Congenital myasthenic syndrome

The cardinal symptom of all myasthenic disorders is muscle weakness that is induced or worsened by exertion. This is referred to as fatigable weakness. In healthy people, physical activity causes a small decrease in the number of ACh quanta released from the nerve terminal that does not impair the safety margin of neuromuscular transmission, but it is incapacitating in myasthenic patients in whom the safety margin is already reduced.

Congenital myasthenic syndromes are caused by alterations (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.

A generic diagnosis of a CMS can be made on clinical grounds from a history of fatigable weakness involving ocular muscles, bulbar muscles (muscles of the face, and muscles used for speaking and swallowing), and limb muscles since infancy or early childhood, a history of similarly affected relatives, and a variety of tests.


Congenital Myopathy

The subtypes of CM have highly variable severity of muscle loss symptoms and differ in the age of onset.

There is still emerging research on the causes of CM and mutations in more than twenty genes have been associated with CM. Genes responsible for calcium ion balance in muscle cells have been implicated in some inherited forms of the disease. Calcium ion balance is important in muscle cells because calcium is a signal for muscle cells to contract. Other mutations described in CM patients occur in genes that lead to malformed filaments in muscle cells. These filaments are normally responsible for the contraction of muscles.

Congenital myopathy is an extremely rare disorder that generally affects males and females in equal numbers. There are subsets of centronuclear myopathy, i.e. XLMTM that affect males more than females.

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

Congenital hypotonia is a non-progressive neuromuscular disorder that is present at birth. This condition is characterized by decreased muscle tone or floppiness with no known cause or may be a symptom of another disorder. Newborns with this disorder have muscle weakness and generalized weakness. In many children, the symptoms improve as the child ages.

Adults with congenital myopathy should be encouraged to get adequate exercise and to avoid unhealthy dietary and sedentary habits that may lead to obesity. Affected adults may experience episodes of mild muscle weakness, but generally there are no major physical disabilities.


Congenital pulmonary lymphangiectasia

Congenital pulmonary lymphangiectasia (CPL) is a rare developmental disorder that is present at birth (congenital). Affected infants have abnormally widened (dilated) lymphatic vessels within the lungs. The lymphatic system helps the immune system in protecting the body against infection and disease. It consists of a network of tubular channels (lymph vessels) that drain a thin watery fluid known as lymph from different areas of the body into the bloodstream. Lymph accumulates in the tiny spaces between tissue cells and contains proteins, fats, and certain white blood cells known as lymphocytes.

Much of the older medical literature suggests that CPL has an extremely high mortality rate. However, recent studies suggest that the disorder does not have as poor a prognosis as described and that symptoms may improve with age in some cases.

The exact cause of CPL is unknown. Most cases occur randomly, for no apparent reason (sporadically). The disorder may be caused by a congenital defect in the development of the lung or result from obstruction of the lymph vessels in the lungs (pulmonary lymphatics). Some cases have been associated with genetic multisystem disorders including Noonan syndrome, Turner syndrome, Hennekam syndrome or Fryns syndrome. CPL may be inherited as dominant, recessive, or X-linked inheritance pattern.

According to some reports CPL occurs more often in males than females. However, the data is not conclusive and CPL may occur in males and females in equal numbers. The exact number of cases of CPL is unknown. In the past, the disorder was associated with high mortality in the newborn period. CPL was first described in the medical literature in 1856.

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

A diagnosis of CPL may be made based upon a thorough clinical evaluation, identification of characteristic symptoms and a variety of specialized imaging tests. These may include high resolution helical chest computed tomography (CT) scans. During CT scanning, a computer and x-rays are used to create a film showing cross-sectional images of an organ's tissue structure. In individuals with CPL, CT scans may reveal fluid build up in the chest cavity or lung tissue, showing the characteristic diffuse thickening of the interstitium. An imaging procedure called lymphoscintigraphy may be used to provide pictures of the lymphatic system, and it is very useful to detect diffuse aspects of congenital lymphatic dysplasia, such as lymphedema.


先天性蔗糖酶异麦芽糖酶缺乏

Congenital sucrase-isomaltase deficiency (CSID) is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. This enzyme complex (sucrase-isomaltase) assists in the breakdown of a certain sugars (i.e., sucrose) and certain products of starch digestion (dextrins). The sucrase-isomaltase enzyme complex is normally found within the tiny, finger-like projections (microvilli or brush border) lining the small intestine. When this enzyme complex is deficient, nutrients based on ingested sucrose and starch cannot be absorbed properly from the gut.

CSID is a rare inherited metabolic disorder characterized by the deficiency or absence of the enzymes sucrase and isomaltase. When the concentration of this enzyme complex is low or absent, the breakdown of the disaccharide sucrose and starch and the subsequent absorption of smaller molecular components cannot take place.

CSID is inherited as an autosomal recessive genetic trait. The faulty gene has been tracked to chromosome 3 (3q25-q26).

CSID is a metabolic disorder that affects males and females in equal numbers and is diagnosed in approximately 0.2 percent of North Americans. This disorder has a higher frequency among Greenland and Canadian Inuit populations, with a reported incidence of approximately 10 percent. In addition, researchers report a higher degree of homozygosity among these more frequently affected groups than among other groups. Also, as a diagnosis may be easily missed, especially in those individuals with mild symptoms, many researchers suspect there may be a higher incidence of this disorder than is actually reported in the medical literature.

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

Congenital lactase deficiency (lactose intolerance) is an extremely rare metabolic disorder characterized by the severe deficiency or absence of the enzyme lactase. This enzyme, found in the brush border membrane of the intestine, aids in the breakdown of the disaccharide lactose, found in mother’s milk. Symptoms appear within a few hours or days of birth and may include severe diarrhea with dehydration, malnutrition, undigested lactose in the stool, and/or excoriation of the skin of the buttocks. Research has shown that affected children exhibit normal progress in growth and development when kept on a lactose-free diet. In addition, an adult form of inherited lactase deficiency is quite common among the world’s population. Symptoms of this adult-onset disorder may include abdominal pain, abnormal amounts of gas or air in the digestive system (flatulence), and/or diarrhea. Both congenital and adult-onset lactase deficiency are inherited as autosomal recessive genetic traits.


Congenital syphilis

Congenital syphilis is a chronic infectious disease caused by a spirochete (treponema pallidum) acquired by the fetus in the uterus before birth. Symptoms of this disease may not become apparent until several weeks or months after birth and, in some cases, may take years to appear. Congenital syphilis is passed on to the child from the mother who acquired the disease prior to or during pregnancy. The infant is more likely to have congenital syphilis when the mother has been infected during pregnancy although it is not uncommon for an infant to acquire congenital syphilis from a mother who was infected prior to pregnancy. Symptoms of early congenital syphilis include fever, skin problems and low birth weight. In late congenital syphilis, the symptoms of the disease do not usually become apparent until two to five years of age. In rare cases, the disease may remain latent for years with symptoms not being diagnosed until well into adulthood.

Congenital syphilis is acquired by the fetus when the treponema pallidum spirochete is present in the mother. Pregnant women with syphilis may have a reduction in estrogen while serum progesterone levels may increase. Symptoms of early congenital syphilis usually appear at three to fourteen weeks of age but may appear as late as age five years. Symptoms may include inflammation and hardening of the umbilical chord, rash, fever, low birth weight, high levels of cholesterol at birth, aseptic meningitis, anemia, monocytosis (an increase in the number of monocytes in the circulating blood), enlarged liver and spleen, jaundice (yellowish color of the skin), shedding of skin affecting the palms and soles, convulsions, mental retardation, periostitis (inflammation around the bones causing tender limbs and joints), rhinitis with an infectious nasal discharge, hair loss, inflammation of the eye’s iris and pneumonia.

Congenital syphilis is a chronic infectious disease caused by the spirochete treponema pallidum and transmitted by an infected mother to the fetus in the womb. Adults transmit syphilis through sexual contact. (For information on syphilis in adults choose Syphilis as your search term in the Rare Disease Database).

In 1998, the National Syphilis Elimination Plan went into effect. One of the goals of this plan was to reduce the incidence of congenital syphilis (CS) to fewer than 40 cases per 100,000 live births. The incidence of congenital syphilis in newborns under a year old rose in the United States from 180 cases in 1957 to 422 cases in 1972. More recently there has been a dramatic increase of congenital syphilis, especially in urban areas, that has been attributed in part to crack cocaine use. In the year 2000, the incidence rate was about 13.4 per 100,000 live births, which represented about 529 cases.

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

Bejel, or endemic syphilis, is an infectious disease caused by an organism (treponema pallidum II) related to and identical in appearance to that causing venereal syphilis. This infection causes lesions of the skin and bone and is common among children in the Mediterranean countries of the Middle East, northern Africa, parts of eastern Europe, Arabia, subsaharan Africa, and Southeast Asia. In the United States, however, it is rare. Bejel is transmitted by physical, non-sexual contact and the sharing of eating and drinking utensils. (For more information on this disease choose Bejel as your search term in the Rare Disease Database)


Congenital tracheomalacia

Many patients with congenital tracheomalacia do not have symptoms. The most common symptoms include:

Congenital tracheomalacia can be associated with:

The prevalence of congenital tracheomalacia is roughly estimated to be around 1 in 2,100 livebirths. It is often associated with certain genetic conditions or structural birth defects (see Causes).

Tracheobronchomalacia – the cartilage of both the trachea and bronchi are weakened, causing them to collapse when exhaling

Congenital tracheomalacia is diagnosed by bronchoscopy to visualize the airway collapsing as the patient breathes. The patient is awake but numbed so they can take deep breaths during the procedure. Additional imaging may include a CT scan, a chest x-ray and/or an MRI to determine if a blood vessel is compressing the airway.

Since many cases of congenital tracheomalacia resolve before two years of age, the objective is to manage any symptoms by a multidisciplinary team of professionals. These therapies may include:


先天性纤溶酶原激活物抑制剂1型缺乏症

Congenital Type 1 Plasminogen Deficiency

The signs and symptoms of type 1 plasminogen deficiency can vary from one person to another, even among members of the same family with the same genetic variants and enzyme levels. Oftentimes, initial signs are present in infants or young children. Symptoms may be persistent and lifelong, may wax and wane or be intermittent or may not appear until later in life. Some individuals appear to remain asymptomatic and may be diagnosed based upon testing of clinically apparent family members. Lesions may develop spontaneously or be ‘triggered’ by infection, trauma or injury and may be localized to one area of the body or affect multiple body systems.

Congenital type 1 plasminogen deficiency is caused by changes (mutations or pathogenic variants) in the plasminogen (PLG) gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a pathogenic variant of a gene is present, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

Congenital type 1 plasminogen deficiency is a rare disorder that occurs worldwide. Slightly more females have been identified than males. The exact incidence or prevalence of the disorder is not completely established, but the current best estimate places the incidence at 1.6 people per 1,000,000 in the general population. Incidence is the rate of new or newly diagnosed people with a disorder. Prevalence is the overall number of people who have the disorder at a given time. People with no symptoms or a mild case with localized symptoms may remain undiagnosed.

A diagnosis of congenital plasminogen deficiency is based upon identification of characteristic symptoms, family medical history, detailed patient history and a thorough clinical evaluation. Some affected individuals may be identified due to another family member’s diagnosis even if they are without symptoms. Diagnosis is confirmed by specific laboratory tests that measure the activity and immunoreactive level (also called the antigen level) of plasminogen; the activity level is decreased while the immunoreactive level is normal or near normal. These tests are available in most clinical coagulation laboratories.


Congenital varicella syndrome

Congenital Varicella Syndrome is an extremely rare disorder in which affected infants have distinctive abnormalities at birth (congenital) due to the mother’s infection with chickenpox (maternal varicella zoster) early during pregnancy (i.e., up to 20 weeks gestation). Affected newborns may have a low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body. The range and severity of associated symptoms and physical findings may vary greatly from case to case depending upon when maternal varicella zoster infection occurred during fetal development.

Affected newborns may have low birth weight and characteristic abnormalities of the skin; the arms, legs, hands, and/or feet (extremities); the brain; the eyes; and/or, in rare cases, other areas of the body.  The range and severity of symptoms and physical findings may vary greatly from case to case depending upon when maternal chickenpox occurred during fetal development.  For example, while some affected infants may exhibit only characteristic skin and limb malformations, others may have only specific eye abnormalities (e.g., cataracts) and/or may experience symptoms associated with brain involvement.

Congenital varicella syndrome is an extremely rare disorder in which affected infants demonstrate distinctive abnormalities at birth due to the mother’s infection with chickenpox (maternal varicella zoster) early during pregnancy.

Congenital varicella syndrome is an extremely rare disorder that appears to affect male and female newborns in equal numbers.  Symptoms and physical characteristics associated with the disorder are apparent at birth.

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

A diagnosis of congenital varicella syndrome is usually suggested by confirmation of maternal varicella zoster infection early during pregnancy and the presence of certain characteristic symptoms and physical findings in the developing fetus or newborn.


X-连锁显性点状软骨发育不良

X-linked dominant chondrodysplasia punctata

The symptoms, progression and severity of Conradi-Hünermann syndrome can vary dramatically, even among members of the same family. The disorder can cause serious complications at birth or be so mild that individuals may not be identified until adulthood (usually after having a child with Conradi-Hünermann syndrome). It is important to note that individuals with Conradi-Hünermann syndrome may not have all of the symptoms discussed below. Individuals with Conradi-Hünermann syndrome should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. The classic symptoms of Conradi-Hünermann syndrome involve the skeleton, skin and eyes. Intelligence is usually unaffected.

Conradi-Hünermann syndrome is caused by particular changes that disrupt the function of the emopamil-binding protein (EBP) gene. This gene codes for a substance called 3β-hydroxysteroid-∆8,∆7- isomerase or sterol-∆8-isomerase, that works to excite a reaction (enzyme). This enzyme is important in the final steps of the production of cholesterol. Cholesterol is a waxy, fat substance that is present in all the cells of the body. Cholesterol is produced by our cells and obtained by the food we consume. Although too much cholesterol increases our risk for heart disease, cholesterol plays an important role in development before and after birth. The lack of cholesterol has been shown to disrupt certain molecular signaling that impacts the development of the limbs of a fetus. As a result of the dysfunction of sterol-∆8-isomerase, there is an accumulation of substances that precede cholesterol (precursor compounds) called sterols that accumulate and are toxic. How exactly the disruption of cholesterol production results in the signs and symptoms associated with Conradi-Hünermann syndrome are not fully understood.

Conradi-Hünermann syndrome is a rare disorder that almost exclusively affects females. The exact incidence of the disorder in the general population is unknown, but one estimate is that 1 in 100,000 to 1 in 200,000 individuals are born with Conradi-Hünermann syndrome. The disorder is often apparent at birth (congenital), but some individuals with mild cases may not be identified until adulthood.

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

A diagnosis of Conradi-Hünermann syndrome is based upon identification of characteristic symptoms, a detailed medical history, thorough clinical evaluation and a variety of specialized tests. X-ray (radiographic), eye (ophthalmologic), skin (dermatological), tissue examination (histological exam) and biochemical examinations may be performed to help diagnose Conradi-Hünermann syndrome.


自身免疫性间质性肺病-关节炎综合征

Autoimmune interstitial lung disease-arthritis syndrome

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about the disorder is not fully understood. Several factors including the small number of identified patients, the lack of large clinical studies, and the possibility of other genes or factors (e.g. environmental factors) influencing the disorder 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. Individuals and parents should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.

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

Initial reports have shown more females being affected than males. Larger groups of patients will need to be identified to confirm whether women are affected more often than men. Less than 100 families have been identified with this disorder in the medical literature, but the exact number of people who have this disorder is unknown. The low number of people identified with this disorder is because COPA syndrome was only first defined as a disorder in 2015, and genetic testing has only recently become available. In general, rare disorders often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. COPA syndrome is likely underrecognized and underdiagnosed.

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

A diagnosis of COPA syndrome is based upon identification of characteristic symptoms, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. Molecular genetic testing can confirm a diagnosis. Two findings that are suggestive of COPA syndrome are diffuse alveolar hemorrhaging and follicular bronchiolitis. Follicular bronchiolitis is when there is an overgrowth (hyperplasia) of lymphoid tissue within the small airways (bronchioles) of the lungs causing inflammation of those airways. Lymphoid tissue is the tissue in the body that produces white blood cells and antibodies.


Triatrial heart

Cor triatriatum is an extremely rare congenital (present at birth) heart defect. Normally, the human heart has four chambers of which two are the atria. These two are separated from each other by a partition (septum) called the atrial septum. The other two chambers, known as ventricles, are also separated by a septum. In cor triatriatum there is a small extra chamber above the left atrium of the heart. The pulmonary veins, returning blood from the lungs, drain into this extra third atrium. The passage of blood from the lungs into the heart (left atrium and ventricle) is slowed by this extra chamber. Cor triatriatum may eventually lead to features of congestive heart failure and obstruction over time.

The symptoms of cor triatriatum vary greatly, depending on the size of the opening between the extra chamber and the left atrium.  If the opening is small, symptoms usually develop early in infancy and probably will include abnormally rapid breathing (tachypnea), wheezing, coughing, and/or abnormal accumulation of fluid in the lungs (pulmonary congestion).  Progressive enlargement of the heart (cardiomegaly) occurs and often results in congestive heart failure along with abnormally high pressure within the artery that leads to the heart from the lungs (pulmonary artery).  Some newborns with cor triatriatum may also have abnormal heart sounds or heart murmurs.

The exact cause of cor triatriatum is not known.

Cor triatriatum is an extremely rare congenital heart condition that affects males and females in equal numbers.  In the USA, this disorder accounts for an extremely small percentage (0.1% to 0.4%) of all infants with congenital heart disease.

Symptoms of the following disorders can be similar to those of cor triatriatum.  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 side of the heart, and excessive blood flow to the lungs.  The symptoms, which may occur 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 of the blood system (embolism).  (For more information on this disorder, choose Atrial Septal Defects as your search term in the Rare Disease Database.)

Infants with cor triatriatum should be referred to a hospital that can perform sophisticated diagnostic procedures and cardiovascular surgery. Most patients with cor triatriatum will require surgery at a young age, usually before the age of one year.


Corneal Dystrophies

Corneal dystrophies are a group of genetic, often progressive, eye disorders in which abnormal material often accumulates in the clear (transparent) outer layer of the eye (cornea). Corneal dystrophies may not cause symptoms (asymptomatic) in some individuals; in others they may cause significant vision impairment. The age of onset and specific symptoms vary among the different forms of corneal dystrophy. The disorders have some similar characteristics – most forms of corneal dystrophy affect both eyes (bilateral), progress slowly, do not affect other areas of the body, and tend to run in families. Most forms are inherited as autosomal dominant traits; a few are inherited as autosomal recessive traits.

The symptoms of corneal dystrophies result from the accumulation of abnormal material within the cornea, the clear outer layer of the eye. The cornea serves two functions – it protects the rest of the eye from dust, germs and other harmful or irritating material, and it acts as the eye’s outermost lens, bending incoming light onto the inner lens, where the light is then directed to the retina (a membranous layer of light-sensing cells in the back of the eye). The retina converts light to images, which are then transmitted to the brain. The cornea must remain clear (transparent) to be able to focus incoming light.

Most cases of corneal dystrophy are inherited as an autosomal dominant trait with variable expressivity. 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.

Corneal dystrophies affect women and men in equal numbers, except for Fuchs corneal dystrophy which affects women about four times as often as men. The corneal dystrophies can affect individuals of any age. The incidence of corneal dystrophies is unknown. Because some individuals do not have symptoms (asymptomatic), determining the true frequency of these disorders in the general population is difficult.

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

The presence of a corneal dystrophy may be found incidentally during a routine eye examination. A diagnosis may be confirmed by a thorough clinical evaluation, a detailed patient history and a variety of tests, such as a slit lamp examination, in which a special microscope (slit lamp) allows a physician to view the eye through high magnification. Some specific corneal dystrophies can be diagnosed with molecular genetic tests even before symptoms develop.


Cornelia de Lange syndrome

Cornelia de Lange syndrome (CdLS) is a rare genetic disorder that is generally apparent at birth (congenital). Associated symptoms and findings typically include delays in physical development before and after birth (prenatal and postnatal growth delay); characteristic appearance of the head and facial (craniofacial) area, resulting in a distinctive facial appearance; malformations of the hands and arms (upper limbs); and mild to severe intellectual disability. Many infants and children with the disorder have an unusually small, short head (microbrachycephaly); a prominent vertical groove between the upper lip and nose (philtrum); a depressed nasal bridge; upturned nostrils (anteverted nares); and a small chin (micrognathia). Additional characteristic facial features may include thin, downturned lips; low-set ears; arched, well-defined eyebrows that grow together across the base of the nose (synophrys); an unusually low hairline on the forehead and the back of the neck; and curly, unusually long eyelashes. Affected individuals may also have distinctive malformations of the limbs, such as unusually small hands and feet, inward deviation (clinodactyly) of the fifth fingers, and webbing (syndactyly) of certain toes. Less commonly, there may be absence of the forearms, hands, and fingers. Infants with CdLS may also have feeding and breathing difficulties; an increased susceptibility to respiratory infections; a low-pitched growling cry and low voice; heart defects; delayed skeletal maturation; hearing loss; or other physical differences. The range and severity of associated symptoms and findings may be extremely variable from person to person.

CdLS is a very rare disorder characterized by growth delays; distinctive facial features; malformations of the hands, feet, arms, and/or legs (limb anomalies); other physical differences; intellectual disability and/or developmental delays. The range and severity of symptoms and physical characteristics may vary greatly from person to person.

CdLS can be inherited as an autosomal dominant condition or an X-linked condition. Most affected individuals have an abnormal gene as a result of a new gene mutation. Seven genes have been found to be associated with CdLS including the NIPBL gene on chromosome 5, the SMC1A gene on the X chromosome, the SMC3 gene on chromosome 10, the Rad21 gene on chromosome 8, the HDAC8 gene on the X chromosome, the ANKRD11 on chromosome 16 and the BRD4 gene on chromosome 19. Approximately 60% of those affected have a NIPBL gene mutation and a small percentage (about 10%) have mutations in the other genes. Other genes may be found to be associated with CdLS in the future.

CdLS is a very rare disorder that is apparent at birth (congenital). Males and females appear to be affected in equal numbers. It has been estimated that CdLS occurs in approximately one in every 10,000 live births in the United States. More than 400 cases have been reported in the medical literature, including affected individuals within several families (kindreds). Multiple affected siblings have been reported in some families. It is estimated that there is a 1-2 % rate of recurrence within affected families.

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

Coffin-Siris syndrome is an extremely rare genetic disorder that is present at birth (congenital). Infants with this disorder typically have underdeveloped (hypoplastic) or missing fifth fingers on both hands. The toenails may be underdeveloped or absent. Affected individuals may also exhibit characteristic abnormalities of the head and facial (craniofacial) area including a small head (microcephaly), broad nose, wide mouth with thick lips, low nasal bridge, widely-spaced eyes (ocular hypertelorism), droopy upper eyelids (ptosis), thick eyelashes, dental abnormalities and/or sparse scalp hair. During infancy, many affected individuals have feeding difficulties, vomiting, slow growth and/or frequent respiratory infections. During the first two years of life, developmental delays, unusually short stature, and varying degrees of intellectual disability may become apparent. Some children with Coffin-Siris syndrome may also have additional physical differences including abnormally loose joints (laxity) that may result in frequent dislocations, particularly of the elbows; mild to severe muscle weakness (hypotonia); motor delays; sideways curvature of the spine (scoliosis) and/or other skeletal, gastrointestinal, genitourinary and/or cardiac malformations. In some cases, Coffin-Siris syndrome may occur randomly, for no apparent reason (sporadically); in other cases, the disorder may be inherited as an autosomal recessive genetic trait. (For more information on this disorder, choose Coffin Siris as your search term in the Rare Disease Database.)


Costello syndrome

Costello syndrome is an extremely rare disorder that affects multiple organ systems of the body. This condition is characterized by growth delays after birth; short stature; extra loose skin on the neck, palms of the hands, fingers, and soles of the feet; noncancerous tumors (papillomata) around the face and anus; developmental delay and intellectual disability; and a characteristic facial appearance. Other physical features may include the development of dry hardened skin on the palms of the hands and the soles of the feet (palmoplantar hyperkeratosis), abnormally deep creases on the palms and soles, and/or abnormally flexible joints of the fingers (hyperextensible). There is an increased incidence of congenital abnormalities of the heart and thickening of the heart muscle called a cardiomyopathy. Characteristic craniofacial features may include an abnormally large head (macrocephaly); coarse facial features; unusually thick lips; and/or abnormally wide nostrils (nares). Affected individuals have an increased lifetime risk to develop specific malignant tumors. Costello syndrome is an autosomal dominant genetic condition caused by mutations in the HRAS gene.

Infants with Costello syndrome typically have a normal or high birth weight, but show poor sucking ability, have swallowing difficulties, and fail to grow and gain weight at the expected rate (failure to thrive). Growth delay after birth typically results in short stature during childhood and adulthood. Affected children may have developmental delay or mild to moderate intellectual disability. In some individuals, speech development and/or the ability to walk is significantly delayed. Children with Costello syndrome generally have warm, sociable personalities.

Costello syndrome is inherited as an autosomal dominant genetic condition and is caused my mutations in the HRAS gene. Mutations in this gene result in production of an abnormal H-Ras protein that leads to continuous cell growth and division.

Costello syndrome is a very rare disorder that affects males and females in relatively equal numbers. Approximately 350 affected individuals have been reported worldwide.

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

Cardiofaciocutaneous (CFC) syndrome is an extremely rare inherited disorder characterized by multiple defects that affect various parts of the body. The major features of this disorder include growth failure; characteristic facial appearance; sparse hair; variable skin disease; heart defects; and/or mild to moderate intellectual disability. Characteristic facial features may include an abnormally large head (macrocephaly) with a prominent forehead (frontal bossing), widely-spaced eyes (ocular hypertelorism), a short upturned nose, and/or unusually shallow eye socket ridges (hypoplastic orbital ridges). CFC syndrome is a dominant genetic disorder caused by a gene abnormality (mutation) in one of three genes named BRAF, MEK1 and MEK2. Some affected individuals do not have a mutation in one of these genes, suggesting that other genes are also associated with CFC. (For more information on this disorder, choose cardiofaciocutaneous as your search term in the Rare Disease Database.)


Craniofrontonasal dysplasia

Craniofrontonasal dysplasia (CFND) is a very rare inherited disorder characterized by body – especially facial – asymmetry, midline defects, skeletal abnormalities, and dermatological abnormalities. Major symptoms of this disorder may include widely spaced eyes (ocular hypertelorism), a groove (cleft) on the tip of the nose, an unusually wide mouth, malformations of the fingers and toes, and/or underdevelopment of portions of the face (midface hypoplasia), such as the forehead, nose, and chin. In addition, the head may have an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis). CFND is an X-linked genetic disorder that occurs mostly in females and is caused by a mutation in the EFNB1 gene.

The symptoms of CFND vary greatly in number and severity among affected individuals. The most common symptoms of this disorder include widely spaced eyes (ocular hypertelorism), a vertical groove (cleft) on the tip of the nose, shoulder and limb abnormalities and/or underdevelopment of the middle portion of the face (e.g., forehead, nose, and/or chin). The head typically has an unusual shape due to premature closure of the fibrous joints (sutures) between certain bones in the skull (coronal synostosis) resulting in facial asymmetry.

CFND is an X-linked disorder caused by a mutation in the EFNB1 gene. There have been at least 33 different mutations of the EFNB1 gene identified. All daughters of affected males are affected, consistent with X-linked inheritance.

CFND is a very rare genetic disorder that affects females more often than males. Females have a more severe form of the disorder.

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

Aarskog syndrome is an extremely rare genetic disorder marked by stunted growth that may not become obvious until the child is about three years of age, broad facial abnormalities, musculoskeletal and genital anomalies, and mild intellectual disability. Aarskog syndrome is inherited as an X-linked recessive genetic condition.  (For more information on this disorder, choose Aarskog as your search term in the Rare Disease Database.)


Congenital muscular dystrophy

CMD is often first noticed within the first few weeks of life. The early symptoms of CMD are difficulty eating and breathing.

CMD is a genetic condition caused by changes (mutations) in the genes ANKH or GJA1. The function of ANKH is to move a chemical called pyrophosphate in the body. The function of GJA1 is to create a passage for chemicals in the body between cells.

CMD is a very rare disorder. Males and females are affected equally. Little is known about how many people have CMD.

Pyle’s disease has features similar to CMD. Pyle’s disease is a disorder of the bones. Pyle’s disease and CMD both have widening of the long bones of the arms and legs. Persons with Pyle’s disease have wide collar bones (clavicle), ribs, or bones in the fingers and hands. These bones are usually not wide in persons with CMD. Pyle’s and CMD can have delayed presence of adult teeth. Pyle’s disease can also have misplacement of the teeth, muscle weakness, and pain in the joints.

A diagnosis of CMD can be made by an examination by a doctor familiar with craniofacial disorders. X-rays or other imaging are often required to diagnose and treat CMD. Genetic testing can also help diagnose CMD.


Craniopharyngioma

They are almost always benign but they can cause symptoms by compressing closely located important anatomical structures such as the pituitary gland, the hypothalamus, and the crossing of the two optic nerves (optic chiasm). Limb weakness (paresis), difficulty walking, seizures, and psychiatric symptoms such as paranoid delusions can also occur from compression of the brain. Another general consequence of tumor compression is a raise in intracranial pressure, which can cause symptoms such as headache and nausea. As craniopharyngiomas are difficult to treat and located in an anatomical location difficult to access and close to many important structures, patients can experience many symptoms that are related to the treatment of the disease rather than the disease itself.

Craniopharyngiomas are caused by malformations of embryonic tissue in the sellar and parasellar regions. Adamantinomatous craniopharyngioma, which occur mostly in children, and papillary craniopharyngioma, which occur mostly in adults, have different embryological origins.

Craniopharyngiomas occur in around 0.5 to 2 people per million each year and represent around 1.2 to 4% of all intracranial tumors in children. They mostly develop in two age groups (bimodal incidence peaks): children aged 0 to 14 years and adults aged 50 to 74 years. They occur in men and women equally. Adamantinomatous craniopharyngioma are more common, representing 86 to 89% of all craniopharyngiomas.

Disorders that can damage or compress structures in proximity to the sellar region, such as the pituitary gland, the hypothalamus, and the optic chiasm, can have clinical manifestations similar to those of a craniopharyngioma. Examples of entities that can lead to compression or damage include tumors, cysts, and blood vessel disruptions.

A diagnosis of craniopharyngioma is based on three main modalities: clinical history and physical exam, laboratory testing, and imaging.


X-连锁肌酸转运蛋白缺乏

X-linked creatine transporter deficiency

The severity of CTD varies from patient to patient. Global developmental delays affect all children with this disorder and may be the first sign, appearing before other symptoms. Intellectual disability of variable severity is typically present with prominent speech and language delay, autistic behavior and seizures.

CTD is caused by a change (called a variant or mutation) in the creatine transporter gene, SLC6A8. This mutation results in a block in the transport of creatine to the brain and muscle.

CTD is estimated to account for 1-2% of all unexplained X-linked intellectual disabilities. It is the most common of the three cerebral creatine deficiency syndromes.

Children with CTD often have autism or global developmental delays.

Testing in both urine and plasma is recommended by measuring the concentration of creatine (Cr), guanidinoacetate (GAA) and creatinine (Crn). A positive screen for CTD is based on normal plasma GAA and creatine, with abnormally elevated urine creatine being elevated (maybe normal in females).


Creutzfeldt-Jakob Disease

All types of Creutzfeldt-Jakob disease (CJD) are extremely rare degenerative brain disorders (i.e., spongiform encephalopathies), characterized by the sudden onset of cognitive impairments and neuromuscular symptoms. Specific signs and symptoms of each type are outlined below.

All types of CJD are caused by the presence of abnormal prion proteins in the brain. Abnormal changes in the prion protein are thought to play some role in causing deterioration in certain areas of the brain, appearing as sponge-like holes and gaps (thus, the term spongiform encephalopathy). Such spongiform deterioration in turn results in the progressive neurological and neuromuscular symptoms associated with CJD.

CJD affects males and females in equal numbers. It is rare, arising in approximately one to two individuals per million people each year.

Symptoms of the following disorders may be similar to those of Creutzfeldt-Jakob disease (CJD). Comparison may be useful for a differential diagnosis:


Wolf-Hirschhorn syndrome

The symptoms of cri du chat syndrome vary from case to case. The characteristic high-pitched, shrill cry associated with cri du chat syndrome is present during the first few weeks of life. The cry, which resembles the mewing of a cat, becomes less pronounced as affected infants grow older.

Cri du chat syndrome is a chromosomal disorder caused by a partial deletion (monosomy) of a varying length of the short arm (p) of chromosome 5. Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Pairs of human chromosomes are numbered from 1 through 22, and an additional 23rd pair of sex chromosomes which include one X and one Y chromosome in males and two X chromosomes in females. Each chromosome has a short arm designated p and a long arm designated q.

Cri du chat syndrome affects females more often than males. The incidence ranges from 1-15,000 to 50,000 live births. Some cases of cri du chat syndrome may go undiagnosed making it difficult to determine the true frequency of this disorder in the general population.

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

In newborns, the diagnosis of cri du chat syndrome is confirmed by a thorough clinical evaluation, identification of characteristic findings (e.g., cat-like cry) and chromosomal studies (karyotyping) that reveal a deletion on the short arm of chromosome 5. A specific test known as fluorescence in situ hybridization (FISH) may be used to confirm a diagnosis of cri du chat syndrome.


Crigler-Najjar syndrome

familial nonhemolytic unconjugated hyperbilirubinemia

The symptoms of Crigler-Najjar syndrome type I become apparent shortly after birth. Affected infants develop severe, persistent yellowing of the skin, mucous membranes and whites of the eyes (jaundice). These symptoms persist after the first three weeks of life.

Crigler-Najjar syndrome is caused by an alteration (mutation) in the UGT1A1 gene. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a mutation of a gene occurs, the protein product may be faulty, inefficient, or absent. Depending upon the functions of the particular protein, this can affect many organ systems of the body, including the brain.

Crigler-Najjar syndrome affects males and females in equal numbers. The incidence is estimated to be 1 in 750,000-1,000,000 people in the general population. Many researchers believe that the disorder often goes undiagnosed or misdiagnosed making it difficult to determine its true frequency in the general population. It is likely more common than estimated.

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

A diagnosis may be suspected within the first few days of life in infants with persistent jaundice. A diagnosis may be confirmed by a thorough clinical evaluation, characteristic findings, detailed patient history, and specialized testing. For example, in infants with this disorder, blood tests reveal abnormally high levels of unconjugated bilirubin in the absence of increased levels of red blood cell degeneration (hemolysis), as in Rh disease (isoimmunization). In addition, bile analysis reveals no detectable bilirubin glucuronides and urine analysis may demonstrate a lack of bilirubin.

Treatment is directed toward lowering the level of unconjugated bilirubin in the blood. Early treatment is imperative in Crigler-Najjar syndrome type I to prevent the development of kernicterus during the first few months of life. Because Crigler-Najjar syndrome type II is milder and responds to phenobarbital, treatment is different.


Cronkhite-Canada syndrome

allergic granulomatous angiitis of Cronkhite-Canada

Cronkhite-Canada syndrome (CCS) is an extremely rare disease characterized by various intestinal polyps, loss of taste, hair loss, and nail growth problems. It is difficult to treat because of malabsorption that accompanies the polyps. CCS occurs primarily in the older population (average age 59) and predominantly occurs in males. It is considered to be an acquired, not hereditary, disease.

The symptoms of Cronkhite-Canada syndrome occur because of multiple polyps occurring in the stomach, small intestine, colon and, less frequently, the esophagus. These include chronic or recurring watery diarrhea, cramps, and abdominal discomfort. These people may also have abnormally low levels of protein in the blood (protein-losing enteropathy), causing a feeling of general ill health (cachexia), malnutrition, nausea and vomiting.

The exact cause of Cronkhite-Canada syndrome is unknown. It seems to occur for no known reason (sporadically) and is not thought to be hereditary.

Cronkhite-Canada syndrome is an extremely rare disorder that affects males predominantly. (The ratio seems to be approximately 3 males to 2 females.) Typically, the age of onset is during the middle years or old age. The average is about 59 years with a range of 31 to 86 years. Worldwide, over 500 cases have been reported in the past 50 years, primarily in Japan but also in the United States and other countries.

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

Familial adenomatous polyposis (FAP) is a rare inherited cancer predisposition syndrome characterized by hundreds to thousands of precancerous colorectal polyps (adenomatous polyps) appearing on average at age 16 years. If left untreated, affected individuals inevitably develop cancer of the colon and/or rectum at a relatively young age. FAP is inherited in an autosomal dominant manner and caused by abnormalities (mutations) in the APC gene. (For more information on this disorder, choose FAP as your search term in the Rare Disease Database.)


Crouzon syndrome

Crouzon syndrome, also known as craniofacial dysostosis, is primarily characterized by premature closure of the fibrous joints (cranial sutures) between certain bones in the skull (craniosynostosis) and distinctive facial features. Cranial and facial malformations may vary, ranging from mild to potentially severe, including among members of the same family (kindred).

Crouzon syndrome is caused by changes (pathogenic variants or mutations) in one of the FGFR genes, most commonly FGFR2. Genes provide instructions for creating proteins that play a critical role in many functions of the body. When a variant in a gene occurs, the protein product may be faulty, inefficient or absent. Depending upon the functions of the protein, this can affect many organ systems of the body.

Crouzon syndrome affects males and females. Some articles in the medical literature report that males are affected more often than females. Crouzon syndrome is estimated to affect about 1.6 in 100,000 people in the general population. All forms of craniosynostosis are estimated to affect about 1 in 2,000-2,5000 live births.

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

Crouzon syndrome is usually diagnosed at birth or during infancy based upon a thorough clinical evaluation, identification of characteristic physical findings and a variety of specialized tests. Such testing may include advanced imaging techniques, such as computerized tomography (CT) scanning or magnetic resonance imaging (MRI) or other imaging studies.


Cryptococcosis

Cryptococcosis is caused by a fungus known as Cryptococcosis neoformans. The infection may be spread to humans through contact with pigeon droppings or unwashed raw fruit. Contact with an infected individual may also spread the infection. Individuals with disorders characterized by lowered immunity (for instance, HIV infection) are at high risk for contracting these infections.

The pulmonary forms of this disease include acute infections and chronic pulmonary infections.  The disseminated forms include central nervous system (brain) infections, cutaneous (skin) infections, and infections involving other organs or systems.

Cryptococcosis is caused by the fungus Cyptococcus neoformans.  It is spread by contact with pigeon droppings, unwashed raw fruit or by infected individuals.  People with immune deficiencies or lowered immunity (such as people undergoing cancer chemotherapy or organ transplants or those infected with HIV-AIDS) are at high risk for contracting this fungal infection.

Cryptococcosis occurs worldwide.  In the United States it occurs predominately in the Southeastern states and usually in adults aged forty to sixty years of age.  It tends to occur more often in males than females. Individuals with disorders involving reduced or impaired immunity to infection are particularly at risk.

Meningitis is a possible complication of cryptococcosis.  Meningitis is an inflammation of the membranes surrounding the brain and spinal cord.  There are many types of Meningitis, caused by many different infectious agents with the severity of infection ranging from mild to severe.

The diagnosis depends on proof of the presence of Cyptococcus neoformans in either a bodily fluid or body tissue. The presence of the fungus may be seen under a light microscope in some circumstances; other circumstances require growing the organism from samples of fluid taken from a patient. An immunological test designed to detect the substance that would be mobilized in the body to fight this fungus if it were present (antigen) is available in commercial kits.


严重智力障碍-进行性痉挛性截瘫综合征

Severe intellectual disability-progressive spastic diplegia syndrome

CTNNB1 neurodevelopmental disorder (CTNNB1-NDD)

CTNNB1 syndrome is a collection of signs and symptoms that can vary between affected individuals. 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.

CTNNB1 syndrome is caused by changes (pathogenic variants or mutations) in the CTNNB1 gene. Genes provide instructions for creating (encoding) proteins that play a critical role in many functions of the body. When a variation in a gene occurs, the protein that is created may be faulty, inefficient, absent or overproduced. Depending upon the functions of the protein, this can affect many parts of the body.

CTNNB1 syndrome is believed to affect females and males in equal numbers. The exact number of people who have this disorder is unknown. According to CTNNB1 Connect & Cure, as of March 2023, there are 300 individuals around the world known to have CTNNB1 syndrome. Rare disorders like CTNNB1 syndrome often go misdiagnosed or undiagnosed, making it difficult to determine their true frequency in the general population. As molecular genetic testing becomes more widely used, it is estimated that approximately 3 individuals in every 100,000 births may be affected by CTNNB1 syndrome.

Clinical features of the following disorders can be similar to those of CTNNB1 syndrome. Comparisons may be useful for a differential diagnosis.

A diagnosis of CTNNB1 syndrome is based on characteristic clinical features, a detailed patient and family history, a thorough clinical evaluation and a variety of specialized tests. No formal clinical diagnostic criteria have been established for CTNNB1 syndrome. A diagnosis can only be made through molecular genetic testing.


Cushing Syndrome

People with Cushing syndrome gain an excessive amount of weight. Obesity extends to include fat deposits around the face causing a moon-shaped or rounded appearance. Fat also accumulates around the neck (supraclavicular) and upper back (dorsal cervical) areas. Obesity also occurs in the trunk of the body (centripetal obesity), but the arms and legs remain slender. People with Cushing syndrome may have skin that is reddened, thin, fragile and slow to heal. The connective tissue may also become weak, resulting in the appearance of reddish-blue stretch marks on the arms, breasts, underarms (axillae), abdomen, buttocks and/or thighs.

Cushing syndrome is a rare endocrine disorder caused by abnormally excessive amounts of the hormone cortisol.

Many cases of Cushing syndrome are due to exogenous corticosteroid medication. It is reported that the incidence of endogenous Cushing syndrome is approximately 13 per million people annually.

The following disorders can have symptoms similar to those of Cushing syndrome, even though people with these disorders do not have abnormally elevated cortisol levels. Comparisons may be useful for a differential diagnosis:

Polycystic ovary syndrome (PCOS) is characterized by absent or irregular menstruation, excessive hair on the face and/or body (hirsutism), weight gain, acne, male pattern balding and impaired insulin action and diabetes mellitus.


Cutaneous T-Cell Lymphomas

The signs and symptoms associated with cutaneous T-cell lymphomas vary greatly from case to case, depending upon the specific type of lymphoma present and how far the disease has progressed (i.e., staging). (For further information on stages, please see the section entitled Standard Therapies: Diagnosis [Staging] below.)

The exact underlying cause of cutaneous T-cell lymphomas is unknown. Researchers speculate that genetic and immunologic abnormalities, environmental factors (e.g., exposure to ultraviolet rays, certain chemicals, ionizing radiation [carcinogens]; certain viral infections; bacterial skin infections, etc.), diet, stress, and/or additional factors may play varying contributing roles in causing specific types of cancer. Investigators at the National Institutes of Health (NIH)/National Cancer Institute, across the United States, and around the world are conducting ongoing basic research to learn more about the many factors that may result in cancer. (The National Cancer Institute is listed in the Resources section of this report below.)

According to the medical literature, CTCL affects males twice as often as females. In the majority of cases, diagnosis is made between 40 and 60 years of age. One study estimated that from .5 to 5 percent of all CTCLs occur in children. CTCLs occur twice as often in individuals of African-American descent as in individuals of European or Asian descent.

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

A variety of disorders are associated with CTCL, including small plaque parapsoriasis, large plaque parapsoriasis (poikiloderma atrophicans vasculare) and follicular (alopecia) mucinosa. Significant debate exists in the medical literature as to whether these disorders are distinct premalignant conditions or early forms of CTCL. Individuals with these disorders have a greater chance than the general population of developing CTCL later during life. Approximately 10-30 percent of cases of large plaque parapsoriasis progress to CTCL.


Cutis Laxa

Cutis laxa encompasses a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of cutis laxa and the presence and extent of associated symptoms. The specific symptoms and severity can vary even among individuals with the same subtype and even among members of the same family. In addition, some subtypes of cutis laxa have only been reported in a handful of individuals, which prevents 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. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis. Despite the wide variety in presentation, most affected individuals develop the characteristic skin abnormalities and joints problems described above.

Cutis laxa is 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. For disorders classified as cutis laxa, these mutations can be inherited in an autosomal recessive or autosomal dominant trait.

Cutis laxa is a rare disorder that affects males and females in equal numbers. The disorder has been reported in approximately 400 families worldwide. Cutis laxa is estimated to affect 1 in 1,000,000 individuals in the general population. However, because cases may go misdiagnosed or undiagnosed determining the true frequency of cutis laxa in the general population is difficult. Cutis laxa affects individuals of all races and every ethnic group.

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

A diagnosis of cutis laxa is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories.


先天性毛细血管扩张性大理石样皮肤

Cutis Marmorata Telangiectatica Congenita

Cutis marmorata telangiectatica congenita (CMTC) is a rare congenital (present at birth)disorder characterized by discolored patches of skin caused by widened (dilated) surface blood vessels. As a result, the skin has a purple or blue marbled or fishnet appearance (cutis marmorata). In some affected individuals, ulcerations or congenital skin defects (aplasia cutis) can be present. The latter association can be part of Adams-Oliver syndrome. Additional associated abnormalities have been reported including pink or dark red, irregularly shaped patches of skin (nevus flammeus); loss of muscle tissue (wasting) on one side of the body (hemiatrophy); elevated fluid pressure within the eye (glaucoma); and/or undergrowth (hypotrophy) of one leg. However, many if not all of those cases represent forms of Klippel-Trenaunay syndrome or related disorders, in particular Cowden’s disease. The most common association of true CMTC is with soft tissue (subcutaneous fat and muscle) hypoplasia. The disorder formerly known as macrocephaly-cutis marmoratatelangiectatica congenital (M-CMTC) is a distinct genetic disease and is now called macrocephaly-capillary malformation (M-CM/MCAP) Virtually all cases of CMTC occur randomly for no apparent reason (sporadically). It is thought that CMTC represents a form of genetic mosaicism.

The symptoms of CMTC are present at birth (congenital). Affected infants have discolored patches of skin caused by widened (dilated) surface blood vessels (livedoreticularistelangiectases). The affected areas of skin have a marbled or fishnet appearance (cutis marmorata). In most cases, skin abnormalities affect the arms and legs (limbs), although the trunk may also be involved. Facial involvement is very rare. The skin symptoms associated with classical CMTC improve with age and usually disappear completely around puberty. Atrophic patches may remain. The soft tissue hypoplasia can likewise remain present, in particular if muscles are affected. This has no consequences for normal functionality. In an affected leg, the greater saphenous vein may be too wide. It is not yet known whether this will lead to venous insufficiency later in life.

The exact cause of CMTC is not known. Most cases occur randomly, for no apparent reason (spontaneously). Researchers believe that the disease results from genetic mosaicism. One theory suggests that abnormal pericyte recruitment can cause skin capillaries to contract inappropriately. In a few rare cases, it has appeared that CMTC may occasionally run in families (familial cases).

CMTC affects males and females in equal numbers and is present at birth (congenital). Fewer than 300 cases of CMTC have been reported in the medical literature. Since many cases of CMTC are mild and clear up without treatment, the disorder may be under-diagnosed making it difficult to determine the true frequency of CMTC in the general population.

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

Cutis marmorata is a transient skin disorder in which the skin has a bluish red marbling pattern when exposed to cold temperatures. This condition is found most often in infants but may also affect adults. When the skin is warmed the condition disappears. Cutis marmorata is very common in premature infants and usually disappears completely at two months of age. Cutis marmorata may occur in conjunction with other syndromes but is not diagnostic.


Cyclic Vomiting Syndrome

Cyclic vomiting syndrome (CVS) is an uncommon disorder affecting both children and adults and characterized by recurrent episodes of severe nausea and vomiting. An episode may last for a few hours to several days and is then followed by a period of time during which affected individuals are relatively free of severe nausea and vomiting. Some can experience milder symptoms between attacks. This alternating pattern of disease and disease-free periods distinguishes cyclic vomiting syndrome from other gastrointestinal disorders. For each person who suffers from this condition, the episodes are similar to each other. The associated nausea and vomiting can be severe enough to incapacitate the individual who may be unable to walk or talk and/or be bedridden. Additional symptoms often present during an episode including dizziness, paleness of the skin (pallor), lack of energy (listlessness) and, abdominal pain and headaches. Oftentimes, nausea is the most disturbing symptom, more so than vomiting. Some affected children outgrow these episodes as they get older but for many others, CVS transitions into migraine headache. Cyclic vomiting syndrome may affect children more often than adults. The exact causes of cyclic vomiting syndrome remains unknown in many people, but a cause or risk factors can be determined in many others.

The hallmark of cyclic vomiting syndrome is recurrent episodes of severe nausea and vomiting. In children, these episodes usually last for several hours to a few days. In adults, episodes tend to occur less frequently, but can last longer, even over a week. These recurrent, characteristic episodes are quite similar within each individual, often beginning at the same time of day, with similar severity, duration and associated symptoms as in previous episodes. Episodes often occur in the early morning hours or upon awakening in the morning. Affected individuals may only experience episodes several times a year or as frequently as several times a month. On occasion, after years of cycling, episodes can coalesce together with daily nausea and vomiting between severe attacks such that there is no symptom-free period.

Although nausea and vomiting are the main features of cyclic vomiting syndrome, researchers now believe that the primary system affected is the nervous system, including the brain and peripheral nerves. There are more nerve cells (neurons) in the abdomen than in the head, and symptoms of the disorder develop due to abnormalities in the normal interaction between neurons in the brain and in the gut (thus, brain-gut disorder).

Cyclic vomiting syndrome affects females somewhat more often than males (55:45). It most commonly occurs in children between the ages of three and seven, although it can begin at any age, from early infancy through to old age (73 is the oldest reported). Because CVS it is sometimes not recognized or misdiagnosed as stomach flu, a correct diagnosis is often delayed for many years. Although CVS is found more often in children, it is being recognized with greater frequency in adults. The incidence of CVS is unknown, although it is not rare. Two studies in Scotland and Australia have suggested that as many as 2% of all Caucasian school-aged children suffer from CVS. However, researchers believe the disorder is underdiagnosed, making it difficult to estimate its true frequency in the general population.

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

A diagnosis of cyclic vomiting syndrome may be suspected based upon a thorough clinical evaluation with the identification of characteristic findings. Diagnostic criteria are currently based upon the consensus criteria of the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition and the Rome IV Committee. The determination of CVS can only be made after other causes of recurrent vomiting have been ruled out. There is no test to prove the presence of cyclic vomiting syndrome, although the presence of urine ketosis early in an episode may be helpful. A variety of tests of may be used to rule out other causes of recurrent nausea and vomiting. In particular, it is important to rule out a physical/structural blockage of the intestines, including malrotation, with an upper gastrointestinal series of radiographs. Standard blood chemistries testing is important to detect abnormal levels of sodium and potassium (electrolytes) and well as pancreatitis (lipase).


Cystic fibrosis

Cystic fibrosis is a genetic disorder that often affects multiple organ systems of the body. Cystic fibrosis is characterized by abnormalities affecting certain glands (exocrine) of the body especially those that produce mucus. Saliva and sweat glands may also be affected. Exocrine glands secrete substances through ducts, either internally (e.g., glands in the lungs) or externally (e.g., sweat glands). In cystic fibrosis, these secretions become abnormally thick and can clog up vital areas of the body causing inflammation, obstruction and infection. The symptoms of cystic fibrosis can vary greatly in number and severity from one individual to another. Common symptoms include breathing (respiratory) abnormalities including a persistent cough, shortness of breath and lung infections; obstruction of the pancreas, which prevents digestive enzymes from reaching the intestines to help break down food and may result in poor growth and poor nutrition; and obstruction of the intestines. Cystic fibrosis is slowly progressive and often causes chronic lung damage, which eventually results in life-threatening complications. Because of improved treatments and new treatment options, the outlook and overall quality of life of individuals with cystic fibrosis has improved and over 50 percent of individuals with the disorder are adults. Cystic fibrosis is caused by mutations to the cystic fibrosis transmembrane conductance regulator (CFTR) gene and is inherited as an autosomal recessive trait.

The symptoms of cystic fibrosis result because mucus secretions are abnormally thick and sticky, whereas normally they are thin and slippery and serve as a protective lubricant. Other secreted material such as saliva, sweat and digestive juices may also be affected. These abnormal secretions can clog up vital tubes, ducts and passageways throughout the body.

Cystic fibrosis is caused by mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. This defective gene 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.

Cystic fibrosis is the most common, life-limiting recessive genetic disorder in Caucasians. Approximately 30,000 people have cystic fibrosis in the United States. One thousand new cases are diagnosed each year, with males and females affected in equal numbers. The disorder occurs predominately among Caucasians, occurring in approximately one of every 3,200 live Caucasian births compared to one in 3,900 live births of all Americans. Among African Americans, CF is manifest in about one in 15-17,000 live births. There is also a small but significant number of Americans of Asian descent who are affected by the disorder.

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

A diagnosis of cystic fibrosis may be suspected based upon newborn screening, identification of characteristic symptoms (e.g., pulmonary disease, pancreatic insufficiency) or a positive family history. The standard diagnostic test for cystic fibrosis is the sweat test, a painless and simple procedure that measures the amount of salt in the sweat. Genetic testing can identify carriers of the defective gene. In May 2005, the U.S. Food and Drug Administration (FDA) approved the first DNA-based blood test to help detect cystic fibrosis. The Tag-It Cystic Fibrosis Kit directly analyzes human DNA to find genetic variations indicative of the disease. All 50 States have newborn screening for CF. In most states, immunoreactive trypsinogen (IRT) assays are performed on dried blood spots from newborns. Trypsinogen is synthesized in the pancreas and IRT levels are elevated in CF. Abnormal IRT results are followed up with sweat testing and/or molecular genetic (DNA-based) testing to confirm the diagnosis.


Cysticercosis

Symptoms usually appear years after becoming infection with the eggs of the pork tapeworm (T. solium). Symptoms may last for many years if medical treatment is not received.

Cysticercosis is an infection in both humans and pigs. Pigs acquire the infection through the ingestion of segments of the pork tapeworm (proglottids), infected human feces, or food contaminated by infected human feces. Following ingestions, the embryos hatch in the small intestine, get into the blood stream, and travel through the pig’s body to the brain, muscle, and/or other tissues. After three to eight weeks, a fluid filled cyst with an invaginated scolex (tissue cysticerci) develops in the tissue where the embryo travelled.

Cysticercosis can affect anyone at any age and affects males and females in equal numbers. Cysticercosis is most seen in endemic regions (Central and South America, sub-Saharan Africa, and Asia (including China, southeast Asia, and India)), where 10 to 20 percent of individuals have evidence of the disease. Within these endemic regions, cysticercosis is most common in rural areas, where pigs roam freely and eat human feces, and where sanitary conditions are less than optimal. Cysticercosis can also be found in non-endemic regions, especially where there are high numbers of immigrants, or in people who have traveled to endemic regions and to countries where sanitation may be substandard and where the water supply may be unsafe. Individuals with no history of pork consumption or travel to endemic areas can also develop cysticercosis, via household contacts of people with an adult pork tapeworm infection (taeniasis).

Tapeworms can be acquired from various uncooked meats, including beef and fish, but only pork tapeworms appear to produce larvae capable of invading human muscle and forming cysts.

Cysticercosis should be suspected in individuals with seizures and/or symptoms of increased pressure in the brain (increased intracranial pressure). The diagnosis of cysticercosis is made based on the combination of characteristic signs and symptoms obtained via a detailed patient history, neuroimaging findings, and exposure to risk factors, such as living in an endemic region, household exposure to a carrier of the adult pork tapeworm infection (taeniasis), or a history of prolonged travel or residence in an endemic region. Neuroimaging studies should include computed tomography (CT), and magnetic resonance imaging (MRI). A special blood test that looks at the immune system (serologic testing with enzyme-linked immunotransfer blot) is recommended as a confirmatory test in people who are suspected of having neurocysticercosis. Very rarely, if the neuroimaging and serology are unable to make the diagnosis, a piece of the suspected infected brain tissue is taken (biopsy) and examined by a specialist (pathologist) to look for neurocysticercosis.


Cystinosis

At one time, nephropathic cystinosis was fatal at a very young age. However, improvements in kidney transplantation and the development of a medication known as cysteamine (which lowers the levels of cystine in the cells of the body) have transformed cystinosis from a fatal kidney disorder to a chronic, multisystem disorder with a life expectancy well into adulthood.

All types of cystinosis are caused by disease-causing variants in the CTNS gene. The CTNS gene contains instructions for producing (encoding) a protein called cystinosin that is required to transport the amino acid cystine out of lysosomes and into the rest of a cell. Lysosomes break down (degrade) certain proteins into their component amino acids such as cystine. Cystine is then transported out of the lysosome by cystinosin. Deficient levels of functional cystinosin result in the accumulation of cystine in the lysosomes of various tissues and organs of the body, eventually damaging the affected organs. The accumulated cystine forms crystals in many cell types.

Cystinosis affects males and females in equal numbers. The disorder is estimated to occur in 1 in 100,000-200,000 people in the general population. Cystinosis has been reported worldwide, in all ethnic groups. Cystinosis is the most common cause of renal Fanconi syndrome in children and accounts for approximately 5 percent of all childhood cases of kidney failure.

Many different disorders can cause renal Fanconi syndrome in children including Lowe syndrome, Wilson disease, tyrosinemia type I, galactosemia and glycogen storage diseases. Additional disorders that may have symptoms similar to those found in cystinosis include Bartter’s syndrome and diabetes insipidus. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)

A diagnosis of cystinosis is based upon identification of characteristic symptoms (e.g., symptoms of renal Fanconi syndrome), a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. A prompt diagnosis of cystinosis is critical to maximize the preventive and therapeutic benefits of cystine depleting medications.


Cystinuria

Cystinuria is an inherited metabolic disorder characterized by excessive amounts of undissolved cystine in the urine, as well as three chemically similar amino acids: arginine, lysine, and ornithine. Excess cystine in the urine can lead to the formation of crystals and stones (calculi) in the kidney, bladder, and/or urinary tract (ureters). Some people with cystinuria do not form stones, while others frequently form stones.

People with cystinuria excrete abnormally high levels of cystine in the urine. The level of cystine is so high that it remains undissolved in the urine. The amino acids lysine, arginine, and ornithine are also excreted in massive amounts by people with this disorder, but they dissolve more readily in the urine and are not associated with any particular symptoms.

Cystinuria is caused by changes (mutations) in the SLC3A1 and SLC7A9 genes. These mutations result in the abnormal transport of cystine in the kidney and this leads to the symptoms of cystinuria.

Cystinuria is an inherited metabolic disorder that affects males and females in equal numbers. Symptoms of this disorder typically begin between 10 and 30 years of age, although elevated cystine excretion may be found in infancy. The disorder occurs in approximately 1 in 7,000 to 1 in 10,000 people in the United States. The prevalence of cystinuria varies in different countries.

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

Kidney stones are hard deposits of minerals and salts that form inside the kidneys. Kidney stones form when urine contains more crystal-forming substances such as calcium, oxalate and uric acid than the fluid in the urine can dilute. Signs and symptoms of kidney stones can include severe, sharp pain in the side and back, below the ribs; pain that radiates to the lower abdomen and groin; pain that comes in waves and fluctuates in intensity; and pain or burning sensation while urinating.

The primary objective of treatment for cystinuria is to reduce the cystine concentration in the urine. Consumption of large amounts of fluid both day and night maintains a high volume of urine and reduces cystine concentration in the urine. Making the urine more alkaline (alkalization) helps cystine to dissolve more readily in the urine and may also prevent the formation of stones. Drugs that may be prescribed to make the urine more alkaline include potassium citrate and acetazolamide. This treatment is accompanied by dietary salt and animal protein restriction.


Cytochrome C Oxidase Deficiency

孤立性细胞色素C氧化酶缺乏症

Cytochrome C Oxidase deficiency is a very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome C oxidase (COX), or Complex IV, an essential enzyme that is active in the subcellular structures that help to regulate energy production (mitochondria). Deficiency of COX may be limited (localized) to the tissues of the skeletal muscles or may affect several tissues, such as the heart, kidney, liver, brain, and/or connective tissue (fibroblasts); in other cases, the COX deficiency may be generalized (systemic). Four distinct forms of Cytochrome C Oxidase deficiency have been identifed. The first form of this disorder is known as COX deficiency, benign infantile mitochondrial myopathy. Affected infants exhibit many of the same symptoms as those with the more severe infantile form of the disease; however, because the COX deficiency is limited (localized) to tissues of the skeletal muscles, they typically do not have heart or kidney dysfunction.

Cytochrome C Oxidase (COX) deficiency is a very rare inherited metabolic disorder characterized by a deficiency of the enzyme cytochrome C oxidase or Complex IV. Cytochrome C oxidase is an essential enzyme that is active in subcellular structures that help to regulate energy production (mitochondria). Four distinct forms of Cytochrome C Oxidase deficiency have been identified. The range and severity of symptoms varies greatly from case to case.

Researchers believe that most cases of Cytochrome C Oxidase deficiency are inherited in an autosomal recessive pattern. (For example, research seems to indicate that COX deficiency French-Canadian type has a recessive mode of inheritance.) Human traits, including the classic genetic diseases, are the product of the interaction of two genes, one received from the father and one from the mother.

Cytochrome C Oxidase (COX) Deficiency is a very rare metabolic disorder that appears to affect males and females in equal numbers. The overall incidence rates of various forms of the disorder (i.e., infantile mitochondrial myopathic forms and Leigh’s disease) are unclear. However, COX deficiency French-Canadian type has been reported in the French-Canadian population of the Saguenay-Lac-Saint-Jean region of northeastern Quebec with an estimated incidence of 1 in 2,473 births.

Symptoms of the following disorders may be similar to those of Cytochrome C Oxidase deficiency. Comparisons may be useful for a differential diagnosis:

MELAS syndrome, one of a group of rare disorders known as mitochondrial encephalomyopathies, is characterized by recurring, stroke-like episodes in which there are sudden headaches followed by vomiting and seizures. Short stature, an accumulation of lactic acid in the blood (lactic acidosis), and muscular weakness on one side of the body (hemiparesis) are typically present. Visual symptoms may include impaired vision or blindness in one half of the visual field (hemianopsia) and/or blindness due to lesions in the area of the brain involved with vision (cortical blindness). MELAS syndrome is thought to be inherited due to abnormal changes in genetic material (mutation) found within mitochondria (mtDNA). (For more information on this disorder, choose MELAS as your search term in the Rare Disease Database.)


Cytomegalovirus Infection

特发性播散性巨细胞病毒感染

Cytomegalovirus infection (CMV) is a viral infection that rarely causes obvious illness. The virus that causes CMV is part of the herpes virus family and, like other herpes viruses, may become dormant for a period of time and then be reactivated. CMV affects young children mainly, but it is estimated that by age 30 in the United States, half of all adults are, or have been, infected. The virus can pass from an infected, pregnant mother to her child through the shared blood supply (umbilical cord).

Most of those who are infected with CMV (children or adult) do not develop symptoms.  When symptoms are present, there may be a great range in the type and severity of symptoms experienced.  Among the 10 to 20% of infants who do have symptoms, they may range from such benign signs as the presence of CMV in the urine to dangerous conditions such as hemorrhagic anemia, liver damage and central nervous sytem (CNS) damage.

Cytomegalovirus infection is caused by the human cytomegaloviruses (also known as salivary gland viruses). These are a subgroup of infective agents closely related to the herpes group of viruses.  Like other herpes viruses, they may remain latent for years in people.

Cytomegalovirus infection has increased in the United States in recent years, possibly because of the increased use of daycare facilities.  Recent studies of the percent of children with CMV virus in daycare facilities compared to the percent of children with CMV who are cared for at home found that about 60% of the children in daycare facilities have CMV compared to only 20% of the children cared for at home.  If a woman is infected during pregnancy, fetal infections known as cytomegalic inclusion disease (CID) can occur.

The CMV virus is closely related to the herpes group of viruses.  (For more information on Cytomegalovirus Infection and other herpes viruses, use CMV and Herpes as your search terms in the Rare Disease Database.)

CMV infections can be controlled by drug therapy but, as yet, cannot be cured. Two drugs that keep the infection from getting worse are ganciclovir and foscarnet. These are delivered intravenously, and treatment must continue over a long period of time. A tablet form of ganciclovir, approved for CMV infections of the eye, has become available.


Dandy Walker Malformation

Dandy-Walker malformation (DWM) is a brain malformation that occurs during embryonic development of the cerebellum and 4th ventricle. The cerebellum is the area of the brain that helps coordinate movement, and is also involved with cognition and behavior. The 4th ventricle is a space around the cerebellum that channels fluid from inside to around the outside of the brain. DWM is characterized by underdevelopment (small size and abnormal position) of the middle part of the cerebellum known as the cerebellar vermis, cystic enlargement of the 4th ventricle and enlargement of the base of the skull (posterior fossa). DWM is sometimes (20-80%) associated with hydrocephalus, in which blockage of the normal flow of spinal fluid leads to excessive amounts of fluid accumulating in and around the brain. This leads to abnormally high pressure within the skull and swelling of the head, and can lead to neurological impairment.

The symptoms of Dandy Walker syndrome typically include developmental delay, low tone (hypotonia) or later high tone (spasticity), poor coordination and balance (ataxia), and sometimes enlarged head circumference and increased pressure within the skull due to hydrocephalus.  Mental retardation occurs in fewer than half, most often in those with severe hydrocephalus, chromosome abnormalities or other birth defects. Seizures occur in 15-30% of those affected.   Respiratory control centers in the brainstem are sometimes affected and can lead to respiratory failure, again most likely with severe hydrocephalus.  The age at diagnosis varies depending on the onset and severity of hydrocephalus, and presence of other birth defects or medical problems.

DWM results from defects in early embryonic development of the cerebellum and surrounding structures.  A few patients have chromosome abnormalities including deletion of chromosome 3q24.3 (the location of the first DWM genes, known as ZIC1 and ZIC4), 6p25 or 13q32.2-q33.2, or duplication of 9p.  In the remainder, it is probably due to other more complex genetic and perhaps environmental factors (teratogens) as the recurrence risk in siblings less than 5%.  A few examples of affected siblings with isolated Dandy-Walker malformation have been reported, suggesting autosomal recessive or X-linked inheritance, but most of these are probably CVH and not typical DWM.  In these families, the recurrence risk is higher, up to 25%.  DWM may also occur as part of a genetic syndrome that includes multiple birth defects, such as the PHACES syndrome of facial hemangioma, heart and sternal defects and DWM.  Many other syndromes and chromosome abnormalities have been reported with DWM, but most of these appear to have CVH rather than typical DWM.

The frequency of Dandy Walker malformation in the US is approximately 1 per 25,000 -35,000 live births and affects more females than males.

Symptoms of the following disorders can be similar to those of Dandy-Walker malformation.  Comparisons may be useful for a differential diagnosis:

Hydrocephalus is a condition in which abnormally widened (dilated) cerebral spaces in the brain (ventricles) inhibit the normal flow of cerebrospinal fluid (CSF). The cerebrospinal fluid accumulates in the skull and puts pressure on the brain tissue. An enlarged head in infants and increased cerebrospinal fluid pressure are frequent findings but are not necessary for the diagnosis of hydrocephalus. There are several different forms of hydrocephalus: communicating hydrocephalus, non-communicating hydrocephalus or obstructive hydrocephalus, internal hydrocephalus, normal pressure hydrocephalus, and benign hydrocephalus.  (For more information on this disorder, choose hydrocephalus as your search term in the Rare Disease Database.)


Danon disease

LAMP2缺乏所致糖原贮积病

Danon disease is a rare genetic disorder characterized by an X-linked dominant inheritance pattern, so males are more severely affected than females. Among boys, the key features are diseased heart muscle (cardiomyopathy), weakness of the body muscles (skeletal myopathy) and intellectual disability ranging from mild learning problems to overt intellectual disability. In many males, the disease progresses until a heart transplant is required or death occurs in the second to third decade of life. Females are also affected, although usually more mildly, and often onset is delayed until they reach adulthood. However, some females will progress to being considered for cardiac transplantation during their second decade of life, similar to what is observed in males. Other features include heart arrhythmias, which can lead to a need for medications or a pacemaker, and eye disease affecting the retina; the retinal disease does not always affect vision, especially early in the disease. Danon disease is not usually evident at birth unless blood tests are done in a suspected case (i.e., a son born to a mother known to have the disease).

Symptoms of Danon disease vary from person to person and depend on gender. Boys usually show early signs of muscle problems (difficulty sitting or walking), and motor skills may be awkward or delayed. Intellectual disability is usually noticed by parents and/or teachers and can be quite mild. The development of heart disease can lead to further fatigue and shortness of breath. Visual complaints are also prevalent with serious color vision disturbances and near-complete loss of retinal pigment in some patients.

Danon disease is caused by a change (mutation or variant) in a gene called LAMP2. To date, there are over 160 different variants in the LAMP2 gene identified in case reports and databases that could lead to Danon disease. Variants that lead to a complete absence of the LAMP2 protein have been shown to be most detrimental in terms of prognosis. Other variants that lead to a partial LAMP2 protein deficiency maybe less severe clinically.

At present, it is thought that Danon disease can affect all ethnic populations. The prevalence of Danon disease is unknown but may be rising due to increased detection from wider availability of LAMP2 gene testing. Histories of affected patients at birth are usually normal. As discussed, males are more severely affected in this X-linked dominant disease.

Until recently, Danon disease and Pompe disease were thought to be closely related because in both conditions, skeletal and cardiac muscles are involved. Under the microscope, Danon disease shows many features (i.e., increased glycogen content), that are typical of Pompe disease. Two main features distinguish the two diseases: 1) the inheritance pattern in Pompe disease is autosomal recessive while that in Danon disease is X-linked dominant, and 2) the enzyme deficient in Pompe disease (acid maltase or acid alpha glucosidase) is present in normal amounts in Danon disease.

Because Danon disease is rare and unfamiliar to most physicians, diagnosis is difficult and takes substantial time. The diagnosis is suggested based on a family history compatible with X-linked dominant inheritance and symptoms in affected relatives (cardiomyopathy, skeletal myopathy, intellectual disability, Wolff-Parkinson White, etc.). Skeletal muscle biopsy is done in some males to determine the cause of muscle weakness. If, while examining the biopsy materials, glycogen buildup and/or empty spaces appear in the cells of the muscle tissue (vacuolization), Danon disease must be considered. This also holds true for the analysis of a heart biopsy. A muscle biopsy that yields evidence of glycogen build-up and empty spaces in the muscle cells are key signs and indications that a diagnosis of Danon disease is a high probability.


De Barsy syndrome

autosomal recessive cutis laxa type 3 (ARCL3)

Although researchers have been able to establish a clear syndrome with characteristic or core symptoms, much about de Barsy syndrome is not fully understood. Several factors including the small number of identified cases, the lack of large clinical studies, and the possibility of other genes influencing the disorder prevent physicians from developing a complete picture of 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.

Some cases of de Barsy syndrome are caused by mutations in either the PYCR1 or ALDH18A1 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. Some individuals with de Barsy syndrome do not have mutations in either of these genes suggesting that as-yet-unidentified genes cause the disorder.

De Barsy syndrome affects males and females in equal numbers. Fewer than 50 cases have been reported in the medical literature. The exact incidence and prevalence of this disorder is unknown. Because cases may go misdiagnosed or undiagnosed, determining the true frequency of de Barsy syndrome in the general population is difficult. De Barsy syndrome is usually obvious at birth or early infancy.

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

A diagnosis of de Barsy syndrome is based upon identification of characteristic symptoms, a detailed patient history, a thorough clinical evaluation and a variety of specialized tests. Surgical removal and microscopic examination (biopsy) of affected skin can reveal characteristic changes in elastic fibers. Distinguishing between the specific genetic forms of cutis laxa can be difficult. Molecular genetic testing can confirm a diagnosis of an inherited form cutis laxa and establish the specific, underlying subtype in some cases. Molecular genetic testing can detect mutations in specific genes known to cause cutis laxa, but is available only as a diagnostic service at specialized laboratories.