for a differential diagnosis.

A diagnosis of BABS is based upon identification of characteristic symptoms and molecular genetic testing that reveals a pathogenic variant in the ODC1 gene. Consensus clinical diagnostic criteria have not been established.


Balantidiasis

Balantidiasis is a rare intestinal infection caused by the bacterium, Balantidium coli, a single celled parasite (ciliate protozoan) that frequently infects pigs but on occasion (rarely) infects humans. Some infected people may have no symptoms or only mild diarrhea and abdominal discomfort but others may experience more severe symptoms reminiscent of an acute inflammation of the intestines. Symptoms of Balantidiasis may be similar to those of other infections that cause intestinal inflammation, for example, amoebic dysentery.

Most people with Balantidiasis are asymptomatic or present mild symptoms.  Some individuals may become acutely ill with abnormally high temperatures, nausea, vomiting, abdominal pain, and bloody diarrhea.  Such conditions may result in the excessive loss of water from the body (dehydration) and extreme exhaustion (prostration), especially if B. coli attacks the intestinal lining causing inflammation and possibly crater-like areas of damage (ulceration).  In very severe cases, the ulcers may be deep enough to puncture the intestinal wall (perforation) resulting in acute inflammation of the peritoneum, the membrane that lines the abdomen (peritonitis). Occasionally, the ulcer may diminish lung function.

Balantidiasis is a rare infectious disease caused by the single celled (protozoan) parasite Balantidium coli.  This parasite may be passed directly to humans by contact with pig feces or indirectly by drinking contaminated water.  Poor nutrition, a compromised immune system, or other illnesses may make a person vulnerable to more severe symptoms of this disease.

Balantidiasis is a rare infection that affects males and females in equal numbers.  It typically occurs in tropical regions such as Brazil, New Guinea, and southern Iran.

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

Ulcerative Colitis is an acute inflammatory bowel disease characterized by diarrhea and blood in the stools because of multiple, irregular ulcerations of the bowel.  The initial symptoms of this disorder may include a general feeling of weakness (malaise) and fatigue.  There may be abdominal discomfort, along with a change in the frequency and consistency of stools. Other symptoms may include abdominal pain, cramping, and the urgent need to have a bowel movement (tenesmus).  Weight loss and a decrease in appetite are also associated with Ulcerative Colitis.  (For more information on this disorder, choose Ulcerative Colitis as your search term in the Rare Disease Database.)

Balantidiasis can be diagnosed by laboratory testing of the stool. Immature B. coli parasites (trophozoites) are usually recoverable from the stool. A more complex and more invasive diagnostic method involves scraping the ulcer and examining the tissue for trophozoites.


Balo Disease

Balo Disease is a rare and progressive variant of multiple sclerosis. It usually first appears in adulthood, but childhood cases have also been reported. While multiple sclerosis typically is a disease that waxes and wanes, Balo Disease is different in that it tends to be rapidly progressive. Symptoms may include headache, seizures, gradual paralysis, involuntary muscle spasms, and cognitive loss. The alternative names for Balo Disease, concentric sclerosis or Balo concentric sclerosis, refer to the fact that Balo Disease is characterized by bands of intact myelin (the sheath of fatty substances surrounding nerve fibers), alternating with rings of loss of myelin (demyelination), in various parts of the brain and brain stem. The symptoms of Balo Disease vary, according to the areas of the brain that are affected. Symptoms may progress rapidly over several weeks or more slowly over two to three years.

Most cases are characterized by the gradual onset of symptoms that might be found in the more common type of MS, including muscle spasms and paralysis. Other neurological symptoms develop depending on the areas of the brain that are affected and may include intellectual impairment and/or physiological abnormalities. However, in its most serious form, Balo Disease may also suggest the presence of an infectious disease, starting with a high fever and painful headaches.

The cause of MS and its variants remains unknown. However, some studies indicate that autoimmune factors may play a role in the development of Balo Disease. Autoimmune disorders are caused when the body’s natural defenses against foreign or invading organisms (e.g., antibodies) begin to attack healthy tissue for unknown reasons.

Balo Disease is a rare disorder that affects males and females in equal numbers. More cases have been reported from China and the Philippines than elsewhere.

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

Adrenoleukodystrophy is a rare inherited metabolic disorder characterized by the loss of the fatty covering (myelin sheath) around nerve fibers in the brain (cerebral demyelination) and the progressive degeneration of the adrenal gland. The symptoms of this disorder may include generalized muscle weakness (hypotonia), exaggerated reflex responses (hyperreflexia), impaired ability to coordinate movement (ataxia), spastic partial paralysis, and/or tingling or burning sensations in the arms or legs. (For more information on this disorder, choose Adrenoleukodystrophy as your search term in the Rare Disease Database.)

Treatment is symptomatic and supportive. Corticosteroids are usually useful in decreasing severity of acute presentations through their anti-inflammatory actions. Treatment to relieve symptoms, such as spasticity, weakness, pain, or ataxia, includes pharmacologic and rehabilitative modalities.


Bannayan-Riley-Ruvalcaba syndrome

Individuals with BRRS have clinical findings that vary from one person to another. They can be separated into different categories: skin, facial differences, skeletal abnormalities, thyroid gland tumors, gastrointestinal tract, central nervous system, ocular abnormalities, muscular system and other findings. Children with BRRS also tend to be bigger and longer at birth and can have blood vessel changes (hemangiomas) which are seen as raised red birthmarks. Growth slows down with age and patients tend to have normal size and height as adults. This is not a complete list of possible findings. Some are found in case reports and are added to the list of possible findings.

Approximately 60% of patients with BRRS have an inborn change (mutation) in the PTEN tumor suppressor gene in all cells of their bodies. A tumor suppressor is a gene that slows down cell division, repairs damage to the DNA of cells, and tells cells when to die, a normal process called apoptosis. Mutations in a tumor suppressor gene often lead to overgrowth and/or cancer. The PTEN gene results in the production of an enzyme called phosphatase and tensin homolog (from which the name ‘PTEN’ is derived). PTEN is important for stopping cell growth and starting apoptosis. Researchers believe that the PTEN gene plays a broad role in the development of human cancers.

BRRS was previously reported as three different conditions: Riley-Smith, Bannayan-Zonana and Ruvalcaba-Myhre-Smith syndromes. To facilitate diagnosis and medical care, BRRS is considered to be a component of PTEN hamartoma tumor syndrome (PHTS) for all patients having a germline PTEN mutation. Males and females are affected equally and PHTS is found in all racial and ethnic groups.

Symptoms of the following disorders can be similar to those of BRRS. Comparisons may be useful for purposes of formulating a genetic differential diagnosis.

BRRS may be suspected based upon identification of characteristic physical features (e.g., macrocephaly, penile lentigines, hamartomatous polyposis, characteristic facial abnormalities, skeletal malformations, etc.). The diagnosis may be confirmed by a thorough clinical evaluation and detailed patient and family histories. The diagnosis can also be confirmed when a germline mutation in the PTEN gene is identified.


甲状旁腺功能减退-感音神经性耳聋-肾功能障碍

Hypoparathyroidism-sensorineural deafness-renal disease syndrome

First described by Barakat, et al in 1977, the Barakat syndrome, also known as HDR syndrome is a clinically variable (heterogeneous), rare genetic disorder characterized by the triad of hypoparathyroidism (decreased function of the parathyroid glands which are small endocrine glands in the neck whose main function is to maintain the body calcium level), sensorineural deafness and renal disease.

Since newborn hearing screening and prenatal ultrasonography are now performed routinely, deafness and congenital anomalies of the kidney and urinary tract have become the more common modes of presentation. Patients may also present with symptoms associated with low blood calcium (hypocalcemia) caused by malfunction of the parathyroid glands such as muscle weakness, tetany and convulsions, or signs of kidney disease such as proteinuria, hematuria and chronic kidney disease. Deafness may be a presenting symptom or may be found on a routine hearing test at any age.

Barakat syndrome is inherited in an autosomal dominant pattern. Dominant genetic disorders occur when only a single copy of a non-working gene is necessary to cause a particular disease. The non-working gene can be inherited from either parent or can be the result of a changed (mutated) gene in the affected individual. The risk of passing the non-working gene from an affected parent to an offspring is 50% for each pregnancy. The risk is the same for males and females.

The exact prevalence is unknown, but the disease is considered to be rare. So far, about 200 patients have been reported in the literature worldwide. Clinical awareness of this syndrome will certainly increase the number of patients diagnosed and reported. There is equal prevalence across ethnic groups, genders and ages of diagnosis (from newborns to age 60 years).

Differential diagnoses of the syndrome include familial isolated hypoparathyroidism and chromosome 22q11.2 deletion syndrome.

The diagnosis of this syndrome is based on the clinical findings of hypoparathyroidism, deafness and renal disease. The following studies should be performed: parathormone (PTH) and calcium levels, hearing test, urinalysis, imaging studies of the kidneys and possibly a kidney biopsy in the presence of nephrotic syndrome, hematuria or proteinuria. Molecular genetic testing for mutations in the GATA3 gene may be performed in specialized genetic labs. The syndrome should be considered in infants who have been prenatally diagnosed with a chromosome 10p abnormality or congenital anomalies of the kidney and urinary tract. Siblings and family members should be studied for hypoparathyroidism, deafness and renal disease and offered GATA3 gene testing.


Bardet-Biedl syndrome

The cardinal features of BBS are truncal obesity, intellectual impairment, renal anomalies, polydactyly, retinal degeneration and hypogenitalism. Each feature is discussed in detail below. The term ‘truncal obesity’ refers to a condition where fat is disproportionately distributed onto the abdomen and chest rather than the arms and legs. Individuals can be described as having an apple-shape body type. Weight is usually normal at birth but weight gain is quickly evident through the first year of life in as many as 90% of people with BBS. Diabetes mellitus (specifically, type II diabetes, non-insulin dependent) has been estimated to affect up to 45% of patients with BBS. Weight management problems may further complicate problems with the heart and blood vessels seen in patients with BBS. The heart functions as a pump for the blood, moving the blood through the vessels that bring it throughout the body. The heart relies on valves that keep the flow moving in the forward direction. With age, stiffening of the heart valves is completely normal. The stiffening is due to calcium laying down on the valves, and this process if described by the word stenosis. Patients with BBS may experience stenosis of their heart valves prematurely. They may also have defects of the heart’s muscular walls. The heart muscle is designed such that every motion is smoothly orchestrated. Defects in the heart muscle predispose people with BBS to heart beat abnormalities, referred to as arrhythmias. Most patients with BBS will experience the loss of a particular population of cells in the eye, specifically in the retina. The retina is part of the eye involved in detecting and decoding incoming images. Incoming light is focused onto the retina at the back of the eye. The retina is composed of cells called rods and cones. They translate incoming light into nerve impulses the brain can use. This gradual loss of the rod and cone cells on the retina is described as dystrophy. Symptoms associated with cone-rod dystrophy may not become apparent until 7 or 8 years of age when children begin to complain of an inability to see in dimly lit environments, such as a sidewalk lit only by streetlights. This night blindness may progress to variable degrees. In most people, the vision becomes progressively weaker through the first and second decades of life. Affected individuals often first lose peripheral vision, and see only what is directly in front of their focus point. They see in what is termed ‘tunnel vision’. Many affected individuals also eventually lose central vision and become legally blind, often by their mid-teens. In some people, the degeneration of the retina may follow a characteristic course, referred to as retinitis pigmentosa, (RP). RP begins with night blindness, followed by a loss of the ability to discriminate colors from one another, and finally to a progressive tunnel vision. (For more information, choose Retinitis Pigmentosa as your search term in the Rare Disease Database). Additional effects on the eye characteristic to individuals with BBS include: lazy eye (strabismus), clouding of the lens of the eyes (cataracts), and an increased pressure within the eyes that can result in damage to the optic nerve conducting signals to the brain (glaucoma).

BBS can be caused by changes (mutations) in more than 20 different genes. It is usually inherited as an autosomal recessive condition. Below you will find a more technical description of the genetic changes that underlie BBS and known clinical associations.

BBS affects males and females in equal numbers. The prevalence is estimated to be 1 in 100,000 in the non-related (non-consanguineous) populations of Northern Europe and America. In Sweden, the prevalence is estimated to be 1 in 160,000. The disorder occurs with greater frequency in the Bedouin population of Kuwait (1 in 13,500) and in certain populations of Newfoundland (1 in 17,500). A specific mutation (K243lfsX15) in the BBS10 gene is particularly common in South Africa.

The conditions below are ones which may clinically resemble BBS. The list below can be useful in establishing a differential diagnosis.

BBS is generally diagnosed based upon identification of characteristic findings described above (eg: visual problems due to retinal dystrophy, truncal obesity, post-axial polydactyly). As diagnosis is based on clinical findings and BBS is associated with variable expression of the classical features, some patients may not have a clear diagnosis for many years. Difficulties with diagnosis arise when a child demonstrates learning disabilities and problems with weight management but who was not born with any congenital abnormality. For these children, diagnosis may remain uncertain until they begin to manifest vision loss symptoms. Diagnosis of retinal disease may require consultation with an ophthalmologist and an examination including an electroretinogram (ERG). The ERG is a procedure that measures the electrical response of the retina to light stimulation. Genetic testing may help confirm the diagnosis for some patients (e.g., individuals with certain BBS1 and BBS10 gene mutations). However, such testing may not be covered by insurance and available only through research laboratories with a special interest in BBS.


Barth syndrome

X linked endocardial fibroelastosis (EFE)

Barth syndrome is mainly found in early infancy or childhood. However, in some patients, symptoms appear in adulthood. Symptoms can present differently and can vary from one person to another.

Barth syndrome is caused by mutations in the TAZ gene. The TAZ gene produces a protein called tafazzin. Tafazzin helps in altering a fat called cardiolipin. Cardiolipin is present in the inner membrane of structures called mitochondria. Mitochondria are structures in the cell which helps in making energy. Loss of tafazzin protein mainly affects energy requiring organs like heart and skeletal muscles. However, more research is required to understand how the loss of tafazzin leads to cardiomyopathy and neutropenia.

Barth syndrome affects all ethnic groups. The incidence of Barth syndrome is estimated to be 1 in 300,000 to 1 in 400,00 in United States. As of 2013, there have been 151 patients reported in the medical literature.

Researchers have seen that mutations in the TAZ  gene causes a wide range of symptoms. There have been patients reported with several heart conditions like dilated cardiomyopathy, noncompaction of left ventricle and endocardial fibroelastosis but without other Barth syndrome symptoms like low white blood count, growth delay and increased biochemical levels of 3-methyglutaconic acid and 2-ethyl hydracrylic acid.

Barth syndrome is usually diagnosed during infancy or early childhood, but has been diagnosed later in some patients. Diagnosis is based upon clinical evaluation, identification of characteristic physical findings, a complete patient and family history, and a variety of specialized tests.


Bartonellosis

Diseases in humans that have been identified to be caused by one of the Bartonella spp include cat scratch disease, Carrion’s disease, and trench fever.

Bartonella bacteria invade red blood cells (erythrocytes) and the lining of the blood vessels (endothelial cells), where the organism proliferates. Inside the erythrocytes, it is protected from the host’s primary and secondary immune response, thus explaining bacterial persistence that can occur in some cases.

Cat scratch disease caused by B. henselae infection occurs in approximately 1 per 10,000 persons. Cat-scratch disease has been shown in some studies to occur more frequently in males than females with a ratio of 3:2. However, other studies have shown equal rates between males and females. One hypothesis to explain a greater incidence among males than females is the tendency toward rougher play with cats and consequently an increased risk of bites and scratches. A database analysis in 2016 showed 33% of patients with CSD were 14 years of age or younger.

Certain features of the following disorders may be similar to those of bartonellosis:

Most cases of CSD can be diagnosed by the individual’s symptoms and history, such as the development of papules or pustules after vector exposure or a cat scratch or bite. Development of swollen lymph nodes and fever further reinforce a clinical diagnosis. Blood (serological) testing is available to confirm the diagnosis. PCR and culture tests may also be used in certain cases.


Bartter syndrome

salt-losing tubulopathy with secondary hyperaldosteronism

The age of onset, severity and specific symptoms associated with Bartter syndrome can vary greatly from one person to another, even among individuals who have the same subtype. Some individuals may have mild cases; others may experience severe, potentially life-threatening complications, at birth.

Bartter syndromes are caused by recessive mutations in the SLC12A1 gene (type 1), the KCNJ1 gene (type 2), the CLCNKB gene (type 3), the BSND gene (type 4A), or both the CLCNKA and CLCNKB genes (type 4B). Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Bartter syndrome is inherited in an autosomal recessive manner, except for type 5, which is inherited in an X-linked recessive matter.

The Bartter syndromes affect males and females in equal numbers. They are estimated to affect approximately one in 100,000 people in the general population. However, many cases go undiagnosed or misdiagnosed, making it difficult to determine the true frequency in the general population. Bartter syndromes can occur in individuals of any race or ethnic background.

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

A diagnosis of one of the Bartter syndromes is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests.


Beckwith-Wiedemann syndrome

Beckwith-Wiedemann syndrome (BWS) is the most common overgrowth and cancer predisposition disorder. BWS is caused by changes on chromosome 11p15.5 and is characterized by a wide spectrum of symptoms and physical findings that vary in range and severity from person to person. Associated features include a large tongue (macroglossia),  abdominal wall abnormalities (omphalocele, umbilical hernia or diastasis recti), abnormal enlargement of one side or structure of the body (lateralized overgrowth) resulting in unequal (asymmetric) growth, an increased risk of developing certain childhood cancers, most commonly Wilms tumor (kidney tumor) and hepatoblastoma (liver tumor) and low blood sugar levels in the first few days of life (neonatal hypoglycemia) or beyond leading to persistent low blood sugars (hyperinsulinism). BWS may also be associated with above-average birth weight (large for gestational age), increased growth after birth (macrosomia), enlargement of certain internal organs (organomegaly), distinctive grooves in the ear lobes (ear creases and ear pits), and a characteristic facial appearance.

The characteristic features of BWS vary greatly from person to person, which can make clinical diagnosis based on physical exam findings and molecular diagnosis based on genetic testing challenging. Sometimes, the clinical and molecular diagnoses do not match because clinically the patients may not have many obvious physical features of BWS even if they have changes in the BWS critical region based on genetic testing. Some individuals may appear mildly affected while others appear more significantly affected. Affected individuals may not have all the symptoms listed. The range of clinical features due to changes on chromosome 11p15.5 has been redefined as the Beckwith-Wiedemann spectrum.

Genetics is the study of genes whereas epigenetics is the study of how those genes are turned on or off (gene expression). BWS results from various abnormalities affecting the proper expression of genes that control growth within a specific region of chromosome 11(11p15.5). This region is referred to as the BWS critical region.

BWS affects males and females in equal numbers. It is estimated to occur in 1 in 10,340 individuals in the general population. Because people who are mildly affected may go undiagnosed, it is difficult to determine the true frequency of BWS in the general population.

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

Simpson-Golabi-Behmel syndrome is an X-linked recessive genetic disorder due to mutations in the GPC3 or GPC4 genes. Simpson-Golabi-Behmel syndrome is characterized by overgrowth before and after birth (macrosomia); a particular facial appearance including widely spaced eyes (hypertelorism), coarse facial features, large mouth (macrostomia), large head (macrocephaly), large tongue (macroglossia), and mild to severe intellectual disability. (For more information on this disorder, choose Simpson dysmorphia as your search term in the Rare Disease Database.)


Behçet Syndrome

Behçet’s syndrome is a rare multisystem inflammatory disorder characterized by ulcers affecting the mouth and genitals, various skin lesions and abnormalities affecting the eyes. Symptoms include mucous membrane lesions of the mouth (canker sores) and genitals (ulcers) that tend to disappear and recur spontaneously. Inflammation of the eyes (anterior uveitis, posterior uveitis, or panuveitis) also affects individuals with Behçet’s syndrome. Additional systems of the body may also be affected including the joints, blood vessels, central nervous system and/or digestive tract. The exact cause of Behçet’s syndrome is unknown.

The earliest symptom of Behçet’s syndrome is usually painful canker sores on the mucous membranes that line the mouth (aphthous stomatitis). The sores are usually round or oval with reddish (erythematous) borders that may occur anywhere within the mouth. They may be shallow or deep and may appear as a single lesion or a cluster of multiple lesions. The sores typically heal within a few days, up to a week or more, without scarring, but frequently recur. They may precede other symptoms of Behçet’s syndrome by several years. Sometimes similar sores may appear on the genitals, specifically the scrotum and shaft of the penis in males and the vulva in females. The sores are also round and painful but may be larger and deeper than those affecting the mouth. These sores also recur, but unlike oral lesions, may tend to scar.

The exact cause of Behçet’s syndrome is not known. Studies suggest that some people may have a genetic predisposition to the condition. A genetic predisposition means that a person may carry a gene for a disease, but it may not be expressed unless something in the environment triggers the disease. Researchers have demonstrated that certain individuals with Behçet’s syndrome, especially those of Middle Eastern and Asian descent, have an increased frequency of certain human leukocyte antigens (HLAs) in the blood. Individuals with Behçet’s syndrome are more likely to have HLA-B51 than the general population. The possible role of HLA-B51 in predisposing individuals to Behçet’s syndrome and its overall association with the disorder is unknown. Other genetic markers and their role in the development of Behçet’s disease are being studied. Viral or bacterial infections have also been suggested as a possible cause for the disorder. Still another theory is that the disease is an auto-inflammatory disorder in which the body loses the ability to appropriately regulate and control inflammation.

Behçet’s syndrome is a rare disorder in the United States and Western Europe. It occurs most frequently in the Middle East and Asia, along ancient trading routes between the Mediterranean basin and eastern Asia, known as the Silk Road. Turkey has the highest prevalence rate (80-370 cases per 100,000); Japan, Korea, China, Iran, and Saudi Arabia also have high prevalence rates. The disorder is the leading cause of blindness in Japan. The age of onset is typically between 30 and 40 years.

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

Reactive arthritis, previously known as Reiter’s syndrome, is a rare infectious disorder characterized by arthritis, inflammation of the urinary tract (non-gonococcal urethritis), and inflammation of the membranes that line the eyes (conjunctivitis). Lesions may also appear on the skin and mucous membranes. The symptoms may not all appear at once. There may be spontaneous remissions and recurrences. Symptoms may include pus in the urine, swollen painful joints and ulcers in the mouth. Occasionally the iris of the eyes may become inflamed (iritis). This disorder can be transmitted through sexual contact. (For more information on this disorder, choose reactive arthritis as your search term in the Rare Disease Database.)


Bell Palsy

欧洲非罕见：特发性面神经麻痹

Bell’s palsy is a non-progressive neurological disorder of the facial nerve (7th cranial nerve). This disorder is characterized by the sudden onset of facial paralysis that may be preceded by a slight fever, pain behind the ear on the affected side and weakness on one side of the face. Paralysis results from decreased blood supply (ischemia) and/or compression of the 7th cranial nerve. The exact cause of Bell’s palsy is not known. Viral (e.g., herpes zoster virus) and immune disorders are frequently suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy.

The early symptoms of Bell’s palsy may include a slight fever, pain behind the ear and weakness on one side of the face. The symptoms may begin suddenly and progress rapidly over several hours and sometimes follow a period of stress or reduced immunity. The whole side of the face is affected.

The exact cause of Bell’s palsy is not known. Viral and immune disorders are often suggested as a cause for this disorder. There may also be an inherited tendency toward developing Bell’s palsy. Symptoms develop due to deficiency of blood supply and pressure on the 7th cranial nerve as a result of nerve swelling.

Bell’s palsy affects males and females in equal numbers. It is estimated that 25-35 per 100,000 people in the United States are affected with Bell’s palsy. Approximately 40,000 individuals are diagnosed with Bell’s palsy in the United States each year.

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

Ramsay Hunt syndrome is a rare neurological disorder that typically affects adults over 60 years of age. The disorder is characterized by facial weakness or paralysis of the facial nerve and a rash affecting the ear or mouth. Symptoms are usually on one side of the face. Ringing in the ears (tinnitus) and hearing loss may also be present. Ramsay Hunt syndrome is caused by the varicella zoster virus (VZV), the same virus that causes chickenpox in children and shingles (herpes zoster) in adults. In Ramsay Hunt syndrome, previously inactive (dormant) varicella-zoster virus is reactivated and spreads to affect the facial nerve.  (For more information in this disorder, choose Ramsay-Hunt syndrome as your search term on the Rare Disease Database.)


Benign Essential Blepharospasm

In the early stages, benign essential blepharospasm is characterized by frequent or forced blinking and eye irritation that is often worsened by certain stimuli including bright lights, fatigue, emotional tension and environmental factors such as wind or air pollution. BEB virtually always affects both eyes (bilateral).

The cause of benign essential blepharospasm is unknown. Researchers speculate that the cause of BEB may be multifactorial (e.g., caused by the interaction of certain genetic and environmental factors).

Benign essential blepharospasm affects women more often than men. The average age of onset is 56.

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

Meige syndrome (cranial dystonia), is a rare neurological disorder that is characterized by spasms of all the muscles of the face, including the tongue and jaw. People in late middle age are most often affected. Just as in blepharospasm, involuntary eyelid closure may result from spasms of the muscles around the eyes. (For more information on this disorder, choose Meige syndrome as your search term in the Rare Disease Database.)


FGFR2-related bent bone dysplasia

FGFR2基因相关性弯曲骨发育不良综合征

Physical exams and imaging studies of infants with BBDS may identify signs and symptoms in many body systems:

Bent bone dysplasia syndrome (BBDS) is caused by a variant in the FGFR2 gene. These disease-causing variants occur randomly and spontaneously and are not inherited from either parent. Variants disrupt the structure and transportation of the FGFR2 protein produced by this gene leading to low concentrations and function of the protein on the surface of cells and abnormal signaling in cells mostly associated with bone formation. These cells do not multiply correctly and do not properly form the skeleton. The bones of affected infants then have inadequate and abnormal growth.

The relatively recent identification of the disorder and low number of patients means that the population affected by this condition cannot be accurately determined at this time.

Babies with BBDS have premature fusion of cranial sutures (craniosynostosis). Craniosynostosis is found in more than 150 genetic disorders. All the FGFR-related craniosynostosis conditions have autosomal dominant inheritance.

A diagnosis of BBDS may be suspected based on a thorough medical and family history, physical exams and imaging studies. Genetic testing for variants in the FGFR2 gene is necessary to confirm the diagnosis.


Bernard-Soulier syndrome

Bernard-Soulier syndrome (BSS) is a rare inherited disorder of blood clotting (coagulation) characterized by unusually large platelets, low platelet count (thrombocytopenia) and prolonged bleeding time (difficulty in clotting). Affected individuals tend to bleed excessively and bruise easily. Most cases of Bernard-Soulier syndrome are inherited in an autosomal recessive genetic pattern.

The symptoms of Bernard-Soulier syndrome, which are typically apparent at birth and continue throughout life, may include the tendency to bleed excessively from cuts and other injuries, nosebleeds (epistaxis), and/or an unusually heavy menstrual flow in women. Some babies and children with BSS have no symptoms and the disorder does not present until adult life. People with this disease also bruise easily and the bruises tend to linger. Bleeding from very small blood vessels under the skin (subcutaneous) may cause small or widespread areas of small red or purple colored spots (purpura or petechiae).

BSS is a genetic disorder that affects the ability of the platelets in the circulating blood to bind with a damaged blood vessel and hence to clot blood. These platelets are missing an essential protein called the glycoprotein Ib-IX-V complex (GPIb). The Gp1b complex is composed of 4 protein subunits that bind closely together (GP1b-alpha, GP1b-beta, GP9 and GP5). BSS is caused by mutations in one of the Gp1b complex genes- so far mutations have been found in BP1b-alpha, Gp1b-beta and GP9 but no mutations have been found in GP5. Normally the GP1b complex sticks out of the platelet’s surface and binds with another protein found in the circulating blood called von Willebrand factor. If one of these proteins is missing or abnormal, they cannot bind correctly to begin the clotting process and excessive bleeding results.

Bernard-Soulier syndrome is a rare bleeding disorder that affects males and females in equal numbers. Recent estimates suggest that Bernard Soulier syndrome affects 1 in a million people. More than 200 cases have been reported worldwide.

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

May-Hegglin anomaly is a rare inherited disorder of blood platelets and certain white blood cells characterized by abnormally large platelets. Some people with this disorder have symptoms from birth while others are without symptoms for life. Symptoms may include nosebleeds, purple colored spots on the skin (purpura), excessive bleeding from the mouth during dental work, and/or headaches. Some people with May-Hegglin anomaly may experience muscular weakness on one side of the body because of abnormal bleeding inside the brain (intracranial hemorrhage). (For more information on this disorder, choose May Hegglin as your search term in the Rare Disease Database.) May Hegglin does not usually cause bleeding in newborn babies unlike BSS.


Chronic beryllium disease

Berylliosis is a form of metal poisoning caused by inhalation of beryllium dusts, vapors, or its compounds or implantation of the substance in the skin. The toxic effects of beryllium most commonly occur due to occupational exposure. Beryllium is a metallic element used in many industries, including electronics, high-technology ceramics, metals extraction, and dental alloy preparation.

Acute berylliosis is a rare condition that develops suddenly due to exposure to beryllium.  The condition is primarily characterized by severe inflammation of the lungs (pneumonitis).  Associated symptoms typically include an abrupt onset of coughing, and difficulties breathing (dyspnea).  Some affected individuals may also develop a sore throat (pharyngitis); inflammation of the mucous membranes of the nose (rhinitis) and associated nasal discharge; and inflammation of the windpipe and air passages of the lungs (tracheobronchitis).  In addition, in some cases, other areas of the body may be affected, such as the skin or eyes.  Although most individuals with acute berylliosis have a complete recovery with no residual effects, potentially life-threatening complications may result without prompt, appropriate treatment.  The severity of the condition may depend upon the duration of beryllium exposure, the concentration of the irritant, and/or other factors.

Berylliosis is caused by inhalation of beryllium dusts, fumes, or its compounds or entrance of the substance through the skin.  Beryllium is a natural metallic chemical element that forms strong, lightweight alloys with various metals.  (Alloys are formed by the fusion of two or more metals.)  Due to such properties, beryllium has numerous industrial uses including aerospace, electronic, and nuclear components; high-technology ceramics; and dental alloys.  In addition, prior to the 1950s, beryllium was often used in the manufacture of fluorescent lights.  The risk of beryllium exposure occurs in any setting in which beryllium or its compounds may become airborne in the form of vapors, fumes, small particles, or dust.

The toxic effects of beryllium most commonly affect individuals who work in occupational settings in which beryllium or its components may become airborne.  As discussed above, beryllium is used in numerous industries, including electronics, high-technology ceramics, dental alloy preparation, and metals extraction.

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

Sarcoidosis is a multisystem disorder characterized by the abnormal formation of inflammatory masses or nodules (granulomas) consisting of granular white blood cells in certain organs of the body.  The granulomas that are formed are thought to affect the normal structure of and, potentially, the normal functioning of the affected organs, causing symptoms associated with the particular body systems in question.  In individuals with sarcoidosis, such granuloma formation most commonly affects the lungs.  However, in many cases, the upper respiratory system, lymph nodes, skin, or eyes may also be involved.  In addition, in some individuals, other organs may be affected, including the liver, bone marrow, spleen, musculoskeletal system, heart, salivary glands, or nervous system (i.e., central or peripheral nervous system).


Best vitelliform macular dystrophy

Best卵黄样黄斑营养不良

Best vitelliform macular dystrophy (BVMD) is a genetic form of macular degeneration (damage to a part of the eye called the macula) that occurs in about 1 in 10,000 individuals. The physical cause of BVMD is breakdown of the tissue in the retina called retinal pigment epithelium (RPE). The condition gets worse over time, starting with blurred central vision, and possibly leading to complete loss of central vision. Peripheral vision (vision from the sides of the eye) and the ability of the eye to adjust to dark are unaffected. The age of onset of BVMD can vary. Many individuals with BVMD have symptoms in childhood or early adulthood. BVMD is associated with a harmful genetic change (mutation) in the BEST1 gene. There is no cure for BVMD, although some treatments and medications exist that can minimize the damage caused by breakdown of the RPE including anti-VEGF therapy (medicine used to prevent growth of new blood vessels in the eye), laser photocoagulation (laser treatment used to destroy leaky blood vessels), and photodynamic therapy (a combination of medicine and laser treatment used to get rid of bad eye cells).

BVMD has an average age of onset between age 5 and 10 but can vary from person to person. Affected individuals initially have normal vision and then experience blurred vision, reduced sharpness or clarity of vision or the appearance of objects that have a distorted shape (metamorphosia). BVMD affects central vision but usually not peripheral vision and varies in severity.

The macula is the region of the retina that contains the light-sensing cells necessary for central vision. Individuals with BVMD develop a yellowish material under the macula that resembles an egg yolk (vitelliform means yolk-like). This material eventually breaks up and spreads throughout the macula, leading to a reduction in central vision. Lipofuscin, a chemical made by the body, makes up this yolk-like material.

BVMD is fairly common form of macular degeneration affecting about 1 in 10,000 individuals. Typical age of onset is between the ages of 5 and 10 but can occur earlier or later. BVMD occurs equally often in men and women. This condition has been diagnosed in individuals of European, African and Hispanic ancestry.

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

Adult vitelliform macular dystrophy is an autosomal dominant form of macular dystrophy that usually begins in middle age. A yolk-like mass is often present on the macula, but a special light test used to evaluate the function of the layer of cells between the retina and eye wall (retinal pigment epithelium) is usually normal. Some affected individuals have an abnormality in either the BEST1 or PRPH2 gene.


Beta-thalassemia major

The symptoms and severity of beta thalassemia varies greatly from one person to another. Individuals with beta thalassemia minor do not develop symptoms of the disorder but may have a mild anemia. Many individuals with beta thalassemia minor go through life never knowing they carry an altered gene for the disorder.

Most beta thalassemia cases are caused by a mutation in the HBB gene. In extremely rare cases, a loss of genetic material (deletion) that includes the HBB gene causes the disorder. Genes provide instructions for creating proteins that play a critical role in many body functions. When a gene mutation occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. Individuals with beta thalassemia minor have a mutation in one HBB gene and are carriers for the disorder. Individuals with beta thalassemia intermedia or major have mutations in both HBB genes.

Beta thalassemia is relatively rare in the United States, but is one of the most common autosomal recessive disorders in the world. The incidence of symptomatic cases is estimated to be approximately 1 in 100,000 individuals in the general population. The disorder is particularly prevalent in the Mediterranean, Middle East, Africa, central Asia, the Indian subcontinent, and the Far East. Individuals in other parts of the world whose families are from these regions carry a greater risk of having beta thalassemia.

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

A diagnosis of beta thalassemia is based upon identification of characteristic symptoms, a clinical evaluation and a variety of specialized tests. With beta thalassemia major, initial symptoms often become apparent during the first two years of life and include failure to thrive, a swollen abdomen and symptoms of anemia. Beta thalassemia intermedia may be suspected in individuals who present with similar (yet milder) symptoms, but at a later age.


Beta-mannosidosis

The signs and symptoms, progression and severity of beta-mannosidosis vary widely among affected individuals. Individuals may develop signs and symptoms between infancy and adulthood. It is important to note that every individual is unique and how the disorder affects one person can be different from how it affects another.

Beta-mannosidosis is caused by changes (variants or mutations) in the MANBA gene. The MANBA gene contains instructions for creating a type of protein (enzyme) called beta-mannosidase. Inside cells throughout the body are specialized compartments called lysosomes that contain enzymes to break down (metabolize) and recycle materials to support normal body functions. One type of material is glycoproteins that are composed of chains of sugar molecules (oligosaccharides). During metabolism, the chain is taken apart by separating the sugar molecules. Beta-mannosidase helps this process in certain oligosaccharides that contain a particular sugar molecule called mannose. The enzyme’s function is to specifically separate mannose from its neighboring sugar molecule and help break down the chain.

Beta-mannosidosis affects females and males in equal numbers. The exact number of people who have this disorder is unknown. Beta-mannosidosis may often go misdiagnosed or undiagnosed, especially in individuals with mild or non-specific symptoms, making it difficult to determine its true frequency in the general population. As of May 2023, the International Society for Mannosidosis and Related Diseases estimates approximately 20 individuals in the world are reported to be affected.

Clinical features of the following disorders can be similar to those of beta-mannosidosis.

A diagnosis of beta-mannosidosis is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. A blood test to measure beta-mannosidase enzyme activity in blood plasma or white blood cells (leukocytes) can reveal less activity than expected. A urine test (urinalysis) can show a higher amount of mannose-containing oligosaccharides in the urine. A diagnosis of beta-mannosidosis can be confirmed with molecular genetic testing.


Congenital bile acid synthesis defect

Although researchers have been able to establish clear syndromes with characteristic or core symptoms, much about bile acid synthesis disorders is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing these disorders prevent 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. Parents should talk to their children’s physician and medical team about their specific case, associated symptoms and overall prognosis.

Bile acid synthesis disorders are caused by mutations in specific genes. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body. In all known BASDs, these mutations are believed to be inherited in an autosomal recessive pattern.

Bile acid synthesis disorders affect males and females in equal numbers. Individuals of any race or ethnic group can be affected. The incidence and prevalence of BASDs are unknown. These disorders have been estimated to account for as many as 1-2% of all childhood cholestatic disorders. However, many cases go undiagnosed or misdiagnosed making it difficult to determine their true frequency in the general population. CTX has an estimated prevalence of 1 in 70,000 individuals in the general population. It is estimated that BASDs have prevalence of 1 in 50,000 in the general population.

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

A diagnosis of a bile acid synthesis disorder should be suspected in infants or young children who have jaundice, other symptoms of cholestatic liver disease with an unknown cause, or fat soluble vitamin deficiency and growth failure. The identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation can support a suspected diagnosis. However, symptoms of BASDs overlap with numerous other liver disorders. Confirmation of a BASD requires examination by tests performed at or assessed by specialized diagnostic laboratories.